WO2017065623A1

WO2017065623A1 - Stable composition of vitamin c and zinc tablet

Info

Publication number: WO2017065623A1
Application number: PCT/PH2015/000016
Authority: WO
Inventors: Wendell MENDOZA; Rita Josefina SANTOS; Kennie DEE
Original assignee: Mendoza Wendell; Santos Rita Josefina; Dee Kennie
Priority date: 2015-10-16
Filing date: 2015-10-16
Publication date: 2017-04-20
Also published as: KR102089721B1; BR112018007634A2; KR20180064420A; MY191729A; CN108347990A; PH12018500791B1; HK1257130A1; PH12018500791A1; TW201716063A

Abstract

The present invention relates to non-effervescent swallow 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.

Description

STABLE COMPOSITION OF VITAMIN C AND ZINC TABLET

BACKGROUND OF THE INVENTION

1. Field of the Invention

2. Background of the Invention

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.

When combined with zinc, the Vitamin C supplement is normally available as a capsule, or an effervescent format, usually combined with other vitamins and minerals. Vitamin C and capsules are not compatible. For gelatin capsules specifically, the aldehyde group of Vitamin C reacts with the a-amino groups of gelatin causing protein crosslinking which retards dissolution. Capsules also have high moisture content, about 5-6% for vegetable capsules and up to 16% for gelatin capsule. This moisture causes Vitamin C oxidation leading to darkening of the fill and formation of carbon dioxide. Since some consumers are known to empty the contents of several capsules into a glass of water before intake, this darkening might discourage consumers from using the product.

A far more important but less appreciated problem is the formation of carbon dioxide which leads to bloating of common unit dose pack such as blister and aluminum foil. In the case of multiple units packed in bottles, the gas pressure eventually destroys the seal of the protective liner, allowing moisture from the environment to enter the bottle, thereby causing more degradation. The issue of carbon dioxide formation is not limited to capsules, but to all improperly formulated solid dosage formats.

An alternative to capsules is to combine Vitamin C and zinc in a tablet format. Due to the poor compression properties of Vitamin C and zinc, the tablets are usually effervescent formats with significant amount of excipients to improve compression. The amount of Vitamin C in an effervescent Vitamin C/zinc tablet is 10-22%, and normally includes other vitamins and minerals to improve compressibility. The disadvantages of effervescent formats include: 1.) high amount of sodium from sodium bicarbonate or sodium carbonate which is the base used in the acid-base couple to produce gas for effervescence; 2.) expensive manufacturing process at low humidity of 20% RH to prevent moisture uptake during production; 3.) expensive multiple unit containers to prevent moisture uptake on storage of final product; 4.) inconvenience requiring preparation before intake; and 5.) taste fatigue. Vitamin C and zinc can also be combined in a swallow tablet, but normally the Vitamin C is present at less than 10% w/w. For example Centrum Multivitamins and Minerals (Pfizer/Wyeth, NY) contains only 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. As disclosed in US 2014/0220151A1, this low level of Vitamin C is already extremely difficult to stabilize and requires the composition to be substantially free of mobile bound water. Mobile bound water means water of hydration and substantially free means less than 0.3% w/w of the composition.

Centrum Multivitamins and Minerals 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 2014/0220151A1 , is to reduce the mobile bound water. The preferred zinc salts in the present invention are the highly bioavailable soluble salts zinc sulfate, zinc gluconate and zinc acetate. These soluble salts are hygroscopic in their anhydrous forms, therefore their commercially available hydrated forms, zinc sulfate monohydrate, zinc gluconate trihydrate, and zinc acetate dihydrate are preferably used in the present invention. The composition of the present invention can contain significantly more mobile bound water than the required limit taught by US 2014/0220151A1. Further, US 2014/022015 lAl does not teach how to make swallow tablets of Vitamin C and Zinc, wherein the Vitamin C is present at high concentration and stable against oxidation and formation of carbon dioxide, even with compositions containing up to 2% w/w of mobile bound water.

