WO2006046111A1 - Utilisation de xylitol en tant qu'agent agissant contre la sensation de craie en bouche dans des compositions destinees a une utilisation par voie orale et comprenant un compose contenant du calcium en tant que substance active - Google Patents

Utilisation de xylitol en tant qu'agent agissant contre la sensation de craie en bouche dans des compositions destinees a une utilisation par voie orale et comprenant un compose contenant du calcium en tant que substance active Download PDF

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Publication number
WO2006046111A1
WO2006046111A1 PCT/IB2005/003179 IB2005003179W WO2006046111A1 WO 2006046111 A1 WO2006046111 A1 WO 2006046111A1 IB 2005003179 W IB2005003179 W IB 2005003179W WO 2006046111 A1 WO2006046111 A1 WO 2006046111A1
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Prior art keywords
calcium
containing compound
use according
xylitol
composition
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PCT/IB2005/003179
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English (en)
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Jimmy Hirschsprung Schlyter
Peder Mohr Olsen
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Nycomed Pharma As
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Publication of WO2006046111A1 publication Critical patent/WO2006046111A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • xylitol as an anti-chalk acting agent in compositions for oral use containing a calcium-containing compound as an active substance
  • the present invention relates to the use of xylitol as an anti-chalk acting agent in a nutriceutical and/or pharmaceutical composition for oral use containing a calcium- containing compound.
  • the composition is in the form of tablets that are designed so that they have an acceptable mouthfeel, whereby the tablets are chewable or suckable.
  • Calcium is essential for a number of key functions in the body, both as ionized calcium and a calcium complex.
  • a number of diseases, especially bone-related diseases, are treated/prophylactically treated by intake of a sufficient amount of a calcium-containing compound.
  • calcium Normally, calcium must be orally administered in a relatively high amount, which makes especially dosage forms like e.g. chewable or suckable tablets suitable.
  • one of the major problems in this respect is to obtain compositions that have a sufficient customer compliance in order to achieve a correct and efficient treatment. This problem is related to the unpleasant mouthfeel of calcium-containing compounds, which mouthfeel is very difficult to mask.
  • xylitol is able to circumvent the undesired mouthfeel of a calcium-containing compound.
  • this undesired mouthfeel is the chalky-like, gritty-like, dusty like and/or dry sensation normally characterized by e.g. calcium carbonate.
  • Xylitol is a normally used as an artificial sweetening agent and has as such been employed in various pharmaceutical compositions, but to the best of the inventor's knowledge it has not been recognized that xylitol possesses unique properties to counteract or circumvent the bad mouthfeel resulting from the intake of a calcium containing product.
  • the present inventor has found that the elimination or significant reduction of the bad mouthfeel of compositions containing a calcium-containing compound by use of xylitol has an outstanding effect both with respect to an initial effect, i.e. upon intake of the composition xylitol exerts its mouthfeel-masking effect, and with respect to an on-going effect, i.e. the effect lasts for a prolonged period of time (such as, e.g., for about 10 min or more after administration).
  • the present invention provides a novel use of xylitol as an anti-chalk acting agent.
  • anti-chalk means the characteristic mouthfell of e.g. calcium carbonate, which normally is regarded as chalky, dusty, gritty, dry and unpleasant.
  • the invention relates to the use of xylitol as an anti-chalk acting agent for the manufacture of compositions containing a calcium-containing compound as an active substance to counteract the chalky or unpleasant mouthfeel of the calcium- containing compound.
  • xylitol as an anti-chalk acting agent can be assed by testing whether a composition has an acceptable taste and mouthfeel when tested by a professional/skilled sensory test panel of at least 6 test persons.
  • a professional/skilled sensory test panel denotes test persons that have the ability or have been trained to have the ability of evaluating taste and mouthfeel of ingestible products. Suitable test are e.g. ISO- 6564, Sensory analysis - Methodology - Flavour profile methods and ISO- 5495 Sensory Analysis - Methodology - Paired comparison test.
