CN108853011A - A kind of calcium gluconate-L-calcium lactate oral solution and preparation method thereof - Google Patents
A kind of calcium gluconate-L-calcium lactate oral solution and preparation method thereof Download PDFInfo
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- CN108853011A CN108853011A CN201810608904.0A CN201810608904A CN108853011A CN 108853011 A CN108853011 A CN 108853011A CN 201810608904 A CN201810608904 A CN 201810608904A CN 108853011 A CN108853011 A CN 108853011A
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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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
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- 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
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Abstract
The present invention relates to a kind of calcium supplements, and in particular to a kind of calcium gluconate-L-calcium lactate oral solution and preparation method thereof belongs to pharmaceutical technology field, which includes following raw material composition：Calcium gluconate 45-60 parts by weight；L-calcium lactate 38-48 parts by weight；Lactic acid 2-5 parts by weight；Purified water 900-1100 parts by weight；Wherein D-ALPHA-Hydroxypropionic acid calcium content≤2.0wt% in L-calcium lactate, the above ingredient, which cooperates, is made the oral solution with compared with high calcium-containing amount and stability.
Description
Technical field
The present invention relates to a kind of calcium supplements, and in particular to a kind of calcium gluconate-L-calcium lactate oral solution and its preparation side
Method belongs to pharmaceutical technology field.
Background technique
Calcium gluconate oral solution with effect is most wide one of the calcium supplement of application range, is mainly used for preventing and treating calcium deficiency
Disease, such as osteoporosis, tetany, dysosteogenesis, rickets, and the calcium supplement of gestation and breast feeding women.Due to Portugal
Grape Calciofon saturation solubility is only 10%, unstable in placement process, is easy to crystallize, precipitating, in order to improve gluconic acid
The stability of calcium, conventional method is to reduce the content of calcium gluconate at present, at present the preferable calcium gluconate of shelf-stability
For calcium content mostly between 2.4-5.3mg/ml, so low calcium content forces patient that must take a large amount of grapes daily in oral solution
Saccharic acid calcium solution can be only achieved the purpose of disease preventing and treating.
For example, in order to reduce calcium-zinc gluconate oral liquid crystalline deposit, Chinese patent literature CN105412061A is disclosed
A kind of preparation method of calcium-zinc gluconate oral liquid is existed by the addition of solubilizer lactic acid, control pH in disclosed prescription
Between 3.6-4.1, guarantee calcium-zinc gluconate finished product in low temperature environment, the calcium gluconate in oral solution will not crystallize analysis
Out, but calcium content is lower (5.0-6.0mg/ml) in this kind of calcium gluconate oral solution with effect.
Therefore it is improved in calcium gluconate oral solution with effect while how improving gluconic acid calcium stability, reduce percent crystallization in massecuite
Calcium content is those skilled in the art's issue to be resolved always, is of great significance.
Summary of the invention
First problem to be solved by this invention is that existing calcium gluconate oral solution with effect shelf-stability is low, is easy knot
The problem of crystalline substance precipitates and reduces drug effect, second technical problem to be solved by this invention is calcium gluconate in the prior art
The low problem of oral solution calcium content.
For this purpose, the technical scheme adopted by the invention is as follows：A kind of calcium gluconate-L-calcium lactate oral solution, including following original
Material composition：
Calcium gluconate：45-60 parts by weight；
Calcium lactate：38-48 parts by weight；
Lactic acid：2-5 parts by weight；
Purified water：900-1100 parts by weight；
Wherein D-ALPHA-Hydroxypropionic acid calcium content≤2.0wt% in L-calcium lactate.
Further preferably, including following raw material forms：
Calcium gluconate：50-55 parts by weight；
L-calcium lactate：40-45 parts by weight；
Lactic acid：3-4 parts by weight；
Purified water：950-1050 parts by weight；
Wherein D-ALPHA-Hydroxypropionic acid calcium content≤1.0wt% in L-calcium lactate.
It further preferably, further include the essence of 0.05-0.2 parts by weight.
Further preferably, the essence is the mixture of liquid orange flavor and solid-state orange flavor, and the liquid is fragrant
Essence and the mass ratio of solid-state essence are 1:1-1:3.