SUMMARY OF THE INVENTION

We have surprisingly found that stable swallow tablets of Vitamin C and Zinc where Vitamin C is present at a high concentration can be prepared by inclusion of crospovidone with a particle size of d50 less than 90 μπι, preferably less than about 60 μ^ηι, more preferably less than about 40 μηι, and most preferably less than about 30 μι^η. These tablets are coated, with good coating yield, and are stable against oxidation and formation of carbon dioxide. DETAILED DESCRIPTION OF THE INVENTION

The vitamin C is preferably ascorbic acid, but other pharmacologically acceptable salts of ascorbic acid such as sodium ascorbate, potassium ascorbate, calcium ascorbate, and magnesium ascorbate can also be used. The ascorbic acid, or its salt, is preferably present at a concentration of at least about 30% w/w, more preferably at least about 40% w/w, and most preferably at least about 50% w/w. The Vitamin C and its salts preferably are already in granular form ready for compression. These direct-for-compression Vitamin C or Vitamin C salts are commercially available containing about 1-5% binder and very low moisture typically below 0.15% w/w.

Zinc compounds useful in this invention can be in any of the forms commonly used for oral supplementation, such as zinc sulfate, zinc chloride, zinc gluconate, zinc oxide, zinc stearate, zinc picolinate, zinc acetate, zinc lactate, zinc citrate, and mixtures thereof. The preferred zinc salts are the soluble zinc salts zinc sulfate, zinc gluconate, and zinc acetate. 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.

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. Crospovidone is a disintegrant extensively used in pharmaceutical formulations. Crospovidone is available from BASF, Germany, under the brand name Kollidon CL (d50 90-110 μηι), Kollidon CL-F (d50 20-40 μπι), Kollidon CL-SF (d50 10- 30 μm), and Kollidon CL-M (d50 3-10 μηι). The first three grades are used as tablet disintegrants. Kollidon CL is the standard grade. When Kollidon CL is used in uncoated tablets stored at high humidity, visible surface roughness may occur due to moisture absorption. In this case, Kollidon CL-F with smaller particle size is used to reduce surface roughness. Kollidon CL-SF is used for fast disintegrating buccal tablets since it gives a very smooth cream-like mouth feel. Kollidon CL-M is seldom used as a disintegrant; it is used as a stabilizer for oral and topical suspensions. Similar grades of crospovidone are available from other suppliers. For example, Ashland, USA, sells an equivalent of Kollidon CL under the brand name Polyplasdone Ultra (d50 1 10-140 μηι), and an equivalent of Kollidon CL-F under the brand name Polyplasdone Ultra- 10 (d50 25-40 μ^ηι). Crospovidone of the correct particle size is used in the present invention to improve coating yield, and to improve the stability of Vitamin C in compositions with high mobile bound water. The particle size of the Crospovidone is less than 90 μπι, preferably less than about 60 μπι, more preferably less than about 40 μιη, and most preferably less than about 30 μηι. It is within the skills of a person ordinarily skilled in the art to combine various grades of crospovidone to arrive at the desired particle size. All particle sizes in this present invention refer to volume averaged diameter d50. The crospovidone is present in the formulation at 1-15% w/w, preferably at 2-10% w/w, and most preferably at 3-8% w/w.

The pharmaceutical compositions may also include pharmaceutically acceptable excipients like binders, diluents, glidants, and lubricants. Binders which may be used include gums like acacia, guar gum, alginic acid, sodium alginate; starch, carbomer, dextrin, gelatin, ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy ethylcellulose, polyvinylpyrrolidone, copovidone, starch, pregelatinized starch, polymethacrylates, and the like. The binder may be present in an amount ranging from about 1% to about 12% 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).

Diluents may be selected from cellulose-derived materials such as powdered cellulose, microcrystalline cellulose, microfme cellulose, and the like; lactose, starch, pregelatinized starch, sugars and sugar alcohols such as mannitol, sorbitol, erythritol and the like; dextrates, dextrin, dextrose, inorganic diluents like calcium carbonate, calcium sulphate, dibasic calcium phosphate and its hydrate, tribasic calcium phosphate and its hydrate, magnesium carbonate, magnesium oxide, potassium chloride, sodium chloride or mixture of one or more of such diluent. Particularly suitable diluents are lactose, microcrystalline cellulose, dibasic calcium phosphate, or mixtures thereof. The diluent may be present in an amount ranging from about 20% to about 70% w/w of the composition.

