CN113244182A - Alpha-ketoglutarate calcium vitamin C effervescent tablet and preparation method thereof - Google Patents

Alpha-ketoglutarate calcium vitamin C effervescent tablet and preparation method thereof Download PDF

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CN113244182A
CN113244182A CN202110482495.6A CN202110482495A CN113244182A CN 113244182 A CN113244182 A CN 113244182A CN 202110482495 A CN202110482495 A CN 202110482495A CN 113244182 A CN113244182 A CN 113244182A
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alpha
vitamin
mixing
effervescent tablet
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张发成
曹瑞山
万竹青
吴保祥
韩凯
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Polifarma Nanjing Co ltd
ABA Chemicals Corp
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Polifarma Nanjing Co ltd
ABA Chemicals Corp
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • A—HUMAN NECESSITIES
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Abstract

The invention relates to an alpha-ketoglutarate calcium vitamin C effervescent tablet, which is prepared by taking alpha-ketoglutarate calcium and vitamin C as raw material medicines and taking sodium bicarbonate, mannitol, citric acid, orange essence, aspartame, silicon dioxide, polyethylene glycol 6000, sunset yellow and adhesive as auxiliary materials. The invention also relates to a preparation method of the alpha-ketoglutarate calcium vitamin C effervescent tablet, which comprises the steps of wet granulation, drying, granule finishing, total mixing, tabletting, packaging and the like. The effervescent tablet has stable property, is suitable for clinical application, and has the advantages of simple and convenient operation, good reproducibility and uniform quality of the prepared product.

Description

Alpha-ketoglutarate calcium vitamin C effervescent tablet and preparation method thereof
Technical Field
The invention relates to a medicinal preparation characterized by special physical shape, in particular to an effervescent tablet preparation.
Background
In recent years, a great deal of research has found that Alpha-Ketoglutaric Acid (AKG) is an important intermediate product of muscle metabolism. During muscle exercise, both the tricarboxylic acid cycle and glutamate deamination reactions can produce large amounts of AKG. Research has shown that AKG plays an important role in protein synthesis, skeletal muscle development and metabolism, calcium homeostasis and other aspects, and AKG can regulate physiological processes such as muscle and skeletal development, cell metabolism, immune inflammation and stem cell development through complex signal pathways, and the progress has important reference value for AKG application.
Calcium alpha-ketoglutarate (Ca-AKG) is an important source of alpha-ketoglutarate anion. The alpha-ketoglutarate anion is an intermediate of the Krebs cycle of eukaryotes and is the material basis for the function of AKG in organisms. Therefore, the alpha-ketoglutarate calcium has wide medical application prospect.
Vitamin C, also known as vitamin C, is a polyhydroxy compound, is necessary for antibody and collagen formation, tissue repair (including certain redox actions), metabolism of phenylalanine, tyrosine and folic acid, utilization of iron and carbohydrate, synthesis of fat and protein, maintenance of immune function, hydroxylation of 5-hydroxytryptamine, blood vessel integrity maintenance, non-heme iron absorption promotion and the like, and simultaneously has the functions of antioxidation, anti-free radical and tyrosinase inhibition.
In order to realize the application of the alpha-ketoglutarate calcium in medicines, health products and foods, the alpha-ketoglutarate calcium needs to be prepared into a safe, effective and convenient dosage form. Patent document WO2018200736A3 (publication No. 2019-11-28) discloses a calcium α -ketoglutarate composition consisting essentially of a therapeutically effective amount of calcium α -ketoglutarate salt (Ca-AKG) and vitamin C, and discloses that the composition can be formulated into oral administration forms such as tablets, powders, suspensions, slurries, emulsions, capsules, granules, pills, gels, solutions or syrups. However, the document does not further disclose a specific formulation and a preparation method for preparing the alpha-ketoglutarate calcium salt composition.
