Directly Compressible Xylitol and Method

Europaisches Patentamt European Patent Office © Publication number: 0 561 815 B1 Office europeen des brevets

@ Date of filing: 29.11.91

© Priority: 12.12.90 US 626495 © Proprietor: XYROFIN OY Sokeritehtaantie @ Date of publication of application: SF-48210 Kotka (Fl) 29.09.93 Bulletin 93/39 @ Inventor: OLINGER, Philip M. © Publication of the grant of the patent: 1400 North Meacham Road 06.09.95 Bulletin 95/36 Schaumburg, IL 60172 (US) Inventor: KARHUNEN, Auli © Designated Contracting States: Rakertajantie 1A AT BE CH DE DK ES FR GB GR IT LI LU NL SE SF-00370 Helsinki (Fl)

© References cited: EP-A- 0 305 356 © Representative: Hansen, Bernd, Dr. EP-A- 0 329 977 Dipl.-Chem. et al EP-A- 0 409 279 Hoffmann, Eitle & Partner Patent- und Rechtsanwalte, Postfach 81 04 20 D-81904 Munchen (DE)

00 lo oo co lo Note: Within nine months from the publication of the mention of the grant of the European patent, any person ® may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition CL shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee LU has been paid (Art. 99(1) European patent convention). Rank Xerox (UK) Business Services (3. 10/3.09/3.3.3) 1 EP 0 561 815 B1 2

Description One approach to fighting dental caries is to reduce or eliminate the amount of fermentable car- This invention relates to a directly compress- bohydrates such as sucrose in pharmaceutical or ible xylitol granulate. The granulate comprises food contexts. The replacement of fermentable car- xylitol and a physiologically acceptable, non- 5 bohydrates by sugar substitutes which cannot be cariogenic binder taken from the group consisting fermented, or are less easily fermented by S, of polymerized reducing sugars, an alkali carbox- mutans and other bacteria has been shown to ymethylcellulose, and hydrogenated starch decrease the development of dental caries. hydrolysate, and combinations thereof, binders Xylitol has been used as a sugar substitute in which do not detract from the taste profile of xylitol; io certain contexts (e.g. chewing gum: U.S. Patent No. polydextrose is a preferred polymerized reducing 4,514,422 (Yang) and 3,422,184 (Patel)) with prac- sugar, and sodium carboxymethylcellulose is a pre- tical and commercial success. The use of xylitol is ferred alkali carboxymethylcellulose. The invention attractive because of its taste and technological also relates to a method of producing a directly advantages. Xylitol is a naturally occurring five car- compressible xylitol granulate which can be used 75 bon sugar alcohol which has the same sweetness in tableting contexts, and to tablets which contain as sugar and a caloric content which is less than xylitol as a sweetening agent which exhibit high that of sugar. Xylitol is found in small amounts in hardness, low friability, are non-cariogenic and ex- many fruits and vegetables and is produced in the hibit a noted cooling effect when consumed. human body during normal metabolism. Xylitol is The most commonly used sweetener for food 20 particularly attractive because of its known meta- and pharmaceutical contexts is sucrose. Sucrose is bolic, dental and technical characteristics. used for its well-known sweetening properties and From a metabolic perspective, xylitol is metab- also for bulking purposes. Although a wide variety olized largely independent of insulin, so it can be of alternate sweeteners are available, sucrose is safely consumed by non-insulin dependent dia- generally considered to be the optimum sweetener 25 betics. Further, xylitol has been shown to delay with regard to taste profile and technological prop- gastric emptying and to possibly suppress food erties. However, sucrose has been implicated as a intake which means it may have an important role contributory factor in many diseases including hy- in weight reducing diets. pertension, coronary heart disease, arterial sclero- A significant advantage of xylitol is that it is not sis and dental caries. These health concerns have 30 fermented by S, mutans and other bacteria found led health care professionals to analyze the effects in the mouth and, therefore, does not produce of sucrose and its prominent role in the diet. acids which, as described herein, contribute to the Perhaps the most significant, well-documented formation of dental caries. Xylitol is well estab- effect of sucrose is its contribution to tooth decay. lished as a non-cariogenic substance, Le. xylitol The mouth contains a number of bacterial strains 35 does not contribute to caries formation. Significant which ferment common dietary carbohydrates such data also exists which supports the view that xylitol as sucrose. This fermentation generates acid as an is not only non-cariogenic, but actively suppresses end product which lowers the pH in the mouth; the the formation of new caries and may even reverse lowered pH leads to a demineralization of tooth existing lesions by inducing remineralization, i.e. it enamel and finally to the formation of dental le- 40 is a cariostatic material. A summary of clinical data sions or caries. regarding the effects of xylitol and its possible It is well known that it is not the total quantity mechanisms is set forth in Bar, Albert, Caries of sugar consumed per se, but the frequency of Prevention With Xylitol: A Review of the Sci- consumption that contributes to dental caries. entific Evidence, 55 Wld. Rev. Nutr. Diet. 183-209 Thus, the presence of sucrose and other ferment- 45 (1983). The mechanism or mechanisms by which able carbohydrates in regular meals is not the xylitol effects any cariostatic properties is not yet principal cause of tooth decay. The consumption of known, but some possible mechanisms which have fermentable carbohydrates between meals in the been suggested include a reduction of oral levels form of confections and sweetened pharmaceut- of S, mutans, a reduction in the development of icals (and the frequency of such consumption) 50 plaque, the stimulation of the flow of protective have been shown to have a close relationship to saliva, the favorable alteration of the composition of the formation of dental caries. Long after the candy saliva, the retardation of demineralization and an or drug has been consumed, the fermentable car- enhancement of remineralization of tooth enamel. bohydrate stays in the mouth and is fermented by Xylitol also has significant technological advan- Streptococcus mutans and other cariogenic bac- 55 tages, particularly with respect to taste profile. teria, lowering the mouth pH and promoting dental Xylitol produces a pleasant cooling effect in the caries as described above. mouth when consumed in the crystalline state. The energy required to dissolve one gram of xylitol is

