Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/30—Zinc; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to palatable lozenge tablets containing vitamin C and zinc, wherein the vitamin C is present at high concentration and is stable against oxidation and formation of carbon dioxide.
• Zinc is one of the most important mineral nutrients. One third of the global population is believed to be zinc deficient. Zinc deficiency is associated with impaired immune function. Vitamin C is the most widely used vitamin for immunity. Vitamin C and zinc are combined in a single formulation to complement their immunity benefits. However, combining Vitamin C and zinc is difficult because Vitamin C is particularly susceptible to oxidation, and this oxidation is enhanced by polyvalent metals such as zinc. This oxidation is facilitated by moisture, and leads to spotting, darkening, and carbon dioxide formation.
• Solid dosage formats of vitamin C and zinc include capsules, coated tablets, effervescent tablets, and lozenges. Due to the high sodium content of effervescent tablets, lozenges are more suitable for pediatric and geriatric patients who have difficulty swallowing. However, vitamin C and zinc lozenges are very difficult to make palatable. Further, since lozenges cannot be coated, they must be very stable since any slight spotting/darkening is readily apparent and unacceptable to consumers. While it is relatively easy to hide spotting/darkening in a swallow tablet by coating the tablet, it is extremely difficult with lozenges since the spotting/darkening is still apparent even with colored tablets.
• Lozenges can refer to molded lozenges, which are hard candies, or to compressed lozenges, which are essentially produced the same way as compressed pharmaceutical tablets. Molded lozenges are more difficult to make and require high manufacturing temperature up to more than 100°C, which can cause significant degradation of the vitamin C. Therefore, this instant invention is limited to compressed lozenges which we will hereafter refer to as lozenge tablets, and includes both orodispersible and chewable tablets.
• US 2014/0220151A1 discloses stable formulations of vitamin C with at least one polyvalent metal such as zinc wherein the tablet is substantially free of mobile bound water.
• Mobile bound water refers to water of hydration and substantially free means less than 0.3% w/w of the composition.
• US 2014/0220151A1 is used in Centrum Multivitamins and Minerals tablet (Pfizer/Wyeth, NY).
• Centrum is a coated tablet containing 60 mg of Vitamin C, 15 mg of zinc, other vitamins and polyvalent metals, wherein the Vitamin C is less than 5% of tablet weight.
• Centrum tablet uses zinc oxide as the source of zinc. Zinc oxide is poorly absorbed, but the main reason for using zinc oxide, as inferred from US 2014/0220151 Al, is to reduce the mobile bound water.
• Most zinc salts other than zinc oxide are hygroscopic and are commercially available as their stable hydrates.
• US 6,316,008B1 teaches that when vitamin C is combined with zinc in a lozenge, the foul taste of zinc, which can last for more than 24 hours, is normally orders of magnitude stronger than zinc alone.
• US 6,316,008B1 discloses that palatability can be improved by combining the zinc with a mono-carboxylic amino acid, and wherein the vitamin C is magnesium ascorbate or an ascorbyl ester.
• the examples of US 6,316,008B1 are molded lozenges wherein the vitamin C and zinc are added to the melted hard candy base at 104°C.
• US 6,316,008B 1 does not disclose how much of the vitamin C is degraded during production, nor the stability of this residual vitamin C with time.
• the commercially available vitamin C and zinc lozenge tablets are generally large tablets wherein the tablet weight is from 1.5 to 4 grams.
• the reason for these huge tablets is to dilute the vitamin C and zinc by adding a large amount of the monosaccharide sweeteners glucose and fructose, and flavors to improve palatability. These large tablets can pose a choking hazard if accidentally swallowed.
• the present invention relates to palatable lozenge tablets containing vitamin C and zinc, wherein the vitamin C is present at high concentration and is stable against oxidation and formation of carbon dioxide.
• the composition of the present invention can contain significantly more mobile bound water than the required limit taught by US 2014/0220151A1 to produce stable tablets.
• stable and palatable lozenge tablets of Vitamin C and zinc where Vitamin C is present at high concentration can be prepared by using a citrate or malate salt of zinc, sodium ascorbate or a mixture of ascorbic acid and sodium ascorbate with about 65% to 100% of the vitamin C coming from sodium ascorbate, and sweeteners; wherein the vitamin C and zinc are not microencapsulated, coated or melt granulated, and wherein the formulation is substantially free of monosaccharide, organic acid, and monocarboxylic amino acid.
• the composition of the present invention is stable even with very high level of mobile bound water.