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 Disintegration time was measured according to USP 38 without the use of a disk. The test was conducted by placing the core tablet in a basket-rack assembly, immersing the assembly in water at 37° C, and raising and lowering the basket a distance of about 5.5 cm at a frequency of about 30 cycles per minute. The time for the complete disappearance of the tablet is the disintegration time. The disintegration time is a surrogate measure of dissolution. The disintegration time of the core tablet is preferably less than about 30 minutes, more preferably less than about 20 minutes, and most preferably less than about 15 minutes.

Friability was measured in an Erweka TAR20. Briefly, ten tablets were placed inside a baffled 287 mm ID drum. The drum was rotated at 25 rpm for 4 minutes. The difference in the total tablet weight before and after rotating the drum divided by the initial tablet weight is the friability. In tablet coating, prior art requires a friability of less than 1 %, preferably less than 0.5% for the tablets to survive the coating process.

EXAMPLE 1

Tablets with 500 mg Vitamin C and 10 mg elemental zinc from zinc sulfate were prepared according to Table 1, each with a batch size of 5 kg.

Table 1 (in mg/tablet)

Kollidon CL (90-1 10 μηι) 0 0 45 0

Kollidon CL-F (20-40 μπι) 0 0 0 45

Lactose Fast Flo SD 336.4 246.4 246.4 246.4

Talc 11.6 1 1.6 11.6 11.6

Magnesium Stearate 9.0 9.0 9.0 9.0

Core weight (mg) 900 900 900 900

Disintegration time (min) 30 22 8 7

Hardness (kp) 15-19 15-20 15-18 15-19

Friability (%) 0.37 0.33 0.30 0.30

Coating loss (%) 3.8 4.2 47.5 0.7

Ascorbic acid C-97 (Aland, China) is Vitamin C granulated with 3% starch for direct compression; the moisture content is less than 0.15% w/w. Povidone K30 (BASF, Germany) is a dry binder used in direct compression. Lactose Fast Flo (Foremost Farms, USA) is a spray-dried lactose monohydrate that is used as a tableting aid.

Lactose Fast Flo and zinc sulfate monohydrate were passed through a Fitzmill comminuting machine using a mesh 20 screen. These ingredients were mixed with the rest of the ingredients, except for talc and magnesium stearate, in a sigma mixer for 10 minutes. Talc and magnesium stearate were then added and the granules mixed for one minute. The granules were then tableted using a 0.744" x 0.34" elliptical punch, and the tablets coated with 5% w/w of Opadry 85G Green (Colorcon, USA). Opadry 85G is an aqueous PVA-based film coating.

Example 1 A is a reference formulation without crospovidone. When core tablets of Example 1A were stored in aluminum flex foil at 40°C/75% RH for 6 months, tablet darkening was not acceptable. An attempt was made to coat Example 1A, but the proportion of broken and edge-chipped tablets was unacceptably high. This is unusual because when the core tablets are hard and the friability is low, a person ordinarily skilled in the art should not expect any coating problem. When the coated edge-chipped tablets of Example 1A were packed in aluminum flex foil and stored at 80°C for 3 days, there was significant bloating of the packaging due to carbon dioxide formation from the oxidation of Vitamin G. In contrast, good coated tablets from the same batch did not bloat when stored under the same condition. It is therefore important to reduce the proportion of bad tablets since sorting prior to packaging might miss these edge-chipped tablets. The proportion of bad tablets during coating should be less than 2%, more preferably less than 1%.

Example IB includes 10% w/w of Povidone K30, which is a dry binder used extensively in the pharmaceutical art to improve tablet strength. Addition of povidone did not reduce the proportion of bad tablets formed during coating. Note that the friability of Example 1A and IB are both below 0.5%, a level known in the prior art to produce good coated tablets.

Example 1C contains 5% w/w each of Povidone K30 and Kollidon CL. Kollidon CL was added to improve disintegration, which it did, but the proportion of bad coated tablets increased to more than 40% in spite of the fact that the friability is less than 0.5%, and the tablet hardness, a measure of tablet strength, is the same as Examples 1 A and IB. Kollidon CL is not known in the prior art to produce a high proportion of bad coated tablets when the core tablet is hard and its friability is low.