2 3 EP 0 561 815 B1 4

34.6 calories, the highest known value for sugars ceutical and food tablets are designed to be and and sugar alcohols; this produces a physical cool- are consumed at frequent and/or regular intervals ing effect which is desirable in many contexts. throughout the day. For this reason, some dental Xylitol is as sweet as sugar and does not typically researchers have suggested switching from su- manifest unpleasant aftertastes. 5 crose, maltose, lactose, dextrose to a non-acid Other polyols, such as sorbitol, mannitol, lac- producing sweetener such as xylitol in pharmaceu- titol and others have also been substituted for tical and food contexts. sucrose in a variety of contexts. All of these polyols Tablets can be formed by compression or by have certain advantages - such as non-cariogenic- molding. Simple compression techniques have ity - over sucrose. However, none of the other io been known for centuries; in 1577 Hieronymous polyols have been demonstrated to have a Bosch, in his Kreuttenbuch, describes a simple cariostatic effect. press, used for making medicines. The sugar coat- One context in which xylitol has been here- ing of "pills" was first attributed to Jean de Renou tofore utilized with only limited success is as a in 1606, and one of the first patents for the manu- constituent in tablets. In pharmaceutical contexts, 15 facture of "pills and medical lozenges" was grant- tablets are used for bringing active substances into ed to one Thomas Brockedon in Great Britain in a size, shape and texture that can be dosaged, 1843. Many types of tablets exist including chewa- chewed, sucked, swallowed whole or dissolved in ble tablets, lozenges, effervescent, coated centers, water for drinking. In food contexts, tablets can take film coated tablets, enteric coated tablets, time the form of compressed, fruit or mint flavored con- 20 release tablets (for release of ingredients over time) fections which consist of a sweetener(s), flavor(s) multi-layered tablets and others. and optionally color and acid. Because of its taste Modern compression tableting techniques - ir- and cariostatic properties as described above, respective of the type (and ultimate shape of the xylitol is a potentially attractive constituent in tab- end product) - utilize a piston like device with three lets for both food and pharmaceutical purposes. 25 stages in each cycle: (1) filling - adding the con- Other polyols have been utilized in tablet contexts stituents of the tablet to the compression chamber; as diluents, flavoring agents and binders, but xylitol (2) compression - forming the tablet; and (3) ejec- has not heretofore been used extensively in this tion - removing the tablet. The cycle is then re- context. peated. A representative tablet press is a MAN- Sweetness in pharmaceutical tablets fulfills the 30 ESTY Novapress, manufactured by Manesty Ma- purpose of making the product more pleasant to chines Ltd., Liverpool, England, and many others eat and to mask any unpleasant taste of the active are available. ingredient(s). Today, many pharmaceutical tablets In order to make tablets, preferably all ingre- are sweetened with sucrose, lactose and other fer- dients - or at least the carrier or diluent which mentable carbohydrates which are also used as 35 typically makes up the bulk of the tablet - must diluents. Replacing sucrose and other fermentable have certain physical characteristics, including the carbohydrates with xylitol in those applications ability to flow freely, and acceptable cohesion (or which must be sweetened would eliminate the use compressibility). Because many materials have of cariogenic formulations in medicaments such as some, or none, of these qualities, techniques must throat lozenges, cough tablets, vitamins, chewable 40 be developed to impart these characteristics to the tablets and others, and also takes advantage of the constituents. In this context, free flowing means other attributes of xylitol discussed above, such as that the particles to be compressed must enter the its noted cooling effect and metabolic characteris- compression chamber as discreet particles; com- tics. pressible means the particles form a tablet after In food contexts, tablets are usually sucked or 45 compression and do not remain in a powdered or chewed by the user and are often used as breath substantially powdered form. mints. Sucrose is the sweetener of choice in these Two critical criteria in the quality of a tablet are contexts and has bulking properties as well. Re- crushing strength (or hardness) and friability. The placing sucrose with xylitol would enable tablets to resistance of the tablet to chipping, abrasion, or exploit the unique advantages of xylitol, particularly 50 breakage under conditions of storage, transporta- its anti-caries properties, and its pronounced cool- tion and handling before usage depends on its ing effect. hardness. Hardness is measured by determining The cariostatic effect of xylitol is particularly lateral breaking strength (expressed in Newtons or important because clinical studies have shown that Strong Cobb Units wherein 7 N = 1 S.C.U.) ex- it is not the quantity of sucrose (or other acid 55 erted on a single tablet at the moment of rupture. A producing substances such as maltose, lactose and representative hardness tester is the Model HT-300 dextrose), but the frequency of sucrose intake that manufactured by Key International, Inc. Acceptable is critical for caries development. Many pharma- hardness depends on the desired mouthfeel and