The effervescent tablet contains disintegrant, and can generate gas when meeting water to form effervescent tablet. The effervescent tablet is put into water, and generates a large amount of CO due to the action of the effervescent disintegrant2The bubbles enable the effervescent tablet to disintegrate rapidly. The effervescent tablet can generate CO by neutralization reaction when encountering body fluid or water, organic acid and alkali2Gas, the gas escaping to form many holes in the effervescent tablet, water continuously entering the tablet to cause chain reaction, and sufficient CO being produced2And certain pressure is formed, so that the effervescent tablet is thoroughly disintegrated, and the medicine is dissolved and released. Generally, the effervescent tablet has small volume, smooth and beautiful surface, is convenient to carry and take, and is particularly suitable for children, old people or people who have difficulty in swallowing. The medicine can be taken in the form of solution, so that the medicine has quick effect and high bioavailability, and is more convenient to carry compared with a liquid preparation. When the effervescent tablet is prepared, auxiliary materials such as an acid source, an alkali source, a filling agent, an adhesive, a lubricant, a flavoring agent and the like are required to be added, and each auxiliary material has multiple choices.
The effervescent tablet is easy to absorb moisture and deteriorate, so the temperature and the humidity of the environment must be strictly controlled during the preparation, production, storage and transportation of the effervescent tablet, and when the humidity of the external environment is higher, the effervescent tablet is easier to deteriorate.
The calcium alpha-ketoglutarate contains carbonyl and carboxyl groups, is active in nature and is easy to chemically react under normal storage and transportation conditions, so that sufficient attention needs to be paid to the stability of the calcium alpha-ketoglutarate preparation.
In conclusion, how to prepare the alpha-ketoglutarate calcium and the vitamin C into the effervescent tablet which has stable property and is suitable for clinical application becomes a technical problem to be solved urgently.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel alpha-ketoglutarate calcium vitamin C effervescent tablet which has stable property and is suitable for clinical application.
The invention also aims to provide a preparation method of the alpha-ketoglutarate calcium vitamin C effervescent tablet, which ensures that the method has simple and convenient operation, good reproducibility and uniform quality of the prepared product.
In order to solve the technical problems, the invention adopts the following technical scheme:
the effervescent tablet is prepared from alpha-ketoglutaric acid calcium and vitamin C as raw materials, and sodium bicarbonate, mannitol, citric acid, orange essence, aspartame, silicon dioxide, polyethylene glycol 6000, sunset yellow and adhesive as adjuvants.
Preferably, the adhesive is 10% by mass of povidone K30 aqueous solution.
Preferably, the mass ratio of the raw material medicines to the auxiliary materials is as follows: 378 parts of alpha-ketoglutarate calcium, 500 parts of vitamin C, 565-690 parts of sodium bicarbonate, 220 parts of mannitol, 690 parts of citric acid 565-690 parts, 45-55 parts of orange essence, 27-33 parts of aspartame, 54-66 parts of silicon dioxide, 600054-66 parts of polyethylene glycol, 1.3-1.7 parts of sunset yellow pigment and 90-110 parts of 10 mass percent povidone K30 water solution.
Preferably, the mass ratio of the raw material medicines to the auxiliary materials is as follows: 378 parts of alpha-ketoglutarate calcium, 500 parts of vitamin C, 625 parts of sodium bicarbonate, 200 parts of mannitol, 625 parts of citric acid, 50 parts of orange essence, 30 parts of aspartame, 60 parts of silicon dioxide, 600060 parts of polyethylene glycol, 1.5 parts of sunset yellow pigment and 96 parts of povidone K30 aqueous solution with the mass percentage of 10%.
