DEXTROSE TABLETS WITH IMPROVED MOUTHFEEL

Abstract

The invention relates to an oral chewable tablet suitable for improved mouthfeel, comprising dextrose in an amount from 50 to 95% by weight of the tablet; one or more active ingredients; and one or more binders, wherein the ratio between the one or more binders and dextrose is from 1:250 to 1:8.

Claims

1-99. (canceled)

100. An oral chewable tablet suitable for improved mouthfeel, comprising dextrose in an amount from 50 to 95% by weight of the tablet; one or more active ingredients; and one or more binders, wherein a ratio between the one or more binders and the dextrose is from 1:250 to 1:8.

101. The oral chewable tablet according to claim 100, wherein the ratio between the one or more binders and the dextrose is from 1:200 to 1:10.

102. The oral chewable tablet according to claim 100, wherein the ratio between the one or more binders and the dextrose is from 1:250 to 1:25 if the tablet comprises the dextrose in an amount from 70 to 95% by weight of the tablet.

103. The oral chewable tablet according to claim 100, wherein the ratio between the one or more binders and the dextrose is from 1:100 to 1:8 if the tablet comprises the dextrose in an amount from 50 to 70% by weight of the tablet.

104. The oral chewable tablet according to claim 100, wherein the ratio between the one or more binders and the one or more active ingredients is from 1:75 to 1:8.

105. The oral chewable tablet according to claim 100, wherein the dextrose is present in an amount from 70 to 95% by weight of the tablet.

106. The oral chewable tablet according to claim 100, wherein the oral chewable tablet is consisting essentially of the dextrose, the one or more active ingredients and the one or more binders, except for auxiliary ingredients present up to about 5% by weight of the tablet.

107. The oral chewable tablet according to claim 100, wherein the dextrose comprises at least 90% dextrose equivalents calculated on a dry basis.

108. The oral chewable tablet according to claim 100, wherein the dextrose comprises 100% dextrose equivalents calculated on a dry basis.

109. The oral chewable tablet according to claim 100, wherein the dextrose comprises at least 30% by weight of particles in a range of 100 to 500 microns.

110. The oral chewable tablet according to claim 100, wherein the dextrose comprises at least 80% by weight of particles below 500 microns.

111. The oral chewable tablet according to claim 100, wherein the one or more binders is present in an amount of 0.4 to 5% by weight of the tablet.

112. The oral chewable tablet according to claim 100, wherein the one or more binders is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and combinations thereof.

113. The oral chewable tablet according to claim 100, wherein the one or more active ingredients is present in an amount of 5 to 50% by weight of the tablet.

114. The oral chewable tablet according to claim 100, wherein the one or more active ingredients comprises an immune supporting active ingredient.

115. The oral chewable tablet according to claim 100, wherein the one or more active ingredients comprises a mixture of vitamins, minerals, and herbals.

116. The oral chewable tablet according to claim 100, wherein the one or more active ingredients comprise an active pharmaceutical ingredient.

117. The oral chewable tablet according to claim 100, wherein the oral chewable tablet comprises one or more disintegrants operable to disintegrate the tablet within a period of 2 minutes or less in contact with oral saliva.

118. The oral chewable tablet according to claim 100, wherein the oral chewable tablet comprises one or more disintegrants selected from the group consisting of sodium croscarmellose, crospovidone, sodium starch glycolate, and combinations thereof.

119. The oral chewable tablet according to claim 100, wherein the one or more active ingredients is present in an amount of 1 to 1000 mg.

120. The oral chewable tablet according to claim 100, wherein the oral chewable tablet comprises a further tablet module that is different in composition.

Description

DETAILED DESCRIPTION

[0199] The invention will now be described in more details with respect to certain aspects and embodiments of the invention. These aspects and embodiments are intended to be understood in connection with the rest of the description, including the Summary of the Invention and the Examples of the invention.

[0200] The verb “to comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements are present, unless the context clearly requires that there is one and only one of the elements. The indefinite article “a” or “an” thus usually means “at least one”. Additionally, the words “a” and “an” when used in the present document in connection with the word comprising or containing denote “one or more.” The expression “one or more” is intended to mean one, two, three or more.

[0201] As used herein, the term “approximately” or “about” in reference to a number are generally taken to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value).

[0202] As used herein the term “oral chewable tablet” is considered a tablet for oral use. Particularly, the oral tablet is considered as formed by tableting, i.e., compression of a particle composition, comprising a population of particles. Thus, the tablet is considered a compressed tablet formed by a plurality of particles. Typically, the oral chewable tablet may also be referred to as a tablet or oral tablet.

[0203] The term “particle size” relates to the ability of the particles to move through or be retained by sieve holes of a specific size. As used herein, the term “particle size” refers to the average particle size as determined according to European Pharmacopoeia 9.1 when using test method 2.9.38 particle size distribution estimation by analytical sieving, unless otherwise specifically is mentioned.

[0204] The term “particle” or similar wording is intended to denote a single, discrete composition of solid matter, such as a granule or individual elements in powder, having a certain size that may deviate considerable.

[0205] The term “weight of the oral tablet” or similar wording meaning the same is defined in the present context as weight of the oral tablet, not including the weight of an outer coating, such as a hard coating, soft coating, and the like.

[0206] By the phrase “texture” is meant a qualitative measure of the properties of the oral tablet and of the overall mouth-feel experienced by the user during use. Thus, the term “texture” encompasses measurable quantities such as hardness as well as more subjective parameters related to the feel experienced by a user.

[0207] The term “release” in the present context is intended to mean under “in vitro” conditions if not stated otherwise. In particular, the “release rate” during a certain period of time is intended to mean the amount in percentage of active ingredients that is released during the period. In the present context the term “release” refers to the released substance being liberated from the water-soluble matrix. In some embodiments, the process of releasing a substance corresponds to the substance being dissolved in saliva.

