CN112336731B

CN112336731B - Vitamin oral liquid and preparation method and application thereof

Info

Publication number: CN112336731B
Application number: CN202011206056.4A
Authority: CN
Inventors: 田兵; 黄娜; 李磊; 米俊成; 王娟
Original assignee: Beijing Nuokangda Pharmaceutical Technology Co ltd
Current assignee: Beijing Nuokangda Pharmaceutical Technology Co ltd
Priority date: 2020-11-02
Filing date: 2020-11-02
Publication date: 2021-12-14
Anticipated expiration: 2040-11-02
Also published as: CN112336731A

Abstract

The invention relates to the technical field of pharmaceutical preparation processing, and particularly discloses a vitamin oral liquid as well as a preparation method and application thereof. The vitamin oral liquid comprises vitamin B₂Vitamin D and vitamin E, and the preparation method comprises the following steps: (1) mixing sorbitol aqueous solution with vitamin B₂Mixing to obtain a first mixed solution; (2) mixing vitamin E with a surfactant to obtain a second mixed solution, and adding the second mixed solution into the first mixed solution to obtain a third mixed solution; (3) adding a thickening agent into the mixed solution III to obtain a mixed solution IV; (4) and adding an ethanol solution of vitamin D into the mixed solution IV. The oral liquid containing water-soluble and fat-soluble vitamins obtained by the invention has good physicochemical and microbial stability.

Description

Vitamin oral liquid and preparation method and application thereof

Technical Field

The invention relates to the technical field of pharmaceutical preparation processing, in particular to a vitamin oral liquid and a preparation method and application thereof.

Background

Vitamins (vitamines) are a generic name for a series of organic compounds. They are micronutrients required by human body, but generally can not be produced by human body, and need to be obtained by means of diet and the like. The vitamins have the function of regulating the metabolism of the human body.

Vitamins can be classified into water-soluble and fat-soluble vitamins according to their solubility. The fat-soluble vitamins include vitamin A, vitamin D, vitamin E and vitamin K, and the rest is water-soluble vitamins. When multivitamins are formulated into tablets, their absorption in the body is often poor. The stability problem is particularly prominent when the medicine is prepared into oral solution.

Chinese patent CN103690561A discloses a preparation method of an oral liquid. The preparation method comprises the following steps: obtaining simple syrup; collecting vitamin B₂Mixing with second water, adding alkali for dissolving to obtain a first premix; collecting L-lysine hydrochloride, nicotinic acid, zinc sulfate, ferric glycerophosphate, citric acid, and vitamin B₁Vitamin B₆Mixing the preservative, the folic acid and the third water to obtain a second premix; mixing vitamin E with ethanol to obtain vitamin E solution; mixing the simple syrup, the first premix, the second premix and the vitamin E solution, heating for the second time, cooling, adding the edible essence and the balance of water, mixing uniformly, filtering, and adjusting the pH value to 3.1-3.9. It provides a method for dissolving vitamin B by adding alkali₂Increase vitamin B₂The solubility in the medicinal liquid can increase vitamin B in oral liquid₂The content becomes possible. However, the iron-containing oral liquid is mainly prepared, the unstable property of the vitamin molecular structure is ignored, the simple syrup, the first premix, the second premix and the vitamin E solution are mixed, the vitamin content is not monitored or researched after the second heating, and the content of various vitamins in the stability sample detection indexes is not detected.

There are other literature reports of the use of salified materials, such as vitamin B, in the preparation of various vitamins₂Phosphates, vitamin E acetate, etc. increase its stability. However, when the vitamin is salified, the water solubility of the vitamin is greatly improved, the fat solubility is reduced, and the permeability is also greatly reduced in the transmembrane transport process, so that the problem of low bioavailability is caused.

Therefore, further studies on the stability of vitamin oral liquid are needed to solve the above technical problems.

Disclosure of Invention

In view of the deficiencies of the prior art, it is an object of the present invention to provide a process for the preparation of vitamin oral solutions containing both water-soluble and fat-soluble vitamins, no preservatives, and good physicochemical and microbial stability.