It further preferably, further include the sweetener of 0.2-0.3 parts by weight.
Further preferably, the sweetener is aspartame, in stevioside, fructose, honey, glucose, Sucralose
One or several kinds of mixtures.
It is a further object of the present invention to provide a kind of methods for preparing above-mentioned oral solution, include the following steps：
(1) purified water is quantitatively weighed, heating is boiled, and continues to be heated to reflux 30-50min after boiling, and is then separated
The purified water of 15%-30% is spare；
(2) calcium gluconate, lactic acid and L-calcium lactate are weighed, is successively slowly added in the above-mentioned purified water being heated to reflux,
Continue to be heated to reflux 30-50min after mixing, stops heating, cooling, obtained medical fluid；
(3) the fresh purified water boiled for taking step (1) to separate is cooling, and quantitative sweetener is added, and stirs sufficiently dissolution
It is added in medical fluid made from step (2), stirs evenly afterwards；Then the cooling purifying of new boiling is added into the medical fluid that sweetener is added
Water dilutes constant volume, stirs evenly, then add essence, stir evenly；
(4) encapsulating after filtering, sterilizing, vacuum leak hunting.
Further preferably, in step (3), the cooling purified water of new boiling, stirring are added into the medical fluid that sweetener is added
After uniformly, 12-24h is stood overnight at 18-26 DEG C, adds essence.
Further preferably, in step (2), logical circulating water is to 30-40 DEG C after medicine liquid heating reflux；Step (3)
In, sweetener dissolution is added after the purifying newly boiled is water-cooled to 55-65 DEG C；In step (3), that adds into return tank is new
The temperature for boiling cooling water is 30-40 DEG C.
Further preferably, in step (4), sterilising temp is 115 DEG C, sterilization time 45-60min.
Compared with prior art, the application has the following advantages that：
(1) the application preparation calcium gluconate-L-calcium lactate oral solution in, with glucose calcium lactate, L-calcium lactate and
Lactic acid is that primary raw material forms calcium supplement oral solution, the addition that the prescription of the application passes through calcium gluconate in suitably reduction raw material
Amount, the additional amount for promoting L-calcium lactate can not only improve gluconic acid calcium stability, reduce percent crystallization in massecuite, while improve glucose
Calcium content in sour Ca oral liquid；
(2) in calcium gluconate-L-calcium lactate oral solution of the application preparation, D-ALPHA-Hydroxypropionic acid calcium contains in restriction L-calcium lactate
Amount is less than or equal to 2wt%, so that the dissolubility and stability of oral solution significantly improve, calcium content increases, and good in taste.
(3) in the application calcium gluconate-L-calcium lactate oral solution preparation method, Portugal is added into the purified water boiled
Grape Calciofon, lactic acid and L-calcium lactate stir evenly, and are then refluxed for heating 30-50min, lactic acid can be promoted preferably to play increasing
Molten effect, and it is synergistic with L-calcium lactate, promote the dissolution of calcium gluconate, improves the stability of oral solution.
(4) it in the application calcium gluconate-L-calcium lactate oral solution preparation method, stands overnight 12-24h and is conducive to Portugal
Grape acid calcium tiny seed crystals are generated, are precipitated, and are filtered by post-order process and removed in time, and the stability for improving oral solution is conducive to.
It (5) is 45- by control sterilization time in the application calcium gluconate-L-calcium lactate oral solution preparation method
60min, sterilising temp are 115 DEG C, can not only remove the microbe colony in oral solution, but also can be improved oral solution
Stability improves the generation of microscopic grains.
Specific embodiment
In the embodiment of the present invention in L-calcium lactate the content assaying method of D-ALPHA-Hydroxypropionic acid calcium according to GB25555-2010；Glucose
Determination of calcium content method in sour Ca oral liquid is according to second EDTA titration of pharmacopeia；The pH of calcium gluconate oral solution with effect is measured
Method is according to the method in pharmacopeia annex VI H.