• FIG. 1 is a graph showing the degree of spotting/discoloration as a function of the percentage of Vitamin C from sodium ascorbate when the zinc salt is zinc citrate (Example 1) and zinc oxide (Example 2).
• FIG. 2 is a graph showing the degree of bloating as a function of the percentage of Vitamin C from sodium ascorbate when the zinc salt is zinc citrate (Example 1) and zinc oxide (Example 2).
• the vitamin C is sodium ascorbate or a mixture of ascorbic acid and sodium ascorbate, wherein at least about 65% of the vitamin C is from sodium ascorbate, more preferably at least about 70%, and most preferably at least about 75%.
• the vitamin C is not microencapsulated, coated or melt granulated.
• the vitamin C is preferably present at a concentration of at least about 10% w/w, more preferably at least about 15% w/w, and most preferably at least about 20% w/w.
• the amount of vitamin C is preferably about 50-250 mg/tablet, more preferably about 75-200 mg/tablet.
• the ascorbic acid and sodium ascorbate are preferably already in granular form ready for compression. These directly compressible vitamin C and sodium ascorbate are commercially available containing about 1-5% binder and very low moisture typically below 0.15% w/w.
• Zinc compounds useful in this invention are the citrate, malate, citrate malate mixed salts, and combinations thereof.
• the preferred zinc salt is zinc citrate, preferably the commercially available dihydrate and trihydrate forms.
• the amount of elemental zinc is preferably at least about 3 mg/tablet, more preferably at least about 5 mg/tablet, and most preferably at least about 10 mg/tablet.
• the zinc is not microencapsulated, coated or melt granulated.
• composition of the present invention is substantially free of any monosaccharide, organic acid, and mono-carboxylic amino acid.
• Monosaccharides include, but are not limited to, glucose, galactose and fructose.
• Organic acids include, but are not limited to, tartaric, citric and malic acid.
• Mono-carboxylic amino acids include all the amino acids disclosed in US 6,316,008B1. By the term “substantially free” it is understood that the monosaccharide, organic acid, or monocarboxylic amino acid content is non- existent or low that the pharmaceutical compositions of the present invention is still palatable and stable against oxidation and formation of carbon dioxide.
• the sweeteners of the present invention include, but are not limited to, sugar disaccharides such as sucrose and lactose; sugar alcohols such as sorbitol, xylitol, mannitol, lactitol, erythritol, maltitol and isomalt. These sweeteners are preferably combined with a high-intensity sweetener such as sucralose, aspartame, acesulfame, and saccharin.
• the preferred sweeteners are sucrose, lactose, maltitol, and mixtures thereof, combined with sucralose. Sucrose, lactose, and maltitol are preferably used in their commercially available directly compressible grades.
• the amount of sweetener is preferably at least about 40% w/w, more preferably at least about 50% w/w, and most preferably at least about 60% w/w.
• the lozenge tablets of the present invention contain only vitamin C and zinc.
• the compositions of the present invention may optionally contain other vitamins and minerals.
• Vitamins include, but are not limited, to Vitamin E, thiamine (Vitamin Bl), riboflavin (Vitamin B2), niacin (Vitamin B3), pyridoxine (Vitamin B6), folic acid, cobalamins (Vitamin B12), Pantothenic acid (Vitamin B5), Biotin, Vitamin A (and Vitamin A precursors), Vitamin D, Vitamin K, other B complex vitamins, B complex related compounds such as Choline and Inositol, and carotenoids such as lutein, lycopene, zeaxanthin, and astaxanthin.
• Minerals include, but are not limited to, iron, iodine, magnesium, selenium, copper, calcium, manganese, silicon, molybdenum, vanadium, boron, nickel, tin phosphorus, chromium, cobalt, chloride, and potassium. It is within the ability of one ordinarily skilled in the art to determine which vitamins and minerals can be incorporated into the composition of the present invention without affecting stability and palatability.
• the pharmaceutical compositions may also include pharmaceutically acceptable excipients like binders, diluents, distintegrants, glidants, and lubricants.
• the total amount of these excipients must be kept low to reduce their effect on the palatability of the lozenge.
• the total amount of these excipients combined is preferably less than about 20% w/w, more preferably less than about 15% w/w, and most preferably less than about 10% w/w.
• Binders which may be used include gums like acacia, guar gum, alginic acid, sodium alginate; starch, carbomer, dextrin, gelatin, ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, copovidone, pregelatinized starch, polymethacrylates, and the like.
• the binder may be present in an amount ranging from about 1% to about 10% by weight of the composition.