3 5 EP 0 561 815 B1 6 the expected end use and packaging conditions of crystalline xylitol produces tablets which are too the tablet, but in most contexts, tablet hardness coarse in many contexts. The use of milled xylitol must be greater than about 10 S.C.U. to be com- (less than 200 micron average particle size) pro- mercially useful. duces a dry blended product (with sorbitol, for Friability is also a standard test known to one 5 example) wherein flowability of the blend is ex- skilled in the art. Friability is measured under stan- tremely poor (near zero). Tableting machinery dardized conditions by weighing out a certain num- equipped with a force feeder is required. Because ber of tablets (generally 20 or more), placing them this is not a desired characteristic, use of milled in a rotating plexiglass drum in which they are xylitol in conjunction with another polyol is not a lifted during replicate revolutions by a radial louver, io viable commercial alternative. A granulated form of and then dropped through the diameter of the xylitol would be much preferred. drum. After replicate revolutions, the tablets are Finnish Patent No. 81004, granted on Septem- reweighed and the percentage of powder "rubbed ber 10, 1990 discloses the use of a granulate which off" or broken pieces is calculated. Friability in the comprises xylitol in the range of about 94% to range of about 0% to 3% is considered acceptable is about 98% by weight and another physiologically for most drug and food tablet contexts. Friability acceptable polyol which serves as the binder in the which approaches 0% is particularly preferred. range of about 1 - 5% by weight. The granulate Tablets of insufficient hardness exhibit capping can be compressed to form tablets, but although and/or lamination and can easily break apart or the mouthfeel, initial hardness and friability is im- disintegrate under normal handling and packaging 20 proved over tablets made from crystalline xylitol, it conditions. Tablets of insufficient hardness cannot is not acceptable for some commercial applica- be used for lozenges or mints which are designed tions, and the granulate must be prepared under to be sucked in the mouth, releasing the active controlled conditions to prevent attack by atmo- ingredient(s) or flavor over time, and may have an spheric moisture. undesirable powdery, grainy or coarse mouthfeel. 25 Additional work has been done with xylitol Xylitol is not considered to be directly com- granulates. Granulation is a process carried out pressible, Le. crystalline xylitol cannot be com- today by various methods including fluidized bed pressed into tablets of sufficient hardness and low techniques, centrifugal fluidizing, compacting and friability. Therefore, in order to utilize xylitol in vacuum techniques. Granulation requires the use of tablets, a variety of approaches to impart these 30 a "binder" which assists in formulation of granules, characteristics have been used, without complete i.e. it brings the particles into a granulated, free success. flowing form. Binders which are often used include One method has been to compress xylitol into starch, gelatin, sugars such as sucrose, dextrose, tablets of relatively low initial hardness (e.g. about and lactose, natural and synthetic gums, micro- 6 S.C.U.) and "finish" the outer surface. The finish- 35 crystalline cellulose and others. ing step takes advantage of the unique crystalliza- These binders are not necessarily particularly tion properties of xylitol and its low melting point. acceptable for use with xylitol because they may Basically, the compressed tablets - which have a impair or eliminate the taste, cariostatic, metabolic low initial hardness - are heated by exposing the and other properties of xylitol which make it an surface of the tablets to hot air at temperatures 40 attractive constituent of pharmaceutical and food greater than 94 °C which cause a phase change in tablets. Some binders, including gum arabic, if the xylitol from solid to liquid. After cooling, re- utilized as a binder for xylitol, will reduce the per- crystallization occurs quickly and a "glass" hard ceived cooling effect of xylitol created by xylitol's surface layer is formed. This finishing step, how- significant negative heat of solution. Other binders ever, adds another significant step to the produc- 45 may impart a nondesired and unacceptable mouth- tion process (thereby increasing the cost and de- feel. Gelatin, if used as a binder, in addition to creasing the efficiency), cannot be used in all tablet masking the cooling effect of xylitol, may not be contexts, and does not result in a tablet with uni- desired for ethnic reasons. Starches and other form hardness. cariogenic fermentable carbohydrates, if utilized as Xylitol has also been admixed with other 50 binders, are not desired because of their negative polyols to form a mixture which is then com- impact on oral health. pressed. U.K. Patent No. 1,526,020 discloses a It has now been discovered, surprisingly and method for the production of compressed tablets unexpectedly, that certain compounds such as wherein xylitol is dry blended with another polyol polymerized reducing sugars like polydextrose, al- (e.g. sorbitol, mannitol, maltitol) so that the xylitol is 55 kali carboxymethylcellulose and hydrogenated present in about 10 - 90% by weight in the final starch hydrolysate when used as binders produce product. However, the use of a xylitol/additional a directly compressible xylitol granulate which can polyol blend can create disadvantages. The use of be compressed to tablets of high hardness and low