  • xylitol should be used in a sufficient amount depending on the particular calcium-containing compound employed and the specific quality thereof. As demonstrated in the examples herein, the concentration of xylitol is at least about 10% w/w based on the total weight of the calcium-containing compound contained in the composition.
  • the concentration of xylitol is at least about 15% w/w such as, e.g., at least about 20% w/w, at least about 25% w/w, at least about 30% w/w, at least about 35% w/w or about 40% w/w or more based on the total weight of the calcium- containing compound contained in the composition.
  • Calcium-containing compound The use of xylitol according to the invention is especially relevant for a calcium- containing compound that is a physiologically tolerable calcium-containing compound and that is therapeutically and/or prophylactically active.
  • Calcium is essential for a number of key functions in the body, both as ionized calcium and a calcium complex (Campell AK.CIin Sci 1987; 72:1-10). Cell behaviour and growth are regulated by calcium. In association with troponin, calcium controls muscle contraction and relaxation (Ebashi S. Proc R Soc Lond 1980; 207:259-86).
  • Calcium selected channels are a universal feature of the cell membrane and the electrical activity of nerve tissue and the discharge of neurosecretory granules are a function of the balance between intracellular and extra cellular calcium levels (Burgoyne RD. Biochim Biophys Acta 1984;779:201-16). The secretion of hormones and the activity of key enzymes and proteins are dependent on calcium. Finally calcium as a calcium phosphate complex confers rigidity and strength on the skeleton (Boskey AL. Springer, 1988:171-26). Because bone contains over 99% of the total body calcium, skeletal calcium also serves as the major long-term calcium reservoir.
  • Calcium salts such as, e.g., calcium carbonate is used as a source of calcium especially for patients suffering from or at risk of osteoporosis. Moreover, calcium carbonate is used as an acid-neutralizing agent in antacid tablets.
  • osteopenia affects cancellous bone more than cortical bone and may not be completely reversible with calcium supplementation. If the animal is growing reduced calcium intake leads to stunting. In the premature human neonate the higher the calcium intake, the greater the increase in skeletal calcium accretion which, if high enough, can equal gestational calcium retention. During growth chronic calcium deficiency causes rickets. Calcium supplements in both pre- and postpubertal healthy children leads to increased bone mass. In adolescents the higher the calcium intake, the greater the calcium retention, with the highest retention occurring just after menarche.
  • Calcium salts like e.g. calcium carbonate is used in tablets and due to the high dose of calcium required, such tablets are often in the form of chewable tablets. It is a challenge to formulate e.g. chewable tablets containing a calcium salt, which tablets have a pleasant taste and an acceptable mouth feel without the characteristic dominating feeling of chalk.
  • a calcium-containing compound for use according to the invention may be e.g. bisglycino calcium, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium citrate malate, calcium cornate, calcium fluoride, calcium glubionate, calcium gluconate, calcium glycerophosphate, calcium hydrogen phosphate, calcium hydroxyapatite, calcium lactate, calcium lactobionate, calcium lactogluconate, calcium phosphate, dicalcium phosphate, calcium pidolate, calcium stearate, ⁇ -tricalcium phosphate and tricalcium phosphate.
  • Other calcium sources may be water-soluble calcium salts, or complexes like e.g.
  • Use of bone meal, dolomite and other unrefined calcium sources is discouraged because these sources may contain lead and other toxic contaminants. However, such sources may be relevant if they are purified to a desired degree.
  • the calcium-containing compound may be used alone or in combination with other calcium-containing compounds.
  • Of specific interest is bisglycino calcium, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium citrate malate, calcium cornate, calcium fluoride, calcium glubionate, calcium gluconate, calcium glycerophosphate, calcium hydrogen phosphate, calcium hydroxyapatite, calcium lactate, calcium lactobionate, calcium lactogluconate, calcium phosphate, calcium pidolate, calcium stearate and tricalcium phosphate.
  • Mixtures of different calcium-containing compounds may also be used.
  • calcium carbonate is especially suitable for use as a calcium-containing compound and calcium carbonate has a high content of calcium.