[0208] The term “sustained release” or “extended release” is herein intended to mean prolonged release over time. The term “rapid release” or “quick release” or “high release” is herein intended to mean a higher content released for a given period of time. The term “controlled release” is intended to mean a release of a substance from an oral tablet by the aid of active use of the oral tablet in the oral cavity of the subject, whereby the active use is controlling the amount of substance released.

[0209] In the present context the term “turn into liquid” is intended to mean that the tablet disintegrates and the fragments or particles of the tablet are either suspended or dissolved in saliva, perceived as liquid by a test person.

[0210] As used herein, the term “disintegrate” refers to a reduction of an object to components, fragments or particles. Disintegration time may be measured in vitro or in vivo. Unless otherwise stated, the in vitro measurements are carried out in accordance to European Pharmacopeia 9.0, section 2.9.1, Disintegration of tablets and capsules.

[0211] As used herein, the term “dissolve” is the process where a solid substance enters a solvent (oral saliva) to yield a solution. Unless otherwise stated, dissolving implies a full dissolving of the compound in question.

[0212] As used herein, the terms “disintegrant” refers to an ingredient facilitating disintegration of an FDT-module, when the FDT-module comes into contact with saliva. Disintegrants usable within the scope of the invention may include starch, pregelatinated starch, modified starch (including potato starch, maize starch, starch 1500, sodium starch glycolate and starch derivatives), cellulose, microcrystalline cellulose, alginates, and superdisintegrants, such as crosslinked cellulose (such as sodium carboxy methyl cellulose), crosslinked polyvinyl pyrrolidone (PVP), crosslinked starch, crosslinked alginic acid, natural superdisintegrants, and calcium silicate. Disintegrants may often be considered as measure promoting the break-up of the module into smaller fragments upon administration to facilitate nicotine release and eventual absorption. Crospovidone may comprise various grades, such as Kollidon CL-F or Kollidon CL-SF available from BASF.

[0213] When referring to induced saliva generation, it is noted that this induced saliva generation exceeds any saliva generation without the use of the tablet of the invention, or with a content of less than 50% dextrose. Particularly, in an embodiment, the induced saliva generation exceeds saliva generation when using conventional tablets without dextrose or with less than 50% dextrose. Then, induced saliva generation is increased over any saliva generation associated with conventional products, e.g. by comparing with a tablet without dextrose or with less than 50% dextrose.

[0214] When referring to induced saliva generation, the saliva generation may be tested using the following method:

[0215] Test subject abstain from eating and drinking at least 30 minutes before initiation of any test. Immediately before introducing of the tablet into the oral cavity, the test subject swallows. The test subject refrains from swallowing during the test. Immediately after introducing of the tablet into the oral cavity, the test subject starts masticating the tablet at a frequency of 1 chew per second for 20 seconds. Then, saliva and any remains of the tablet is kept in the mouth within chewing for 10 second. 30 seconds after starting the test, the test subject discards saliva including any tablet fragments into a plastic cup, which is weighted. Saliva discarded also at 90 seconds after onset of mastication, at 180 seconds after onset of mastication, at 300 seconds after onset of mastication, at 420 seconds after onset of mastication, and at 600 seconds after onset of mastication. At all times, the test subject makes as little movement as possible, and refrains from swallowing.

[0216] As used herein 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, but also other active substances such as nutraceuticals or immune supporting active ingredients.

[0217] In the following raw materials will refer to the mixed particles to be compressed into a tablet according to embodiments of the invention unless otherwise stated.

[0218] The following description outlines explanations of how the tablet of the invention may be produced and further details of what may be added to the inventive composition.

[0219] Typically, the process of manufacture of the inventive tablet may be performed in a single tablet press, such as a rotary tablet press. But it may be a benefit under some circumstances to apply a separate tablet press.

[0220] Preferably, the upper punch is convex which gives the upper face of the pressed tablet a concave form.

[0221] It should of course be noted that the shape of the punches may vary depending on the desired tablet shape.

[0222] In some embodiments of the invention, pressing of the tablets are performed at a force of 10 to 50 kN. In some embodiments of the invention, pressing of the tablets are performed at a force of 10 to 40 kN. In some embodiments of the invention, pressing of the tablets are performed at a force of 10 to 30 kN.

[0223] The oral tablet according to the invention is manufactured by applying pressure to a content of particles by suitable compression means. The particles or powder is then pressed into a compact coherent tablet. The particles may for example comprise so-called primary particles or aggregated primary particles. When these are pressed, bonds are established between the particles or granules, thereby conferring a certain mechanical strength to the pressed tablet.

[0224] It should be noted that the above-introduced terms: powder, primary particles and aggregated primary particles may be somewhat misleading in the sense that the difference between primary particles and aggregated primary particles may very often be looked upon differently depending on the background of the user. Some may for instance regard a sweetener as a primary particle in spite of the fact that this particle due to the typically preprocessing performed when delivered to the customer should rather be regarded as some sort of aggregated primary particles. The definition adopted in the description of this invention is that aggregated primary particles refer to macro-particles comprising more or less preprocessed primary particles.

[0225] When pressure is applied to the particles, the bulk volume is reduced, and the amount of air is decreased. During this process energy is consumed. As the particles come into closer proximity to each other during the volume reduction process, bonds may be established between the particles or granules. The formation of bonds is associated with a reduction in the energy of the system as energy is released. Volume reduction takes place by various mechanisms and different types of bonds may be established between the particles or granules depending on the pressure applied and the properties of the particles or granules. The first thing that happens when a powder is pressed is that the particles are rearranged under low compaction pressures to form a closer packing structure. Particles with a regular shape appear to undergo rearrangement more easily than those of irregular shape. As the pressure increases, further rearrangement is prevented, and subsequent volume reduction is obtained by plastic and elastic deformation and/or fragmentation of the tablet particles. Brittle particles are likely to undergo fragmentation, i.e. breakage of the original particles into smaller units. Plastic deformation is an irreversible process resulting in a permanent change of particle shape, whereas the particles resume their original shape after elastic deformation. Evidently, both plastic and elastic deformation may occur, when compressing an oral tablet.