4 7 EP 0 561 815 B1 8 friability and yet allow the full range of xylitol's fied, and/or partially neutralized or neutralized form, taste, cariostatic and other properties to be ex- and sodium carboxymethylcellulose. A consumable pressed in a tablet context. Use of these binders tablet wherein said tablet is sweetened with a will allow, for the first time, the use of xylitol in granulate comprising about 97% xylitol and about large scale, commercial tableting processes to pro- 5 3% polydextrose by weight is particularly pre- duce pharmaceutical and food tablets sweetened ferred. A consumable tablet wherein said tablet is with xylitol, tablets that exhibit remarkable hard- sweetened with a granulate comprising about ness, low friability that in some cases approaches 99.5% to about 97% by weight xylitol and about zero, excellent taste profile, and are non-cariogenic 0.5% to about 3.0% by weight sodium carbox- and potentially cariostatic. io ymethylcellulose is preferred, with a granulate The present invention contemplates a directly comprising about 98.5% xylitol and about 1 .5% by compressible, non-cariogenic xylitol granulate weight sodium carboxymethylcellulose being par- which comprises xylitol and a binder in the range ticularly preferred. of about 0.1% to about 5% by weight, wherein the A consumable tablet wherein said tablet is binder is physiologically acceptable, non-cariogenic is sweetened with a granulate comprising about 95% and is taken from the group consisting of polymer- to about 99% xylitol and about 1% to about 5% ized reducing sugars, alkali carboxymethylcellulose hydrogenated starch hydrolysate by weight is pre- and hydrogenated starch hydrolysate. Binders ferred, with a granulate comprising about 97% which are particularly preferred are polydextrose, in xylitol and about 3% hydrogenated starch a partially purified or purified and/or a partially 20 hydrolysate being particularly preferred. neutralized or neutralized form, and sodium carbox- The invention also contemplates a consumable ymethylcellulose. The use of a polydextrose binder tablet which additionally includes an intense sweet- in the range of about 0.5% to about 5% by weight ener. A particularly preferred intense sweetener is is preferred, with polydextrose present in the taken from the group consisting of dipeptide sweet- amount of about 3% by weight being particularly 25 eners, saccharin, acesulfame K, stevioside, preferred. The use of a sodium carboxymethylcel- cyclamate, neohesperidin dihydrochalcone and lulose binder in the range of about 0.5% to about sucralose. 3% by weight is preferred, with sodium carbox- The invention also contemplates a method for ymethylcellulose present in the amount of about the production of a directly compressible, non- 1.5% by weight being particularly preferred. The 30 cariogenic xylitol granulate which consists of use of hydrogenated starch hydrolysate in the granulating milled xylitol with an average particle amount of about 1% to about 5% by weight is size of between about 40 to about 180 microns preferred, with hydrogenated starch hydrolysate (with an average particle size of between about 40 present in the amount of about 3% by weight being to about 120 being preferred) with a physiologically particularly preferred. 35 acceptable, non-cariogenic binder taken from the The invention also contemplates a directly group consisting of polymerized reducing sugars, compressible xylitol granulate which additionally in- alkali carboxymethylcellulose and hydrogenated cludes an intense sweetener. Intense sweeteners starch hydrolysate in the range of about 0.5% to taken from the group consisting of dipeptide sweet- about 5% by weight and screening the resulting eners, saccharin, acesulfame K, stevioside, 40 granulate. In one method, an aqueous binder solu- cyclamates, neohesperidin dihydrochalcone and tion is added to milled xylitol, and the resulting sucralose are preferred. granulate is dried and screened. Milled xylitol with The invention also contemplates a relatively an average particle size of between about 50 and stable, non-cariogenic consumable tablet which ex- about 90 microns is particularly preferred. Polydex- hibits a noted cooling effect, a tablet which is 45 trose, in a partially purified or purified and/or par- sweetened with a granulate which comprises xylitol tially neutralized or neutralized form, sodium car- in the range of about 90% to about 99% by weight, boxymethylcellulose and hydrogenated starch and a physiologically acceptable non-cariogenic hydrolysate are particularly preferred binders. binder taken from the group consisting of polymer- The invention also contemplates a directly ized reducing sugars, alkali carboxymethylcellulose 50 compressible granulate which comprises a polyol and hydrogenated starch hydrolysate in the range such as mannitol, lactitol, sorbitol, isomalt and mal- of about 0.1% to about 5% by weight, wherein said titol or a sweetener suitable for diabetic applica- tablet exhibits hardness of at least 10 Strong Cobb tions such as crystalline fructose and/or mixtures Units and a friability of less than about 3%. A tablet thereof, and a polydextrose binder present in the which exhibits hardness of at least 10-40 Strong 55 range of about 0.1% to about 5% by weight. Cobb Units and a friability of less than about 1 % is The granulate of the present invention exhibits particularly preferred. Particularly preferred binders excellent flowability and compressibility when used include polydextrose in a partially purified or puri- in typical tableting equipment, such as a Manesty

5 9 EP 0 561 815 B1 10

Betapress or other tableting presses which are Suitable commercial granulators or granulating known to one of ordinary skill in the art. The xylitol systems include the Lodige horizontal blender used to form the granulate is xylitol milled to an (Gebruder Lodige GmbH) in combination with a average particle size of between about 40 to about fluidized bed dryer, the Glatt vertical fluidized bed 180 microns. Crystalline xylitol can be milled, 5 granulator (Glatt GmbH, Binzen, West Germany), ground or otherwise comminuted to reach the pre- the Aeromatic vertical fluidized bed granulator ferred particle size. (Aeromatic AG, Bubendorf, Switzerland) and the The binder contemplated by the present inven- Schugi granulator (Schugi, BV, Lelystad, Holland). tion is a physiologically acceptable, non-cariogenic Other granulation devises commonly known to binder. Surprisingly and unexpectedly, polydex- io those skilled in the art can be utilized in the prac- trose - a polymerized reducing sugar - functions as tice of our invention. an excellent binder in this context; polydextrose The produced and dried granulate is usually has heretofore been utilized solely as a bulking screened following the granulation step to remove agent for use in baked goods, baking mixes, frozen coarse particles. A suitable sieve size for this pur- desserts, pudding, chocolate, hard candy and soft 15 pose is a 16 mesh (1.2 mm) screen. The coarse candy and has not been utilized as a binder in the particles can either be reworked, milled or dis- pharmaceutical or compressed candy contexts. solved for further use. Polydextrose is available from the Pfizer Chemical The granulate can be utilized as a sweetening, Division, New York, New York. Polydextrose is a flavor or bulking agent and/or as a diluent in food water-soluble, randomly bonded condensation poly- 20 and pharmaceutical contexts alone, or in combina- mer of dextrose, containing minor amounts of tion with other sweeteners (such as intense sweet- bound sorbitol and citric acid. Polydextrose is avail- eners), other polyols and/or other binding agents. able in four forms: (1) polydextrose type "A"; (2) polydextrose type "N" (which contains some free Example 1 : Laboratory Scale Production of Directly acid in liquid form); (3) polydextrose "K" (a partially 25 Compressible Granulate neutralized version which is treated with sodium carbonate to diminish the acidity of the polydex- 500 grams of milled, 90 urn xylitol was served trose); (4) "new" polydextrose, a purified version of into a HOBART N-50 blender and mixed at the polydextrose type "A". Other physiologically ac- slowest speed for 30 seconds. A 50% solution of ceptable, non-cariogenic polymers of reducing su- 30 polydextrose K (Pfizer) was added slowly during gars may also function as binders in this context. mixing, the mixing speed increased to intermediate Another binder is an alkali carboxymethylcel- and then continued for 30 seconds. The resulting lulose such as sodium carboxymethylcellulose. So- granules were sieved through a 120 mesh (125 dium carboxymethylcellulose can be utilized in a linn) sieve and dried in a BRUCK'S drying drum at wide range of cosmetic, food, pharmaceutical and 35 30 rpm for 15 - 60 minutes, and then overnight at industrial applications, but has heretofore not been 40 ° C in a drying cabinet. The dried granules were utilized as a binder with xylitol in tableting contexts. sieved again through a 120 mesh (125 urn) sieve. Sodium carboxymethylcellulose is available from A granulate with good flowability which was not Aqualon Company, Wilmington, Delaware. Sodium excessively lumpy, sticky or moist was produced. carboxymethylcellulose is a cellulose ether pro- 40 The granulate was formed into tablets by mix- duced by reacting alkali cellulose with sodium ing the granulates with 1% Magnesium stearate (a monochloroacetate under controlled conditions. So- lubricator) in a TWIN SHELL dry blender (Patter- dium carboxymethylcellulose is available in food, son-Kelly Co.) for 3 minutes. Tablets were made pharmaceutical and standard grades with varying using a KORSCH tableting machine at forces of degrees of substitution (from 0.38 to 1.4) and vis- 45 9.4, 20 and 32.0 kN. The resulting tablets exhibited cosity characteristics in solution with water. crushing strengths of about 10, 17 and 14 Strong A further binder is hydrogenated starch Cobb Units at the respective compression forces of hydrolysate. Hydrogenated starch hydrolysate is 9.4, 20 and 32.0 kN. Each tablet exhibited a good the catalytically hydrogenated product of high malt- finish and a pleasing sweetness and cooling sensa- ose syrup and is commercially available from a 50 tion. wide variety of sources. Granulation of the xylitol and binder can be Example 2: Production of a Directly Compression achieved with any of the standard means of granu- Xylitol Granulate lation available. In bench type applications, milled xylitol is combined with polydextrose syrup, mixed 55 6000 g of xylitol milled to an average particle in a blender, sieved and dried. The dried granulate size of 50 microns was charged into a type FKM is further sieved to produce particles of uniform 50 Lodige horizontal blender and mixed at a rate of size and shape. 60 rpm. 528.6 g of a polydextrose syrup compris-