Surprisingly, in Example I D, the use of Kollidon CL-F to replace Kollidon CL of Example 1C led to a significant reduction in the proportion of bad coated tablets, in spite of the fact that the tablet hardness and friability are similar to Examples 1A, IB and 1C. The particle size of Kollidon CL-F is significantly smaller than Kollidon CL. The use of small particle size crospovidone in tablets containing vitamin C and zinc, wherein the Vitamin C is present at high concentration, to reduce the proportion of bad coated tablets when the core tablets are hard and friability is low is not known in the prior art.

When Example ID was packed in aluminum flex foil and stored at 40°C/75% RH for 6 months, the coated tablet did not discolor, nor did the unit packaging bloat. Further, the assay of the Vitamin C did not change confirming that significant oxidation did not occur. The amount of mobile bound water in the core tablet from the zinc salt and lactose is 1.7% w/w. This is also 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 Example ID contains more than 50% of Vitamin C, which is more difficult to stabilize because of the high level of Vitamin C.

EXAMPLE 2

Tablets with 500 mg Vitamin C and 10 mg elemental zinc from zinc sulfate were prepared according to Table 2, each with a batch size of 5 kg. The tablet size was 0.744" x 0.34" elliptical. Same coating material was used as in Example 1.

Table 2 (in mg/tablet)

Disintegration time (min) 31 6 5 5 19

Hardness (kp) 19-23 18-22 18-23 18-24 18-23

Friability (%) 0.30 0.24 0.34 0.27 0.37

Coating loss (%) 5.3 23.8 0.38 0.49 0.68

Example 2A is a formulation with 5% Kollidon VA64 Fine (BASF, Germany). Kollidon VA64 is copolyvidone and is a widely used dry binder for increasing tablet strength. Note that although the friability is less than 0.5%, and the tablet is hard, the proportion of bad coated tablets is still high. Example 2B is Example 2A with addition of 5% Kollidon CL. As expected, being a disintegrant, Kollidon CL reduced the disintegration time. However, although the tablet hardness and friability are similar to Example 2A, the proportion of bad coated tablets was more than four times higher.

Examples 2C, 2D, and 2E are the same formulation as Example 2B except for replacement of Kollidon CL with progressively smaller particle size. As shown in Table 2, crospovidone of d50 less than 40 μπι gives tablets with good coating yield, in spite of the fact that the tablet strength and friability are the same as Kollidon CL (d50 90-1 10 μπι).

When Examples 2C, 2D and 2E were packed in aluminum flex foil and stored at 40°C/75% RH for 6 months, the coated tablets did not discolor, nor did the unit packaging bloat. Further, the assays of Vitamin C for the three formulations did not change confirming that significant oxidation did not occur. The amount of mobile bound water in the core tablets of the three formulations is 1.7% w/w.

EXAMPLE 3 Tablets with 500 mg Vitamin C and 10 mg elemental zinc from zinc sulfate were prepared according to Table 3, each with a batch size of 5 kg. The tablet size was 0.744" x 0.34" elliptical. Same coating material was used as in Example 1.

Table 3 (in mg/tablet)

These two formulations have no dry binder, but surprisingly, their coating yields are excellent, indicating that a binder is optional in the present invention.

Equally surprising, when Examples 3A and 3B were packed in aluminum flex foil and stored at 40°C/75% RH for 6 months, the coated tablets did not discolor, nor did the unit packaging bloat. Further, the assays of Vitamin C for these two formulations did not change confirming that significant oxidation did not occur. The mobile bound moisture from the zinc and lactose is 2.2% w/w.

EXAMPLE 4

Tablets with 500 mg Vitamin C from sodium ascorbate and 10 mg elemental zinc from zinc sulfate were prepared according to Table 4, each with a batch size of 5 kg. The tablet size was 0.744" x 0.34" elliptical. Same coating material was used as in Example 1.