In order to achieve the purpose, the technical scheme of the invention is as follows:

a method for preparing vitamin oral liquid containing vitamin B₂Vitamin D and vitamin E, which include:

(1) mixing sorbitol aqueous solution with vitamin B₂Mixing to obtain a first mixed solution;

(2) mixing vitamin E with a surfactant to obtain a second mixed solution, and adding the second mixed solution into the first mixed solution to obtain a third mixed solution;

(3) adding a thickening agent into the mixed solution III to obtain a mixed solution IV;

(4) adding an ethanol solution of vitamin D into the mixed solution IV;

the concentration of the sorbitol in the vitamin oral liquid is 250-350g/L, and preferably 300 g/L.

When the vitamin oral liquid is prepared, because the dissolution properties of different vitamins are different, the stability problem is often particularly prominent when multiple vitamins are simultaneously added into the same oral liquid. Specifically, the invention researches the stability problem of three common vitamins with different solubility properties when the vitamins are matched to prepare the oral liquid. Discovery of vitamin B₂Although water-soluble vitamins are often difficult to be directly dissolved, vitamin D and vitamin E are fat-soluble vitamins, but are easy to aggregate (disperse unevenly) or precipitate due to the change of the polarity of a solvent in an oral liquid system, so that a method for improving the stability of the oral liquid containing the three vitamins is needed to improve the product quality and the storage period. Therefore, the formula, the preparation and the charging steps of the oral liquid are repeatedly researched, so that the product which is stable in property and can be stored for a long time is obtained.

In detail, the invention uses a larger amount of sorbitol, which is first prepared as an aqueous solution (preferablyDissolving the vitamin B under heating and stirring, controlling the temperature to be 80-90 ℃), and then adding the insoluble vitamin B₂Stirring and dissolving, and cooling to obtain a first mixed solution (preferably, the temperature is controlled to be 20-30 ℃). Vitamin B in this step₂Can be dissolved easily, and can not be separated out due to cooling, thereby being beneficial to ensuring the stability of the subsequent preparation. Then, the vitamin E with stronger fat solubility is selected, the surfactant is added firstly, and then the vitamin E is prevented from being separated out or aggregated due to the surface tension through the combined action of the sorbitol and the surfactant. Next, the invention finds that even if vitamin D is dissolved by ethanol and then added into the oral liquid, the vitamin D is still easy to separate out due to the change of the polarity of the microenvironment solvent, therefore, before the vitamin D is added into the oral liquid, a specific mixed liquid system is formed by adopting a thickening agent, sorbitol and a surfactant system, so that the smooth dispersing addition of the vitamin D is further ensured, and the stable existence of other added vitamin components is also ensured. The obtained oral liquid does not contain any preservative component, has good physicochemical stability, can maintain microbial stability, has long storage period, and can avoid the damage to human body caused by long-term intake of the preservative.

In the present invention, preferably the surfactant is tween 80; and/or the mass ratio of the vitamin E, the sorbitol and the Tween 80 is 1: (250-350): (6-8), preferably 1: 300: 7.

the invention searches for the surfactant and the dosage thereof aiming at the matching characteristic of the system, and finds that the scheme of the invention can better promote the stability of the oral liquid system. And the influence of the Tween 80 on the mouthfeel of the oral liquid can be overcome, so that the compliance of a patient is improved.

In the invention, the thickening agent is sodium carboxymethyl cellulose; the molecular weight of the sodium carboxymethyl cellulose is 90000-120000; the mass-to-volume ratio of the sodium carboxymethylcellulose to the water in the mixed solution III is 17-23mg/mL, preferably the molecular weight is 100000, and the mass-to-volume ratio is 20 mg/mL.

In the invention, the mass ratio of the vitamin D to the sodium carboxymethyl cellulose is 1: (10000 14000), preferably 1: 12000.

under the use method of the preferable thickening agent, the dissolution stability of each component can be ensured, and the filtration link is not influenced in the subsequent processing.

In the invention, the step (1) further comprises a step of adding a first active substance into the sorbitol aqueous solution; the first active substance is a poorly soluble drug, preferably vitamin B₁₂One or more of calcium lactate and calcium glycerophosphate;

and/or, in the step (3), a step of adding a second active substance into the third mixed solution is further included; the second active substance is a soluble drug, preferably vitamin B₁Vitamin B₆One or more of vitamin C, lysine hydrochloride, nicotinamide and D-panthenol.