[0226] Several studies of the bond types in pressed tablets have been made over the years, typically in the context of pharmaceuticals and several techniques of obtaining pressed tablets on the basis of available powders has been provided. Such studies have been quite focused on what happens when the volume reduction is performed and how the end-product may be optimized for the given purpose. Several refinements with respect to pressed tablets has for instance been made in the addition of for example binders in the tablet raw materials for the purpose of obtaining a sufficient strength to the final pressed tablet while maintaining acceptable properties, e.g. with respect to release.

[0227] By the method of the invention, it is possible to form one-layered or multi-layered tablets, such as two-layered tablets or three-layered tablets.

[0228] In accordance with the invention, the tableted oral tablet according to the invention may comprise about 0.1 to about 75% by weight of an outer coating applied onto the oral tablet centre. Thus, suitable coating types include hard coatings, film coatings and soft coatings of any composition including those currently used in coating of tableted oral tablet.

[0229] One presently preferred outer coating type is a hard coating, which term is used in the conventional meaning of that term including sugar coatings and sugar-free (or sugarless) coatings and combinations thereof. The object of hard coating is to obtain a sweet, crunchy layer, which is appreciated by the consumer and it may moreover protect the oral tablet centres for various reasons. In a typical process of providing the oral tablet centres with a protective sugar coating, the oral tablet centres are successively treated in suitable coating equipment with aqueous solutions of crystallisable sugar such as sucrose or dextrose, which, depending on the stage of coating reached, may contain other functional ingredients, e.g. fillers, binding agents, colours, etc. In the present context, the sugar coating may contain further functional or active compounds including flavour compounds and/or active compounds.

[0230] In a typical hard coating process as it will be described in detail in the following, a suspension containing crystallisable sugar and/or polyol is applied onto the oral tablet centres and the water it contains is evaporated off by blowing with air. This cycle must be repeated several times, typically 3 to 80 times, in order to reach the swelling required. The term “swelling” refers to the increase in weight or thickness of the products, as considered at the end of the coating operation by comparison with the beginning, and in relation to the final weight or thickness of the coated products. In accordance with the present invention, the coating layer constitutes about 0.1 to about 75% by weight of the finished oral tablet element, such as about 10 to about 60% by weight, including about 15 to about 50% by weight.

[0231] In further useful embodiments, the outer coating of the oral tablet element of the invention is an element that is subjected to a film coating process and which therefore comprises one or more film-forming polymeric agents and optionally one or more auxiliary compounds, e.g. plasticizers, pigments and opacifiers. A film coating is a thin polymer-based coating applied to an oral tablet centre of any of the above forms. The thickness of such a coating is usually between 20 and 100 μm.

[0232] Generally, the film coating is obtained by passing the oral tablet centres through a spray zone with atomized droplets of the coating materials in a suitable aqueous or organic solvent vehicle, after which the material adhering to the oral tablet centres is dried before the next portion of coating is received. This cycle is repeated until the coating is complete.

[0233] In one embodiment the tablet according to the invention comprises a pharmaceutically, cosmetically or biologically active substance. Examples of such active substances, a comprehensive list of which is found e.g. in WO 00/25598, which is incorporated herein by reference, include drugs, dietary supplements, antiseptic agents, pH adjusting agents, anti-smoking agents. Examples of useful active substances in the form of antiseptics include salts and derivatives of guanidine and biguanidine the following types of substances with limited water-solubility: quaternary ammonium compounds (e.g. ceramine, chloroxylenol, crystal violet, chloramine), aldehydes (e.g. paraformaldehyde), derivatives of dequaline, polynoxyline, phenols (e.g. thymol, p-chlorophenol, cresol), hexachlorophene, salicylic anilide compounds, triclosan, halogenes (iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols (3,4 dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), cf. also Martindale, The Extra Pharmacopoeia, 28th edition, pages 547-578; metal salts, complexes and compounds with limited water-solubility, such as aluminum salts, (for instance aluminum potassium sulphate A1K(SO4)2, 12H2O) and salts, complexes and compounds of boron, barium, strontium, iron, calcium, zinc, (zinc acetate, zinc chloride, zinc gluconate), copper (copper chloride, copper sulphate), lead, silver, magnesium, sodium, potassium, lithium, molybdenum, vanadium should be included.

[0234] Examples of active substances in the form of agents adjusting the pH in the oral cavity 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, sulphates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.

