DESC:Related Application
The present application claims the benefit of priority to Indian Provisional Patent Application no. 202041034379 filed on Aug 11, 2020 and the entire provisional specification.
Field of Invention
Present invention relates to effervescent formulation of anti-aging agent. Particularly, effervescent granule formulation of anti-aging agent comprising calcium alpha ketoglutarate for improved patient compliance. More particularly, the present invention relates to a composition, preferably an effervescent granules having a controllable rate of effervescence.
Background of the invention
Aging is a natural process which reflects all the changes taking place over the course of life. According to World Health Organization, aging is a course of biological reality which starts at conception and ends with death. Aging is associated with changes in different factors involved in biological, physiological, environmental, behavioral, psychological and social processes. Healthiest, aesthetically fit people also cannot escape the age-related changes like greying of hair, wrinkled skin and a fair amount of physical decline. In old age, physical impairment, functional disability, dependency increases slowly. In most of the developed countries, the age of 60 is considered equivalent to retirement age and it is said to be the beginning of old age. According to World Health Organization, in the year 1990, there were more than 280 million people belonging to the age 60 years or over in developing regions of the world, and 58% of the world’s elderly were living in less-developed regions. According to US Department of Health and Human Services, the proportion of elderly in developing countries is rising more rapidly, in comparison with developed ones. The United States Bureau of the census discloses Speed of population aging in developed countries (Figure 1) and Speed of population aging in developing countries (Figure 2).
Though aging is natural part of human life, recent research shows different pharmacological approaches that can be utilized for the improvement and possibly, for the delay in aging process. As skin ages, it becomes thinner and more easily damaged. Intensifying this effect is indicative of reducing ability of skin to heal itself as person ages. Other factors such as decrease in elasticity and volume is noted and characterized by laxity (sagging), rhytids (wrinkles), photoaging like erythema (redness), brown discoloration, yellowing, abnormal growth (keratosis) and poor texture. The effects of aging can have an effect on multiple layers of a person’s skin.
Various theories related to aging diseases and methods derived from these theories show that the mitochondrial pathways (called reactive oxygen species, or ROS) is prominently involved in aging process. The Oxidation reactions involve the removal of one or more electrons from a chemical species. Free radical is formed when oxidation reaction results in one or more mismatched electrons. Evans P. et. al. “Free radicals and hearing”, Ann N Y Acad Sci, 884 (1999), 19, describes that free radicals are having short half-life, high reactivity and damaging activity towards macromolecules like proteins, DNA and lipids. These species may be either oxygen derived also known as Reactive Oxygen Species i.e. ROS and nitrogen derived known as Reactive Nitrogen Species i.e. RNS. The oxygen derived species include O2– (superoxide), HO (Hydroxyl), HO2 (Hydroperoxyl), ROO (Peroxyl), RO (alkoxy) as free radicals and H2O2 (hydrogen peroxide), HOCl (hypochlorous acid), O3 (ozone) and 1O2 (singlet oxygen) as non-radicals. Similarly, nitrogen derived oxidant species are mainly NO (nitric oxide), ONOO- (peroxynitrite), NO2 (Nitrogen dioxide) and N2O3 (dinitrogen trioxide).
Oxidative stress is defined as imbalance between the production of free radicals and necessary antioxidant defenses. Uncontrolled oxidation can damage various cellular components. Potential damage involves lipids, proteins, cell membranes, deoxyribonucleic acid (DNA), carbohydrates, and various enzymes, which can lead to cell death and contribute to aging process. In humans, oxidative stress is thought to be involved in the development of ADHD, cancer, Parkinson's disease, Lafora disease, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction, fragile X syndrome, sickle-cell disease, lichen planus, vitiligo, autism, infection, chronic fatigue syndrome (ME/CFS), and depression and seems to be characteristic of individuals with Asperger syndrome.
An antioxidant is a molecule that inhibits oxidation. The cellular chain reactions started by free radicals can be inhibited by an antioxidant, which is accomplished in several ways including donation of an electron, removal of free radical intermediates, interference of other oxidative reactions and self-oxidation of the antioxidant in order to inhibit oxidation reactions. Antioxidants can protect against the damage induced by free radicals acting at various levels. Thus, the use of antioxidants is to inhibit, reduce, slow or prevent aging.
Alpha-ketoglutarate of formula-1 is a chemical found in the body, used to make medicine.
Formula-1
Alpha-ketoglutarate (AKG) can improve peak athletic performance. Suppliers of athletic nutritional supplements claim alpha-ketoglutaric acid may be an important addition to proper diet and training for the athlete for peak performance. Liu et. al. “The antioxidative function of alpha ketoglutarate and its applications” BioMed Research International, Volume 2018, Article ID 3408467, page no 6, describes AKG can be converted into glutamine by glutamate dehydrogenase (GDH) and glutamine synthetase (GS), which is a sign of antioxidative function. It is evident that AKG improves antioxidative capacity by promoting glutamine content and antioxidative systems. He, L. Q. et. al, “The Physiological Basis and Nutritional Function of Alpha-ketoglutarate”, in Curr Protein Pept Sc 2015, 16, 576-581 and Bayliak, M. et. al., “Assessment of antioxidant properties of alpha-keto acids in vitro and in vivo” in Eur Food Res Technol 2016, 242, 179-188 describes Alpha-ketoglutarate (AKG) has been shown to protect different animal models against oxidative stress effectively. Also, further studies indicate that AKG could improve antioxidative function against oxidative imbalance in cells, which further contributed to the prevention and treatment of various diseases induced by oxidative stress. The conversion of AKG into glutamate and glutamine is illustrated in figure 3. It has been established that AKG can act as a true antioxidant, since it directly reacts with hydrogen peroxide (H2O2) to form succinate, water, and carbon dioxide. Long et al. (2011) reported that AKG released by several cell types could decrease H2O2 levels by conversion to succinate (Figure 4). AKG supplementation could directly or indirectly stimulate endogenous antioxidant defense. Recent studies demonstrate that AKG serves as a glutamate source for the synthesis of glutathione, a key low-molecular-mass thiol antioxidant that also negatively affects ROS levels.
Various salt of AKG are known in the prior art. Typically, these include alpha-ketoglutarate in conjugation with calcium, ornithine, sodium, and so on. Calcium alpha ketoglutarate (Formula-2) is special form mineral calcium that can be used to restore calcium concentration level in the blood back to normal.