The preparation method of the alpha-ketoglutarate calcium vitamin C effervescent tablet comprises the following steps:
(1) wet granulation
Preparing a first particle: placing Ca-AKG, sodium bicarbonate and mannitol in a wet mixing granulator according to the prescription amount, starting low-speed mixing and chopping for 3 minutes, mixing uniformly, starting high-speed mixing and chopping, adding an adhesive, mixing for 3-5 minutes, and preparing into wet granules I;
preparing granules II: placing vitamin C and citric acid in a formula amount in a wet mixing granulator, starting low-speed mixing and chopping for 3 minutes, uniformly mixing, starting high-speed mixing and chopping, adding an adhesive, and mixing for 3-5 minutes to prepare wet granules II;
(2) drying
Drying the two kinds of wet granules respectively by a fluidized bed or an oven at the drying temperature of 60 ℃ until the moisture is within 3 percent, and keeping no moist feeling when the hand touches;
(3) whole grain
Granulating the two kinds of dry particles by using a swing granulator respectively, and sieving the granules by using a 20-mesh sieve; or granulating with a 1.2mm sieve by using a high-shear granulator;
(4) total mixing
Adding the granules I and the granules II into the same mixer, mixing for 30 minutes, adding the formula amounts of orange essence, aspartame, silicon dioxide, polyethylene glycol 6000 and sunset yellow pigment, and mixing for 5 minutes;
(5) tabletting and packaging to obtain the finished product.
The beneficial technical effects of the invention are mainly embodied in the following aspects:
1. the alpha-ketoglutarate calcium vitamin C effervescent tablet of the invention has the advantages of rapid disintegration, difficult moisture absorption, large foaming amount and stable quality.
The Ca-AKG is compatible with the vitamin C, so that the stability of the vitamin C in the preparation can be enhanced.
3. The citric acid is compatible with mannitol, and can enhance the stability of Ca-AKG in the preparation.
3. The citric acid is compatible with mannitol, and can improve hygroscopicity of citric acid.
The technical effects of the present invention can be demonstrated by the following tests.
Test example 1 Filler screening test
1.1 materials and methods
1.1.1 materials
Ca-AKG; mannitol; lactose; starch; dextrin; microcrystalline cellulose.
1.1.2 test methods
Determination of the moisture absorption percentage of different excipients
Precisely weighing 7 parts of Ca-AKG (calcium alkyl ketene dimer) which is sieved by a sieve of 80 meshes, wherein each part is 1.50g, placing the Ca-AKG into a weighing bottle, then respectively adding mannitol, lactose, starch, dextrin and microcrystalline cellulose which are equal in quantity, uniformly mixing, then opening a cover of the weighing bottle, placing the weighing bottle in a drier for drying, and removing water for later use.
And (3) precisely weighing the dried weighing bottle, placing the dried weighing bottle in a drug stability test box with the relative humidity of 75% and the temperature of 25 ℃, taking out the weighing bottle from 24 hours after the weighing bottle is placed in the drug stability test box, and precisely weighing the dried weighing bottle after a cover is added. The assay was performed 3 times in parallel and the mean value was taken. Percent moisture absorption was calculated as the ratio of the difference in weight of the particles before and after moisture absorption to the weight of the particles before moisture absorption.
1.2 results
Moisture absorption percentage of different excipients
The test results are shown in table 1, and the results show that the absorption percentage of the raw material drug added with mannitol, lactose and microcrystalline cellulose is about 10 percent, and the raw material drug can be used as an alternative filler of the effervescent tablet; the moisture absorption percentage of starch and dextrin is more than 20 percent, so that the starch and dextrin are not suitable to be used as the filling agent of the effervescent tablet.
TABLE 1 moisture absorption percentage of different excipients
Auxiliary materials Percentage of moisture absorption (%)
Mannitol 10.3
Lactose 11.2
Microcrystalline cellulose 9.9
Starch 21.3
Dextrin 23.1
Test example 2 Effect of Filler on drug substance stability
2.1 materials and methods
2.1.1 materials
Ca-AKG; vitamin C; mannitol; lactose.
2.1.2 test methods
The Ca-AKG and the vitamin C are precisely weighed according to the proportion of the prescription of the invention, are uniformly mixed, and then mannitol and lactose which are equal to the mixed raw material medicines are respectively added; taking a portion of mixed powder of Ca-AKG and vitamin C, adding no auxiliary material as a blank control 1, and taking vitamin C, adding no auxiliary material as a control 2. Respectively irradiating at 60 deg.C, high humidity RH 75% +40 deg.C and 4500lx + -500 lx (near ultraviolet is not less than 200 W.hr/m)2) After 30 days, the content of the two raw materials was tested for changes.