  • a calcium- and xylitol-containing tablet contains an amount of the calcium- containing compound corresponding to from about 100 to about 1000 mg Ca such as, e.g., from about 150 to about 800 mg, from about 200 to about 700 mg, from about 200 to about 600 mg or from about 200 to about 500 mg Ca.
  • Calcium carbonate can be in three different crystal structures: calcite, aragonite and vaterite. Mineralogically, these are specific mineral phases, which relate to the distinct arrangement of the calcium, carbon and oxygen atoms in the crystal structure. These distinct phases influence the shape and symmetry of the crystal forms.
  • calcite is available in four different shapes: scalenohedral, prismatic, spherical and rhombohedral, and aragonit crystals can be obtained as e.g. discrete or clustered needle-like shapes. Other shapes are also available such as, e.g., cubic shapes (Scoralite 1A + B from Scora).
  • a particular suitable quality of calcium carbonate is calcium carbonate having a mean particle size of 60 ⁇ m or less such as, e.g., 50 ⁇ m or less or 40 ⁇ m or less.
  • Calcium carbonate 2064 Merck available from Merck, Darmstadt, Germany
  • a mean particle size of 10 - 30 ⁇ m an apparent bulk density of 0.4 to 0.7 g/mL, and a specific surface area of 0.3 m 2 /g;
  • Calcium carbonate 2069 Merck (available from Merck, Darmstadt, Germany) that has a mean particle size of approx. 3.9 ⁇ m, and an apparent bulk density of 0.4 to 0.7 g/mL;
  • Scoralite 1A (available from Scora Watrigant SA, France) has a mean particle size of 5 to 20 ⁇ m, an apparent bulk density of 0.7 to 1.0 g/mL, and a specific surface area of 0.6 m 2 /g;
  • Scoralite 1 B (available from Scora Watrigant SA, France) has a mean particle size of 10 -25 ⁇ m, an apparent bulk density of 0.9 to 1.2 g/mL, and a specific surface area of 0.4 to 0.6 m 2 /g;
  • Scoralite 1A + B (available from Scora Watrigant SA, France) have a mean particle size of 7 - 25 ⁇ m, an apparent bulk density of 0.7 to 1.2 g/mL, and a specific surface area of 0.35 to 0.8 m 2 /g;
  • Pharmacarb LL (available from Chr. Hansen, Mahawah New Jersie) L has a mean particle size of 12 - 16 ⁇ m, an apparent bulk density of 1.0 to 1.5 g/mL, and a specific surface area of 0.7 m 2 /g;
  • Sturcal L has a mean particle size of approx. 7 ⁇ m, an apparent bulk density of 0.78 to 0.96 g/mL, Sturcal L consists of scalenohedral shaped crystals;
  • Sturcal H has a mean particle size of approx. 4 ⁇ m, an apparent bulk density of 0.48 to 0.61 g/mL;
  • Sturcal F has a mean particle size of approx. 2.5 ⁇ m, an apparent bulk density of 0.32 to 0.43 g/mL;
  • Sturcal M has a mean particle size of 7 ⁇ m, an apparent bulk density of 0.7 to 1.0 g/ mL, and a specific surface area of 1.0 m 2 /g; Mikhart 10, SPL, 15, 40 and 65 (available from Provencale, Provencale, France); Mikhart 10 has a mean particle size of 10 ⁇ m, Mikhart SPL has a mean particle size of 20 ⁇ m, Mikhart 15 has a mean particle size of 17 ⁇ m, Mikhart 40 has a mean particle size of 30 ⁇ m, an apparent bulk density of 1.1 to 1.5 g/mL;
  • Mikhart 65 has a mean particle size of 60 ⁇ m, an apparent bulk density of 1.25 to 1.7 g/mL;
  • Omyapure 35 (available from Omya SAS 1 Paris, France) has a mean particle size of 5 - 30 ⁇ m, and a specific surface area of 2.9 m 2 /g;
  • Socal P2PHV (available from Solvay, Brussels, Belgium) has a mean particle size of 1.5 ⁇ m, an apparent bulk density of 0.28 g/mL, and a specific surface area of 7.0 m 2 /g;
  • Calci Pure 250 Heavy, Calci Pure 250 Extra Heavy and Calci Pure GCC HD 212 with a mean particle size of 10-30 ⁇ m, an apparent bulk density of 0.9 - 1.2 g/ml, and a specific surface area of 0.7 m 2 /g (available from Particle Dynamic Inc., St. Louis Montana).