Formula-2
Calcium alpha ketoglutarate helps in delaying age-related disease, reversing age-related frailty, revitalizing cellular energy to restore vitality, maintaining DNA structure that may have been damaged by inflammation, improving and maintaining bone structure, reducing protein breakdown, providing energy for cells, helping in the production of collagen, improving the absorption of iron, supporting the immune system, helping to identify and fight pathogens, significantly increasing circulating levels of insulin, maintains a healthy digestive system, support kidney function, improve athletic performance and improve recovery when taken alongside L-Citrulline.
Various non-patent and patent literatures disclosed Pharmaceutical composition of AKG and their use for various disease.
US20030039690A1 discloses a controlled release oral formulation of pharmaceutically active compounds. More particularly, the invention relates to controlled release oral formulations of salts of arginine particularly arginine a-ketoglutarate.
CN101011372A discloses an alpha-ketoglutaric acid-arginine salt, the process of preparing and use thereof, wherein the salt is prepared through combining alpha-ketoglutaric acid and arginine with a preferred ratio of 1:1 and 1:2. Pharmacological experiment shows that, the salt can be used for treating liver damages.
WO2008058993A3 discloses the use of at least one member selected from the group consisting of alpha-ketoglutaric acid (AKG) pharmaceutically acceptable salts of alpha-ketoglutaric acid and amides of alpha-ketoglutaric acid for the manufacture of a pharmaceutical preparation or a food or feed supplement for the treatment or prophylaxis of diseases related to infection of pathogenic strains of Helicobacter pylori in birds and mammals, including man.
US20160354334A1 discloses use of alpha-keto glutarate for manufacturing a pharmaceutical preparation for treating cancer, a neurodegenerative disease, a neurological disorder, a cardiovascular disease, a metabolic disease, or arthritis.
However, calcium alpha ketoglutarate monohydrate is an anti-aging agent available in the form of tablets in US. The tablet form is difficult to consume in case of old age people. Hence, present invention is related to easy to consume effervescent formulation for old age people to improve the patient compliance. The present invention discloses the noble effervescent formulation of calcium alpha ketoglutarate monohydrate. More particularly; the present invention discloses the preparation of the effervescent granules of calcium alpha ketoglutarate monohydrate with controllable rate of effervescence.
Object of invention
It is an object of the present invention to provide effervescent formulation of anti-aging agent which results in better patient compliance.
It is another object of the present invention to provide effervescent composition of anti-aging agent comprising calcium alpha ketoglutarate.
It is a further object of the present invention to provide effervescent composition for patients who need or prefer to take a liquid formulation, particularly elderly patients and those with dysphagia.
It is yet another object of the present invention to provide a palatable liquid dosage form to an alternative to the solid form. Hence it is more acceptable to patients and results in greater adherence to the prescribed therapy regimen.
It is yet further object of an invention to provide effervescent granules having stability of a dry formulation and easy to convert into liquid form.
Summary of the invention
In accordance with one aspect the invention provides effervescent composition of an anti-aging agent.
In accordance with another aspect the present invention provides an effervescent composition comprising:
i. Calcium alpha ketoglutarate;
ii. an acidic agent; and
iii. a basic agent.
According to one embodiment the present invention provides an effervescent composition, wherein acidic agent is selected from the group consisting of tartaric acid, citric acid and salts of acid or mixture thereof.