The content of Ca-AKG is determined by high performance liquid chromatography 0512 in four parts of Chinese pharmacopoeia (2020 edition).
Chromatographic conditions were as Hypersil C18(4.6 mm. times.150 mm, 5 μm) as a column; the mobile phase A is methanol, the mobile phase B is 0.1mol/L (NH)4)H2PO4(pH2.65), gradient elution, elution program as shown in Table 2, flow rate of 1.0m L/min; and an ultraviolet detector for detecting the wavelength of 240 nm. The system suitability test is that the number of theoretical plates is not less than 3000 calculated by alpha-ketoglutarate peak.
TABLE 2 gradient elution Table
Time (min) Mobile phase ratio A: B
0→25 15:85→70:30
26→30 70:30→15:85
31→40 15:85
Precisely weighing about 40mg of alpha-ketoglutarate calcium reference substance in the reference substance solution, placing the reference substance solution in a 25mL measuring flask, adding 20% methanol to dissolve and dilute the reference substance to a scale, and shaking up to obtain a reference substance solution 1; precisely weighing about 20mg of vitamin C reference substance, placing into a 25mL measuring flask, adding 20% methanol to dissolve and dilute to scale, and shaking to obtain reference substance solution 2;
the measurement method comprises precisely measuring 10 μ L of the sample solution and the reference solution, respectively injecting into a liquid chromatograph, recording chromatogram, and calculating according to external standard method by peak area.
2.2 test results
The test results are shown in tables 3, 4 and 5, and the results show that:
under the condition of high temperature (60 ℃), the property of the vitamin C is extremely unstable, and the content is obviously reduced. Under the condition of high temperature (60 ℃), the Ca-AKG and the vitamin C form a mixture, wherein the Ca-AKG is more stable and the content is reduced less; the vitamin C is more stable, the content is reduced less, and the Ca-AKG has the function of enhancing the VC stability. The results also show that the effect of using various fillers alone on increasing the stability of both drug substances is not significant.
Illumination (4500lx +/-500 lx, near ultraviolet is not less than 200W.hr/m2) Under the condition, the property of the vitamin C is extremely unstable, and the content is obviously reduced. Under the condition of illumination (4500lx +/-500 lx, near ultraviolet is more than or equal to 200W.hr/m2), the mixture of Ca-AKG and vitamin C has unstable Ca-AKG content and reduced content; wherein the vitaminsC is more stable, and the content is reduced less, which shows that Ca-AKG has the function of enhancing VC stability. The results also show that the effect of using various fillers alone on increasing the stability of both drug substances is not significant.
Under the condition of high humidity (RH 75% +40 ℃), the vitamin C property is extremely unstable, and the content is obviously reduced. Under the condition of high humidity (RH 75% +40 ℃), the Ca-AKG in the mixture of Ca-AKG and vitamin C is unstable, and the content is obviously reduced; the vitamin C is more stable, the content is reduced less, and the Ca-AKG has the function of enhancing the VC stability. The results also show that the effect of using various fillers alone on increasing the stability of both drug substances is not significant.
TABLE 3 Effect of bulking agent on bulk drug stability at high temperature
Figure BDA0003048969470000071
TABLE 4 Effect of bulking agent on drug substance stability under high humidity conditions
Figure BDA0003048969470000072
Figure BDA0003048969470000081
TABLE 5 Effect of Filler on drug stability under light conditions
Figure BDA0003048969470000082
Test example 3 high humidity test
3.1 materials and methods
3.1.1 materials
The alpha-ketoglutarate calcium vitamin C effervescent tablet is prepared according to the embodiments 1, 2 and 3.
Comparing the alpha-ketoglutarate calcium vitamin C effervescent tablet-1, the self-made preparation is prepared according to the comparative example 1, and the citric acid in the preparation prescription is replaced by the same amount of tartaric acid.
Comparing the alpha-ketoglutarate calcium vitamin C effervescent tablet-2, the preparation is self-made according to the comparative example 2, and mannitol in the preparation prescription is replaced by the same amount of lactose.
