FIELD OF THE INVENTION
The present invention relates to a solid oral pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts and a method of preparing the same.

BACKGROUND OF THE INVENTION
Vitamin C, also known as Ascorbic acid, is an essential nutrient involved in the repair of tissues and enzymatic production of neurotransmitters. It is also required for proper functioning of various enzymes besides being vital for function of immune system.
Zinc is one of the most important essential trace elements and its deficiency is linked to impairment of immune system.
Ascorbic acid and Zinc are administered together to complement their immunity benefits. However, combining Ascorbic acid and Zinc in a single dosage form is challenging since ascorbic acid is a highly hygroscopic as well as incompressible substance. Additionally, it is prone to oxidation which is augmented in presence of multivalent metals like Zinc. This oxidation is facilitated by moisture and leads to spotting, darkening, and carbon dioxide formation as well as enhanced disintegration times which may negatively affect availability of components for utilization by the body. Formation of carbon dioxide leads to bloating of common unit dose packs such as blister and aluminum foil. Furthermore, ascorbic acid is incompatible with many of the commonly used pharmaceutical excipients such as polyvinylpyrrolidone, starch, ethyl cellulose etc.
Owing to the ease of administration of drugs by oral route, solid oral dosage forms are the most preferred dosage forms for intake of drugs. However, solid oral dosage forms suffer from limitations such as poor stability in the gastric milieu, slow absorption and poor bioavailability of the dosage form. Further, owing to very high dosage of ascorbic acid (1000 mg), administration of the drug in tablet dosage form is not feasible due to large size of the tablets which leads to difficulty in swallowing for pediatric and geriatric patients. In order to surmount slow absorption, poor bioavailability and swallowability issues of solid oral dosage forms, effervescent dosage forms have been developed as an alternate dosage form since effervescent dosage forms are dissolved in water before administration. Additionally, it is also possible to improve unpleasant taste and reduce gastric irritation due to localized concentration of the active pharmaceutical ingredient. Furthermore, effervescent dosage forms have been reported to augment absorption of a number of active ingredients. However, development of effervescent dosage forms is complicated by the fact that these dosage forms should be porous and not too rigid to dissolve in water. This porous structure of effervescent dosage forms poses stability problems arising out of humidity during production, packaging and transportation.
Effervescent tablets containing ascorbic acid and Zinc are currently available in the market but there remains a need in the market of effervescent tablets comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts which are manufactured by a simple and commercially viable process since majority of the currently marketed effervescent dosage forms are manufactured by processes which not only involve number of operations but also require significant amount of time and equipment. Further, there also remains a need for effervescent tablets comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts exhibiting desirable chemical and physical properties, disintegration and stability.
The applicants have successfully developed effervescent tablets comprising high amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, prepared by a process which is not only simple but also economically feasible and amenable to execution at ambient temperature. The effervescent tablets prepared by the process of the invention are not only readily soluble in water resulting a palatable solution but are also stable when subjected to testing at a temperature of 40°C. and relative humidity ("RH") of 75% for a period of at least six months.

SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a solid oral pharmaceutical composition comprising high amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts.
Further object of the present invention is to provide an effervescent solid oral pharmaceutical composition comprising high amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts.
Another object of the present invention is to provide a process for preparing an effervescent solid oral pharmaceutical composition comprising high amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, wherein said composition exhibits disintegration and stability, comparable to Redoxon® Double Action Effervescent Tablets (1000 mg/10 mg) by Bayer, by virtue of the steps involved in the manufacturing process.
The following embodiments further describe the objects of the present invention, however, the disclosed invention is not restricted to the particular embodiments hereinafter described and extends to cover the modifications obvious to one of ordinary skill in the art.
In a preferred embodiment, the effervescent solid oral pharmaceutical composition comprises about 32% by weight ascorbic acid or its pharmaceutically acceptable salts and about 1% by weight Zinc citrate or its pharmaceutically acceptable salts based on the total weight of the composition wherein the composition is not subjected to drying in the final step.
Another embodiment of the present invention provides a process for the preparation of an effervescent solid oral pharmaceutical composition comprising high amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, comprising the step of dry granulating Zinc or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient, mixing the granules with a blend of ascorbic acid or its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, lubricating the blend, compressing the lubricated blend into a solid pharmaceutical composition.
In the effervescent pharmaceutical composition or dosage form or formulation of the present invention, pharmaceutically acceptable salts of zinc include but are not limited to, zinc sulfate, zinc chloride, zinc gluconate, zinc oxide, zinc stearate, zinc picolinate, zinc acetate, zinc lactate, zinc citrate, and mixtures thereof. The preferred pharmaceutically acceptable salt of zinc for the composition of the present invention is citrate salt or its pharmaceutically acceptable solvates or hydrates. Pharmaceutically acceptable salts of ascorbic acid such as sodium ascorbate, potassium ascorbate, calcium ascorbate, and magnesium ascorbate are also contemplated within the scope of the invention.
In the effervescent solid oral pharmaceutical composition of the present invention, the pharmaceutically acceptable excipient comprises diluents, lubricants, acidifying agents, buffering agents, alkalizing agents, coloring agents and sweetening agents.