[0235] Active ingredients may comprise the below mentioned compounds or derivates thereof but are not limited thereto: Acetaminophen, Acetylsalicylic acid, Buprenorphine, Bromhexin, Celcoxib, Codeine, Diphenhydramin, Diclofenac, Etoricoxib, Ibuprofen, Indometacin, Ketoprofen, Lumiracoxib, Morphine, Naproxen, Oxycodon, Parecoxib, Piroxicam, Pseudoefedrin, Rofecoxib, Tenoxicam, Tramadol, Valdecoxib, Calciumcarbonat, Magaldrate, Disulfiram, Bupropion, Nicotine, Azithromycin, Clarithromycin, Clotrimazole, Erythromycin, Tetracycline, Granisetron, Ondansetrone, Prometazin, Tropisetron, Brompheniramine, Ceterizin, leco-Ceterizin, Chlorcyclizine, Chlorpheniramin, Chlorpheniramin, Difenhydramine, Doxylamine, Fenofenadin, Guaifenesin, Loratidin, des-Loratidin, Phenyltoloxamine, Promethazin, Pyridamine, Terfenadin, Troxerutin, Methyldopa, Methylphenidate, Benzalcon. Chloride, Benzeth. Chloride, Chloride, Ecabet-sodium, Haloperidol, Allopurinol, Colchinine, Theophylline, Propanolol, Prednisolone, Prednisone, Urea, Actot, Glibenclamide, Glipizide, Metformin, Miglitol, Repaglinide, Rosiglitazone, Apomorfin, Cialis, Sildenafil, Vardenafil, Diphenoxylate, Simethicone, Cimetidine, Famotidine, Ranitidine, Ratinidine, cetrizin, Loratadine, Aspirin, Benzocaine, Dextrometorphan, Phenylpropanolamine, Pseudoephedrine, Cisapride, Domperidone, Metoclopramide, Acyclovir, Dioctylsulfosucc., Phenolphtalein, Almotriptan, Eletriptan, Ergotamine, Migea, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan, Aluminum salts, Calcium salts, Ferro salts, Ag-salts, Zinc-salts, Amphotericin B, Miconazole, Triamcinolonacetonid, Melatonine, Phenobarbitol, Caffeine, Benzodiazepiner, Hydroxyzine, Meprobamate, Phenothiazine, Buclizine, Brometazine, Cinnarizine, Cyclizine, Difenhydramine, Dimenhydrinate, Buflomedil, Amphetamine, Caffeine, Ephedrine, Orlistat, Phenylephedrine, Phenylpropanolamin, Pseudoephedrine, Sibutramin, Ketoconazole, Nitroglycerin, Nystatin, Progesterone, Testosterone, Vitamin B12, Vitamin C, Vitamin A, Vitamin D, Vitamin E, Pilocarpin, Aluminumaminoacetat, Cimetidine, Esomeprazole, Famotidine, Lansoprazole, Magnesiumoxide, Nizatide and or Ratinidine.

[0236] The invention is suitable for increased or accelerated release of active agents selected among the group of dietary supplements, antiseptic agents, pH adjusting agents, anti-smoking agents, sweeteners, flavorings, aroma agents or drugs. Some of those will be described below.

[0237] The active agents to be used in connection with the present invention may be any substance desired to be released from the tablet. The active agents, for which a controlled and/or accelerated rate of release is desired, are primarily substances with a limited water-solubility, typically below 10 g/100 mL inclusive of substances which are totally water-insoluble. Examples are medicines, dietary supplements, oral compositions, anti-smoking agents, highly potent sweeteners, pH adjusting agents, flavorings etc.

[0238] Other active ingredients are, for instance, paracetamol, benzocaine, cinnarizine, menthol, carvone, caffeine, cyclizine hydrochloride, 1,8-cineol, nandrolone, miconazole, mystatine, nicotine, other quaternary ammonium compounds, vitamin E, vitamin A, vitamin D, glibenclamide or derivatives thereof, progesterone, acetylsalicylic acid, dimenhydrinate, cyclizine, metronidazole, sodium hydrogen carbonate, the active components from ginkgo, the active components from propolis, the active components from ginseng, methadone, oil of peppermint, salicylamide, hydrocortisone or astemizole.

[0239] Examples of active agents in the form of dietary supplements are for instance salts and compounds having the nutritive effect of vitamin B2 (riboflavin), B12, folinic acid, folic acid, niacine, biotine, poorly soluble glycerophosphates, amino acids, the vitamins A, D, E and K, minerals in the form of salts, complexes and compounds containing calcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese, chromium, selenium, molybdenum, potassium, sodium or cobalt.

[0240] Furthermore, reference is made to lists of nutritionists accepted by the authorities in different countries such as for instance US code of Federal Regulations, Title 21, Section 182.5013.182 5997 and 182.8013-182.8997.

[0241] Examples of active agents in the form of antiseptics are for instance salts and compounds of guanidine and biguanidine and the following types of substances with limited water-solubility: quaternary ammonium compounds (for instance ceramine, chloroxylenol, crystal violet, chloramine), aldehydes (for instance paraformaldehyde), compounds of dequaline, polynoxyline, phenols (for instance thymol, para chlorophenol, cresol) hexachlorophene, salicylic anilide compounds, triclosan, halogenes (iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols (3,4 dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol, phenylethanol), cf. furthermore Martindale, The Extra Pharmacopoeia, 28th edition, pages 547-578; metal salts, complexes and compounds with limited water-solubility, such as aluminum salts, (for instance aluminum potassium sulphate A1K(SO4)2,12H2O) and furthermore 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 should be included.

[0242] Examples of active agents in the form of agents adjusting the pH in the oral cavity include for instance: 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, hydrogen carbonates, phosphates, sulfates or oxides of sodium, potassium, ammonium, magnesium or calcium, especially magnesium and calcium.

[0243] Examples of active agents in the form of anti-smoking agents include for instance: nicotine, tobacco powder or silver salts, for instance silver acetate, silver carbonate and silver nitrate.

[0244] Further examples of active agents are medicines of any type.