  • the content of the calcium-containing compound is normally in a range from about 40% to about 100% w/w such as, e.g., from about 45% to about 98% w/w, from about 50% to about 95% w/w, from about 55% to about 90% w/w or at least about 60% w/w, at least about 65% w/w, at least about 70% w/w or at least about 75% w/w based on the total weight of the composition.
  • the dose of calcium for therapeutic or prophylactic purposes is from about 350 mg (e.g. newborn) to about 1200 mg (lactating women) daily.
  • the amount of the calcium-containing compound in the tablets can be adjusted so that the tablets are suitable for administration 1-4 times daily, preferably once or twice daily.
  • compositions for use according to the invention may also be employed as an anti-chalk acting agent in compositions containing a calcium-containing compound and one or more nutrients such as, e.g., one or more vitamins or minerals.
  • a D-vitamin such as, e.g., D 3 vitamin, D 2 vitamin or derivatives thereof.
  • compositions for use according to the invention may comprise a further therapeutically and/or prophylactically active substance.
  • D-vitamin compounds are one or more D-vitamin compounds.
  • Non-limitating examples are dry vitamin D3, 100 CWS available from Roche and dry vitamin D3 100 GFP available from BASF.
  • a tablet for use according to the invention may comprise a further therapeutically and/or prophylactically active substance, or it may contain one or more nutrients such as, e.g. one or more vitamins or minerals.
  • nutrients such as, e.g. one or more vitamins or minerals.
  • vitamins or minerals e.g. one or more vitamins or minerals.
  • vitamin B vitamin C
  • vitamin D vitamin D
  • vitamin K minerals
  • minerals like e.g. zink, magnesium, selenium etc.
  • D-vitamin compounds such as, e.g., Vitamin D 2 (ergocalciferol) and Vitamin D 3 (cholecalciferol) including dry vitamin D 3 , 100 CWS available from Roche and dry vitamin D 3 100 GFP available from BASF.
  • vitamin D In addition to its action on calcium and skeletal homeostasis, vitamin D is involved in the regulation of several major systems in the body.
  • the actions of vitamin D are medicated at the genome by a complex formed by 1 ,25-(OH) 2 vitamin D mainly produced in the kidney, with the vitamin D receptor (VDR).
  • VDR vitamin D receptor
  • the 1 ,25-(OH) 2 vitamin D/VDR complex has important regulatory roles in cell differentiation and in the immune system. Some of these actions are probably dependant on the ability of certain tissues other than the kidney to produce 1 ,25-(OH) 2 vitamin D locally and act as a paracrine (Adams JS et al. Endocrinology 1996; 137:4514-7).
  • Vitamin D insufficiency the preclinical phase of vitamin D deficiency, also causes a reduced calcium supply and secondary hyperparathyroidism, albeit of a milder degree than found with deficiency. If this state remains chronic, osteopenia results.
  • the biochemical process underlying this state of calcium insufficiency is probably inappropriate level of 1 ,25-(OH) 2 vitamin D due to a reduction in its substrate 25-OHD (Francis RM et al. Eur J Clin Invest 1983; 13:391-6).
  • the state of vitamin D insufficiency is most commonly found in the elderly. With age there is a decrease in serum 25-OH vitamin D due to decreased sunlight exposure and possible to decreased skin synthesis.
  • the invention provides a composition comprising i) a calcium-containing compound as an active substance, ii) xylitol as an anti-chalk acting agent, and iii) optionally one or more pharmaceutically acceptable excipients.