DETAILED DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, and other inert ingredient(s). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical compositions of the invention include, but are not limited to, granules, tablets, modified release tablets, mini-tablets and the like. Preferably, the pharmaceutical composition refers to effervescent tablets. More preferably, the pharmaceutical composition refers to single layer effervescent tablets.
The term “effervescent” as used herein, refers to pharmaceutical compositions comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, which do not contain any disintegrant and produce gas bubbles upon contact with water.
The term "about" as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term "high amount of ascorbic acid" as used herein, means more than about 600 mg of ascorbic acid in a single composition, and preferably more than about 800 mg of ascorbic acid in a single composition. Preferably, the amount of ascorbic acid in a composition containing a high level of ascorbic acid is equal to or more than about 1000 mg of ascorbic acid.
Unless otherwise stated the weight percentages expressed herein are based on the final or total weight of the composition or formulation or dosage form.
The present invention relates to a cost effective effervescent solid oral pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts.
A first aspect of the present invention provides an effervescent solid oral pharmaceutical composition comprising high amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, wherein the composition comprises:
a) Diluent
b) Acidifying agent
c) Alkalizing agent
d) Buffering agent
e) Optionally Sweetening agent
f) Optionally Coloring agent
g) Optionally Flavouring agent
It was found by the inventors of the present invention that an effervescent solid oral pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts wherein the composition is not subjected to drying exhibited desirable disintegration time and storage stability. Additionally, omission of curing or drying step led to a significant reduction in the manufacturing time of the composition. Curing or drying is a critical step in the manufacture of effervescent compositions since it ensures removal of moisture from the composition and is also responsible for increased hardness of the composition. Duration of this drying step in the manufacture of effervescent composition ranges from 6 to 12 hours. Present inventors, by omitting the curing or drying step, were not only able to considerably reduce the duration and cost of the manufacturing process but also arrive at a product possessing technical attributes comparable to the reference product.
Water-insoluble compounds are generally not used during the preparation of effervescent solid oral pharmaceutical compositions since they negatively affect the technical attributes of the effervescent solid oral pharmaceutical compositions. For example, magnesium stearate has been reported to give rise to over-blending related problems. Contrary to popular belief, it was found by inventors of the present invention that use of a water-insoluble compound, such as magnesium stearate in the form of a continuous spray on punches of the compression machine, is pivotal to improve manufacturability of the effervescent solid oral pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts.
According to one embodiment of the above aspect, the effervescent solid oral pharmaceutical composition is an immediate release composition.
According to another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition disintegrates in water within about 5 minutes.
According to another embodiment of the above aspect, pH of the effervescent solid oral pharmaceutical composition in an aqueous solution is from about 4.0 to 5.0. Preferably, the pH of the effervescent solid oral pharmaceutical composition in an aqueous solution is from about 4.0 to 4.5.
According to another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition is in the form of powder, granules, pellets, capsules, mini tablets or tablets. In a preferred embodiment, the effervescent solid oral pharmaceutical composition is in the form of effervescent tablets.
According to another embodiment of the above aspect, the pharmaceutically acceptable salt of zinc comprises zinc sulfate, zinc chloride, zinc gluconate, zinc oxide, zinc picolinate, zinc acetate, zinc lactate, zinc citrate, and mixtures thereof. Preferably, the pharmaceutically acceptable salt of zinc for the composition of the present invention is citrate salt or its pharmaceutically acceptable solvates or hydrates. Pharmaceutically acceptable salts of ascorbic acid such as sodium ascorbate, potassium ascorbate, calcium ascorbate, and magnesium ascorbate are also contemplated within the scope of the invention.
According to another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition comprises a therapeutically effective amount of Zinc or its pharmaceutically acceptable salts. Zinc or its pharmaceutically acceptable salt as per the composition of the present invention is present in an amount of about 10 mg to about 40 mg. Preferably, the effervescent solid oral pharmaceutical composition comprises about 32 mg of zinc citrate trihydrate (equivalent to 10 mg of Zinc).
According to another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition comprises a therapeutically effective amount of ascorbic acid or its pharmaceutically acceptable salts. Ascorbic acid or its pharmaceutically acceptable salt as per the composition of the present invention is present in an amount of about 500 mg to about 2000 mg. Preferably, the effervescent solid oral pharmaceutical composition comprises about 1000 mg of ascorbic acid.
In accordance with still another embodiment of the above aspect, there is provided an effervescent solid oral pharmaceutical composition comprising a therapeutically effective amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts prepared by wet granulation, dry granulation, dry blending, dry mixing or direct compression process. Other formulation techniques are also contemplated within the scope of the present invention. Wet granulation can be performed using Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like; dry blending can be performed using V-blender or key blender; and dry granulation can be performed using roller compacter or slugging techniques or by any other method known in the art. Any pharmaceutically acceptable granulating solvent can be used for wet granulation.
In accordance with still another embodiment of the above aspect, there is provided a solid oral pharmaceutical composition comprising a therapeutically effective amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts wherein, the composition comprises from about 20% to about 60% by weight of ascorbic acid or its pharmaceutically acceptable salts and from about 0.5% to about 5% by weight of zinc or its pharmaceutically acceptable salts based on the total weight of the composition.