3.1.2 test methods
The desiccator containing a certain amount of saturated sodium chloride solution was allowed to stand at 25 ℃ for 1 day so that the relative humidity inside the desiccator was constant at 75%. Drying the weighing bottle to constant weight, putting the test piece reagent at the bottom of the weighing bottle, precisely weighing, putting the weighing bottle into a dryer (the cover of the weighing bottle should be opened), and testing for 0, 5 and 10 days:
percent moisture absorption: weigh and calculate the percent moisture absorption by the following formula: the moisture absorption percentage is (W2-W1)/W1 x 100%, wherein W1 refers to the weight of the tablet before moisture absorption, and W2 refers to the weight of the tablet after moisture absorption.
Disintegration time limit: measured according to 0921 disintegration time limit inspection method in four parts of the Chinese pharmacopoeia (2020 edition).
Foaming amount: taking a 25mL test tube with a plug scale, precisely adding 10mL of water, carrying out constant-temperature water bath at 25 ℃ for 5min, then putting a piece of effervescent tablet, blocking for 10min, observing and recording the maximum foaming volume.
3.2 test results
The test results are shown in table 6, and the results show that the effervescent tablets (examples 1, 2 and 3) of the invention have low moisture absorption rate, short disintegration time and large foaming amount, and are suitable for clinical application.
Compared with the detection result of the comparison 1, the inventors have easily found that if tartaric acid is used as an acid source, the finished effervescent tablet has long disintegration time and less foaming amount although the moisture absorption rate of the finished product is low, so that the effect of tartaric acid as the acid source is inferior to that of citric acid.
The difference between the comparative example 2 and the example 3 is that the preparation formula is different from the filling agent, the comparative example 2 adopts lactose as the filling agent, the effervescent tablet prepared by the comparative example 2 is easier to absorb moisture, and the disintegration effect is also deteriorated along with the moisture absorption. Therefore, compared with the detection result of comparative example 2, the detection result shows that mannitol is beneficial to improving the defect that citric acid is easy to absorb moisture.
TABLE 6 high humidity test
Figure BDA0003048969470000101
Test example 4 accelerated stability test
4.1 materials and methods
4.1.1 materials
The alpha-ketoglutarate calcium vitamin C effervescent tablet is prepared according to the embodiments 1, 2 and 3.
Compared with the alpha-ketoglutarate calcium vitamin C effervescent tablet-1, the effervescent tablet is prepared according to the comparative example 1, and the preparation formula does not contain citric acid.
Comparing the alpha-ketoglutarate calcium vitamin C effervescent tablet-2, the preparation is self-made according to the comparative example 2, and mannitol in the preparation prescription is replaced by lactose.
4.1.2 test methods
Taking each sample, sealing and packaging the sample by a plastic bottle, placing the sample in an environment with the temperature of 40 +/-2 ℃ and the RH of 75 +/-5%, and respectively sampling and detecting the sample in 1/2/3 months after placing, wherein the detection items are disintegration time limit and content.
Disintegration time limit: measured according to 0921 disintegration time limit inspection method in four parts of the Chinese pharmacopoeia (2020 edition).
The content determination method comprises the following steps: taking 5 pieces of sample, and adding water to prepare a solution containing Ca-AKG40mg per 1 mL; the rest is referred to the above test example 2.
4.2 results
The results of the accelerated stability test are shown in Table 7. The results show that the Ca-AKG effervescent tablets of the invention (i.e. examples 1, 2 and 3) are stable for 3 months under accelerated conditions.
The results also show that if citric acid is replaced by tartaric acid in the formulation (i.e. comparative example-1), the Ca-AKG content of the formulation decreases to a large extent from 1 month of acceleration. Test results show that the citric acid in the formula of the preparation plays a key role in increasing the stability of the effervescent tablet (namely preventing the reduction of Ca-AKG content).
The results also show that if the formulation is formulated with a combination of lactose + citric acid, there is a large decrease in the Ca-AKG content of the formulation from 1 month on acceleration. Test results show that in the formula of the preparation, citric acid and mannitol have a certain synergistic effect, and the combination of citric acid and mannitol can play a role in improving the stability of the effervescent tablet (namely preventing the content of Ca-AKG from being reduced), and the two effects cannot be used.