[0245] Examples of active agents in the form of medicines include caffeine, salicylic acid, salicyl amide and related substances (acetylsalicylic acid, choline salicylate, magnesium salicylate, sodium salicylate), paracetamol, salts of pentazocine (pentazocine hydrochloride and pentazocinelactate), buprenorphine hydrochloride, codeine hydrochloride and codeine phosphate, morphine and morphine salts (hydrochloride, sulfate, tartrate), methadone hydrochloride, ketobemidone and salts of ketobemidone (hydrochloride), beta-blockers, (propranolol), calcium antagonists, verapamil hydrochloride, nifedinpine as well as suitable substances and salts thereof mentioned in Pharm. Int., November 85, pages 267-271, Barney H. Hunter and Robert L. Talbert, nitroglycerine, erythrityl tetranitrate, strychnine and salts thereof, lidocaine, tetracaine hydrochloride, etorphine hydrochloride, atropine, insulin, enzymes (for instance papain, trypsin, amyloglucosidase, glucoseoxidase, streptokinase, streptodornase, dextranase, alpha amylase), polypeptides (oxytocin, gonadorelin, (LH.RH), desmopressin acetate (DDAVP), isoxsuprine hydrochloride, ergotamine compounds, chloroquine (phosphate, sulfate), isosorbide, demoxytocin, heparin.

[0246] Other active ingredients include beta-lupeol, Letigen®, Sildenafil citrate and derivatives thereof.

[0247] Further examples of active ingredients include vitamins. Vitamins include A, B1, B2, B6, B12, Folinic acid, Folic acid, niacin, Pantothenic acid, biotine, C, D, E, K. Minerals include Calcium, phosphor, magnesium, iron, Zinc, Copper, Iod, Mangan, Crom, Selene, Molybden. Other active ingredients include: Q10®, enzymes. Natural drugs including Ginkgo Biloba, ginger, and fish oil.

[0248] Further examples of active ingredients include migraine drugs such as Serotonin antagonists: Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan, Eletriptan; nausea drugs such as Cyclizin, Cinnarizin, Dimenhydramin, Difenhydrinat; hay fever drugs such as Cetrizin, Loratidin, pain relief drugs such as Buprenorfin, Tramadol, oral disease drugs such as Miconazol, Amphotericin B, Triamcinolonaceton; and the drugs Cisaprid, Domperidon, Metoclopramid. In a preferred embodiment the invention relates to the release of Nicotine and its salts.

[0249] In an advantageous embodiment of the invention the active ingredient is selected from active ingredients for the throat selected from acetylcysteine, ambroxol, amylmetacresol, benzocaine, bisacodyl, bismuth sub salicylate, bromhexine, cetirizine, 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, spearmint, zinc, or any combination thereof; active ingredients for the gastrointestinal tract selected from alginate, atenolol, aspirin (acetylsalicylic acid), ampicillin, aminosalicylates, anhydrous citric acid, aspirin, bisacodyl, bismuth subsalicylate, bupropion, caffeine, calcium, calcium carbonate, cetirizine, cimetidine, cisapride, clarithromycin, desloratadine, dexlansoprazole, diphenhydramine HCl, diphenhydramine citrate, dimenhydrinate, docusate erythromycin, dopamine, esomeprazole, famotidine, fexofenadine HCl, guaifenesin, hydrotalcite, ibuprofen, ketoprofen, lactase enzyme, lansoprazole, loratadine, lorcaserin, loperamide, loperamide 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, prednisolone, prednisone, progesterone, propranolol, propantheline bromide, pseudoephedrine HCl, phentermine, rabeprazole, ranitidine, roflumilast, scopoloamine 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 sulphate, scopoloamine butyl hydroxide, sumatriptan, triamcinolonacetonid, and any combination thereof.

[0250] In one aspect of the invention, the “tablet” is intended to mean a “fast disintegrating tablet” (“FDT”), or similar wording, such as “orally disintegrating tablet” (“ODT”). If not stated otherwise, if the tablet according to the invention is made as one module, contrary to two or more modules, then the tablet is intended to be an FDT tablet. If on the other hand, the tablet is made of more than one module, such as two modules, such additional module is intended to be a “lozenge” module or “chewing gum module”, which provides a longer disintegration time compared to the FDT module according to the invention. The combination of an “FDT” module and a “lozenge” module (or a “chewing gum module) contributes to another aspect of the invention. A “lozenge” module or “chewing gum module” according to the invention may also comprise elements from the “FDT” modules but is generally different in composition, providing an extended disintegration time.

[0251] The term “module” is generally intended to be composed of a composition of matter with substantially the same characteristics throughout the module. Hence, if two module are present, then the two modules are different in composition and generally have two different characteristics throughout each module. In the present context, if only one module is present, then this module is considered an FDT tablet. On the other hand, if two modules are present, then the tablet is composed of an FDT tablet or FDT tablet module fused with a lozenge tablet or lozenge module. The term “fused” is intended to mean that the tablet is gathered together by means of compression force. Usually, if two modules are present, the lozenge module is made as the first module and the FDT module is made as the second module. The tablet may be composed of more than two module. The lozenge module may in certain embodiments be replaced by a gum base module. In the present context, the invention provides an attractive bi-phasic delivery of masking, even if the delivery of nicotine is “single-phased”.

EXAMPLES

Example 1

[0252] Preparation of Dextrose Tablets

[0253] In a first step, dextrose was added to a mixing container. Binders, flavors, high-intensity sweeteners and optional other components were added to the container. In some of the comparative examples, binders were omitted. In some examples, one or more active ingredients were added and further specified in the specific examples below. The mixture was sieved and tumbled in a FUCHS Mixomat-A at approximately 25 rpm for 4 minutes. A processing aid was added and the mixture was tumbled at approximately 25 rpm for another 1 minute. Hereafter, the mixture was ready for tableting.

[0254] Dextrose applied according to the examples was C*dex 02001 commercially available from Cargill, unless otherwise indicated. In some examples, comparative grades were used. Particularly, binders applied were HPC and HPMC. HPC was available as Klucel Nutra D from Ashland. HPMC was available as Methocel 4KM from Dow. In some of the comparative examples, other binders were applied. When microcrystalline cellulose was applied as a comparative binder, it was Avicel PH-102 commercially available from Dupont. When maltodextrin was applied as a comparative binder, it was C*dry MD from Cargill.