The term "pharmaceutically acceptable excipients," as used herein, refers to excipients that are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise diluents, lubricants, acidifying agent, buffering agent, alkalizing agents, coloring agents, sweetening agents, and the like.
Suitable fillers or diluents are selected from the group comprising calcium carbonate, calcium phosphate, dibasic anhydrous calcium phosphate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, microcrystailine cellulose, silicified microcrystailine cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, and combinations thereof. In a preferred embodiment, the pharmaceutically acceptable diluent is sorbitol.
Suitable lubricants are selected from the group comprising calcium stearate, glycerine monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, magnesium lauryl sulphate, magnesium stearate, medium-chain triglycerides, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, sucrose stearate and zinc stearate. In a preferred embodiment, the pharmaceutically acceptable lubricant is polyethylene glycol.
Directly compressible grades of pharmaceutically acceptable excipients are also contemplated within the scope of the present invention. Directly compressible excipient is selected from the group comprising anhydrous lactose, spray dried lactose, dibasic calcium phosphate dihydrate, microcrystalline cellulose, powdered cellulose, low substituted hydroxypropyl cellulose, dextrose, sucrose, modified dextrin + sucrose, spray dried maltose, maltodextrin, mannitol, xylitol, sorbitol, lactitol, starch, pre-gelatinized starch and combinations thereof.
Suitable sweetening agent or sweetner is selected from the group comprising maltitol, saccharose, lactose, sucrose, dextrose, fructose, glucose, galactose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, xylitol, erythritol, sucralose, trehalose, propylene glycol, sorbitol, sodium saccharin, thaumatin, sodium cyclamate, aspartame, acesulfame potassium, mogroside, saccharin, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate and the like, or mixtures thereof. In a preferred embodiment, the pharmaceutically acceptable sweetening agent comprises aspartame, acesulfame potassium and sorbitol.
Pharmaceutically acceptable flavoring agents and/ or coloring agents known to a person skilled in the art may be added to impart organoleptic properties such as flavor and color to the pharmaceutical composition. Suitable flavor is selected from the group comprising orange, banana, strawberry, cherry, wild cherry, lemon, cardamom, anis, mint, menthol, vanillin and the like or combinations thereof. In a preferred embodiment, the pharmaceutically acceptable flavoring agent is orange flavor.
Effervescent dosage forms make use of an effervescent couple comprising an acidifying agent and an alkalizing agent which react in presence of water to release carbon dioxide. Acidifying agent or acid component generally comprises organic acids such as citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, adipic acid and the like. Alkalizing agent or base component comprises sodium carbonate, sodium bicarbonate, sodium sesquicarbonate, potassium carbonate, potassium bicarbonate, sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium borate, sodium hydroxide, trolamine and the like. In a preferred embodiment, the pharmaceutically acceptable acidifying agent is citric acid and the pharmaceutically acceptable alkalizing agent is sodium bicarbonate.
Proportion of acidifying agent and alkalizing agent in effervescent formulations is critical in order to obtain a clear solution which is devoid of any residue or precipitate after disintegration of the dosage form. Further, high amount of acidifying agent or alkalizing agent leads to formation of unclear and precipitated solution besides having detrimental effects on the gastrointestinal system. The present inventors were able to attain the desired neutral solution free of any precipitate by adjusting the ratio of acidifying agent to alkalizing agent.
According to one embodiment of the present aspect, the ratio of one or more acidifying agent to one or more alkalizing agent is between 10:1 (w/w) and 1:10 (w/w). Preferably, the ratio of acidifying agents to alkalizing agents is between 0.35:1 (w/w) and 2:1 (w/w).
According to one embodiment of the present aspect, the effervescent formulation is an effervescent tablet.
Preferably, effervescent tablets have a weight of less than about 3500 mg. pH of the effervescent tablets in an aqueous solution is preferably from about 4.0 to 4.5.
According to another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition is free of disintegrant.
According to another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition when administered orally to a patient in need thereof, is bioequivalent to the marketed effervescent tablet formulation. Bioequivalence is established by comparing pharmacokinetic parameters, for example, AUC and Cmax of the pharmaceutical composition of the present invention with marketed effervescent tablet formulation in healthy human subjects in fed as well as fasting conditions.
The term "AUC" refers to the area under the time/plasma concentration curve after administration of the pharmaceutical composition.
The term "Cmax" refers to the maximum concentration of active pharmaceutical ingredient(s) in the blood following administration of the pharmaceutical composition.
According to yet another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition is stable when stored at a temperature of about 40°C. and relative humidity ("RH") of about 75% relative humidity for a period of at least six months.
According to yet another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition does not show any signs of spotting and darkening after storage at a temperature of about 40°C. and relative humidity ("RH") of about 75% relative humidity for a period of at least six months.
A second aspect of the present invention provides a process for the preparation of an effervescent solid oral pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, comprising the following steps:
a) drying of diluent, acidifying agent and alkalizing agent at a temperature in the range of 45°C to 50°C;
b) mixing Zinc or its pharmaceutically acceptable salts with diluent;
c) dry granulating the mixture obtained in step b);
d) blending the granulated material obtained in step c) with ascorbic acid and acidifying agent;
e) the blend obtained in step d) is mixed with alkalising agent and other pharmaceutically acceptable excipients;
f) lubricating the blend obtained in step e);
g) compressing the lubricated blend obtained in step f) into a solid pharmaceutical composition with continuous spraying of magnesium stearate.