• the binder may be incorporated into the composition in two ways, for example, the binder may be mixed with the active ingredients and other excipients and the blend may then be processed into granules by addition of a granulating solvent (wet granulation) or the blend of active ingredients, binder and excipients may be dry mixed or roller compacted without a solvent (dry granulation).
• Disintegrants may be selected from starch, crospovidone, croscarmellose sodium, and sodium starch glycolate.
• Diluents may be selected from cellulose-derived materials such as powdered cellulose, microcrystalline cellulose, microfine cellulose, and the like; starch, pregelatinized starch, and the like; dextrates, dextrin, inorganic diluents like calcium carbonate, calcium sulphate, dibasic calcium phosphate and its hydrate, tribasic calcium phosphate and its hydrate, magnesium carbonate, magnesium oxide, or mixture of one or more of such diluent.
• cellulose-derived materials such as powdered cellulose, microcrystalline cellulose, microfine cellulose, and the like
• starch pregelatinized starch, and the like
• dextrates, dextrin inorganic diluents like calcium carbonate, calcium sulphate, dibasic calcium phosphate and its hydrate, tribasic calcium phosphate and its hydrate, magnesium carbonate, magnesium oxide, or mixture of one or more of such diluent.
• Glidants which may be used include talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and tribasic calcium phosphate.
• the glidant may be present in an amount ranging from 0.5% to 3% w/w of the composition.
• Lubricants which may be used include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, and zinc stearate.
• the lubricant may be present in an amount ranging from about 0.25% to about 3% w/w of the composition.
• the weight of the lozenge tablet of the present invention is preferably less than about 1,200 mg, more preferably less than about 800 mg, and most preferably less than about 600 mg.
• Ascorbic acid C-97 (Aland, China) is Vitamin C granulated with 3% starch for direct compression.
• Sodium ascorbate SA-99 (Aland, China) is sodium ascorbate granulated with 1% starch for direct compression.
• the moisture content of these two vitamin C granules is less than 0.15% w/w.
• Ludipress ® (BASF, Germany) is a directly compressible lactose consisting of 93% lactose monohydrate, 3.5% povidone K30 (binder), and 3.5% crospovidone (disintegrant). Table 1 (in mg/tablet)
• the process for preparation of the granules for tabletting is as follows: 1). premix colorant with crospovidone and pass through a comminuting machine using mesh #30; 2). premix colloidal silicon dioxide with a portion of the compressible sugar (DIPAC ® , Domino Specialty Ingredients, USA) and pass through the comminuting machine; 3). premix sucralose and a portion of the compressible sugar and pass through the comminuting machine; 4). pass the rest of the compressible sugar through the comminuting machine; 5). pass zinc citrate and Ludipress ® through steel mesh #20; 6).
• Bloating is a measure of the carbon dioxide released due to oxidation of vitamin C.
• Figures 1 and 2 show the results of the accelerated stability. Peak instability in the presence of zinc citrate occurs when the vitamin C from sodium ascorbate is about 50%. Improved stability is obtained when at least about 65% of the vitamin C is from sodium ascorbate. This is surprising because prior art teaches that ascorbic acid is more stable than sodium ascorbate (Hiatt et al., J. Agric. Food Chem. 2010, 58, 3532-3540). EXAMPLE 2
• Chewable lozenge tablets with 10 mg elemental zinc from zinc oxide and 105 mg of vitamin C obtained from different combinations of ascorbic acid and sodium ascorbate were prepared according to Table 2, each with a batch size of 5 kg.
• the tablets were prepared essentially as in Example 1.
• Figures 1 and 2 show the results of the accelerated stability. Peak instability in the presence of zinc oxide is similar to zinc citrate and occurs when the vitamin C from sodium ascorbate is about 50%. Overall, the formulation is more stable when zinc citrate is used instead of zinc oxide. This is surprising because zinc oxide is insoluble, 300x more insoluble than zinc citrate, and therefore releases less zinc ion to catalyze the oxidation of vitamin C.
• Example 4E contains 10 mg of elemental zinc from zinc gluconate.
• Zinc gluconate is described in the prior art to have mild, faint taste. However, in the presence of sodium ascorbate, the astringent taste of zinc is very prominent. This is consistent with US 6,316,008B1 which teaches that zinc gluconate cannot be combined with ascorbic acid or sodium ascorbate due to poor taste. In US 6,316,008B1, a palatable hard candy is obtained when zinc gluconate is combined with a mono-carboxylic amino acid, such as glycine, and Vitamin C is selected from magnesium ascorbate and ascorbyl esters.