TABLE 7 stability accelerated test results
Figure BDA0003048969470000111
Figure BDA0003048969470000121
Detailed Description
The technical solution of the present invention is further described below with reference to examples.
EXAMPLE 1 preparation of alpha-ketoglutarate calcium vitamin C effervescent tablets
The preparation prescription is as follows: 378 parts of alpha-ketoglutarate calcium, 500 parts of vitamin C, 565 parts of sodium bicarbonate, 180 parts of mannitol, 565 parts of citric acid, 45 parts of orange essence, 27 parts of aspartame, 54 parts of silicon dioxide, 600054 parts of polyethylene glycol, 1.3 parts of sunset yellow pigment and 90 parts of povidone K30 aqueous solution with the mass percentage of 10%.
The preparation process comprises the following steps:
(1) wet granulation
Preparing a first particle: placing Ca-AKG, sodium bicarbonate and mannitol in a wet mixing granulator according to the prescription amount, starting low-speed mixing and chopping for 3 minutes, mixing uniformly, starting high-speed mixing and chopping, adding an adhesive, mixing for 3-5 minutes, and preparing into wet granules I;
preparing granules II: placing vitamin C and citric acid in a formula amount in a wet mixing granulator, starting low-speed mixing and chopping for 3 minutes, uniformly mixing, starting high-speed mixing and chopping, adding an adhesive, and mixing for 3-5 minutes to prepare wet granules II;
(2) drying
Drying the two kinds of wet granules respectively by a fluidized bed at the drying temperature of 60 ℃ until the moisture is within 3 percent, and keeping no moist feeling when the two kinds of wet granules are touched by hands;
(3) whole grain
Granulating the two kinds of dry particles by using a swing granulator respectively, and sieving the granules by using a 20-mesh sieve;
(4) total mixing
Adding the granules I and the granules II into the same mixer, mixing for 30 minutes, adding the formula amounts of orange essence, aspartame, silicon dioxide, polyethylene glycol 6000 and sunset yellow pigment, and mixing for 5 minutes;
(5) tabletting and packaging to obtain the finished product.
Reproducibility and homogeneity of the process test:
4 batches of effervescent tablets (6 tablets in each batch) prepared from the same raw and auxiliary materials are considered, the reproducibility of the drug content is improved in a stability acceleration test for 1 month, and the RSD is 4.5%, so that the preparation process has better reproducibility.
The uniformity of the drug content of 6 tablets in the same batch is inspected, and the RSD is 2.5 percent in the stability acceleration test for 1 month, which shows that the preparation process has better uniformity.
EXAMPLE 2 preparation of alpha-ketoglutarate calcium vitamin C effervescent tablets
The preparation prescription is as follows: alpha-ketoglutarate calcium 378 parts, vitamin C500 parts, sodium bicarbonate 690 parts, mannitol 220 parts, citric acid 690 parts, orange essence 55 parts, aspartame 33 parts, silicon dioxide 66 parts, polyethylene glycol 600066 parts, sunset yellow 1.7 parts, and povidone K30 aqueous solution 110 parts with the mass percentage of 10%.
The preparation process comprises the following steps:
(1) wet granulation
Preparing a first particle: placing Ca-AKG, sodium bicarbonate and mannitol in a wet mixing granulator according to the prescription amount, starting low-speed mixing and chopping for 3 minutes, mixing uniformly, starting high-speed mixing and chopping, adding an adhesive, mixing for 3-5 minutes, and preparing into wet granules I;
preparing granules II: placing vitamin C and citric acid in a formula amount in a wet mixing granulator, starting low-speed mixing and chopping for 3 minutes, uniformly mixing, starting high-speed mixing and chopping, adding an adhesive, and mixing for 3-5 minutes to prepare wet granules II;
(2) drying
Drying the two kinds of wet granules respectively by a fluidized bed at the drying temperature of 60 ℃ until the moisture is within 3 percent, and keeping no moist feeling when the two kinds of wet granules are touched by hands;
(3) whole grain
Grading the two kinds of dry particles by using a high-shear type grading machine and a 1.2mm screen;
(4) total mixing
Adding the granules I and the granules II into the same mixer, mixing for 30 minutes, adding the formula amounts of orange essence, aspartame, silicon dioxide, polyethylene glycol 6000 and sunset yellow pigment, and mixing for 5 minutes;
(5) tabletting and packaging to obtain the finished product.