6 11 EP 0 561 815 B1 12 ing 35% Polydextrose K (dry basis) and water was observed to have a pleasing sweetness and cooling sprayed into the Lodige over a five minute period sensation. (105.7 g/min). The resulting wet granulate was mixed for an additional five minute period and then Example 4: Production of a Directly Compressible mixed with the Lodige chopper for an additional 5 Xylitol Granulate minute. The resulting admixture was then placed in a Glatt vertical bed fluidized drying system and 6000 g of xylitol milled to an average particle dried to a product temperature of 50 ° C to generate size of 90 urn was granulated with Polydextrose K a granulate with a moisture level of less than about as described for Example 3. The resulting 0.5% by weight. The granulate was then screened io granulate exhibited good flow properties. It had a through a 16 mesh sieve with the resulting overs bulk density of 0.53 g/ml and an average particle being segregated for further processing. The result- size of about 350 urn. Less than 5% of the final ing granulate exhibited good flow properties. product passed through a 177 urn sieve. The The granulate (1980 g) was mixed with magne- granulate contained about 3% polydextrose and sium stearate (20 g) for three minutes and com- is about 0.6% water by weight. pressed into 500 mg tablets (1,1 cm (7/16 inch) Tablets were prepared as described in Exam- diameter utilizing a Manesty Betapress) and 0,625 ple 3. The resulting tablets exhibited a hardness of cm (1/4 inch) precompression at 2.5 tons compres- 18 Strong Cobb Units. Tablet friability was 0.3%. sion force. The resulting tablets exhibited an initial Each tablet exhibited a good finish, was free of hardness of 15.5 Strong Cobb Units and a 24 hour 20 capping or lamination and had a pleasing sweet- hardness of 24.4 Strong Cobb Units. Tablet friabil- ness and cooling effect. ity was less than 2%. Each tablet exhibited a good finish, was free of capping or lamination and was Example 5: Production of a Directly Compressible observed to have a pleasing sweetness and cooling Xylitol Granulate sensation. 25 6000 mg of xylitol milled to an average particle Example 3: Production of a Directly Compressible size of 50 urn was granulated with Polydextrose K Xylitol Granulate utilizing 1163 g of a 5.12% solids Polydextrose solution in water as described for Example 3. The 6000 g of xylitol milled to an average particle 30 resulting granulate exhibited good flow characteris- size of 50 urn was charged into a GPCG 5/9 Glatt tics. It had a bulk density of 0.44 g/ml and an vertical fluidized bed granulator. 1856 g of a poly- average particle size of about 300 urn. Less than dextrose syrup comprising 10% Polydextrose K 10% of the screened produced passed through a (dry basis) and water was sprayed onto the xylitol 149 urn sieve. The granulate contained about 1% over a 20 minute period (92.8 g/min) at 2.5 bar 35 polydextrose. pressure utilizing a 2 mm nozzle located in the Tablets were prepared as described in Exam- middle of the fluidized bed. The Glatt was operated ple 3. The resulting tablets exhibited a hardness of in the WSG mode wherein the polydextrose syrup 21 Strong Cobb Units. Tablet friability was about was applied for 60 seconds and terminated for 4 3%. Each tablet exhibited a good finish and was seconds of dust collector shaking. The granulate 40 observed to have a pleasing sweetness and cooling was dried to a product temperature of 50 °C to sensation. generate a granulate having about 0.2% moisture by weight. The granulate was then screened Example 6: Production of a Directly Compressible through a 16 mesh sieve with the resulting overs Xylitol Granulate being segregated for further processing. The result- 45 ing granulate exhibited good flow properties. It had 7000 g of xylitol milled to an average particle a bulk density of 0.47 g/ml and an average particle size of 50 urn was granulate with Polydextrose K size of about 350 urn The granulate was further utilizing 2455 g of a 15% solids polydextrose solu- characterized in that less than 10% of the product tion in water as described for Example 3. The was less than 149 urn. The granulate contained 50 nozzle opening was reduced to 1.2 mm and the about 3% polydextrose by weight. Polydextrose solution was sprayed at 3 bar pres- The granulate (5,529 g) was mixed with mag- sure. The resulting granulate, containing about 5% nesium stearate (55.8 g) for a period of 3 minutes Polydextrose, was free flowing and suitable for and compressed as described in Example 2 into direct compression. 550 mg tablets. The resulting tablets exhibited a 55 Tablets were prepared as described in Exam- hardness of about 18 Strong Cobb Units. Tablet ple 3. Tablet hardness was 28 strong Cobb Units. friability was 0.2%. Each tablet exhibited a good Tablet friability was 0.8%. Each tablet exhibited a finish, was free of capping or lamination and was good finish and was observed to have a pleasing