• a mono-carboxylic amino acid such as glycine
• Example 4E taste comparison of Example 4E with Example 4A showed similar saltiness, indicating that zinc gluconate does not reduce the saltiness of sodium ascorbate.
• Example 4D contains 10 mg elemental zinc from zinc oxide. Because zinc oxide is insoluble, the zinc taste is not apparent, consistent with the neutral taste of zinc oxide described in the prior art.
• Taste comparison of Example 4D with Example 4A showed similar saltiness, indicating that zinc oxide does not reduce the saltiness of sodium ascorbate.
• Example 4B is less salty than Example 4A, and Example 4C, with higher level of zinc citrate, is not salty and the zinc taste is not perceptible. This is contrary to the teaching of US 6,316,008B1 which teaches that zinc salt, including zinc citrate, cannot be combined with sodium ascorbate due to poor taste.
• Example 5 shows that the addition of organic acid to the compositions of the present invention causes severe oxidation of vitamin C.
• Examples 5A, 5B, and 5C shows that the addition of an organic acid significantly enhances spotting/discoloration of the tablet.
• Sugar-free formulation Examples 5D, 5E, and 5F show similar results.
• the use of organic acid to improve the palatability of prior art formulations is not required in the compositions of the present invention because the taste is already good in the absence of organic acid.
• the addition of organic acid in the compositions of the present invention causes significant vitamin C oxidation. Therefore, the compositions of the present invention are substantially free of organic acid. It is surprising that palatable and stable vitamin C and zinc lozenge tablets can be formulated according to the present invention without the organic acids widely used in prior art commercially available products.
• Example 6 shows that the addition of monosaccharide to the compositions of the present invention causes severe oxidation of vitamin C.
• Chewable lozenge tablets with 105 mg of vitamin C (80% from sodium ascorbate) and 10 mg of elemental zinc from zinc citrate were prepared according to Table 6. The tablets were prepared essentially as in Example 1.
• compositions of the present invention are substantially free of monosaccharides. It is surprising that palatable and stable vitamin C and zinc lozenge tablets can be formulated according to the present invention without the monosaccharides widely used in prior art commercially available products.
• Calcium ascorbate has been used in the prior art as a source of vitamin C. In the compositions of the present invention, calcium ascorbate cannot be used to replace sodium ascorbate.
• Chewable lozenge tablets with 105 mg of vitamin C and 5 mg of elemental zinc from zinc citrate were prepared according to Table 7. The tablets were prepared essentially as in Example 1.
• Example 7A of the present invention contains 80% of vitamin C from sodium ascorbate.
• Example 7B contains 80% of the vitamin C from calcium ascorbate.
• Example 7A is good tasting, while Example 7B is slightly bitter, with perceivable astringent taste of zinc.
• Example 7C contains 100% of vitamin C from calcium ascorbate and possesses the same taste profile as Example 7B.
• Chewable lozenge tablets according to the embodiments of the present invention containing 105 mg of vitamin C and 5-10 mg of elemental zinc from zinc citrate were prepared.
• the 600 mg version was tabletted using an 1 1.5 mm flat faced beveled edge round punch to a hardness of 8-14 kp.
• the samples were individually packed in aluminum flex foil, and stored at 25°C/65% RH for 24 months, and 40°C/75% RH for 6 months. Under these storage conditions, the samples did not show any spotting/discoloration, the packaging did not bloat, and the taste profile was similar to time zero samples. Further, the assays of vitamin C did not change confirming that significant oxidation did not occur.
• the amount of mobile bound water in the tablet from the zinc salt and lactose is 1.6-1.9% w/w. This is surprising, given the disclosure of US 2014/0220151A1 which teaches that the mobile bound water should be less than 0.3% to stabilize Vitamin C in the presence of polyvalent metals. Note that the compositions in US 2014/0220151A1 contain less than 10% w/w of Vitamin C, while the above embodiments of the present invention contain 17.5- 23.3% of Vitamin C, which is more difficult to stabilize because of the high level of Vitamin C.
• the samples were individually packed in aluminum flex foil, and stored at 25°C/65% RH for 24 months, and 40°C/75% RH for 6 months. Under these storage conditions, the samples did not show any spotting/discoloration, the packaging did not bloat, and the taste profile was similar to time zero samples. Further, the assays of vitamin C did not change confirming that significant oxidation did not occur.