Embodiment 1
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 30min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Embodiment 2
(1) it quantitatively weighs purified water 1050ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 50min, the purified water boiled for separating 150ml is spare；
(2) calcium gluconate 50.01g, lactic acid 3.98g and L-calcium lactate 44.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 40min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 40 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 1.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 55 DEG C, and Sucralose 0.20g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 32 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1050ml, stood for 24 hours at 18 DEG C after mixing evenly by purified water (30-40).From upper
State the medical fluid addition 0.10g solid-state orange flavor and 0.10g liquid orange flavor that 20ml is measured in return tank after standing overnight
Dissolution stirs evenly, and essence medical fluid mixed liquor is made, and essence medical fluid mixed liquor obtained is added in above-mentioned return tank, and stirring is equal
It is even；
(5) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 60min, vacuum leak hunting.
Embodiment 3
(1) it quantitatively weighs purified water 950ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 40min, the purified water boiled for separating 300ml is spare；
(2) calcium gluconate 55.01g, lactic acid 3.50g and L-calcium lactate 40.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 50min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 40 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 1.0wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 65 DEG C, and Sucralose 0.28g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 30 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 950ml, 18h is stood at 25 DEG C after mixing evenly, from above-mentioned return tank by purified water
0.025g solid-state orange flavor is added in the middle medical fluid for measuring 10ml after standing overnight and the dissolution of 0.025g liquid orange flavor is stirred
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 55min, vacuum leak hunting.
Embodiment 4
(1) it quantitatively weighs purified water 1100ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 35min, the purified water boiled for separating 250ml is spare；
(2) calcium gluconate 59.96g, lactic acid 2.01g and L-calcium lactate 38.2g are weighed, under constant stirring successively slowly
It is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 45min at 100 DEG C, stop heating after reflux, it is logical to follow
Ring water is cooled to 40 DEG C, and medical fluid is made, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 2.0wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 65 DEG C, and Sucralose 0.28g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 30 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1100ml, 18h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.03g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 50min, vacuum leak hunting.
Embodiment 5
(1) it quantitatively weighs purified water 900ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 45min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 45.02g, lactic acid 5.00g and L-calcium lactate 44.90g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 35min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 40 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 1.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 65 DEG C, and Sucralose 0.25g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 30 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 900ml, 18h is stood at 25 DEG C after mixing evenly, from above-mentioned return tank by purified water
0.1g solid-state orange flavor is added in the middle medical fluid for measuring 10ml after standing overnight and the dissolution stirring of 0.1g liquid orange flavor is equal
It is even, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 53min, vacuum leak hunting.
Comparative example 1 (promotes gluconic acid calcium content)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 61.02g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 30min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 2 (promote gluconic acid calcium content reduces L-calcium lactate content simultaneously)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 61.02g, lactic acid 3.80g and L-calcium lactate 37.51g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 30min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 3 (100 DEG C of water temperature before material is added in the 1- that do not flow back)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, the water temperature that purified water is measured before addition material is 100 DEG C, stirs evenly, leads to circulating water cooling extremely
34 DEG C, medical fluid is made, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 4 (83 DEG C of water temperature before the material that do not flow back-be added)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, the water temperature that purified water is measured before addition material is 83 DEG C, is stirred evenly, and leads to circulating water cooling to 34
DEG C, medical fluid is made, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 5 (return time 20min)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 20min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 6 (flows back) after calcium gluconate is added
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g is weighed, is added in the above-mentioned purified water boiled, continues to heat back at 100 DEG C
30min is flowed, stops heating after reflux, lactic acid 3.80g then is added and then L-calcium lactate 43.50g, stirring and dissolving are led to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 7 (flows back) after calcium gluconate, lactic acid is added
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g and lactic acid 3.80g are weighed, is added in the above-mentioned purified water boiled, at 100 DEG C
Continue to be heated to reflux 30min, stop heating after reflux, L-calcium lactate 43.50g is then added, then stirring and dissolving is led to and followed
Ring water is cooled to 34 DEG C, and medical fluid is made, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 8 (is not stood overnight)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 30min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, stirs evenly, 10ml medical fluid is measured from above-mentioned return tank and is added by purified water
Enter 0.07g solid-state orange flavor and the dissolution of 0.03g liquid orange flavor stirs evenly, essence medical fluid mixed liquor is made, will be made
Essence medical fluid mixed liquor be added in above-mentioned return tank, stir evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 9 (sterilization time is changed to 30min)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 30min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 30min, vacuum leak hunting.