The judgment standard of the insoluble drug and the soluble drug in the invention is based on the method recorded in the general rules of the 2020 edition (four parts) of the Chinese pharmacopoeia.

Other active substances can be added into the oral liquid, particularly insoluble medicines and vitamin B₂The addition of the thickener and the easily soluble drug can be carried out in the step (3). The specific mixed solution three-system of the invention can further accelerate the dissolution of the active substance with good water solubility. Finally, all the substances can be effectively dissolved and stably exist.

In the invention, the temperature of the aqueous solution of the sorbitol is 80-90 ℃; the temperature of the mixed liquid I is 20-30 ℃;

and/or, in the step (3), a step of adding a metal ion complexing agent and a sweetening agent is further included.

The metal ion complexing agent and the sweetener can be selected according to the common knowledge in the field, and can be disodium edetate, acesulfame and the like.

In the present invention, after the step (4), a step of adding a fragrance and a pH adjuster is further included.

Then, the method can also comprise the steps of fixing the volume to the required volume by using water; filtering by using a filter element; and subpackaging the filtered liquid medicine into clean brown glass bottles and capping.

The aromatic agent can be selected according to common knowledge in the art, and can be orange flavor, etc.

pH adjusting agents that may be used include hydrochloric acid, phosphoric acid, acetic acid, lactic acid. A preferred pH adjusting agent is a solution with 20% hydrochloric acid (V/V).

The filtration may use polypropylene (PP) cartridges, Polyethersulfone (PES) cartridges, Cellulose Acetate (CA) cartridges, and the like. The preferred filter element is a 10 μm polypropylene filter element.

The mass ratio of the vitamin D to the ethanol is 1: 10000-5: 10000. the preferable mass ratio is 3: 10000.

the invention also provides vitamin oral liquid which is prepared by the method.

According to the vitamin oral liquid, at the temperature of 30 ℃, the viscosity of the vitamin oral liquid is 50-220 cp, and preferably 150 cp; the pH value is 3.0-4.5.

The invention also provides application of the method in preparing the oral liquid containing vitamins.

The invention has the beneficial effects that:

according to the invention, through research on the preparation raw materials and the method of the oral liquid containing various vitamins with different solubilities, the oral liquid which is good in stability, free of precipitation and degradation risks and free of the content of each vitamin within a qualified range after long-term storage is obtained. The prepared oral liquid with coexisting fat-soluble vitamins and water-soluble vitamins does not need to salify the vitamins, and avoids the condition of reduced absorption in vivo caused by preparing vitamin salts. And the oral liquid has good microbial stability without preservative, and improves the product safety. Provides a new preparation idea for vitamins which are not suitable for being developed into liquid preparations, and provides a new preparation idea for the vitamins which are not suitable for being developed into liquid preparations so as to improve the bioavailability of the vitamins.

Detailed Description

Preferred embodiments of the present invention will be described in detail with reference to the following examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the spirit and scope of this invention.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified. The sodium carboxymethylcellulose used in the embodiments of the present invention has a molecular weight of 100000.

Example 1

This example provides a vitamin oral liquid and a method for preparing the same. The vitamin oral liquid is shown in table 1.

TABLE 1

Weighing purified water with the prescription amount of 60%, adding sorbitol with the prescription amount, and heating and stirring to dissolve (the temperature is controlled to be 80-90 ℃). Then adding prescribed amount of vitamin B₂Stirring to dissolve. After dissolving, cooling the liquid to room temperature to obtain a mixed solution I;

adding the vitamin E with the prescription amount into the Tween 80 with the prescription amount, and stirring to dissolve the vitamin E to obtain a mixed solution II. Then, transferring the mixed solution into the first mixed solution to obtain a third mixed solution;

adding the prescribed amount of edetate disodium, acesulfame potassium and sodium carboxymethylcellulose into the mixed solution III, and stirring to dissolve to obtain a mixed solution IV;

weighing prescription dose of vitamin D₃Preparation of vitamin D₃Adding the ethanol solution into the mixed solution IV;

and adding the orange flavor with the prescription amount into the mixed solution IV, and adjusting the pH value to 3.8 by using a 20% hydrochloric acid (V/V) solution. Fixing the volume to the required volume by water;

filtering by adopting a polypropylene filter element with the aperture of 10 mu m; the obtained vitamin oral liquid has viscosity of 150cp at 30 deg.C.