According to another embodiment the present invention provides an effervescent composition, wherein acidic agent is a mixture of tartaric acid and citric acid.
In certain embodiments the present invention provides an effervescent composition, wherein the ratio of tartaric acid to citric acid ranging from 1.5:0.5 to 2.5:1.5; preferably about 2 : 1.
In another aspect the present invention provides an effervescent composition, wherein basic agent is selected from the group consisting of sodium bicarbonate, sodium carbonate and potassium bicarbonate or mixture thereof.
In certain embodiments the present invention provides an effervescent composition, wherein acidic to basic agent ranging from 0.5:3 to 1.5:4.
In certain embodiments the present invention provides an effervescent composition, wherein basic agent ranging from 50 mg to 1500 mg and acidic agent ranging from 50 to 2000 mg.
In certain embodiments the present invention provides an effervescent composition, wherein acidic agent is the mixture of citric acid, tartaric acid and basic agent is sodium bicarbonate.
In some embodiments the present invention provides an effervescent composition, wherein mixture of citric acid, tartaric acid and sodium bicarbonate are present in a ratio of about 3.44:1:2.
In another aspect the present invention provides a process of preparing effervescent granule composition of Calcium alpha ketoglutarate monohydrate, wherein the process comprises steps of:
i. blending pharmaceutically effective amount of calcium alpha ketoglutarate monohydrate with vitamin, acid agent, basic agent, optionally pharmaceutically acceptable excipient and
ii. preparing a pharmaceutical acceptable dosage forms selected from a group comprising a table, capsule, granules, powder and sachet.
In certain embodiments the acidic agent used in the process is selected from the group consisting of tartaric acid, citric acid and salts of acid or mixture thereof.
In certain embodiments the acidic agent used in the process is a mixture of tartaric acid and citric acid, the ratio of tartaric acid to citric acid ranges between 1.5:0.5 to 2.5:1.5; preferably about 2 : 1.
In certain embodiments the basic agent used in the process is selected from the group consisting of sodium bicarbonate, sodium carbonate and potassium bicarbonate or mixture thereof.
In certain embodiments the ratio of mixture of acidic to basic agent used in the process ranges between from 0.5:3 to 1.5:4.
In certain embodiments acidic agent used in the process is a mixture of citric acid, tartaric acid and basic agent is sodium bicarbonate.
In certain embodiments the mixture of citric acid, tartaric acid and sodium bicarbonate used in the process are present in a ratio of about 3.44:1:2.
In certain embodiments the vitamin used in the process is vitamin A (Retinyl palmitate), or Vitamin D (Cholecalciferol).
In certain embodiments one or more pharmaceutically acceptable excipient are selected from the group consisting of diluents, acidic agent, basic agent, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavoring agent, pH regulating agent, stabilizing agent, lubricant, glidants and coloring agents.
In another aspect the present invention provides an effervescent composition comprising calcium alpha ketoglutarate as an anti-aging agent.
Description of the drawings:
For a more complete understanding of the invention, reference should now be made to the embodiments illustrated in greater detail in the accompanying drawings and described by way of embodiments of the invention.
Figure 1: Illustrates the speed of population aging in developed countries
Figure 2: Illustrates the speed of population aging in developing countries
Figure 3: Illustrates the conversion of AKG into glutamate and glutamine
Figure 4: Illustrates the nonenzymatic oxidative decarboxylation of AKG in hydrogen peroxide decomposition