Comparative example 10 (the D-ALPHA-Hydroxypropionic acid calcium containing 5.0wt%)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and D-ALPHA-Hydroxypropionic acid calcium 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 30min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 5.0wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Comparative example 11 (the D-ALPHA-Hydroxypropionic acid calcium in L-calcium lactate containing 2.5wt%)
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 30min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 2.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, state be cooled to 37 DEG C after adding new boiling in return tank then up
Solution dilution in return tank is settled to 1000ml, 12h is stood at 25 DEG C after mixing evenly, from above-mentioned reflux by purified water
Medical fluid addition 0.07g solid-state orange flavor and 0.03g liquid orange flavor dissolution of the 10ml after standing overnight is measured in tank to stir
It mixes uniformly, essence medical fluid mixed liquor is made, essence medical fluid mixed liquor obtained is added in above-mentioned return tank, is stirred evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
(essence is added) in comparative example 12 before supplying purified water
(1) it quantitatively weighs purified water 1000ml to be placed in return tank, heating is boiled to 100 DEG C, is then continued at 100 DEG C
It is heated to reflux 30min, the purified water boiled for separating 200ml is spare；
(2) calcium gluconate 53.01g, lactic acid 3.80g and L-calcium lactate 43.50g are weighed, is successively delayed under constant stirring
Slowly it is added in above-mentioned return tank, stirs evenly, continue to be heated to reflux 30min at 100 DEG C, stop heating after reflux, lead to
Medical fluid is made to 34 DEG C in circulating water cooling, wherein the content of D-ALPHA-Hydroxypropionic acid calcium is 0.5wt% in L-calcium lactate；
(3) the fresh purified water stirring boiled for taking step (1) to separate is cooled to 60 DEG C, and Sucralose 0.24g is added, stirs
It mixes after completely dissolution plus stating in return tank, stirs evenly, 10ml medical fluid is measured from above-mentioned return tank, 0.07g solid-state orange is added
Sub- essence and the dissolution of 0.03g liquid orange flavor stir evenly, and essence medical fluid mixed liquor is made, essence medical fluid obtained is mixed
Liquid is added in above-mentioned return tank, is stirred evenly, and states be cooled to 37 DEG C of purified water after adding new boiling in return tank then up, will
Solution dilution in return tank is settled to 1000ml, stands 12h at 25 DEG C after mixing evenly；
(4) flame filter press is used, with the drug solution in 0.22 μm of PP filter membrane filtering return tank, plate-frame filtering pressure
Less than or equal to 0.12MPa, then encapsulating, sterilize at a temperature of 115 DEG C 45min, vacuum leak hunting.
Evaluate example
PH, calcium content and the face for observing oral solution of oral solution made from embodiment 1-3 and comparative example 1-12 are measured respectively
Color, appearance, measurement oral solution place 6 months stability under room temperature (23-27 DEG C) and under low temperature (0-5 DEG C)；And with
50 people are sample total, and measurement crowd is subjected to spending and counting for the mouthfeel of oral solution made from embodiment 1-3 and comparative example 12
Calculate percentage.
Compared by table 1 it is found that the oral solution of calcium gluconate-L-calcium lactate of the present invention can not only improve it is oral
Calcium content in liquid, and the stability in this kind of oral solution placement process is improved, it is newborn in contrast to L- is not added in the prior art
The calcium gluconate oral solution with effect of sour calcium, calcium content improves will by about one time；
And the application is by properly increasing L-calcium lactate/calcium gluconate relative value, so that the calcium in oral solution contains
Amount in comparative example 1 and comparative example 2 on the basis of L-calcium lactate/calcium gluconate relative value lower technical solution, more into
One step improves 10% or so；
It is not heated at reflux after calcium gluconate, L-calcium lactate and lactic acid is added compared to comparative example 3-5 or return time
Shorter, the application is heated at reflux by extending to the 30-50min oral solution calcium content with higher made and good stabilization
Property.