According to another embodiment of the above aspect, the process is carried out at a temperature in the range of 20°C to 30°C. Preferably, the process is carried out at a temperature of 25°C.

According to yet another embodiment of the above aspect, the process is carried out at a relative humidity in the range of 5 to 25%. Preferably, the process is carried out at a relative humidity of not more than 20%.

According to yet another embodiment of the above aspect, magnesium stearate is sprayed at a rate of not more than 0.6% gram per hour. Preferably, the spray rate is maintained at 0.2% gram per hour.

The process of the invention makes it possible to prepare a pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, wherein the composition is stable and the process is not only simple but also economically feasible and amenable to execution at ambient temperature.

A third aspect of the present invention relates to an effervescent solid oral pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, prepared by a process comprising the following steps:
a) drying of diluent, acidifying agent and alkalizing agent at a temperature in the range of 45°C to 50°C;
b) mixing Zinc or its pharmaceutically acceptable salts with diluent;
c) dry granulating the mixture obtained in step b);
d) blending the granulated material obtained in step c) with ascorbic acid and acidifying agent;
e) the blend obtained in step d) is mixed with alkalising agent and other pharmaceutically acceptable excipients;
f) lubricating the blend obtained in step e);
g) compressing the lubricated blend obtained in step f) into a solid pharmaceutical composition with continuous spraying of magnesium stearate.
According to another embodiment of the above aspect, the process is carried out at a temperature in the range of 20°C to 30°C. Preferably, the process is carried out at a temperature 25°C.
According to yet another embodiment of the above aspect, the process is carried out at a relative humidity in the range of 5 to 25%. Preferably, the process is carried out at a relative humidity of 20%.
According to yet another embodiment of the above aspect, magnesium stearate is sprayed at a rate of not more than 0.6% gram per hour. Preferably, the spray rate is maintained at 0.2% gram per hour.
A fourth aspect of the present invention provides an effervescent solid oral pharmaceutical composition comprising:
(a) Zinc or its pharmaceutically acceptable salts in an amount of about 0.5% to about 5% by weight,
(b) Ascorbic acid or its pharmaceutically acceptable salts in an amount of about 20% to about 60% by weight,
(c) at least one diluent in an amount of about 10% to about 40% by weight,
(d) at least one acidifying agent in an amount of about 10% to about 40% by weight,
(e) at least one alkalizing agent in an amount of about 10% to about 40% by weight,
(f) at least one buffering agent in an amount of about 0.5% to about 25% by weight,
(g) at least one lubricant in an amount of about 0.5% to about 5.0% by weight,
(h) sweetening agent in an amount of less than about 10.0% by weight,
(i) flavoring agent in an amount of less than about 5.0% by weight,
(j) coloring agent in an amount of less than about 5.0% by weight,
wherein the weight percentage is based on total weight of the composition and the composition is devoid of any binder.
According to another embodiment of the above aspect, the effervescent solid oral pharmaceutical composition is in the form of powder, granules, pellets, capsules, mini tablets or tablets. In a preferred embodiment, the effervescent solid oral pharmaceutical composition is in the form of effervescent tablets.