Detailed description of the invention
In describing the embodiment of the invention, specific terminology is chosen for the sake of clarity. However, it is not intended that the invention be limited to the specific terms so selected and it is to be understood that such specific terms include all technical equivalents that operate in a similar manner to accomplish a similar purpose. As used herein, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there is one and only one of the elements. The disclosure of numerical ranges should be understood as referring to each discrete point within the range, inclusive of endpoints, unless otherwise noted. The term “about” as used in the disclosure of numerical ranges indicates that deviation from the stated value is acceptable to the extent that the deviation is the result of measurement variability and/or yields a product of the same or similar properties.
The terms abbreviated and used interchangeably in the specification are as described.
Aplha keto-glutarate can also be read as AKG. Calcium alpha keto-glutarate can also be read as Ca-AKG. In the present invention the calcium salt of alpha ketoglutarate is provided as anhydrous salt, monohydrate, or dihydrate.
Thus, for example, reference to "an ingredient" includes mixtures of ingredients; reference to "an active pharmaceutical agent" includes more than one active pharmaceutical agent, and the like.
Effervescence can be defined as the evolution of bubbles of gas in a liquid and the term "effervescent mixture" means a granular or particulate mixture comprising an acidic agent, an alkaline agent.
"Treating" or "treatment" of a disease includes (1) preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e. arresting its development, or (3) relieving the disease, i.e. causing regression of the disease.
The present invention relates to effervescent compositions comprising calcium alpha ketoglutarate or salt thereof. The calcium alpha ketoglutarate can be prepared by the process described in WO2020068705.
The effervescent compositions of the present invention may be in the form of composition which is meant to be administered directly in to the gastrointestinal tract via oral route. The effervescent compositions of the present invention may float in the gastrointestinal tract.
The effervescent compositions of the present invention may be in the form of composition which is meant to be added into the glass of water just before administration and the drug solution or dispersion is to be consumed immediately.
The term effervescent composition according to present invention means the composition of calcium alpha ketoglutarate which upon contact with aqueous media produces carbon dioxide.
The term effervescent composition according to present invention also means the composition of calcium alpha ketoglutarate which comprises acidic agent and basic agent.
The effervescent compositions of the present invention offer enhanced dissolution and absorption of calcium alpha ketoglutarate resulting in increased bioavailability. According to present invention calcium alpha ketoglutarate are absorbed better from effervescent formulations as compared to dry, solid tablet formulations.
The effervescent compositions of the present invention provide quick dissolution upon contact with aqueous media, clear aqueous composition after dissolution, pleasant taste and enhanced absorption. The acidic and basic components are chosen such that to neutralize the reaction by realizing carbon dioxide which is harmless by-product of the neutralization process. This carbon dioxide gas is responsible to compress other materials in the formulation to disperse. Once effervescence is complete, the resulting solution can then be used for its intended purpose such as for ingestion to deliver an active pharmaceutical ingredient.