[0255] The mixture was subsequently led to a standard tablet pressing machine (3090i, available from Fette GmbH) comprising dosing apparatus (P 3200 C, available from Fette GmbH, Germany) and pressed into tablets. Alternatively, a Riva Picoola Bi-layer DC-PL-015 was used. The tablets were pressed using a pressing pressure of 20-30 kN, unless otherwise indicated. There were 11 punches on the rotor, and the rotor speed used was 5 rpm. The individual tablets had a weight of approx. 1500 mg unless otherwise stated in the examples below. Punch used: 15.00 mm, circular, shallow concave, B tooling.

Example 2

[0256] Composition of Dextrose Tablets with Different Content of Binder and in Presence of an Active Ingredient in the Same Amount

[0257] Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below. In all of the tablet examples, the amount of the various ingredients is given as % by weight of the tablet.

TABLE-US-00001 TABLE 1 Tablet Number 100-1A 100-1B 100-1C 100-1D 100-1E Content Content Content Content Content Raw material name [%] [%] [%] [%] [%] Dextrose* 96.0 95.0 93.0 91.0 86.0 Binder** — 1.0 3.0 5.0 10.0 Active ingredient*** 0.1 0.1 0.1 0.1 0.1 Flavors/high-intensity 2.9 2.9 2.9 2.9 2.9 sweeteners Processing aids 1.0 1.0 1.0 1.0 1.0 Total 100 100 100 100 100 It was secured that the binders were thoroughly mixed into the dry mixture. *Dextrose was C*dex 02001 commercially available from Cargill. **The binder was HPC. ***The active ingredient was melatonin available from JiaHerb. The tablets were pressed at 30 kN.

[0258] Example 100-1A was a comparative example made in order to establish the effect in the absence of one or more binders.

[0259] The binder containing dextrose tablets of Table 1 were made again as tablet numbers 100-1B*, 100-1C*, 100-1D* and 100-1E* replacing HPC with HPMC as binder.

Example 3

[0260] Composition of Dextrose Tablets with Same Content of Binder and in Presence of an Active Ingredient in Different Amounts

[0261] Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below. In all of the tablet examples, the amount of the various ingredients is given as % by weight of the tablet.

TABLE-US-00002 TABLE 2 Tablet Number 100-2A 100-2B 100-2C 100-2D Content Content Content Content Raw material name [%] [%] [%] [%] Dextrose* 91.8 71.8 51.8 31.8 Binder** 1.0 1.0 1.0 1.0 Active ingredient*** 5.0 25.0 45.0 65.0 Flavors/high-intensity 1.2 1.2 1.2 1.2 sweeteners Processing aids 1.0 1.0 1.0 1.0 Total 100 100 100 100 It was secured that the binders were thoroughly mixed into the dry mixture. *Dextrose was C*dex 02001 commercially available from Cargill. **The binder was HPC. ***The active ingredient was calcium carbonate available from Nutrigranulation. The tablets were pressed at 30 kN.

[0262] Example 100-2D was a comparative example made in order to establish the effect of a content of dextrose below 50% by weight of the tablet.

[0263] The dextrose tablets of Table 2 were made again as tablet numbers 100-2A*, 100-2B*, 100-2C*, and 100-2D* replacing HPC with HPMC as binder.

Example 4

[0264] Composition of Dextrose Tablets with Different Content of Binder and in Presence of an Active Ingredient in Substantially the Same Amount

[0265] Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including an active ingredient in an amount of 675 mg for 100-2E and 100-2C, and 630 mg for 100-2F and 100-2G. In all of the tablet examples, the amount of the various ingredients is given as % by weight of the tablet.

TABLE-US-00003 TABLE 3 Tablet Number 100-2E 100-2C 100-2F 100-2G Content Content Content Content Raw material name [%] [%] [%] [%] Dextrose* 52.8 51.8 52.8 50.8 Binder** — 1.0 3.0 5.0 Active ingredient*** 45.0 45.0 42.0 42.0 Flavors/high-intensity sweeteners 1.2 1.2 1.2 1.2 Processing aids 1.0 1.0 1.0 1.0 Total 100 100 100 100 It was secured that the binders were thoroughly mixed into the dry mixture. *Dextrose was C*dex 02001 commercially available from Cargill. **The binder was HPC. ***The active ingredient was calcium carbonate available from Nutrigranulation. The tablets were pressed at 30 kN.

[0266] Example 100-2E was a comparative example made in order to establish the effect in the absence of one or more binders.

[0267] The dextrose tablets 100-2F and 100-2G of Table 3 were made again as tablet numbers 100-2F*, and 100-2G* replacing HPC with HPMC as binder.

[0268] It is noted that the difference in amounts of 42 respectively 45 percent by weight of active ingredients was considered insignificant.

Example 5

[0269] Composition of Dextrose Tablets with Different Content of Binder and in Presence of an Active Ingredient in the Same Amount

[0270] Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including an active ingredient in an amount of 630 mg. In all of the tablet examples, the amount of the various ingredients is given as % by weight of the tablet.

TABLE-US-00004 TABLE 4 Tablet Number 100-2H 100-2I 100-2J 100-2K Content Content Content Content Raw material name [%] [%] [%] [%] Dextrose* 52.8 50.8 50.8 45.8 MCC binder 3.0 5.0 — — Maltodextrin binder — — 5.0 10.0 Active ingredient*** 42.0 42.0 42.0 42.0 Flavors/high-intensity sweeteners 1.2 1.2 1.2 1.2 Processing aids 1.0 1.0 1.0 1.0 Total 100 100 100 100 It was secured that the binders were thoroughly mixed into the dry mixture. *Dextrose was C*dex 02001 commercially available from Cargill. ***The active ingredient was calcium carbonate available from Nutrigranulation. The tablets were pressed at 30 kN.