7 13 EP 0 561 815 B1 14 sweetness and cooling sensation. A slight "dextrin" linn sieve. The granulate contained about 1.5% flavor was, however, noted. sodium carboxymethylcellulose and about 0.3% water. Example 7: Production of a Directly Compressible Tablets were prepared as described in Exam- Xylitol Granulate 5 pie 3. The resulting tablets had a hardness of 14 Strong Cobb Units and a friability of less than 1%. 6000 g of xylitol milled to an average particle No capping or lamination was observed. The tab- size of 50 urn was granulated with sodium carbox- lets were observed to have a pleasing sweetness ymethylcellulose utilizing 865.7 g of a 7% solids and cooling sensation and had a good finish. No off sodium carboxymethylcellulose (Aqualon 7L2P) in io color was observed. water as described for Example 3. The resulting granulate exhibited good flow characteristics. It had Example 10: Production of a Directly Compressible a bulk density of 0.41 g/ml and an average particle Xylitol Tablet size of about 300 urn. Less than 15% passed through a 149 micron sieve. The granulate con- is 500 grams of milled 50 urn xylitol was sieved tained about 1% sodium carboxymethylcellulose into a blender and mixed as in Example 1 . A 50% and about 0.1% water. solution of FINMALT L (a hydrogenated starch Tablets were prepared as described in Exam- hydrolysate available from Cultor Ltd., Finland) was ple 3. The resulting tablets had a hardness of 24 added and a granulate was produced as in Exam- strong Cobb Units and a friability of 6.1%. Some 20 pie 1. The resulting granulate consisted of about capping was observed. Tablets were observed to 97% by weight xylitol and about 3% by weight have a pleasing sweetness and cooling sensation hydrogenated starch hydrolysate. and had a good finish. The granulate was formed into tablets as in Example 1. The tablets exhibited hardness of be- Example 8: Production of a Directly Compressible 25 tween about 10 and 11 Strong Cobb Units. Each Xylitol Granulate tablet was observed to have a good finish and exhibited a pleasing sweetness and cooling effect. 6000 g of xylitol milled to an average particle The foregoing general discussion and experi- size of 50 urn was granulated with sodium carbox- mental examples are intended to be illustrative of ymethylcellulose utilizing 2651.4 g of a 7% solids 30 the present invention. sodium carboxymethylcellulose solution in water as described for Example 7. The resulting granulate Claims exhibited good flow characteristics. It had a bulk density of 0.36 g/ml and an average particle size of 1. A directly compressible, non-cariogenic xylitol about 500 urn. Less than 5% passed through a 149 35 granulate, characterized in that it comprises linn sieve. The granulate contained about 3% so- xylitol and a physiologically acceptable, non- dium carboxymethylcellulose and about 0.3% wa- cariogenic binder in the range of 0.1% to 5% ter. by weight taken from the group consisting of Tablets were prepared as described in Exam- polymerized reducing sugars, alkali carbox- ple 3. The resulting tablets had a hardness of 40 ymethylcellulose and hydrogenated starch greater than 40 Strong Cobb Units and 0.0% friabil- hydrolysate. ity. No capping or lamination was observed. Tab- lets further exhibited a pleasing sweetness and 2. The directly compressible granulate of claim 1 , cooling sensation and had a good finish. It was characterized in that it comprises xylitol in noted, however, that the tablets had a slight yel- 45 the range of 99.9% to 90% by weight, prefer- low/orange cast. ably 99.5% to 95% by weight.

Example 9: Production of a Directly Compressible 3. The directly compressible granulate of claim 1 Xylitol Granulate or 2 wherein said polymerized reducing sugar 50 is polydextrose. 6000 g of xylitol milled to an average particle size of 90 urn was granulated with sodium carbox- 4. The directly compressible granulate of claim 1 ymethylcellulose utilizing 1305.7 g of a 7% solids or 2 wherein said polydextrose is in a partially sodium carboxymethylcellulose solution in water as purified or purified, and/or partially neutralized described for Example 7. The resulting granulate 55 or neutralized form. exhibited good flow characteristics. It had a bulk density of 0.44 g/ml and an average particle size of 5. The directly compressible granulate of claim 3 about 450 urn. Less than 5% passed through a 177 or 4 wherein said polydextrose is present in