In accordance with a preferred embodiment of the above aspect, the effervescent solid oral pharmaceutical composition comprises Zinc or its pharmaceutically acceptable salts in an amount of about 0.5% to about 1.5% by weight, Ascorbic acid or its pharmaceutically acceptable salts in an amount of about 30% to about 60% by weight, at least one diluent in an amount of about 15% to about 25% by weight, at least one acidifying agent in an amount of about 15% to about 30% by weight, at least one alkalizing agent in an amount of about 15% to about 35% by weight, at least one buffering agent in an amount of about 1.0% to about 3.0% by weight, at least one lubricant in an amount of about 0.5% to about 3.0% by weight, with respect to the total weight of the composition.
According to one embodiment of the above aspect, the tablets have a moisture content below 8% as determined by Karl fisher method.
According to yet another embodiment of the above aspect, the effervescent solid oral tablets do not show any signs of spotting and darkening after storage at a temperature of about 40°C. and relative humidity ("RH") of about 75% relative humidity for a period of at least six months.
According to yet another embodiment of the above aspect, the effervescent solid oral tablets result in a palatable solution when dissolved in water which can be conveniently administered to the patient.
In accordance with yet another embodiment of the above aspects, the effervescent solid oral pharmaceutical composition comprising Zinc or its pharmaceutically acceptable salts and Ascorbic acid or its pharmaceutically acceptable salts is packaged in a suitable package such as tubes, aluminium foil pouches or blister packs. Preferably, the effervescent solid oral pharmaceutical composition comprising Zinc or its pharmaceutically acceptable salts and Ascorbic acid or its pharmaceutically acceptable salts is packaged in polypropylene tubes.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail method for the preparation and testing of pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES
Following examples are set out to illustrate the invention and do not limit the scope of the present invention.
Example I
Effervescent tablets of Ascorbic acid and Zinc were prepared using the quantitative formula as given in Table 1:

TABLE 1
Ingredient Function Range (% w/w) % (w/w)
Zinc citrate trihydrate Active 0.5 – 5.0 1.03
Ascorbic acid Active 20 - 60 32.05
Sorbitol Diluent / Sweetening agent 10 - 40 22.37
Citric acid anhydrous Acidifying agent/ Buffering agent 10 - 40 22.98
Sodium Bicarbonate Alkalizing agent 10 - 40 16.02
Anhydrous sodium carbonate Buffering agent 0.5 – 5.0 1.44
Aspartame Sweetening agent 0.1 - 10 0.48
Acesulfame potassium Sweetening agent 0.1 - 10 0.35
Sodium chloride Buffering agent 0.5 – 5.0 0.16
Color annatto 1% powder Coloring agent q.s. -
Orange flavor Flavoring agent q.s. -
Polyethylene Glycol Lubricant 0.5 – 5.0 0.96

Procedure:
a) Sorbitol, citric acid anhydrous, anhydrous sodium carbonate and sodium bicarbonate were dried at a temperature in the range of 45°C to 50°C;
b) Sorbitol (Ist portion) and Zinc citrate trihydrate were mixed;
c) Mixture obtained in step b) is dry granulated using roller compaction;
d) Granulated material obtained in step c) is blended with ascorbic acid and citric acid anhydrous;
e) Blend obtained in step d) is mixed with sodium bicarbonate, sodium carbonate anhydrous, aspartame, sodium chloride and sorbitol (remaining portion), orange flavor and color annatto 1% powder;
f) blend obtained in step e) is lubricated with polyethylene glycol;
g) the lubricated blend obtained in step f) is compressed into a solid pharmaceutical composition with continuous spraying of magnesium stearate on punches at a temperature not more than 25°C and relative humidity not more than 20% RH.