Table 4 (in mg/tablet)

Sodium ascorbate SA-99 (Aland, China) is sodium ascorbate granulated with 1% starch for direct compression; the moisture content is less than 0.15% w/w. The process for preparing the final granules for tableting is the same as Example 1.

Example 4A is a reference formulation without crospovidone. When core tablets of Example 4A were stored in aluminum flex foil at 40°C/75% RH for 6 months, tablet darkening was not acceptable. An attempt was made to coat Example 4 A, but the proportion of broken and edge-chipped tablets was unacceptably high. When the coated edge-chipped tablets were packed in aluminum flex foil and stored at 80°C for 3 days, there was significant bloating of the packaging due to carbon dioxide formation from the oxidation of Vitamin C. In contrast, good coated tablets from the same batch did not bloat when stored under the same condition. Example 4B contains 8% w/w Kollidon CL. Kollidon CL was added to improve disintegration, which it did, but the proportion of bad coated tablets increased to 37% in spite of the fact that the friability is less than 0.5%, and the tablet hardness, a measure of tablet strength, is the same as Example 4A. Examples 4C and 4D are the same formulation as Example 4B, but with Kollidon CL-SF and Kollidon-M, respectively, replacing Kollidon CL. In spite of the fact that the tablet hardness and friability are simila to Examples 4A and 4B, Examples 4C and 4D, which use crospovidone d50 less than 30 μηι, have surprisingly good coating yield. Example 4E combines 4% Kollidon CL (90-110 μπι) and 4% Kollidon CL-M (3- 10 μηι) giving a crospovidone with d50 of 50-60 μιη. Example 4E has good coating yield compared to Example 4B where the d50 of the crospovidone is 100 μιη. Therefore, in the present invention, the particle size of the crospovidone is less than about 90 μηι, preferably less than about 60 μηι, more preferably less than about 40 μηι, and most preferably less than about 30 μπι. It is within the skills of a person ordinarily skilled in the art to combine various grades of crospovidone to arrive at the desired particle size.

When Examples 4C, 4D and 4E were packed in aluminum flex foil and stored at 40°C/75% RH for 6 months, the coated tablets did not discolor, nor did the unit packaging bloat. Further, the assays of Vitamin C for the three formulations did not change confirming that significant oxidation did not occur. The amount of mobile bound water in the core tablets of the three formulations is 1.8% w/w.

EXAMPLE 5

Tablets with 500 mg Vitamin C from sodium ascorbate and 10 mg elemental zinc from zinc sulfate were prepared according to Table 5, each with a batch size of 5 kg. The tablet size was 0.744" x 0.34" elliptical. Same coating material was used as in Example 1.

Table 5 (in mg/tablet)

Examples 5 A, 5B, 5C, and 5D are further embodiments of the present invention.

When these four formulations were packed in aluminum flex foil and stored at 40°C/75% RH for 6 months, the coated tablets did not discolor, nor did the unit packaging bloat. Further, the assays of Vitamin C for the four formulations did not change confirming that significant oxidation did not occur. The amount of mobile bound water in the core tablets of the three formulations is 1.7-1.9% w/w.

EXAMPLE 6

Tablets with 500 mg Vitamin C from sodium ascorbate and 10 mg elemental zinc from zinc gluconate were prepared according to Table 6, each with a batch size of 5 kg. The tablet size was 0.744" x 0.34" elliptical, Same coating material was used as in Example 1.

Table 6 (in mg/tablet)

Example 6A is a reference formulation without crospovidone. The zinc salt is zinc gluconate trihydrate. When core tablets of Example 6A were stored in aluminum flex foil at 40°C/75% RH for 6 months, tablet darkening was not acceptable. An attempt was made to coat Example 6A, but the proportion of broken and edge-chipped tablets was unacceptably high. When the coated edge- chipped tablets were packed in aluminum flex foil and stored at 80°C for 3 days, there was significant bloating of the packaging due to carbon dioxide formation from the oxidation of Vitamin C. In contrast, good coated tablets from the same batch did not bloat when stored under the same conditions.