8 15 EP 0 561 815 B1 16

the range of 0.5% to 5% by weight, preferably kali carboxymethylcellulose and hydrogenated in an amount of 3% by weight. starch hydrolysate in the range of 0.1% to 10% by weight, preferably 0.5% to 5% by 6. The directly compressible granulate of claim 1 weight to produce a free-flowing granulate; and or 2 wherein said alkali carboxymethylcellulose 5 screening the resulting granulate. is sodium carboxymethylcellulose. 16. The method of claim 15 wherein said milled 7. The directly compressible granulate of claim 6 xylitol has an average particle size of 40 to 120 wherein said sodium carboxymethylcellulose is microns, preferably 50 to 90 microns. present in the range of 0.5% to 3% by weight, 10 preferably in an amount of 1 .5% by weight. 17. A directly compressible granulate which comprises a physiologically acceptable polyol tak- 8. The directly compressible granulate of claim 1 en from the group consisting of mannitol, lac- or 2 wherein said hydrogenated starch titol, sorbitol, isomalt, maltitol or a sweetener hydrolysate is present in an amount of 1% to is suitable for diabetic applications such as cry- 5% by weight, preferably in an amount of 3% stalline fructose, and combinations thereof, and by weight. polydextrose in the range of 0.1% to 5% by weight. 9. The directly compressible granulate of any one of claims 1 to 8 which additionally includes an 20 Patentanspruche intense sweetener. 1. Direkt komprimierbares, nicht-kariogenes Xylit- 10. The directly compressible granulate of claim 9 granulat dadurch gekennzeichnet, dal3 es Xy- wherein said intense sweetener is taken from lit und ein physiologisch akzeptables nicht-ka- the group consisting of dipeptide sweeteners, 25 riogenes Bindemittel, ausgewahlt aus der aus saccharin, acesulfame K, stevioside, polymerisierten reduzierenden Zuckern, Alkali- cyclamate, neohesperidin dihydrochalcone and Carboxymethylcellulose und hydriertem Star- sucralose. kehydrolysat bestehenden Gruppe, in einer Menge im Bereich von 0,1 bis 5 Gew.% ent- 11. A relatively stable, non-cariogenic consumable 30 halt. tablet which exhibits a noted cooling effect when consumed, characterized by being 2. Direkt komprimierbares Granulat nach An- sweetened by a granulate of any one of claims spruch 1, dadurch gekennzeichnet, dal3 es 1 to 10 and having a hardness of at least 10 Xylit in einer Menge im Bereich von 99,9 bis Strong Cobb Units, and a friability of less than 35 90 Gew.%, vorzugsweise 99,5 bis 95 Gew.%, 3%. enthalt.

12. The consumable tablet of claim 11 wherein 3. Direkt komprimierbares Granulat nach An- said tablet exhibits hardness of at least 15 spruch 1 oder 2, in dem der polymerisierte Strong Cobb Units, and a friability of less than 40 reudzierende Zucker Polydextrose ist. 1%. 4. Direkt komprimierbares Granulat nach An- 13. The consumable tablet of claim 11 or 12 which spruch 1 oder 2, in dem die Polydextrose in additionally includes an intense sweetener. partiell gereinigter oder gereinigter Form 45 und/oder in partiell neutralisierter oder neutrali- 14. The consumable tablet of claim 13 wherein sierter Form vorliegt. said intense sweetener is taken from the group consisting of dipeptide sweeteners, saccharin, 5. Direkt komprimierbares Granulat nach An- acesulfame K, stevioside, cyclamate, spruch 3 oder 4, in dem die Polydextrose in neohesperidin dihydrochalcone and sucralose. 50 einer Menge im Bereich von 0,5 bis 5 Gew.%, vorzugsweise in einer Menge von 3 Gew.% 15. A method for the production of a directly com- enthalten ist. pressible xylitol granulate of any one of claims 1 to 10, characterized by granulating milled 6. Direkt komprimierbares Granulat nach An- xylitol with an average particle size of 40 to 55 spruch 1 , in dem die Alkalicarboxymethylcellu- 180 microns with a physiologically acceptable, lose Natriumcarboxymethylcellulose ist. non-cariogenic binder taken from the group consisting of polymerized reducing sugars, al-

9 17 EP 0 561 815 B1 18

7. Direkt komprimierbares Granulat nach An- einer Menge im Bereich von 0,1 bis 10 spruch 6, in dem die Natriumcarboxymethyl- Gew.%, vorzugsweise von 0,5 bis 5 Gew.% cellulose in einer Menge im Bereich von 0,5 unter Bildung eines rieselfahigen Granulats bis 3 Gew.%, vorzugsweise in einer Menge granuliert wird; und das resultierende Granulat von 1 ,5 Gew.% vorliegt. 5 gesiebt wird.

8. Direkt komprimierbares Granulat nach An- 16. Verfahren nach Anspruch 15, in dem das ge- spruch 1, in dem das hydrierte Starkehydroly- mahlene Xylit eine durchschnittliche Teilchen- sat in einer Menge von 1 bis 5 Gew.%, vor- groBe von 40 bis 120 Mikrometer, vorzugswei- zugsweise in einer Menge von 3 Gew.% vor- io se 50 bis 90 Mikrometer hat. liegt. 17. Direkt komprimierbares Granulat, das ein phy- 9. Direkt komprimierbares Granulat nach An- siologisch akzeptables Polyol, ausgewahlt aus spruch 1 bis 8, das zusatzlich einen intensiven der aus Mannit, Lactit, Sorbit, Isomalt, Maltit, SuBstoff enthalt. is bestehenden Gruppe, oder einen SuBstoff, der fur diabetische Anwendungen geeignet ist, wie 10. Direkt komprimierbares Granulat nach An- z. B. kristalline Fructose, sowie Kombinationen spruch 9, in dem der intensive SuBstoff aus der genannten, und Polydextrose in einer Men- der aus Dipeptid-StiBstoffen, Saccharin, Ace- ge von 0,1 bis 5 Gew.% enthalt. sulfam K, Steviosid, Cyclamat, Neohesperidin- 20 dihydrochalcon und Sucralose bestehenden Revendications Gruppe ausgewahlt ist. 1. Granule de xylitol non cariogene directement 11. Relativ stabile, nicht-kariogene verzehrbare Ta- compressible, caracterise en ce qu'il com- blette, die eine deutliche kuhlende Wirkung 25 prend du xylitol et un liant non cariogene phy- aufweist, wenn sie verzehrt wird, dadurch ge- siologiquement acceptable dans la gamme de kennzeichnet, daB sie durch ein Granulat 0,1% a 5% en poids, choisi dans le groupe nach einem der Anspruche 1 bis 10 gestiBt comprenant des sucres reducteurs polymeri- wird, eine Harte von mindestens 10 Strong ses, une carboxymethylcellulose alcaline et un Cobb Units und eine Brockligkeit von weniger 30 hydrolysat d'amidon hydrogene. als 3 % hat. 2. Granule directement compressible selon la re- 12. Verzehrbare Tablette nach Anspruch 11, wobei vendication 1, caracterise en ce qu'il com- die Tablette eine Harte von mindestens 15 prend du xylitol dans la gamme de 99,9% a Strong Cobb-Einheiten und eine Brockligkeit 35 90% en poids, et de preference, de 99,5% a von weniger als 1 % aufweist. 95% en poids.