Subpackaging the filtered liquid medicine into clean brown glass bottles, and capping.

Example 2

This example provides a vitamin oral liquid and a method for preparing the same. It is the same as example 1, except that: the concentration of sorbitol in the vitamin oral liquid is 250g/L, the mass ratio of vitamin E (the content is 15mg/15ml) to sorbitol to Tween 80 is 1: 250: 6. the content of the sodium carboxymethyl cellulose is 153mg/15mL, namely the mass-volume ratio of the sodium carboxymethyl cellulose to the water in the mixed solution III is 17 mg/mL. Vitamin D₃The mass ratio of the sodium carboxymethyl cellulose to the sodium carboxymethyl cellulose is 1: 10000. the obtained vitamin oral liquid has viscosity of 50cp at 30 deg.C.

Example 3

This example provides a vitamin oral liquid and a method for preparing the same. It is the same as example 1, except that: the concentration of sorbitol in the vitamin oral liquid is 350g/L, the mass ratio of vitamin E (the content is 15mg/15ml) to sorbitol to Tween 80 is 1: 350: 8. the content of the sodium carboxymethyl cellulose is 207mg/15mL, namely the mass-volume ratio of the sodium carboxymethyl cellulose to the water in the mixed solution III is 23 mg/mL. Vitamin D₃The mass ratio of the sodium carboxymethyl cellulose to the sodium carboxymethyl cellulose is 1: 14000. the obtained vitamin oral liquid has viscosity of 220cp at 30 deg.C.

Example 4

This example provides a vitamin oral liquid and a method for preparing the same. The vitamin oral liquid is shown in table 2.

TABLE 2

Weighing purified water with the prescription amount of 60%, adding sorbitol with the prescription amount, and heating and stirring to dissolve (the temperature is controlled to be 80-90 ℃). Then sequentially adding the prescribed amount of vitamin B₂Stirring to dissolve. After dissolving, cooling the liquid to room temperature to obtain a mixed solution I;

adding the prescribed amount of vitamin B into the mixed solution III₆Stirring and dissolving nicotinamide, edetate disodium, acesulfame potassium and sodium carboxymethylcellulose to obtain a mixed solution IV;

Example 5

This example provides a vitamin oral liquid and a method for preparing the same. The vitamin oral liquid is shown in table 3.

TABLE 3

Weighing purified water with the prescription amount of 60%, adding sorbitol with the prescription amount, and heating and stirring to dissolve (the temperature is controlled to be 80-90 ℃). Then sequentially adding the prescribed amount of vitamin B₂And stirring the calcium lactate to dissolve. After dissolving, cooling the liquid to room temperature to obtain a mixed solution I;

adding the prescribed amount of vitamin B into the mixed solution III₆Lysine hydrochloride, vitamin B₁Nicotinamide, edetate disodium, acesulfame potassium, D-panthenol and sodium carboxymethylcellulose are stirred to be dissolved to obtain a mixed solution IV;

filtering by adopting a polypropylene filter element with the aperture of 10 mu m; the obtained vitamin oral liquid has viscosity of 162cp at 30 deg.C.

Comparative example 1

The present comparative example provides a vitamin oral liquid and a method of preparing the same. It is the same as the formulation of example 1, except that: during preparation, the specific operation is as follows:

weighing purified water with the prescription amount of 60%, and sequentially adding sorbitol, tween 80, edetate disodium, acesulfame potassium, sodium carboxymethylcellulose and vitamin B₂Heating and stirring to dissolve (the temperature is controlled at 80-90 ℃). After dissolution, the mixture was cooled to room temperature to obtain a mixed solution A.

Mixing vitamin E and vitamin D₃Mixing with ethanol, adding into the mixed solution A, and emulsifying for 5min to obtain mixed solution B.