Example II
Effervescent tablets of Ascorbic acid and Zinc were prepared using the quantitative formula as given in Table 2:
TABLE 2
S. No. Ingredient Function % (w/w)
1. Ascorbic acid Active 30.00
2. Zinc citrate Active 0.74
3. Mannitol Diluent 7.50
4. Aspartame Sweetening agent 0.38
5. Sucralose Sweetening agent 0.10
6. Black Currant Flavor Flavoring agent q.s.
7. Anhydrous Citric acid Acidifying agent/ Buffering agent 16.88
8. Sodium Chloride Buffering agent 2.00
9. Isomalt Sweetening agent 24.23
10. Sodium Hydrogen Carbonate Alkalizing agent 12.50
11. Carmosine Coloring agent q.s.
12. Indigo Carmine Coloring agent q.s.
13. Polyethylene glycol Lubricant 2.00

Procedure:
a) Ascorbic acid, mannitol, citric acid anhydrous, sodium chloride, isomalt, sorbitol and sodium hydrogen carbonate was sifted through sieve # 40.
b) Zinc citrate, aspartame, sucralose, carmosine, indigo carmine, polyethylene glycol and black currant were sifted through sieve # 80.
c) The sifted material from step a) and b) were mixed for 10 minutes.
d) The mixture obtained from step c) was compressed into tablets.

Example III
Effervescent tablets of Ascorbic acid and Zinc were prepared using the quantitative formula as given in Table 3:

TABLE 3
S. No. Ingredient Function % (w/w)
1 Ascorbic acid Active 32.79
2 Anhydrous Citric acid Acidifying agent/ Buffering agent 25.79
3 Mannitol Diluent 6.56
4 Sorbitol Diluent 8.36
Binder
5 Zinc Citrate Trihydrate Active 1.05
6 Isopropyl Alcohol Solvent q.s.
Lubrication
7 Acesulfame Potassium Sweetening agent 0.13
8 Sodium Hydrogen Carbonate Alkalizing agent 20.33
9 Sodium Chloride Buffering agent 0.98
10 Sodium Carbonate anhydrous Alkalizing agent 0.66
11 Aspartame Sweetening agent q.s.
12 Orange Flavor SD9017 Flavoring agent q.s.
13 Color Sunset yellow Coloring agent q.s.

Procedure:
a) Ascorbic acid, mannitol, citric acid was sifted through sieve # 60 and sorbitol was sifted through sieve #30.
b) Zinc citrate trihydrate was mixed with isopropyl alcohol.
c) The sifted material of step a) was granulated using binder solution of step b), dried and further sifted through sieve # 30.
d) The dried granules of step c) were mixed with sifted acesulfame potassium, sodium chloride, sodium bicarbonate, aspartame, anhydrous sodium carbonate, orange flavor and color sunset yellow for 10 minutes.
e) The mixture obtained from step d) was compressed into tablets.

Example IV
Effervescent tablets of Ascorbic acid and Zinc were prepared using the quantitative formula as given in Table 4:

TABLE 4
S. No. Ingredient Function % (w/w)
1 Ascorbic acid Active 32.26
2 Zinc Citrate Active 1.24
3 Mannitol Diluent 7.86
4 Aspartame Sweetening agent q.s.
5 Sorbitol Diluent 13.55
6 Acesulfame Potassium Sweetening agent q.s.
7 Citric acid anhydrous Acidifying agent/ Buffering agent 23.13
8 Sodium Chloride Buffering agent 0.97
10 Sodium Hydrogen Carbonate Alkalizing agent 16.13
11 Anhydrous Sodium Carbonate Alkalizing agent 0.65
12 Orange Flavor Flavoring agent q.s.
13 Polyethylene glycol Lubricant 1.61

Procedure:
a) Asorbic acid, mannitol, citric acid, sodium hydrogen carbonate, anhydrous sodium carbonate, zinc citrate, aspartame was sifted through sieve # 40; acesulfame potassium, sodium chloride, sorbitol was sifted through sieve # 30; Orange flavor and polyethylene glycol was sifted through sieve # 60.
b) The sifted material was mixed for 25 minutes and compressed into tablets.