  • the invention provides a composition
  • a composition comprising i) a calcium-containing compound as an active substance, ii) xylitol as an anti-chalk acting agent, iii) a vitamin D, and iv) optionally one or more pharmaceutically acceptable excipients.
  • a tablet of the invention comprises i) from about 50% to about 90% w/w of the calcium-containing compound, ii) from about 5% to about 45% w/w, preferably from about 10% to about 45% w/w of xylitol iii) optionally, from about 0.00029% to about 0.0135% w/w or to about 0.0122% w/w of a vitamin D, and iii) optionally one or more pharmaceutically acceptable excipients with the proviso that the total amount of ingredients corresponds to about 100% w/w.
  • a composition tablet may comprise i) from about 50% to about 90% w/w of the calcium-containing compound, ii) from about 5 to about 30% w/w, preferably from about 10% to about 30% w/w of xylitol, iii) optionally, from about 0.12% to about 5.4 % w/w or to about 4.9% w/w of a vitamin D iv) optionally one or more pharmaceutically acceptable excipients with the proviso that the total amount of ingredients corresponds to about 100% w/w.
  • composition containing xylitol for use according to the invention
  • the composition is in the form of a tablet, in particular a chewable (including crunchable) and/or suckable tablet.
  • a tablet according to the invention can be prepared by any suitable process known to a person skilled in the art.
  • the process may include wet granulation e.g. in a high shear mixer or in a fluid-bed apparatus or dry granulation e.g. roller compaction and then compressing the obtained powder into tablets or it may be a direct compression process without any granulation.
  • dry granulation e.g. roller compaction
  • a person skilled in the art will know how to employ the different techniques optionally with guidance from Remington's Pharmaceutical Sciences, 28 Ed.
  • pharmaceutically acceptable excipient is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se.
  • a pharmaceutically acceptable excipient may be added to the active drug substance with the purpose of making it possible to obtain a pharmaceutical composition, which has acceptable technical properties.
  • the calcium-containing compound is normally admixed with one or more pharmaceutically acceptable excipients before compression into tablets.
  • excipients include those normally used in formulation of solid dosage forms such as, e.g. fillers, binders, disintegrants, lubricants, flavouring agents, colouring agents, including sweeteners, pH adjusting agents, buffering agents, stabilizing agents, etc.
  • excipients suitable for use in a tablet according to the present invention are given examples of excipients suitable for use in a tablet according to the present invention.
  • sweeteners examples include dextrose, erythritol, fructose, glycerin, glucose, inositol, isomalt, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, etc.
  • Sorbitols e.g. Neosorb P100T, Sorbidex P166B0 and Sorbogem Fines Crystalline Sorbitol available from Roquette Freres, Cerestar and SPI Polyols Inc. respectively.
  • Maltisorb P90 (maltitol) available from Roquette Freres, Xylitol CM50, Fructofin CM (fructose) and Lactitol CM50 available from Danisco Sweeteners, Isomalt ST-PF, Gaio Tagatose and Mannitol available from Palatinit, ArIa Foods and Roquette, Freres respectively.
  • Sorbitol has a sweetening effect (compared to sucrose) of 0.55; maltitol that has a sweetening effect of ⁇ 1 ; xylitol that has a sweetening effect of 1 , isomalt that has a sweetening effect of ⁇ 0.5, etc.
  • the sweetening effect may be of value in connection with choosing the individual sweetening agents. Thus, if a decreased tablet weight and volume are desired, it is suitable to choose a sweetening agent having a high sweetening effect.