The effervescent compositions comprising calcium alpha ketoglutarate of the present invention may be in the form of effervescent tablet, effervescent capsule, effervescent granule, effervescent powder, effervescent disc or effervescent sachet.
The effervescent compositions comprising calcium alpha ketoglutarate may contain one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, acidic agent, basic agent, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavor, pH regulating agent, stabilizing agent, lubricant, glidants and coloring agents.
The effervescent composition can comprise any suitable amount of calcium alpha-ketoglutarate, the amount of calcium alpha-ketoglutarate ranges from 500mg to 1000mg, more preferably 1000mg.
The examples of diluents include but not limited to mannitol, sorbitol, xylitol, cellulose derivatives, starch, maltodextrin, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide or mixture thereof. The amount of diluent in the effervescent composition ranges from 100mg to 200mg, more preferably 200mg.
The examples of acidic agents include but not limited to citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof.
The examples of basic agents include but not limited to sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate or mixture thereof.
The examples of solvents include but are not limited to water, ethanol, isopropanol and methylene chloride or mixture thereof.
The examples of vitamins include but not limited to Vitamin A and Vitamin D.
The examples of binders include but not limited to, ethyl cellulose, gelatine, hydroxyethylcellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropylcellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch or mixture thereof.
The examples of disintegrants include but not limited to croscarmellose sodium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxy methylcellulose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate or mixture thereof.
The examples of solubilizing agent or surfactant include but not limited to polyethylene glycol, polyvinylpyrrolidone, dextran, polysorbate, sodium lauryl sulphate, polyoxyethylene, polyoxypropylene glycol or mixture thereof.
The examples of sweeteners include but not limited to acesulfame potassium, sodium saccharin, cyclamates, sucralose or mixture thereof.
The examples of flavor include but not limited tolemon, lime, orange, grapefruit, apple, peach, apricot, cherry, raspberry, strawberry and grape or combination of two or more.
The examples of pH regulating agent include but not limited to fumarate, citrate, phosphate, carbonate, tartrate, acetate, amino acid salts or mixture thereof.
The examples of stabilizing agent include but not limited to tocopherol, cyclodextrin, tetrasodium edetate, nicotinamide or mixture thereof.
The examples of lubricant include but not limited to calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or mixture thereof.
The examples of glidant include but not limited to silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate or mixture thereof.
The examples of coloring agents include but not limited to titanium dioxide and dye suitable for food such as those known as F.D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika or mixture thereof.
In another aspect of the present invention is to provide process of manufacturing the effervescent compositions comprising Calcium alpha ketoglutarate.
The effervescent compositions comprising Calcium alpha ketoglutarate of the present invention can be manufactured by process such as direct compression, dry granulation (slugging), wet granulation, heat fusion, roller compaction and hot melt extrusion. The process of manufacturing effervescent composition comprising admixture of Calcium alpha ketoglutarate, acidic agent, basic agent optionally along with one or more pharmaceutically acceptable excipient; wherein said admixture can be either filled in to the capsule, sachet or compressed in to the unit dosage form. The compressed unit dosage form may be tablet, caplet and like.
The ratio of acidic to basic agent according to present invention may ranges between 0.5:3 to 1:4. The acidic agents may be like citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, anhydrides and salts of acid or mixture thereof; more preferably acidic agents. More preferably acidic agents may be citric acid. The basic agents may be like sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, arginine carbonate. More preferably basic agent may be sodium bicarbonate.
Acidic agent and basic agent present in the effervescent composition reacts with aqueous media; wherein acid neutralizes base with the liberation of carbon dioxide and formation of acid salt and water.
Another aspect of the invention provides effervescence time for granule formulation starting at 2 sec and exists upto 30-45 sec with large CO2 content which makes the effervescent granules more suitable formulation.
The effervescent compositions comprising calcium alpha ketoglutarate of the present invention can be packaged in suitable air tight containers and moisture proof packs.
Experimental
General method of preparation of Calcium alpha ketoglutarate monohydrate effervescent granules
1. The drug (Calcium alpha ketoglutarate monohydrate), vitamins (Vitamin A or Vitamin D), basic agent (sodium bicarbonate), acidic agent (citric acid and tartaric acid) and mannitol were blended together.
2. All materials used were passed through a fine Screen (#40 mesh).
3. The materials were then dried at 40° C. for 24 hours, preferably in vacuum.
4. All the steps were conducted in an atmosphere having a low relative humidity.
5. Wet granulation was performed by using isopropyl alcohol. Then, granules were then screened and stored at a low relative humidity for subsequent incorporation into a variety of pharmaceutical dosage forms.
Examples:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example:1
F1-A F1-D
Ingredient Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 312 312
Citric acid 96 96
Tartaric acid 192 192
Mannitol 200 200
IPA(Isopropanol) µL 900 900