13. Verzehrbare Tablette nach Anspruch 11 oder 3. Granule directement compressible selon la re- 12, die zusatzlich einen intensiven SuBstoff vendication 1 ou 2, dans lequel ledit sucre enthalt. 40 reducteur polymerise est le polydextrose.

14. Verzehrbare Tablette nach Anspruch 13, bei 4. Granule directement compressible selon la re- der der intensive SuBstoff aus der aus Dipep- vendication 1 ou 2, dans lequel le polydextrose tid-StiBstoffen, Saccharin, Acesulfam K, Stevio- est sous une forme partiellement purifiee ou sid, Cyclamat, Neohesperidindihydrochalcon 45 purifiee, et/ou partiellement neutralised ou neu- und Sucralose bestehenden Gruppe ausge- tralised. wahlt ist. 5. Granule directement compressible selon la re- 15. Verfahren zur Herstellung eines direkt kompri- vendication 3 ou 4, dans lequel le polydextrose mierbaren Xylitgranulats nach einem der An- 50 est present dans la gamme de 0,5% a 5% en spruche 1 bis 10, dadurch gekennzeichnet, poids, et de preference, dans une proportion daB gemahlenes Xylit mit einer durchschnittli- de 3% en poids. chen TeilchengroBe von 40 bis 180 Mikrome- ter (urn) mit einem physiologisch akzeptablen, 6. Granule directement compressible selon la re- nicht-kariogenen Bindemittel, ausgewahlt aus 55 vendication 1 ou 2, dans lequel la carboxyme- der aus polymerisierten reduzierenden Zuk- thylcellulose alcaline est la carboxymethylcel- kern, Alkalicarboxymethylcellulose und hydrier- lulose de sodium. tem Starkehydrolysat bestehenden Gruppe, in

10 19 EP 0 561 815 B1 20

7. Granule directement compressible selon la re- hydrolysat d'amidon hydrogene dans la gam- vendication 6, dans lequel la carboxymethyl- me de 0,1% a 10% en poids, et de preferen- cellulose de sodium est presente dans la gam- ce, de 0,5% a 5% en poids, pour produire un me de 0,5% a 3% en poids, et de preference, granule qui ne s'agglomere pas, et par le tami- dans une proportion de 1 ,5% en poids. 5 sage du granule obtenu.

8. Granule directement compressible selon la re- 16. Procede selon la revendication 15, dans lequel vendication 1 ou 2, dans lequel I'hydrolysat le xylitol broye a une taille moyenne de parti- d'amidon hydrogene est present dans une pro- cule de 40 a 120 microns, et de preference, de portion de 1 % a 5% en poids, et de preferen- io 50 a 90 microns. ce, dans une proportion de 3% en poids. 17. Granule directement compressible qui com- 9. Granule directement compressible selon I'une prend un polyol physiologiquement acceptable quelconque des revendications 1 a 8, qui com- choisi dans le groupe constitue du mannitol, prend en outre un edulcorant intense. is du lactitol, du sorbitol, de I'isomalt, du maltitol ou un edulcorant approprie pour des applica- 10. Granule directement compressible selon la re- tions diabetiques tel que le fructose cristallin, vendication 9, dans lequel I'edulcorant intense et des combinaisons de ceux-ci, et un poly- est choisi dans le groupe comprenant des dextrose dans la gamme de 0,1% a 5% en edulcorants a base de dipeptide, la saccharine, 20 poids. I'acesulfame K, le stevioside, le cyclamate, la neohesperidine dihydrochalcone et le sucralose.

11. Comprime consommable non cariogene relati- 25 vement stable qui presente un effet rafraTchis- sant notable lorsqu'il est consomme, caracterise par le fait qu'il est edulcore par un granule selon I'une quelconque des revendications 1 a 10 et qu'il presente un durete d'au moins 10 30 Unites Strong Cobb et une friabilite inferieure a 3%.

12. Comprime consommable selon la revendication 1 1 , dans lequel le comprime presente une 35 durete d'au moins 15 Unites Strong Cobb et une friabilite inferieure a 1%.

13. Comprime consommable selon la revendication 11 ou 12, caracterise en ce qu'il comprend 40 en outre un edulcorant intense.

14. Comprime consommable selon la revendication 13, dans lequel I'edulcorant intense est choisi dans le groupe comprenant des edulco- 45 rants a base de dipeptide, la saccharine, I'acesulfame K, le stevioside, le cyclamate, la neohesperidine dihydrochalcone et le sucralose.

15. Procede pour produire un granule de xylitol 50 directement compressible selon I'une quelconque des revendications 1 a 10, caracterise par la granulation d'un xylitol broye presentant une taille moyenne de particule de 40 a 180 microns avec un liant non cariogene physiologi- 55 quement acceptable choisi dans le groupe comprenant des sucres reducteurs polymeri- ses, une carboxymethylcellulose alcaline et un