Title of Invention	COMPOSITION COMPRISING ASCORBIC ACID AND PECTIN
Abstract	The present invention relates to composition in the form powder or granules comprising l-ascorbic acid and/or a pharmaceutically acceptable salt thereof, and pectin in a quantity within the raqnge of 0.1 to 10% by weight.

Full Text

The present invention relates to a composition in the form of a powder and/or granules, which contain as principal components L-ascorbic acid and/or a pharmaceutically acceptable salt thereof, together with pectin. The composition according to the present invention is directly compressible into tablets with good taste, sufficient mechanical strength and hardness, with excellent color stability and is free of sugar and starch. The addition of adjuvants and excipients to the composition for producing tablets is optional. Different methods have been suggested for producing L-ascorbic acid powder or granules which are directly compressible into tablets. Hydroxypropylmethylcellulose (HPMC) and starch are today considered as the standard binders for producing such powders and granules. For sugar-free and starch-free tablets, the powder or granules is generally produced with HPMC as binder, although the color stability of such powders or granules, and tablets obtained therefrom, is not sufficient. It was now found that a composition containing L-ascorbic acid and/or its salts together with pectin, maybe obtained in the form ofa powder or of granules with greatly improved color stability. Tablets made from such compositions have good taste, mechanical strength, and/or hardness, and in addition surprisingly have greatly improved color stability. In such a composition the pectin preferably is present in a quantity with in the range of about 0.1 to about 10% by weight, calculated on the total weight of the composition, In one aspect, the present invention relates to a composition in the form of a powder or granu|es comprising; (a) L-ascorbic acid and/or a pharmaceutically acceptable salt thereof, (b) pectin in a quantity within the range of about 0.1 to about 10% by weight, calculated to the total weight of the composition thereof, and (c) optionally, adjuvants and excipients in quantities within the range of O.l to 10% by weight, calculated to the total weight of the composition. In a further aspect, the present invention relates to methods of producing the composition of the present invention. In still another aspect, the present invention relates to tablets obtained from the composition of the present invention. L-ascorbic acid is known per se. Numerous pharmaceutically acceptable salts thereof are known. Preferred from these is sodium ascorbate. Pectin is a polysaccharide and described for example in the book entitled Industrial Gums, third edition, Academic Press, Inc., 1993, pages 257ff. Commercial pectins are generally produced from either citrus peel or apple pomace. Other possible sources are sugarbeet, sunflower and mango. Preferred pectins to be used within the scope of the present invention are citrus pectins, which generally have lighter color than apple pectins and, thus, do not impart significant color to the granule product. Pectin is preferably used in quantities within the range of about 0.1% to about 10% by weight, preferably in quantities of about 0.5% to about 5% by weight and most preferably in quantities of about 0.5% to about 2% by weight, calculated to the total weight of the composition thereof. Experiments have shown that a composition consisting of 95-99% by weight of L-ascorbic acid and/or the pharmaceutically acceptable salt thereof and 5-1% by weight of pectin, the two components totatiing 100% by weight, i.e. with no other components present, yield tablets of very good quality and excellent color stability. Adjuvants may optionally be added. Suitable adjuvants are for example starch, HPMC, polyols. Preferably no adjuvants are added. The composition of this invention may be produced by any method known per se for the production of powders or granules. Preferred are fluidized-bed granulation, high-shear granulation, extrusion, spray-drying and wet granulation. For obtaining the composition of the present invention by spray-drying it is convenient to prepare an aqueous slurry of all the components. The slurry has preferably a solid content of about 10 to 70% by weight, and preferably about 25 to 