Example 6B contains 8% w/w Kollidon CL. Kollidon CL was added to improve disintegration, which it did, but the proportion of bad coated tablets increased to more than 1 1 % inspite of the fact that the friability is less than 0.5%, and the tablet hardness, a measure of tablet strength, is the same as Example 6A. Example 6C is the same formulation as Example 6B, but with Kollidon CL-SF replacing Kollidon CL. In spite of the fact that the tablet hardness and friability are similar to Examples 6A and 6B, Example 6C which uses crospovidone d50 less than 30 μm, has surprisingly good coating yield. Equally surprising, when Example 6C was packed in aluminum flex foil and stored at 40°C/75% RH for 6 months, the coated tablets did not discolor, nor did the unit packaging bloat. Further, the assay of Vitamin C did not change confirming that significant oxidation did not occur. The amount of mobile bound water in the core tablet of Example 6C is 2.1% w/w.

EXAMPLE 7

Tablets with 500 mg Vitamin C from sodium ascorbate and 10 mg elemental zinc from zinc sulfate were prepared according to Table 7, each with a batch size of 5 kg. The tablet size was 0.744" x 0.34" elliptical. Same coating material was used as in Example 1.

Table 7 (in mg/tablet)

Example 7A is a formulation that replaces crospovidone with another extensively used disintegrant sodium croscarmellose (DFE Pharma, Germany). The d50 of this sodium croscarmellose is 58 μπι. The proportion of bad coated tablets is very high when compared with crospovidone of similar particle size. Example 7B uses finer sodium croscarmellose obtained by micronizing the 58 μ^ηι raw material. The tablets of Example 7B are too soft to coat. Therefore, sodium croscarmellose cannot be used to replace crospovidone in the present invention.

Example 7C is a formulation that replaces crospovidone with another extensively used disintegrant sodium starch glycolate (Maple Biotech, India). The d50 of this sodium starch glycolate is 53 μιτι. The proportion of bad coated tablets is very high when compared with crospovidone of similar particle size. Example 7D uses finer sodium starch glycolate obtained by micronizing the 53 μπι raw material. The tablets of Example 7D are too soft to coat. Therefore, sodium starch glycolate cannot be used to replace crospovidone in the present invention.

EXAMPLE 8

Tablets with 500 mg Vitamin C from sodium ascorbate and 10-25 mg elemental zinc from zinc sulfate were prepared according to Table 8, each with a batch size of 5 kg. The tablet size was 0.744" x 0.34" elliptical. Same coating material was used as in Example 1.

Table 8 (in mg/tablet)

Ingredient Ex. 8A Ex. 8B

Sodium Ascorbate SA-99 574 574

Zinc Sulfate Monohydrate 27.5 68.75

Vitamin E Succinate 20 (22 IU) 20 (22 IU)

Vitamin A Acetate 0 9 (2500 IU)

Kollidon CL-SF (10-30 μηι) 40 0

Kollidon CL-M (3-10 μηι) 40 80 Lactose Fast Flo SD 278.5 228.3

Talc 12 12

Magnesium Stearate 8 8

Core weight (mg) 1000 1000

Disintegration time (min) 12 14

Hardness (kp) 30-40 22-28

Friability (%) 0.17 0.14

Coating loss (%) 0.42 0.34

Examples 8 A and 8B are further embodiments of the present invention. Example 8A contains 500 mg of Vitamin C, 10 mg of elemental zinc, and 22 IU of Vitamin E. Example 8B contains 500 mg of Vitamin C, 25 mg of elemental zinc, 22 IU of Vitamin E, and 2500 IU of Vitamin A. When these two formulations were packed in aluminum flex foil and stored at 40°C/75% RH for 6 months, the coated tablets did not discolor, nor did the unit packaging bloat. Further, the assays of Vitamin C for the two formulations did not change confirming that significant oxidation did not occur. The amount of mobile bound water in the core tablets of Examples 8A is 1.7% w/w, and Example 8B is 2.0% w/w.

EXAMPLE 9

Examples 9A and 9B are further embodiments of the present invention where the Vitamin C and zinc sulfate were wet granulated together prior to use.