And adding the orange flavor with the prescription amount into the mixed solution B, and adjusting the pH value to 3.8 by using 20% hydrochloric acid (V/V). Fixing the volume to the required volume by water;

filtering by adopting a polypropylene filter element with the aperture of 10 mu m;

Comparative example 2

weighing purified water with the prescription amount of 60%, and sequentially adding sorbitol, tween 80, edetate disodium, acesulfame potassium, ethanol, sodium carboxymethylcellulose, vitamin E and vitamin D₃Vitamin B₂Heating and stirring to dissolve (the temperature is controlled to be 80-90 ℃) to obtain a mixed solution. After dissolution, the mixture was cooled to room temperature.

The orange flavor with the prescription amount is added into the mixed solution, and the pH value is adjusted to 3.8 by 20 percent hydrochloric acid (V/V). Fixing the volume to the required volume by water;

Comparative example 3

The present comparative example provides a vitamin oral liquid and a method of preparing the same. It is the same as example 1, except that: the surfactant is poloxamer 188; the mass ratio of the vitamin E (the content is 15mg/15ml), the sorbitol and the surfactant is 1: 300: 35.

comparative example 4

The present comparative example provides a vitamin oral liquid and a method of preparing the same. It is the same as example 1, except that: the thickening agent is syrup (sucrose aqueous solution with 45% w/v concentration); vitamin D₃(content 15 microgram/15 ml) and the thickening agent in a mass ratio of 1: 2250000.

the preparation method comprises the following specific steps: weighing purified water with the prescription amount of 40%, adding sorbitol and sucrose with the prescription amount, and heating and stirring to dissolve. Then adding prescribed amount of vitamin B₂Stirring to dissolve the mixture (the temperature is controlled to be 80-90 ℃). After dissolving, cooling the liquid to room temperature to obtain a mixed solution;

the prescribed amount of vitamin E was added to the prescribed amount of tween 80 and stirred to dissolve. Transferring the mixture into a mixed solution;

adding the edetate disodium and the acesulfame potassium in the formula amount into the mixed solution, and stirring to dissolve;

weighing prescription dose of vitamin D₃Preparation of vitamin D₃EthanolAdding the solution into the mixed solution;

filtering by adopting a polypropylene filter element with the aperture of 10 mu m; the obtained vitamin oral liquid has viscosity of 80cp at 30 deg.C.

Comparative example 5

The present comparative example provides a vitamin oral liquid and a method of preparing the same. It is the same as example 1, except that: the amount of sorbitol is 100g/L, and 1g/L sodium benzoate is added when thickener is added.

Experimental example 1

This experimental example tests the content of active substance of the vitamin oral liquid prepared in examples 1 to 5 and comparative examples 1 to 5, according to the following test methods:

(1) calcium carbonate

Taking 4.5ml of a sample to be tested, precisely weighing, adding 50ml of water, adding 15ml of sodium hydroxide test solution and 0.1g of calcium purpurin indicator, and titrating by using ethylene diamine tetraacetic acid disodium titrating solution (0.05mol/L) until the solution turns from brown red to green. Each 1ml of disodium EDTA titrate (0.05mol/L) corresponds to 2.004mg of calcium.

(2) Vitamin B₁Vitamin B₆Nicotinamide and vitamin B₂

And (4) avoiding light.

Preparing a reference substance solution: taking reference substance vitamin B₁15mg of vitamin B₆23mg, nicotinamide 65mg, vitamin B₂Precisely weighing 26mg, placing in a 100ml brown measuring flask, adding mobile phase A to dissolve and fix the volume to scale, shaking up, precisely weighing 5ml of the solution, placing in a 50ml brown measuring flask, fixing the volume to scale with mobile phase A, and shaking up to obtain a control solution.

Preparing a test solution: weighing 15ml of a to-be-detected product, precisely weighing the to-be-detected product in a 100ml brown measuring flask, fixing the volume to scale by using the mobile phase A, shaking up, fully dissolving the product by ultrasonic for a plurality of minutes, filtering the solution by using a 0.45 mu m filter membrane, and discarding the primary filtrate to obtain the product.