50% by weight. The slurry is then spray-dried in a manner known per se. For obtaining the composition of the present invention by fluidized-bed granulation it is convenient to use a known fluidized-bed granulating apparatus which comprises a fluidized-bed drying device fitted with spray means. Preferably the L-ascorbic acid and/or a pharmaceutically acceptable salt thereof form the fluidized bed, which is fluidized by air or an inert gas, e.g. nitrogen. The pectin, as well as optional adjuvants, dissolved in an appropriate amount of water and sprayed in the form of an atomized mist onto the fluidized particles in such a manner that the granulating and drying operations is accomplished in a single step. The granulating process is continued until the desired amount of the pectin binder has been deposited onto the fluidized particles. The granules are sieved to remove the fractions of granules which are either too large or too small. Preferably, the particle size of the granules is within 100 and 1000 micron, more preferably between 125 and 750 micron. The composition thus obtained may be compressed into tablets with conventional tabletting methods and machinery. Optionally the powder or the granules may further be mixed with a lubricant or a mixture of lubricants and then compressed into tablets. If additional lubricant is used it is preferably selected from the group of stearic acid or the magnesium or calcium salt thereof, or glyceryl behenate 45 (Compritol 888 ATO), preferably in an amount of about 0.5 to 4% by weight, calculated to the total weight of the composition. Or the composition may be mixed with excipients. Examples for excipients are dextrinized sucrose (Di Pac sugar), micro-crystalline cellulose or starch. A single tablet as obtained according to the present invention contains preferably 50 mg to 1500 mg, preferably 500 mg to 1000 mg of L-ascorbic acid and/or the pharmaceutically acceptable salt thereof, corresponding to an appropriate daily doses of vitamin C. The following examples illustrate the invention. Example 1 L-ascorbic acid crystals (2475 g, Roche Ascorbic Acid Fine Granular, F. Hoffmann - La Roche AG.), was placed in a stainless container of a wet granulator (Ultra Power model from KitchenAid, Michigan, USA). Pectin (27.36 g, Pectin USP. Danisco Ingredients, Denmark) was dissolved in distilled water (350 g). The pectin solution (151.3 g) was added to the ascorbic acid crystals over a period of 10 minutes with mixing. After the addition of pectin solution, the paste was mixed for another 10 minutes and then pressed through a screen with 2mm-openings to form a noodle-like particles, which was dried in trays in a 45oC / 25% relative humidity (RH) room for 4 hours. The dry particles were milled and sieved to give the particle size distribution as shown in Table lA. Table lA The granules were mixed with other excipients as shown in the following Table IB and compressed at 20 KN to give 786 mg tablets. The hardness of the tablet was 88N. To evaluate the color stability, the granules were dried at 45 °C to about 0.08% moisture content, sealed in aluminum bags and stored at ambient temperature. The Whiteness Index (CIE) of the granules was determined at various time intervals using a Hunlerlab Ultrascan B256 (Hunter Associates Laboratory, Inc.Reston, VA. USA). For comparison, the reduction in whiteness index was obtained by subtracting the whiteness indices determined at various storage times from the initial whiteness index. Granules with poor color stability show high whiteness index reduction. Color Stability: Whiteness Index reduction: 1.07 (after I month), 2.70 (after 2 months) Example 2 Example 1 was repeated with the exception that Hydroxypropylmethyl-cellulose {HPMC)(MethoceI E15LV, The Dow Chemical Co., Michigan, USA) was used in place of pectin. The granule particle size distribution was as given in Table 2. ■ Table 2 Compressed at 20 KN compression force, the hardness of the tablet was 75 N. The color stability was determined according to Example 1. Color Stability: Whiteness Index reduction: 8.49 (after 1 month temperature), 27.1 (after 2 months). A comparison of the tablets obtained acording to Example 1 with those obtained according to Example 2 shows that granules or powder made with pectin as binder are far superior to preparations made with HPMC with regard to tabletting compressibility