Example 6

[0271] Evaluations of Tablets

[0272] For each version of the tablets, a breaking point test, a friability test and a dissolution time measurement were performed. For measuring breaking point, a PTB 311 from Pharma Test was used.

[0273] The friability test was made in accordance to European Pharmacopoeia 9.1, test method 2.9.7. by using a pharmaceutical friability-tester PTF 10E from Pharma Test.

[0274] To test dissolution time, the following method was used. 15 mL of 0.02 M potassium dihydrogen phosphate-buffer (pH adjusted to 7.4) is added to 50 mL of water in a measuring tube with a screw cap. The tablet is inserted in the measuring tube and the screw cap is fastened. The measuring tube is fixated horizontally. The measuring tube is vibrated at about 110 RPM such that the tablet can move back and forth in the measuring tube. The measuring tube is vibrated until the tablet or module thereof in question is completely dissolved and the time of vibration is noted as the dissolution time.

Example 7

[0275] Sensorial Evaluation of Tablets

[0276] Sensoric tests were performed to reveal very important characteristics and properties of the tablets. These sensoric parameters are important as indicators of the structure of the tablet composition. The test set-up was composed of 8 test persons in a test panel. All of the test persons were healthy individuals appointed on an objective basis according to specified requirements. The sensory analysis was performed according to ISO 4121-2003 in testing conditions following ISO 8589. The result is an average of the results of the 8 individuals.

[0277] The test persons gave a rating from “+” to “+++++”, where “+” is poor and “+++++” is excellent. “0” indicated that it was not tested.

[0278] Six different parameters were tested in a test panel:

[0279] “Ease of chewing into liquid”—the impression of the tablet when placed in the mouth and chewed with respect to easiness of chewing the product into liquid. The criteria is that upon completion, there is no sense of particles in the mouth, and the powder of the tablet has dissolved into liquid.

[0280] “Liquid feeling”—the impression of the tablet when placed in the mouth and chewed with respect to the sense of liquid in the mouth. For instance, if more liquid is sensed during and/or after chewing, then the score is high.

[0281] “Mouthfeel”—the overall impression of the tablet during chewing with respect to mouthfeel, including melting and tacking sensations. A high scoring mouthfeel is associated with a clean liquid (no sense of particles), no tablet residuals sticking in teeth and a creamy feeling (higher viscosity than water). On the contrary, a low scoring mouthfeel is associated with sense of particles in the liquid (incomplete dissolution), tablet residuals sticking in the teeth and a watery feeling of the liquid.

[0282] “Overall taste”—the overall impression of the taste of the tablet during chewing. For instance, if the taste was decreasing rapidly, a very low rating was given.

[0283] “Overall sweetness”—the overall impression of the sweetness of the tablet during chewing. For instance, if the sweetness was decreasing rapidly, a very low rating was given.

[0284] “Overall sourness”—the overall impression of the sourness of the tablet during chewing. For instance, if the sourness was decreasing rapidly, a very low rating was given.

Example 8

[0285] Results of Composition of Dextrose Tablets with Different Content of Binder and in Presence of an Active Ingredient in the Same Amount

TABLE-US-00005 TABLE 5 Tablet Number 100-1A 100-1B 100-1C 100-1D 100-1E Ease of chewing +++++ +++++ +++++ ++++ ++ into liquid Mouthfeel +++++ +++++ +++++ ++++ +++ Comments Easy, no Easy, no Easy, no Easy, no Easy, no sticking, no sticking, no sticking, no sticking, no sticking, no grease or grittiness grittiness grittiness grittiness grittiness Friability 1.73 0.87 0.47 0.27 0.20 Tested in compliance with Examples 6 and 7.

[0286] Generally, the results reveal that HPC was a superior binder with resulting low friability as a function of the level of binder. However, friability was clearly inferior when no binder was added. When using a high level of binder, the sensorial parameters were lower than if less binder was applied, although friability was improved. Specifically, it is contemplated that above 5% of binder is unsuitable for the dextrose tablets.

Example 9

[0287] Results of Composition of Dextrose Tablets with Same Content of Binder and in Presence of an Active Ingredient in Different Amounts

TABLE-US-00006 TABLE 6 Tablet Number 100-2A 100-2B 100-2C 100-2D Ease of chewing into +++++ +++++ ++++ ++ liquid Mouthfeel +++++ ++++ ++++ +++ Comments Good mouthfeel, Good mouthfeel, Good mouthfeel, Ok mouthfeel, almost no sense of liquid turns slightly liquid turns slightly liquid turns too coarseness powdery powdery powdery Friability 1.20 0.86 0.47 0.47 Tested in compliance with Examples 6 and 7.

[0288] Generally, the results reveal that the level of active ingredients had an impact on the system. When using a high level of active ingredients and thereby a low level of dextrose, the products were not sensorially acceptable. It is contemplated that below 50% of dextrose is unsuitable for the dextrose tablets. It was not expected that a high amount of active ingredients as used in a number of the examples were possible to add in the dextrose tablets without compromising the suitability of the dextrose tablets. Particularly, it was a surprise that examples 100-2B and 100-2C revealed beneficial sensorial properties even with the high amount of actives used. With respect to example 100-2D, the amount of actives compromised the sensorial properties of the dextrose tablets.

Example 10

[0289] Results of Composition of Dextrose Tablets with Different Content of Binder and in Presence of an Active Ingredient in Substantially the Same Amount

TABLE-US-00007 TABLE 7 Tablet Number 100-2E 100-2C 100-2F 100-2G Ease of chewing into ++++ ++++ ++++ ++++ liquid Mouthfeel ++++ ++++ ++++ +++ Comments Good mouthfeel, Good mouthfeel, Good mouthfeel, Good mouthfeel, liquid turns slightly liquid turns slightly liquid turns slightly liquid turns slightly powdery powdery powdery powdery Friability 1.00 0.47 0.47 0.13 Tested in compliance with Examples 6 and 7.