Reproducibility and homogeneity of the process test:
4 batches of effervescent tablets (6 tablets in each batch) prepared from the same raw and auxiliary materials are considered, the reproducibility of the drug content is improved in a stability acceleration test for 1 month, and the RSD is 4.4% between batches, so that the preparation process has better reproducibility.
The uniformity of the drug content of 6 tablets in the same batch is inspected, and the RSD is 2.6 percent when the stability acceleration test is carried out for 1 month, which shows that the preparation process has better uniformity.
EXAMPLE 3 preparation of alpha-ketoglutarate calcium vitamin C effervescent tablets
The preparation prescription is as follows: 378 parts of alpha-ketoglutarate calcium, 500 parts of vitamin C, 625 parts of sodium bicarbonate, 200 parts of mannitol, 625 parts of citric acid, 50 parts of orange essence, 30 parts of aspartame, 60 parts of silicon dioxide, 600060 parts of polyethylene glycol, 1.5 parts of sunset yellow pigment and 96 parts of povidone K30 aqueous solution with the mass percentage of 10%.
The preparation process comprises the following steps:
(1) wet granulation
Preparing a first particle: placing Ca-AKG, sodium bicarbonate and mannitol in a wet mixing granulator according to the prescription amount, starting low-speed mixing and chopping for 3 minutes, mixing uniformly, starting high-speed mixing and chopping, adding an adhesive, mixing for 3-5 minutes, and preparing into wet granules I;
preparing granules II: placing vitamin C and citric acid in a formula amount in a wet mixing granulator, starting low-speed mixing and chopping for 3 minutes, uniformly mixing, starting high-speed mixing and chopping, adding an adhesive, and mixing for 3-5 minutes to prepare wet granules II;
(2) drying
Respectively drying the two kinds of wet granules in a fluidized bed at the drying temperature of 60 ℃ until the moisture is within 3 percent, and keeping no moist feeling when the granules are touched by hands;
(3) whole grain
Grading the two kinds of dry particles by using a high-shear type grading machine and a 1.2mm screen;
(4) total mixing
Adding the granules I and the granules II into the same mixer, mixing for 30 minutes, adding the formula amounts of orange essence, aspartame, silicon dioxide, polyethylene glycol 6000 and sunset yellow pigment, and mixing for 5 minutes;
(5) tabletting and packaging to obtain the finished product.
Reproducibility and homogeneity of the process test:
4 batches of effervescent tablets (6 tablets in each batch) prepared from the same raw and auxiliary materials are considered, the reproducibility of the drug content is improved in a stability acceleration test for 1 month, and the RSD is 3.9%, so that the preparation process has good reproducibility.
The uniformity of the drug content of 6 tablets in the same batch is inspected, and the RSD is 2.4 percent in the stability acceleration test for 1 month, which shows that the preparation process has better uniformity.
Comparative example 1 preparation of comparative alpha-ketoglutarate calcium vitamin C effervescent tablet-1
Example 3 was followed except that the citric acid in the formulation was replaced by an equal amount of tartaric acid.
COMPARATIVE EXAMPLE 2 preparation of comparative alpha-ketoglutarate calcium vitamin C effervescent tablet-2
Example 3 was followed except that mannitol was replaced by an equal amount of lactose in the formulation.
It should be understood that the above examples are only for clearly illustrating the technical solutions and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (5)

1. The alpha-ketoglutarate calcium vitamin C effervescent tablet is characterized in that the effervescent tablet is prepared by taking alpha-ketoglutarate calcium and vitamin C as raw material medicines and taking sodium bicarbonate, mannitol, citric acid, orange essence, aspartame, silicon dioxide, polyethylene glycol 6000, sunset yellow and adhesive as auxiliary materials.