  • cyclamate salt e.g. calcium cyclamate, sodium cyclamate
  • neohesperidine dihydrochalcone neohesperidine hydrochloride
  • saccharin e.g. ammonium saccharin, calcium saccharin, potassium saccharin, sodium saccharin
  • sucralose e.g. ammonium saccharin, calcium saccharin, potassium saccharin, sodium saccharin
  • Alginic acid - alginates carboxymethylcellulose calcium, carboxymethylcellulose sodium, crospovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), cellulose derivatives such as low-substituted hydroxypropylcellulose (e.g LH 11 , LH 20, LH 21 , LH 22, LH 30, LH 31 , LH 32 available from Shin-Etsu Chemical Co.) and microcrystalline cellulose, polacrilin potassium or sodium, polyacrylic acid, polycarbofil, polyethylene glycol, polyvinylacetate, polyvinylpyrrolidone (e.g.
  • Polyvidon® CL Polyvidon® CL, PoIy- vidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); sodium car- boxymethyl starch (e.g. Primogel® and Explotab®), sodium croscarmellose (i.e. cross- linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®), sodium starch glycolate, starches (e.g potato starch, maize starch, rice starch), pre-gelatinised starch.
  • Primogel® and Explotab® sodium croscarmellose (i.e. cross- linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®)
  • sodium starch glycolate starches (e.g potato starch, maize starch, rice starch), pre-gelatinised starch.
  • the disintegrant used preferably results in the disintegration of the tablet within 30 minutes, more preferable within 15 min, most preferable within 5 min.
  • Effervescent agent e.g. mixture of sodium hydrogen carbonate (carbonates, alkaline, alkaline earth metals) and citric acid (tartaric acid, fumaric acid etc.)
  • Glidants and lubricants may be incorporated such as stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, hydrogenated vegetabable oils, colloidal silica, sodium stearyl fumarate, polyethylenglycols and alkyl sulphates.
  • Suitable glidants and lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and the like.
  • magnesium stearate is used.
  • maltodextrins e.g. Lodex® 5 and Lodex® 10
  • dextrose fructose, glucose, inositol, erythritol, isomalt
  • lactitol lactose (e.g., spray-dried lactose, ⁇ -lactose, ⁇ - lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast-Floe®)
  • maltitol maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol
  • low- substituted hydroxypropylcellulose e.g LH 11 , LH 20, LH 21, LH 22, LH 30, LH 31 , LH 32 available from Shin-Etsu Chemical Co.
  • microcrystalline cellulose e.g., various grades of Avicel®, such as Avicel® PH101 , Avicel®
  • calcium hydrogen phosphate calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate), calcium sulphate, carboxyalkylcellulose, dextrates, dibasic calcium phosphate, gelatine, gummi arabicum, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium carbonate, magnesium chloride, methylcellulose, polyethylene glycol, polyethylene oxide, polysaccharides e.g. dextran, soy polysaccharide, sodium carbonate, sodium chloride, sodium phosphate.
  • calcium phosphate e.g. basic calcium phosphate, calcium hydrogen phosphate
  • calcium sulphate carboxyalkylcellulose, dextrates, dibasic calcium phosphate, gelatine, gummi arabicum, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium carbonate, magnesium chloride, methylcellulose, polyethylene glycol, polyethylene oxide, polysaccharides e.g. dextran, soy polysaccharide,
  • Surfactants may be employed such as
  • Non-ionic e.g., polysorbate 20, polysorbate 21 , polysorbate 40, polysorbate 60, polysorbate 61 , polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, polysorbate 120, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinylalkohol),
  • sorbitan monoisostearate sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinylalkohol
  • anionic e.g., docusate sodium and sodium lauryl sulphate
  • cationic e.g., benzalkonium chloride, benzethonium chloride and cetrimide.
  • Fatty acids, fatty alcohols and fatty esters for example: ethyl oleate, sodium oleate, lauric acid, methyl laurate, oleic acid, sodium caprate
  • bile salts for example: sodium deoxycholate, deoxycholic acid, sodium cholate, cholic acid, sodium glycocholate, sodium glycodeoxycholate, sodium taurocholate, sodium taurodeoxycholate;
  • cytoadhesives for example: lectins (e.g. Lycopersicon Esculentum Agglutinin, Wheat Germ Agglutinin, Urtica Dioica Agglutinin).