• the amount of mobile bound water in the tablet from the zinc salt is 0.31-0.61% w/w. This is surprising, given the disclosure of US 2014/0220151A1 which teaches that the mobile bound water should be less than 0.3% to stabilize Vitamin C in the presence of polyvalent metals. Note that the compositions in US 2014/0220151A1 contain less than 10% w/w of Vitamin C, while the above embodiments of the present invention contain 17.5-23.3%) of Vitamin C, which is more difficult to stabilize because of the high level of Vitamin C.
• Chewable sugar-free lozenge tablets according to the embodiments of the present invention containing 105 mg of vitamin C and 5-10 mg of elemental zinc from zinc citrate were prepared.
• the samples were individually packed in aluminum flex foil, and stored at 25°C/65% RH for 24 months, and 40°C/75% RH for 6 months. Under these storage conditions, the samples did not show any spotting/discoloration, the packaging did not bloat, and the taste profile was similar to time zero samples. Further, the assays of vitamin C did not change confirming that significant oxidation did not occur.
• the amount of mobile bound water in the tablet from the zinc salt is 0.46-0.61% w/w. This is surprising, given the disclosure of US 2014/0220151A1 which teaches that the mobile bound water should be less than 0.3%) to stabilize Vitamin C in the presence of polyvalent metals.
• compositions in US 2014/0220151A1 contain less than 10% w/w of Vitamin C, while the above embodiments of the present invention contain 17.5-23.3% of Vitamin C, which is more difficult to stabilize because of the high level of Vitamin C.
• the tablet is big (> 1,200 mg), the vitamin C concentration is low, taste is bad, and stability is extremely poor (+10 spotting/discoloration, +5 bloating). Poor stability and taste are due to the use of 100% ascorbic acid, zinc gluconate, and fructose.
• Comparative Example 2 Wellness Source Naturals (Source Naturals, Inc. USA). The tablet is big (> 2,200 mg), vitamin C concentration is very low, taste is bad, and stability is extremely poor (+10 spotting/discoloration, +5 bloating). Poor stability and taste are due to use of zinc ascorbate, zinc gluconate, and fructose.
• Comparative Example 3 Puritan's Pride (Puritan's Pride, USA). Vitamin C concentration is low, taste is borderline, and stability is poor (+7 spotting/discoloration, +3 bloating). Poor stability and taste are due to use of 100% ascorbic acid and zinc gluconate.
• Comparative Example 4 rugby (Rugby laboratories, USA). Tablet is big (>1,200 mg), Vitamin C concentration is very low, taste is borderline, and stability is extremely poor (+10 spotting/discoloration, +4 bloating). Poor stability is due to use of 100% ascorbic acid, fructose, citric acid, and malic acid.
• Comparative Example 5 Now (Now Foods, Inc. USA). Tablet is big (> 2,800 mg), Vitamin C concentration is low, taste is bad, and stability is poor (+10 spotting/discoloration, +3 bloating).
• This formulation contains a combination of ascorbic acid and sodium ascorbate but the percentage of vitamin C from sodium ascorbate cannot be ascertained because the sodium level is not disclosed. However, this formulation is outside the scope of the present invention because of the very low vitamin C concentration, and in addition, the poor stability and taste are due to use of zinc gluconate, and fructose.
• Comparative Example 6 Country Life (Country Life LLC, USA).
• Tablet is big (> 1,200 mg), Vitamin C concentration is very low, taste is bad, and stability is extremely poor (+10 spotting/discoloration, +4 bloating).
• the poor stability and taste are due to the use of non-optimal level of sodium ascorbate (38% of vitamin C is from sodium ascorbate), zinc gluconate, fructose, glucose, and citric acid.
• Comparative Example 7 Bluebonnet Nutrition (Bluebonnet Nutrition Corporation, USA). Tablet is big (> 1,200 mg), Vitamin C concentration is very low, taste is borderline, and stability is poor (+7 spotting/discoloration, +3 bloating).
• Comparative Example 9 Bioglan Vitamelts (PharmaCare Europe Ltd, UK). Stability is poor (+6 spotting/discoloration, +2 bloating) due to the use of non- optimal level of sodium ascorbate (30% of vitamin C is from sodium ascorbate), and honey (contains glucose and fructose). Comparative Example 10: Redoxon kids (Bayer, Switzerland). Extremely poor stability (+10 spotting/discoloration, +5 bloating) due to the use of 100% ascorbic acid.
• formulations based on prior art are mostly bad tasting, mostly containing very low level of vitamin C, mostly very large tablet, but more importantly, almost all are unstable.

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