Performing high performance liquid chromatography (0512 in the general regulation of Chinese pharmacopoeia 2015 edition), and using octadecylsilane chemically bonded silica as filler; adjusting pH to 3.7 with 0.03mol/L potassium dihydrogen phosphate-methanol (98: 2) in 10% phosphoric acid solution to obtain mobile phase A and methanol as mobile phase B; the following Table 4 was used for linear gradient elution, and vitamin B was calculated by peak area according to the external standard method₁Vitamin B₆Nicotinamide and vitamin B₂Content (c); the chromatographic conditions are shown in Table 4.

TABLE 4 chromatographic conditions

(3) Vitamin E

Preparing a reference substance solution: taking a proper amount of vitamin E reference substance, precisely weighing, adding mobile phase for dissolving, and quantitatively weighing to obtain solution containing 0.10mg per 1ml as reference substance solution.

Preparing a test solution: taking 5ml of a sample to be tested, precisely weighing, placing in a 50ml brown measuring flask, adding a mobile phase for dissolving, fixing the volume to scale, shaking up, precipitating for 15 minutes, taking supernatant, filtering through a 0.45 mu m filter membrane, and discarding primary filtrate to serve as a sample solution.

Performing high performance liquid chromatography (0512 in the general regulation of Chinese pharmacopoeia 2015 edition), and using octadecylsilane chemically bonded silica as filler; methanol-tetrahydrofuran (90: 10) is used as a mobile phase; calculating the content of vitamin E according to the peak area by an external standard method; the vitamin E chromatographic detection conditions are shown in Table 5.

TABLE 5 vitamin E chromatographic assay conditions

(4) D-panthenol

Preparing a reference substance solution: taking a proper amount of D-panthenol as a reference substance, precisely weighing, adding the mobile phase A for dissolving, and quantitatively weighing to obtain a solution containing 60 μ g of D-panthenol per 1ml as a reference substance solution.

Preparing a test solution: taking 4ml of a sample to be tested, precisely weighing, placing in a 50ml brown measuring flask, adding the mobile phase A for dissolving, fixing the volume to scale, shaking up, filtering through a 0.45 mu m filter membrane, and discarding the primary filtrate to serve as a sample solution.

Performing high performance liquid chromatography (0512 in the general regulation of Chinese pharmacopoeia 2015 edition), and using octadecylsilane chemically bonded silica as filler; taking acetonitrile (98: 2), which is 0.01mol/L potassium dihydrogen phosphate solution, as a mobile phase A, and taking acetonitrile as a mobile phase B; performing linear gradient elution according to the following table, and calculating the content of D-panthenol by peak area according to an external standard method; the chromatographic detection conditions are shown in Table 6.

TABLE 6 chromatographic detection conditions for D-panthenol

(5) Lysine hydrochloride

Preparing a reference substance solution: lysine hydrochloride reference substance 60mg, precisely weighing, placing in a 50ml measuring flask, adding water 5ml, dissolving thoroughly with ultrasound for several minutes, diluting with water to scale, shaking up, and using as reference substance solution.

Preparing a test solution: precisely measuring 3ml of a sample to be tested, placing the sample in a 50ml measuring flask, adding 30ml of water, carrying out ultrasonic treatment for several minutes to fully dissolve the sample, adding a magnetic core, placing the sample on a magnetic stirrer to stir for 30 minutes, taking out the magnetic core, washing the magnetic core with water, merging washing liquor into the measuring flask, diluting the washing liquor to a scale with water, shaking up the solution, filtering the solution through a 0.45-micrometer filter membrane, and discarding primary filtrate to serve as a sample solution.

Preparing blank auxiliary materials: precisely measuring blank auxiliary material 3ml, placing in a 50ml measuring flask, adding water 30ml, performing ultrasonic treatment for several minutes to fully dissolve, adding magnetic core, placing on a magnetic stirrer to stir for 30 minutes, taking out the magnetic core, washing the magnetic core with water, adding washing liquid into the measuring flask, diluting with water to scale, shaking up, filtering with 0.45 μm filter membrane, and discarding the primary filtrate as blank auxiliary material solution.