  • lectins e.g. Lycopersicon Esculentum Agglutinin, Wheat Germ Agglutinin, Urtica Dioica Agglutinin.
  • N-acylated amino acids especially N-[8-(2-hydroxy-4-methoxy)benzoyl]amino caprylic acid (4-MOAC), 4 ⁇ [4-(2-hydroxybenzoyl)amino]butyric acid, sodium N-[8-(2- hydroxybenzoyl)amino]-caprylate);
  • phospholipids for example: hexadecylphosphocholine, dimyristoylphosphatidylglycerol, lysophosphatidylglycerol, phosphatidylinositol, 1 ,2-di(2,4-octadecadienoyl)-sn-glycerol-3-phosphorylcholine and phosphatidylcholines (e.g. didecanoyl-L-phosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine), lysophosphatidylcholine is of particular interest;
  • cyclodextrins for example: ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin, methyl cyclodextrin; especially dimethyl- ⁇ -cyclodextrin is of particular interest;
  • fusidic acid derivatives for example: sodium taurodihydrofusidate, sodium glycodihydrofusidate, sodium phosphate- dihydrofusidate; especially sodium taurodihydrofusidate is of particulare interest;
  • n-lauryl-beta-D-maltopyranoside is of particular interest, alpha 1000 peptide, peptide MW ⁇ 1000 comprising at least 6 mol% of aspartatic- and glutamic Acid, decomposed royal jelly, prebiotica, butyrate, butyric acid, vitamin D 2 , vitamin D 3 , hydroxy-vitamin D 3 , 1.25-dihydroxy-vitamin D 3 , spirulina
  • Hydrofilic film formers such as hydroxypropylmethylcellulose (HPMC) (e.g. HPMC E5, HPMC E15), hydroxyethylcellulose, hydroxypropylcellulose, polydextrose and maltodextrin, SepifilmTM and SepifilmTM LP available from Seppic S.A., Pharmacoat® available from Shin-Etsu Chemical Co.
  • HPMC hydroxypropylmethylcellulose
  • HPMC E5 hydroxypropylmethylcellulose
  • HPMC E15 hydroxypropylmethylcellulose
  • hydroxypropylcellulose e.g. HPMC E5
  • HPMC E15 hydroxyethylcellulose
  • hydroxypropylcellulose hydroxypropylcellulose
  • polydextrose and maltodextrin hydroxypropylcellulose
  • SepifilmTM and SepifilmTM LP available from Seppic S.A.
  • Pharmacoat® available from Shin-Etsu Chemical Co.
  • a film may be coated on the compositions.
  • the sensoric test was carried out by 7 trained persons. Test was done according to ISO 8587 (ranking test) and ISO 5495 (paired test).
  • Pharma-Carb LL The following compositions were starting points. To each of these compositions xylitol was incorporated in concentrations increasing from 10% w/w to about 50% w/w based on the content of calcium carbonate.
  • the granulating fluid is manufactured by dissolving V in X.
  • IV is passed through a suitable screen and mixed together with I or Il or III in a 220 I high shear mixer for 1 min at impeller speed 110 rpm and chopper speed 1500 rpm.
  • the powder mass is wetted with the granulation fluid at impeller speed 110 rpm and chopper speed 1500 rpm. Wet massing is continued for 5 min at impeller speed 220 rpm and chopper speed 1500 rpm.
  • the wet massed powder is dried in a fluid bed until the absolute water content is below 0.5 %.
  • the rest of the excipients are admixed to the dried granulate and tablets are compressed.
  • the granulating fluid is manufactured by dissolving V in X
  • III and IV is screened through a 0.3 mm screen and mixed together with I and Il in a high shear mixer (Fielder PMA 25) for 1 min. at impeller speed 110 rpm and chopper speed 1500 rpm.
  • a high shear mixer Fielder PMA 25
  • the powder mass is wetted by pumping the granulation fluid on the powder at a speed of approx. 125 g/min. at an impeller speed of 110 rpm and chopper speed 1500 rpm. Wet massing is continued for 3 minutes at impeller speed 220 rpm and chopper speed 1500 rpm. The wet massed powder is dried in a fluid bed until the absolute water content is below 0.5 %.