[0290] Generally, the results reveal that HPC was a superior binder with resulting low friability as a function of the level of binder.

Example 11

[0291] Results of Composition of Dextrose Tablets with Different Content of Binder and in Presence of an Active Ingredient in the Same Amount

TABLE-US-00008 TABLE 8 Tablet Number 100-2H 100-2I 100-2J 100-2K Ease of chewing into +++ ++ +++ ++ liquid Mouthfeel ++ ++ ++ + Comments Greasy coat Greasy coat Greasy coat Greasy coat feeling, stickiness feeling, stickiness feeling, stickiness feeling, stickiness Friability 0.53 0.60 0.73 0.73 Tested in compliance with Examples 6 and 7.

[0292] Generally, the results reveal that MCC and maltodextrin were poor binders and the sensorial parameters were poor. HPC was clearly a more appropriate binder providing a superior mouthfeel.

Example 12

[0293] Composition of Dextrose Tablets with Different Active Ingredients Focused on Energy

[0294] Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including caffeine in an amount of 100 mg and optionally vitamin B premix in an amount of 15 mg as active ingredient. In all of the tablet examples, the amount of the various ingredients is given as % by weight of the tablet.

TABLE-US-00009 TABLE 9 Tablet Number 100-3A 100-3B 100-3C 100-3D Content Content Content Content Raw material name [%] [%] [%] [%] Dextrose* 89.8 88.8 89.8 88.8 HPC binder 1.0 1.0 — — HPMC binder — — 1.0 1.0 Caffeine*** 6.8 6.8 6.8 6.8 Vitamin B**** — 1.0 — 1.0 Flavors/high-intensity 1.4 1.4 1.4 1.4 sweeteners Processing aids 1.0 1.0 1.0 1.0 Total 100 100 100 100 It was secured that the binders were thoroughly mixed into the dry mixture. *Dextrose was C*dex 02001 commercially available from Cargill. ***Caffeine available from Siegfried, ****Vitamin B premix available from DSM. The tablets were pressed at 27 kN.

Example 13

[0295] Composition of Dextrose Tablets with Different Active Ingredients Focused on Immune Stimulants

[0296] Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including vitamin C in an amount of 500 mg or a herbal blend with vitamin C and other vitamins/minerals in an amount of 450 mg as active ingredient. In all of the tablet examples, the amount of the various ingredients is given as % by weight of the tablet.

TABLE-US-00010 TABLE 10 Tablet Number 100-4A 100-4B 100-4C 100-4D Content Content Content Content Raw material name [%] [%] [%] [%] Dextrose* 62.8 66.1 62.8 66.1 HPC binder 1.0 1.0 — — HPMC binder — — 1.0 1.0 Vitamin C*** 33.3 — 33.3 — Herbal blend with vitamins* * * * — 30.0 — 30.0 Flavors/high-intensity sweeteners 1.9 1.9 1.9 1.9 Processing aids 1.0 1.0 1.0 1.0 Total 100 100 100 100 It was secured that the binders were thoroughly mixed into the dry mixture. *Dextrose was C*dex 02001 commercially available from Cargill. ***Vitamin C available from DSM, ****Herbal blend with vitamins available from DSM. The tablets were pressed at 70 kN.

Example 14

[0297] Composition of Dextrose Tablets with Different Active Ingredients Focused on Cough and Cold Formulations

[0298] Dextrose tablets based on the procedure in Example 1 were made with the formulations outlined in the examples below, here including active ingredients suitable for treating cough and cold symptoms. In all of these tablet examples, the total tablet weight is 1750 mg, and the amount of the various ingredients is given as mg.

TABLE-US-00011 TABLE 11 It was secured that the binders were thoroughly mixed into the dry mixture. Tablet Number 100-5A 100-5B 100-5C 100-5D 100-5E 100-5F Content Content Content Content Content Content Raw material name [mg] [mg] [mg] [mg] [mg] [mg] Dextrose* 1325 1310 1000 — — — Dextrose** — — — 1325 1310 1000 HPC binder 35 35 35 35 35 35 Acetominophen*** 250 250 250 250 250 250 Dextromethorphan**** — 10 10 — 10 10 Phenylephrine***** — 5 5 — 5 5 Mannitol (Pearlitol DC300) — — 310 — — 310 Flavors/high-intensity 123 123 123 123 123 123 sweeteners/fruit acids Processing aids 17 17 17 17 17 17 Total 1750 1750 1750 1750 1750 1750 *Dextrose was C*dex 02001 commercially available from Cargill. **Dextrose was Emdex commercially available from JRS Pharma. ***Acetominophen available from Mallinckrodt, ****Dextromethorphan HBr available from LGM Pharma, *****Phenylephrine HCl available from Siegfried. The tablets were pressed at 70 kN.

Example 15

[0299] Results of Comparison of Dextrose Tablet 100-4B with a Commercially Available Product Containing Immune Stimulants

TABLE-US-00012 TABLE 12 Tablet Number 100-4B Airborne Ease of chewing into liquid +++++ +++ Mouthfeel ++++ ++ Comments Good mouthfeel, almost Crumble mouthfeel, no sandy mouth-feel sandy mouthfeel Tested in compliance with Examples 6 and 7.

[0300] Generally, the results reveal that dextrose tablet 100-4B was providing a superior mouthfeel and liquifying sensation compared to the commercially available product Airborne which contains the same type of actives as dextrose tablet 100-4B.