WO2023031946A1 - Composition pharmaceutique effervescente d'acide ascorbique et de zinc - Google Patents

Composition pharmaceutique effervescente d'acide ascorbique et de zinc Download PDF

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Publication number
WO2023031946A1
WO2023031946A1 PCT/IN2021/051143 IN2021051143W WO2023031946A1 WO 2023031946 A1 WO2023031946 A1 WO 2023031946A1 IN 2021051143 W IN2021051143 W IN 2021051143W WO 2023031946 A1 WO2023031946 A1 WO 2023031946A1
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Prior art keywords
pharmaceutically acceptable
weight
agent
amount
zinc
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PCT/IN2021/051143
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English (en)
Inventor
Sanjeev Gupta
Rajeev Gupta
Tg CHANDRASHEKHAR
Swati Mukherjee
Amit Gupta
Ankit Vijay
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Kusum Healthcare Pvt. Ltd.
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Publication of WO2023031946A1 publication Critical patent/WO2023031946A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • 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.
  • 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.
  • 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.
  • solid oral dosage forms are the most preferred dosage forms for intake of drugs.
  • solid oral dosage forms suffer from limitations such as poor stability in the gastric milieu, slow absorption and poor bioavailability of the dosage form.
  • 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.
  • effervescent dosage forms have been developed as an alternate dosage form since effervescent dosage forms are dissolved in water before administration.
  • effervescent dosage forms have been reported to augment absorption of a number of active ingredients.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • the pharmaceutically acceptable excipient comprises diluents, lubricants, acidifying agents, buffering agents, alkalizing agents, coloring agents and sweetening agents.
  • 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.
  • the pharmaceutical composition refers to effervescent tablets. More preferably, the pharmaceutical composition refers to single layer effervescent tablets.
  • ffervescent 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.
  • high amount of ascorbic acid 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.
  • 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.
  • 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
  • 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.
  • magnesium stearate has been reported to give rise to over-blending related problems.
  • 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.
  • the effervescent solid oral pharmaceutical composition is an immediate release composition.
  • the effervescent solid oral pharmaceutical composition disintegrates in water within about 5 minutes.
  • pH of the effervescent solid oral pharmaceutical composition in an aqueous solution is from about 4.0 to 5.0.
  • the pH of the effervescent solid oral pharmaceutical composition in an aqueous solution is from about 4.0 to 4.5.
  • the effervescent solid oral pharmaceutical composition is in the form of powder, granules, pellets, capsules, mini tablets or tablets.
  • the effervescent solid oral pharmaceutical composition is in the form of effervescent tablets.
  • 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.
  • 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.
  • 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.
  • the effervescent solid oral pharmaceutical composition comprises about 32 mg of zinc citrate trihydrate (equivalent to 10 mg of Zinc).
  • 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.
  • the effervescent solid oral pharmaceutical composition comprises about 1000 mg of ascorbic acid.
  • 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.
  • 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.
  • pharmaceutically acceptable excipients 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 fdlers 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.
  • 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, mediumchain triglycerides, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, sucrose stearate and zinc stearate.
  • 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.
  • the pharmaceutically acceptable sweetening agent comprises aspartame, acesulfame potassium and sorbitol.
  • 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.
  • 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.
  • 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.
  • 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).
  • the ratio of acidifying agents to alkalizing agents is between 0.35: 1 (w/w) and 2: 1 (w/w).
  • the effervescent formulation is an effervescent tablet.
  • 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.
  • the effervescent solid oral pharmaceutical composition is free of disintegrant.
  • 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.
  • AUC refers to the area under the time/plasma concentration curve after administration of the pharmaceutical composition.
  • 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.
  • 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.
  • the process is carried out at a temperature in the range of 20°C to 30°C.
  • the process is carried out at a temperature of 25°C.
  • 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%.
  • 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.
  • the process is carried out at a temperature in the range of 20°C to 30°C.
  • the process is carried out at a temperature 25 °C.
  • 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%.
  • 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:
  • sweetening agent in an amount of less than about 10.0% by weight
  • flavoring agent in an amount of less than about 5.0% by weight
  • 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.
  • the effervescent solid oral pharmaceutical composition is in the form of powder, granules, pellets, capsules, mini tablets or tablets.
  • the effervescent solid oral pharmaceutical composition is in the form of effervescent tablets.
  • 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.
  • the tablets have a moisture content below 8% as determined by Karl fisher method.
  • 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.
  • the effervescent solid oral tablets result in a palatable solution when dissolved in water which can be conveniently administered to the patient.
  • 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.
  • a suitable package such as tubes, aluminium foil pouches or blister packs.
  • 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.
  • Effervescent tablets of Ascorbic acid and Zinc were prepared using the quantitative formula as given in Table 3 :
  • Effervescent tablets of Ascorbic acid and Zinc were prepared using the quantitative formula as given in Table 5 :
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention concerne une composition pharmaceutique orale solide effervescente comprenant une quantité élevée d'acide ascorbique ou ses sels pharmaceutiquement acceptables et du zinc ou ses sels pharmaceutiquement acceptables et son procédé de préparation. La composition pharmaceutique orale solide effervescente préparée par le procédé de l'invention est également stable lorsqu'elle est soumise à des conditions de contrainte à une température de 40 °C et une humidité relative ("HR") de 75 % pendant une période d'au moins six mois.
PCT/IN2021/051143 2021-09-01 2021-12-08 Composition pharmaceutique effervescente d'acide ascorbique et de zinc WO2023031946A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013072932A2 (fr) * 2011-09-30 2013-05-23 Rubicon Research Private Limited Compositions de soin oral
WO2017065623A1 (fr) * 2015-10-16 2017-04-20 Mendoza Wendell Composition stable contenant de la vitamine c et du zinc

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013072932A2 (fr) * 2011-09-30 2013-05-23 Rubicon Research Private Limited Compositions de soin oral
WO2017065623A1 (fr) * 2015-10-16 2017-04-20 Mendoza Wendell Composition stable contenant de la vitamine c et du zinc

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