Table 9 (in mg/tablet)

Ingredient Ex. 9A Ex. 9B

Ascorbic Acid 500 0

Sodium Ascorbate USP 0 562.4

Zinc Sulfate Monohydrate 27.5 27.5

Starch Regular 15.5 17.6

Kollidon CL-M (3-10 μπι) 80 80 Lactose Fast Flo SD 357 292.5

Talc 12 12

Magnesium Stearate 8 8

Core weight (mg) 1000 1000

Disintegration time (min) 5 8

Hardness (kp) 15-21 18-22

Friability (%) 0.16 0.20

Coating loss (%) 0.81 0.45

The granulations were prepared as follows: add starch regular to purified water at 80-100 °C while mixing. Cool to 40°C, and use this solution to wet granulate ascorbic acid or sodium ascorbate, and zinc sulfate. Dry the wet granulate in a fluid bed dryer to a moisture content of 0.4% w/w, and pass through a Fitzmill comminuting machine using a mesh 10 screen. Pass the lactose Fast Flo through a Fitzmill comminuting machine using a mesh 20 screen. Mix the ascorbic/zinc granules, lactose, and the rest of the ingredients, except for talc and magnesium stearate, in a sigma mixer for 10 minutes. Talc and magnesium stearate were then added and the granules mixed for one minute. The granules were then tableted using a 0.744" x 0.34" elliptical punch, and the tablets coated with 5% w/w of Opadry 85G Green (Colorcon, USA).

When Examples 9A and 9B were packed in aluminum flex foil and stored at 40°C/75% RH for 6 months, the coated tablets did not discolor, nor did the unit packaging bloat. Further, the assays of Vitamin C for these two formulations did not change confirming that significant oxidation did not occur.

EXAMPLE 10

Examples 10A, 10B and IOC are further embodiments of the present invention. The formulations contain 500 mg of ascorbic acid from sodium ascorbate and 10 mg elemental zinc from zinc sulfate. The tablet size was 0.744" x 0.34" elliptical. Same coating material was used as in Example 1.

Table 10 (in mg/tablet)

All three formulations have good coating yield.

Claims

We claim:

A stable coated oral tablet comprising:

i. ) Vitamin C;

ii. ) at least one zinc salt; and

iii. ) a crospovidone with a particle size of d50 less than 90 μιτι.

The vitamin C according to claim 1, wherein the Vitamin C is selected from ascorbic acid, sodium ascorbate, potassium ascorbate, calcium ascorbate, magnesium ascorbate, and mixtures thereof.

The tablet according to claim 1 , wherein the Vitamin C is more than about 30% w/w.

4. The tablet according to claim 3, wherein the Vitamin C is more than about

40% w/w.

5. The tablet according to claim 4, wherein the Vitamin C is more than about

50% w/w. 6. The tablet according to claim 1 , wherein the zinc is selected from zinc sulfate, zinc gluconate, zinc acetate, their hydrates, and mixtures thereof.

7. The tablet according to claim 1 , wherein the zinc is at least 3 mg per tablet.

8. The tablet according to claim 7, wherein the zinc is at least 5 mg per tablet.

9. The tablet according to claim 8, wherein the zinc is at least 10 mg per tablet.

10. The tablet according to claim 1 , wherein the crospovidone is 1-15% w/w.

11. The tablet according to claim 10, wherein the crospovidone is 2- 10% w/w.

12. The tablet according to claim 1 1, wherein the crospovidone is 3-8% w/w.

13. The tablet according to claim 1, wherein the crospovidone has a particle size of d50 less than about 60 μιη.

14. The tablet according to claim 13, wherein the crospovidone has a particle size of d50 less than about 40 μπι.

15. The tablet according to claim 14, wherein the crospovidone has a particle size of d50 less than about 30 μιη.

16. The tablet according to claim 1, wherein the disintegration time is less than about 30 minutes.

17. The tablet according to claim 16, wherein the disintegration time is less than about 20 minutes.

18. The tablet according to claim 17, wherein the disintegration time is less than about 15 minutes.

19. The tablet according to claim 1, wherein the composition is not substantially free of mobile bound water.

20. The tablet according to claim 19, wherein the composition contains about 0.3-3% w/w mobile bound water.

21. The tablet according to claim 20, wherein the composition contains about 0.3-2% w/w mobile bound water.