As shown in Table 2, in the preparation process of the oral solution of calcium gluconate-L-calcium lactate of the present invention, by
Orange flavor is added after standing, not only solubility is good, does not influence the clarity, volume and stability of product, and have
Preferably acceptable degree.
The evaluation index for the oral solution that 1 embodiment of table and comparative example are prepared
The evaluation index for the oral solution that 2 embodiment 1-3 of table and comparative example 12 are prepared
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or
It changes.There is no necessity and possibility to exhaust all the enbodiments.And thus amplify out it is obvious variation or
It changes still within the protection scope of the invention.
Claims (10)
1. a kind of calcium gluconate-L-calcium lactate oral solution, which is characterized in that formed including following raw material：
Calcium gluconate：45-60 parts by weight；
L-calcium lactate：38-48 parts by weight；
Lactic acid：2-5 parts by weight；
Purified water：900-1100 parts by weight；
Wherein D-ALPHA-Hydroxypropionic acid calcium content≤2.0wt% in L-calcium lactate.
2. oral solution according to claim 1, which is characterized in that formed including following raw material：
Calcium gluconate：50-55 parts by weight；
L-calcium lactate：40-45 parts by weight；
Lactic acid：3-4 parts by weight；
Purified water：950-1050 parts by weight；
Wherein D-ALPHA-Hydroxypropionic acid calcium content≤1.0wt% in L-calcium lactate.
3. oral solution according to claim 1 or 2, which is characterized in that further include the essence of 0.05-0.2 parts by weight.
4. oral solution according to claim 1 to 3, which is characterized in that the essence is for liquid orange flavor and admittedly
The mass ratio of the mixture of state orange flavor, the liquid flavor and solid-state essence is 1:1-1:3.
5. oral solution according to any one of claims 1-4, which is characterized in that further include the sweet taste of 0.2-0.3 parts by weight
Agent.
6. any oral solution in -5 according to claim 1, which is characterized in that the sweetener is aspartame, stevia rebaudianum
One of sugar, fructose, honey, glucose, Sucralose or several mixtures.
7. a kind of method for preparing oral solution as claimed in any one of claims 1 to 6, which is characterized in that include the following steps：
(1) purified water is quantitatively weighed, heating is boiled, and continues to be heated to reflux 30-50min after boiling, and then separates 15%-
30% purified water is spare；
(2) calcium gluconate, lactic acid and L-calcium lactate are weighed, is successively slowly added in the above-mentioned purified water being heated to reflux, is mixed
After continue to be heated to reflux 30-50min, stop heating, cooling, medical fluid be made；
(3) the fresh purified water boiled for taking step (1) to separate is cooling, and quantitative sweetener is added, and stirring adds after completely dissolution
Enter in medical fluid made from step (2), stirs evenly；Then the cooling purified water of new boiling is added into the medical fluid that sweetener is added,
Constant volume is diluted, stirs evenly, then adds essence, stir evenly；
(4) encapsulating after filtering, sterilizing, vacuum leak hunting.
8. the preparation method of oral solution according to claim 7, which is characterized in that in step (3), to addition sweetener
The cooling purified water of new boiling is added in medical fluid, dilutes constant volume, after mixing evenly, stands overnight 12-24h at 18-26 DEG C, then plus
Enter essence.
9. according to the preparation method of oral solution described in claim 7 or 8, which is characterized in that in step (2), medicine liquid heating
Logical circulating water is to 30-40 DEG C after reflux；In step (3), sweet tea is added after the purifying newly boiled is water-cooled to 55-65 DEG C
Taste agent dissolution；In step (3), the temperature for the new boiling cooling water added into return tank is 30-40 DEG C.
10. according to the preparation method of the oral solution any in claim 7-9, which is characterized in that in step (4), sterilizing
Temperature is 115 DEG C, sterilization time 45-60min.
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| CN114732132A (en) * | 2020-12-21 | 2022-07-12 | 北京朗迪制药有限公司 | Calcium-magnesium niacin liquid nutrient supplement for improving sleep and preparation method thereof |
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