Example:2
F2-A F2-D
Ingredient (mg) Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 383.2 383.2
Citric acid 112 112
Tartaric acid 224.8 224.8
Mannitol 200 200
IPA(Isopropanol) µL 1200 1200

Example:3
F3-A F3-D
Ingredient (mg) Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 800 800
Citric acid 216 216
Tartaric acid 432 432
Mannitol 200 200
IPA(Isopropanol) µL 1400 1400

Example:4
F4-A F4-D
Ingredient (mg) Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 328.8 328.8
Citric acid 96 96
Tartaric acid 192 192
Mannitol 200 200
IPA(Isopropanol) µL 1000 1000

Example: 5
F5-A F5-D
Ingredient (mg) Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 432 432
Citric acid 96 96
Tartaric acid 192 192
Mannitol 200 200
IPA(Isopropanol) µL 1100 1100

Example:6
F6-A F6-D
Ingredient (mg) Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 600 600
Citric acid 200 200
Tartaric acid - -
Mannitol 200 200
IPA(Isopropanol) µL 1400 1400

Example:7
F7-A F7-D
Ingredient (mg) Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 700 700
Citric acid 200 200
Tartaric acid - -
Mannitol 200 200
IPA(Isopropanol) µL 1300 1300

Example: 8
F8-A F8-D
Ingredient (mg) Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 600 600
Citric acid - -
Tartaric acid 300 300
Mannitol 200 200
IPA(Isopropanol) µL 900 900

Example 9
F9-A F9-D
Ingredient (mg) Amount (mg) Amount (mg)
Drug 1000 1000
Vitamin A (Retinyl palmitate) 0.450 --
Vitamin D (Cholecalciferol) -- 0.0125
Sodium bicarbonate 750 750
Citric acid - -
Tartaric acid 300 300
Mannitol 200 200
IPA(Isopropanol) µL 1100 1100

Evaluation
In present invention, effervescent granules of Calcium alpha ketoglutarate monohydrate prepared which can be easily administered. The colour of the granules was creamy white. The evaluation parameters of the prepared formulations are shown in Table 1.

Table 1: Evaluation parameters of effervescent granules
Parameters F1 F2 F3 F4 F5 F6 F7 F8 F9 ENO
Bulk density (g/mL) 0.367 0.359 0.431 0.378 0.371 0.398 0.414 0.401 0.415 0.915
Tapped density (g/mL) 0.490 0.527 0.550 0.489 0.523 0.509 0.552 0.601 0.611 1.123
Compressibility index 25.00 31.82 21.74 22.73 29.17 21.74 25.00 33.33 32.00 18.52
Housners ratio 1.33 1.47 1.28 1.29 1.41 1.28 1.33 1.50 1.47 1.23
Angle of repose (?) 40.12 41.25 40.27 38.14 40.27 41.42 41.76 42.27 42.27 44.43
Effe starts (sec) 4 2 2 2 2 3 3 2 2 06 sec
Effe lasts for (sec) 40-45 40-60 30-40 20-45 45-60 60-90 40-50 30-40 40-45 60-90
Clarity of solution Not clear Not clear Not clear Not clear Not clear Not clear Not clear Not clear Not clear Clear
pH of solution after eff 6.22 6.5 4.79 6.45 6.66 7.14 7.2 6.7 6.76 5.56
CO2 content g per 0.25g 0.03 0.04 0.029 0.22 0.024 0.04 0.042 0.04 0.05 0.055

The bulk density was varied from a minimum of 0.367 g/mL to a maximum of 0.431 g/mL. Out of the 9 formulations, flow properties of F4 were found to be fair such as Hausner’s ratio 1.29, compressibility index i.e. 22.73 and angle of repose < 40°, indicates a fair flow property of the granules. Whereas, angle of repose, carrs index and Housner’s ration are in passable range for all formulations. The standard values of flow parameter are shown in table 2.