  • the rest of the excipients are admixed to the dried granulate and tablets are compressed.
  • compositions containing xylitol as an anti-chalk acting agent used according to the invention are manufactured by Manufacture of compositions containing xylitol as an anti-chalk acting agent used according to the invention
  • This experiment was carried out in large production with a batch size of approx. 40.000 tablets. The experiment was performed in order to illustrate the use of different manufacturing processes.
  • the granulating fluid is manufactured by dissolving Vl in XIV.
  • IV is passed through a suitable screen and mixed with I in a Glatt fluid bed granulator.
  • the powder mixture is granulated by spraying the granulating fluid on the powder bed while the fluidizing process is ongoing.
  • the remaining parts of the excipients X, XII and XIII are admixed to granulate and tablets are compressed.
  • III or III and IV are passed through a suitable screen and mixed together with I in a 220 I high shear mixer for 1 min at impeller speed 110 rpm and chopper speed 1500 rpm.
  • the powder mixture is granulated using a roller compactor (Gerteis 3W-Polygran) using a roller speed of 10 rpm, a compaction force of 12 kN/cm, a gap width of 3 mm and a screen of 1.5 mm, followed by admixing of the remaining excipients VIII, X, Xl and XIII and finally tablets are compressed.
  • a roller compactor Garteis 3W-Polygran
  • the batch was manufactured according to example 2.
  • the tablets were crushed to powder before they were presented to the panel.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de xylitol en tant qu'agent agissant contre la sensation de craie en bouche dans une composition nutriceutique et/ou pharmaceutique destinée à une utilisation par voie orale et comprenant un composé contenant du calcium. Cette composition est sous forme de comprimés conçus pour avoir une sensation en bouche acceptable, ces comprimés pouvant être mâchés ou sucés.
PCT/IB2005/003179 2004-10-26 2005-10-25 Utilisation de xylitol en tant qu'agent agissant contre la sensation de craie en bouche dans des compositions destinees a une utilisation par voie orale et comprenant un compose contenant du calcium en tant que substance active WO2006046111A1 (fr)

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DKPA200401642 2004-10-26
DKPA200401642 2004-10-26

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WO2006046111A1 true WO2006046111A1 (fr) 2006-05-04

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PCT/IB2005/003179 WO2006046111A1 (fr) 2004-10-26 2005-10-25 Utilisation de xylitol en tant qu'agent agissant contre la sensation de craie en bouche dans des compositions destinees a une utilisation par voie orale et comprenant un compose contenant du calcium en tant que substance active

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018086A1 (fr) * 2006-08-10 2008-02-14 Bajaj Healthcare Limited Composition pharmaceutique ou nutraceutique se dissolvant dans la bouche

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0312249A1 (fr) * 1987-10-14 1989-04-19 Takeda Chemical Industries, Ltd. Préparation pharmaceutique aqueuse pour administration orale
FR2724844A1 (fr) * 1994-09-23 1996-03-29 Innothera Lab Sa Association therapeutique vitamino-calcique, son procede d'obtention et son utilisation
US20010021373A1 (en) * 1999-09-02 2001-09-13 Zyck Daniel J. Coated chewing gum products containing an acid blocker

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0312249A1 (fr) * 1987-10-14 1989-04-19 Takeda Chemical Industries, Ltd. Préparation pharmaceutique aqueuse pour administration orale
FR2724844A1 (fr) * 1994-09-23 1996-03-29 Innothera Lab Sa Association therapeutique vitamino-calcique, son procede d'obtention et son utilisation
US20010021373A1 (en) * 1999-09-02 2001-09-13 Zyck Daniel J. Coated chewing gum products containing an acid blocker

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018086A1 (fr) * 2006-08-10 2008-02-14 Bajaj Healthcare Limited Composition pharmaceutique ou nutraceutique se dissolvant dans la bouche

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