Example V
Effervescent tablets of Ascorbic acid and Zinc were prepared using the quantitative formula as given in Table 5:

TABLE 5
S. No. Ingredient Function % (w/w)
1 Ascorbic acid Active 32.05
2 Anhydrous Citric acid Acidifying agent/ Buffering agent 22.98
Slugging
3 Sorbitol Diluent 17.37
4 Zinc Citrate Trihydrate Active 1.04
Blending
5 Sodium Hydrogen Carbonate Alkalizing agent 16.02
6 Anhydrous Sodium Carbonate Alkalizing agent 1.44
7 Aspartame Sweetening agent q.s.
8 Sodium Chloride Buffering agent 0.16
9 Acesulfame Potassium Sweetening agent q.s.
10 Sorbitol Diluent 5.00
11 Orange Flavor Flavoring agent q.s.
12 Color Annato 1% Powder Coloring agent q.s.
Lubrication
13 Polyethylene glycol Lubricant 0.96

Procedure:
a) Sorbitol, anhydrous citric acid, sodium hydrogen carbonate and sodium carbonate anhydrous was dried at a temperature of 45°C to 50°C.
b) Ascorbic acid and citric acid was sifted through sieve # 30 (part I); sorbitol and zinc citrate trihydrate was sifted through sieve # 30 (part II) and both the parts were mixed together in a geometrical manner.
c) Sorbitol and zinc citrate were compacted using roller compactor and milled. The cycle was repeated till not less than 40% to 50% granules were retained on sieve # 60.
d) Granules from step c) and fines from step b) were mixed for 10 minutes.
e) Sodium hydrogen carbonate, anhydrous sodium carbonate, aspartame, acesulfame potassium, sodium chloride, sorbitol was sifted through sieve # 30; orange flavor and color annatto was sifted through sieve # 60 and mixed with mixture from step d) for 10 minutes.
f) Polyethylene glycol was sifted through sieve # 60 and mixed with mixture from step e) for 5 minutes.
g) The mixture from step f) was compressed into tablets.

Example VI
Effervescent tablets of Ascorbic acid and Zinc prepared as per Example I were stored at temperature/relative humidity of 40°±2°C / 75%±5% RH for six months. The disintegration time of effervescent tablets was determined in 200 ml of water maintained at 15-25°C. The tablets are considered to have disintegrated when the evolution of bubbles of gas around the tablet or its fragment ceases and the tablets are either dissolved or dispersed in water so that no agglomerates of particles remain. The disintegration test was also conducted on the commercially available reference formulation Redoxon® Double Action Effervescent Tablets (1000 mg/10 mg) by Bayer and the results are presented in Table 6.

Example VII
Effervescent tablets of Ascorbic acid and Zinc prepared as per Example I were stored at temperature/relative humidity of 40°±2°C / 75%±5% RH for six months. The moisture content of effervescent tablets was determined using Karl Fischer method. 10 tablets were crushed into powder using mortar and pestle. 500 mg of the powder was titrated in the titration vessel using Karl Fischer solution. Moisture content was also determined for the commercially available reference formulation Redoxon® Double Action Effervescent Tablets (1000 mg/10 mg) by Bayer and the results are presented in Table 6.

Example VIII
Effervescent tablets of Ascorbic acid and Zinc prepared as per Example I were stored at temperature/relative humidity of 40°±2°C / 75%±5% RH for six months. pH of the solution obtained upon dissolution of effervescent tablets was determined in 200 ml of water maintained at 15-25°C. Numerous gas bubbles are evolved. The tablets are considered to have disintegrated when the evolution of bubbles of gas around the tablet or its fragment ceases and the tablets are either dissolved or dispersed in water so that no agglomerates of particles remain. pH of this solution is measured using calibrated pH meter. pH of the solution was also determined for the commercially available reference formulation Redoxon® Double Action Effervescent Tablets (1000 mg/10 mg) by Bayer and the results are presented in Table 6.
Table 6
Parameter Reference (Redoxon® Double Action Effervescent Tablets) Example I
Initial Initial 3 months
Average weight 4660 mg 3123.4 mg 3113.1 mg
Disintegration Time 01 minute 30 seconds 01 minute 12 seconds 01 minute 20 seconds
Moisture Content 8.86% 6.41% 7.19%
pH of solution 4.8 4.09 4.07

Example IX
Effervescent tablets of Ascorbic acid and Zinc prepared as per Example I were subjected to stability testing at temperature/relative humidity of 25°±2°C / 60%±5% RH for twelve months. The tablets were also tested at a more stringent temperature/relative humidity of 40°±2°C / 75%±5% RH for at least 3 months. The tablet dosage form was packaged in polypropylene tubes and analyzed for related substances by a validated High Performance Liquid Chromatography (HPLC) method. Results obtained from stability testing at 25°±2°C / 60%±5% RH are presented in Table 7. Results obtained from stability testing at 40°±2°C / 75%±5% RH are presented in Table 8.
Table 7
Parameter Initial 3 months 6 months 9 months 12 months
Assay (Ascorbic acid) 99.92 99.03 99.52 98.46 99.30
Assay (Zinc) 101.41 100.16 100.24 100.36 99.52

Table 8
Parameter Initial 1 month 6 months
Assay (Ascorbic acid) 102.6 100.0 96.7
Assay (Zinc) 103.9 100.2 102.5
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope, and spirit of this invention.