Table 2: Standard values of flow parameters
Flow Property Angle of repose Compressibility index Housner’s ratio
Excellent 25-30 <10 1.00-1.11
Good 31-35 11-15 1.12-1.18
Fair 36-40 16-20 1.19-1.25
Passable 41-45 21-25 1.26-1.34
Poor 46-55 26-31 1.35-1.45
Very poor 56-65 32-37 1.46-1.59
Very very poor >66 >38 >1.6

,CLAIMS:WE CLAIM:
1. An effervescent composition comprising:
Calcium alpha ketoglutarate; an acidic agent; and
a basic agent.
2. An effervescent composition according to claim 1, wherein acidic agent is selected from the group consisting of tartaric acid, citric acid and salts of acid or mixture thereof.
3. An effervescent composition according to claim 1, wherein acidic agent is a mixture of tartaric acid and citric acid.
4. An effervescent composition according to claim 3, wherein the ratio of tartaric acid to citric acid ranging from 1.5:0.5 to 2.5:1.5; preferably about 2:1.
5. An effervescent composition according to claim 1, wherein basic agent is selected from the group consisting of sodium bicarbonate, Sodium carbonate and potassium bicarbonate or mixture thereof.
6. An effervescent composition according to claim 1, wherein basic agent ranging from 50 mg to 1500 mg and acidic agent ranging from 50 to 2000 mg.
7. An effervescent composition according to claim 1, wherein acidic agent is the mixture of citric acid, tartaric acid and basic agent is sodium bicarbonate.
8. An effervescent composition according to claim 7, wherein mixture of citric acid, tartaric acid and sodium bicarbonate are present in a ratio of about 3.44:1:2.
9. An effervescent composition according to claim 1, further comprises pharmaceutically active agent selected is Vitamins A or Vitamin D.
10. A process of preparing effervescent granule composition of calcium alpha ketoglutarate, wherein the process comprises steps of:
(i) blending pharmaceutically effective amount of calcium alpha ketoglutarate or salt thereof with vitamin, acid agent, basic agent, optionally pharmaceutically acceptable excipient and
(ii) preparing a pharmaceutical acceptable dosage forms selected from a group comprising a table, capsule, granules, powder and sachet.
11. The process claimed in claim 10, wherein acidic agent selected from the group consisting of tartaric acid, citric acid and salts of acid or mixture thereof.
12. The process claimed in claim 10, wherein acidic agent is a mixture of tartaric acid and citric acid, the ratio of tartaric acid to citric acid ranges between 1.5:0.5 to 2.5:1.5; preferably about 2:1.
13. The process claimed in claim 10, wherein basic agent is selected from the group consisting of sodium bicarbonate, sodium carbonate and potassium bicarbonate or mixture thereof.
14. The process of claim 10, wherein the ratio of mixture of acidic to basic agent ranges between from 0.5:3 to 1.5: 4.
15. The process of claim 10, wherein acidic agent is the mixture of citric acid, tartaric acid and basic agent is sodium bicarbonate.
16. The process of claim 10, wherein mixture of citric acid, tartaric acid and sodium bicarbonate are present in a ratio of about 3.44:1:2.
17. The process of claim 10, wherein the vitamin is vitamin A (Retinyl palmitate), or Vitamin D (Cholecalciferol).
18. The process according to claim 10, wherein one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, acidic agent, basic agent, binders, disintegrants, solubilizing agent or surfactant, sweeteners, flavoring agent, pH regulating agent, stabilizing agent, lubricant, glidant and coloring gents.

Dated this 13th day of February 2021