and color stability. Example 3 Sodium L-ascorbate (F. Hoffmann - La Roche AG, Switzerland, particle size etc) was used. A pectin solution was prepared by dissolving 27.3 g of pectin (Pectin USP, 8.4% moisture content, Danisco Ingredients, Denmark) in 1000 g of water. Sodium ascorbate powder was placed in a Glatt FIuidized-Bed granulator (Model Uniglatt, Switzerland) and sprayed with a fme mist of pectin solution. The granulation conditions were as follows: L-Sodium ascorbate: 594 g Pectin solution: 246.6 g Pectin solution spraying rate: 6.7 g/minute Inlet Air temperature: 80oC a) The granules leaving the apparatus had a moisture content of 0,19% by weight, calculated to the granule weight. The granule particles were sieved to give the particle size distribution as shown in Table 3A Table 3A b) The granules (125-750 micron fraction) as obtained above in Example 3 were mixed with the excipients as shown in the following Table 3B and compressed into tablets of 767 mg weight. The tablet hardness at various compression forces is as follows: Hardness {Compression Force): 118 N (5 KN), 145 N (10 KN), ]74 N (15 KN), 203 N (20 KN). 224 N (25 KN), 246 N (30 KN) Example 4 Example 3 was repeated with the exception that Hydroxypropylmethyl-cellulose (HPMC}(Pharmacoat, Shin-Etsu Chemical Co,, Ltd., Tokyo, Japan) was used in place of pectin. The granulation conditions were as follows: L-Sodium ascorbate: 594 g HPMC solution: 246.6 g Pectin solution spraying rate: 6.7 g/minute Inlet Air temperature: 80 °C The granule particles were sieved to give the particle size distribution as shown in Table 4 The granules (125-750 micron fraction) were mixed with the excipients-and compressed into tablets of 767 mg weight. The tablet hardness at various compression forces is as follows: Hardness (Compression Force): 95 N (5 KN), 132 N (10 KN), 151 N (15 KM), 179 N (20 KN), 177 N (25 KN), 200 N (30 KN). A comparison of Example 3 with Example 4 shows that granules or powder made with pectin as binder are far superior to preparations made with HPMC with regard to tabletting compressibility. WE CLAIM : 1. A composition in the form of a powder or granules comprising: (a) L-ascorbic acid and/or a phannaceuticaliy acceptable salt thereof in a quantity within the range of 80% by weight to 99.9% by weight calculated on the total weight of the composition, (b) pectin in a quantity within the range of 0.1 to 10% by weight, calculated on the total weight of the composition thereof, (c) optionally, adjuvants and excipients in quantities within the range of 0.1 to 10% by weight, calculated an the total weight of the composition. 2. The composition as claimed in claim I, wherein the pharmaceutically acceptable saU of L-ascorbic acid is sodium ascorbate. 3. The composition as claimed in claims 1 or 2, wherein the pectin is citrus pectin. 4. The composition as claimed in any one of the claims 1-3, wherein the pectin is present in quantities within the range of 0.5% to 5% by weight, calculated on the total weight of the composition. 5. The composition as claimed in any one of the claims 1-3, wherein the pectin is present in quantities within 0.5% to 2% by weight, calculated on the total weight of the composition. 6. The composition a claimed in any one of the claims 1-5, wherein said composition consists of 95-99% by weight of L-ascorbic acid and/or a pharmaceutically acceptable salt thereof and 5-1% by weight of pectin, the two components totaling 100% by weight. 7. The composition as claimed in any one of the claims 1-6 in the form of a compressed tablet. 8. The composition as claimed in claim 7, containing a lubricant or a mixture of lubricants, preferably selected from the group of stearic acid or the magnesium or calcium salt thereof or glyceryl behenate 45 (Compritol 888 ATO), preferably in an amount of 0.5% to 4% by weight, calculated to the total weight of the composition. 9. The composition as claimed in claims 7 or 8, containing excipients, preferably selected from dextrinized sucrose (Di Pac sugar), microcrystalline cellulose or starch.

Documents:

1110-mas-2000 abstract duplicate.pdf

1110-mas-2000 abstract.pdf

1110-mas-2000 claims duplicate.pdf

1110-mas-2000 claims.pdf

1110-mas-2000 correspondence others.pdf

1110-mas-2000 correspondence po.pdf

1110-mas-2000 description (complete) duplicate.pdf

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