Claims:

We claim:
1. An effervescent solid oral pharmaceutical composition comprising high amount of ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, wherein the composition comprises:
a) Diluent
b) Acidifying agent
c) Alkalizing agent
d) Buffering agent
e) Optionally Sweetening agent
f) Optionally Coloring agent
g) Optionally Flavouring agent
2. The effervescent solid oral pharmaceutical composition as claimed in claim 1 wherein, the ratio of acidifying agents to alkalizing agents is between 10:1 (w/w) and 1:10 (w/w).
3. A process for the preparation of an effervescent solid oral pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, comprising the following steps:
a) drying of diluent, acidifying agent and alkalizing agent at a temperature in the range of 45°C to 50°C.
b) mixing Zinc or its pharmaceutically acceptable salts with diluent;
c) dry granulating the mixture obtained in step a);
d) blending the granulated material obtained in step b) with ascorbic acid and acidifying agent;
e) the blend obtained in step c) is mixed with alkalising agent and other pharmaceutically acceptable excipients;
f) lubricating the blend obtained in step d);
g) compressing the lubricated blend obtained in step e) into a solid pharmaceutical composition.
4. The process as claimed in claim 3 wherein, the process is carried out at a temperature in the range of 20°C to 30°C.
5. A solid oral pharmaceutical composition comprising ascorbic acid or its pharmaceutically acceptable salts and Zinc or its pharmaceutically acceptable salts, prepared by a process comprising the following steps:
a) drying of diluent, acidifying agent and alkalizing agent at a temperature in the range of 45°C to 50°C.
b) mixing Zinc or its pharmaceutically acceptable salts with diluent;
c) dry granulating the mixture obtained in step a);
d) blending the granulated material obtained in step b) with ascorbic acid and acidifying agent;
e) the blend obtained in step c) is mixed with alkalising agent and other pharmaceutically acceptable excipients;
f) lubricating the blend obtained in step d);
g) compressing the lubricated blend obtained in step e) into a solid pharmaceutical composition.
6. The process as claimed in claim 5 wherein, the process is carried out at a relative humidity in the range of 5% to 25%.
7. An effervescent solid oral pharmaceutical composition comprising:
(a) Zinc or its pharmaceutically acceptable salts in an amount of about 0.5% to about 5% by weight,
(b) Ascorbic acid or its pharmaceutically acceptable salts in an amount of about 20% to about 60% by weight,
(c) at least one diluent in an amount of about 10% to about 30% by weight,
(d) at least one acidifying agent in an amount of about 10% to about 40% by weight,
(e) at least one alkalizing agent in an amount of about 10% to about 40% by weight,
(f) at least one buffering agent in an amount of about 0.5% to about 5.0% by weight,
(g) at least one lubricant in an amount of about 0.5% to about 5.0% by weight,
(h) optionally sweetening agent in an amount of about 0.1% to about 10.0% by weight,
(i) optionally flavoring agent in an amount of about 0.5% to about 5.0% by weight,
(j) optionally coloring agent in an amount of about 0.5% to about 5.0% by weight,
wherein the weight percentage is based on total weight of the composition and composition is devoid of any binder.
8. The effervescent solid oral pharmaceutical composition as claimed in claim 7 wherein, the composition is in the form of effervescent tablets.
9. A stable effervescent tablet consisting of:
(a) Zinc citrate trihydrate in an amount of 1.03% by weight,
(b) Ascorbic acid in an amount of 32.05% by weight,
(c) at least one diluent in an amount of 22.37% by weight,
(d) at least one acidifying agent in an amount of 22.98% by weight,
(e) at least one alkalizing agent in an amount of 16.02% by weight,
(f) at least one buffering agent in an amount of 1.60% by weight,
(g) at least one lubricant in an amount of 0.96% by weight
based on the total weight of the composition.
10. The stable effervescent tablet as claimed in claim 9 wherein, the tablet is devoid of any binder.