2. The effervescent tablet of alpha-ketoglutarate calcium vitamin C according to claim 1, characterized in that the binder is povidone K30 aqueous solution with a mass percentage of 10%.
3. The alpha-ketoglutarate calcium vitamin C effervescent tablet according to claim 2, which is characterized in that the mass ratio of the raw material medicines to the auxiliary materials is as follows: 378 parts of alpha-ketoglutarate calcium, 500 parts of vitamin C, 565-690 parts of sodium bicarbonate, 220 parts of mannitol, 690 parts of citric acid 565-690 parts, 45-55 parts of orange essence, 27-33 parts of aspartame, 54-66 parts of silicon dioxide, 600054-66 parts of polyethylene glycol, 1.3-1.7 parts of sunset yellow pigment and 90-110 parts of 10 mass percent povidone K30 water solution.
4. The alpha-ketoglutarate calcium vitamin C effervescent tablet according to claim 3, which is characterized in that the mass ratio of the raw material medicines to the auxiliary materials is as follows: 378 parts of alpha-ketoglutarate calcium, 500 parts of vitamin C, 625 parts of sodium bicarbonate, 200 parts of mannitol, 625 parts of citric acid, 50 parts of orange essence, 30 parts of aspartame, 60 parts of silicon dioxide, 600060 parts of polyethylene glycol, 1.5 parts of sunset yellow pigment and 96 parts of povidone K30 aqueous solution with the mass percentage of 10%.
5. An effervescent tablet of alpha-ketoglutarate calcium vitamin C according to any one of claims 1 to 4, characterised in that it is prepared by the following process:
(1) wet granulation
Preparing a first particle: placing Ca-AKG, sodium bicarbonate and mannitol in a wet mixing granulator according to the prescription amount, starting low-speed mixing and chopping for 3 minutes, mixing uniformly, starting high-speed mixing and chopping, adding an adhesive, mixing for 3-5 minutes, and preparing into wet granules I;
preparing granules II: placing vitamin C and citric acid in a formula amount in a wet mixing granulator, starting low-speed mixing and chopping for 3 minutes, uniformly mixing, starting high-speed mixing and chopping, adding an adhesive, and mixing for 3-5 minutes to prepare wet granules II;
(2) drying
Drying the two kinds of wet granules respectively by a fluidized bed or an oven at the drying temperature of 60 ℃ until the moisture is within 3 percent, and keeping no moist feeling when the hand touches;
(3) whole grain
Granulating the two kinds of dry particles by using a swing granulator respectively, and sieving the granules by using a 20-mesh sieve; or granulating with a 1.2mm sieve by using a high-shear granulator;
(4) total mixing
Adding the granules I and the granules II into the same mixer, mixing for 30 minutes, adding the formula amounts of orange essence, aspartame, silicon dioxide, polyethylene glycol 6000 and sunset yellow pigment, and mixing for 5 minutes;
(5) tabletting and packaging to obtain the finished product.
CN202110482495.6A 2021-04-30 2021-04-30 Alpha-ketoglutarate calcium vitamin C effervescent tablet and preparation method thereof Pending CN113244182A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101011370A (en) * 2007-02-02 2007-08-08 北京和为康医药科技有限公司 Pharmaceutical preparation of alpha-ketoglutaric acid composition, its preparation process and use
CN108157975A (en) * 2018-01-22 2018-06-15 山东天力药业有限公司 A kind of vitamin C effervescent tablet
WO2018200736A2 (en) * 2017-04-25 2018-11-01 The Buck Institute For Research On Aging Formulations for extending lifespan and healthspan

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101011370A (en) * 2007-02-02 2007-08-08 北京和为康医药科技有限公司 Pharmaceutical preparation of alpha-ketoglutaric acid composition, its preparation process and use
WO2018200736A2 (en) * 2017-04-25 2018-11-01 The Buck Institute For Research On Aging Formulations for extending lifespan and healthspan
CN108157975A (en) * 2018-01-22 2018-06-15 山东天力药业有限公司 A kind of vitamin C effervescent tablet

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