Performing high performance liquid chromatography (0512 in the general regulation of Chinese pharmacopoeia 2015 edition), and using octadecylsilane chemically bonded silica as filler; phosphate buffer solution (2.2822 g of dipotassium hydrogen phosphate is taken, water is added for dissolution and dilution to 1000ml, after the pH value is adjusted to 4.8 by phosphoric acid, 1.08g of sodium octane sulfonate) -acetonitrile (895: 105) is added as a mobile phase, the flow rate is 2.0ml/min, and the detection wavelength is 203 nm. And calculating the content of the lysine hydrochloride by peak area according to an external standard method.

The chromatographic conditions are shown in Table 7.

TABLE 7 chromatographic assay conditions for lysine hydrochloride

(6) Vitamin D₃

And (4) avoiding light.

Preparing a reference substance solution: collecting vitamin D₃The appropriate amount of the control was precisely weighed, dissolved with a mobile phase and quantitatively adjusted to a solution containing 6. mu.g per 1ml, as a control solution.

Preparing a test solution: precisely measuring 15ml of a sample to be tested, placing the sample into a 250ml separating funnel, washing the inner wall of a pipette tube by 20ml of water in a dividing funnel, merging washing liquor into the separating funnel, extracting by using chloroform for 3 times, 30ml each time, filtering an extracting solution into a 250ml round-bottom flask through filter paper paved with anhydrous sodium sulfate, washing the filter paper by using a small amount of chloroform, merging filtrate into the flask, evaporating the filtrate in a water bath with the temperature below 40 ℃ under reduced pressure, precisely adding 3ml of a mobile phase into the flask, shaking, carrying out ultrasonic treatment for several minutes to dissolve residues, filtering through a 0.45 mu m filter membrane, and discarding the filtrate at first time to obtain a sample solution.

Performing high performance liquid chromatography (0512 in the general regulation of Chinese pharmacopoeia 2015 edition), and using octadecylsilane chemically bonded silica as filler; acetonitrile-methanol-water (870: 117: 13) is used as a mobile phase; calculating vitamin D by peak area according to external standard method₃Content (c); vitamin D₃The chromatographic detection conditions are shown in Table 8.

TABLE 8 vitamin D₃Chromatographic test stripPiece

(7) Limit of microorganism

The detection is carried out according to the method of 3300 general rules of the 2020 version (four departments) of the Chinese pharmacopoeia.

The results of three replicates of each particular item are shown in table 9.

TABLE 9

Wherein, the oral liquid of the contrast 3-4 does not meet the general requirements of products, so the oral liquid is not further detected.

In example 4, vitamin B₆The content of (B) is 5.92 (+ -0.06) mg/15ml, the content of nicotinamide is 20.11 (+ -0.13) mg/15 ml.

In example 5, the calcium content was 122.24 (+ -1.22) mg/15ml, vitamin B₁The content of (A) is 3.05 (+ -0.04) mg/15ml, vitamin B₆The content of (B) is 5.93 (+ -0.04) mg/15ml, the content of nicotinamide is 19.92 (+ -0.13) mg/15ml, the content of D-panthenol is 14.00 (+ -0.10) mg/15ml, and the content of lysine hydrochloride is 309.98 (+ -2.42) mg/15 ml.

Experimental example 2

This experimental example was conducted to test the stability of the vitamin oral liquids prepared in examples 1 to 5 and comparative example 5 (wherein, vitamin E and vitamin D are shown in comparative examples 1 to 2)₃The content is low, the properties of the oral liquid obtained in the comparative examples 3-4 do not meet the requirements, so further investigation is not carried out), and a test methodThe following were used:

after leaving under accelerated conditions (40 ℃ C. + -. 5 ℃ C., 75% RH. + -. 10% RH) for 1, 2, 3, and 6 months, the test was conducted by the method described in Experimental example 1.

The results of three parallel experiments are shown in tables 10-15:

TABLE 10 test results of example 1

Table 11 test results of example 2

Table 12 test results of example 3

TABLE 13 test results of example 4

TABLE 14 test results of example 5

The oral liquid of example 5 was used to accelerate microbial limit detection after 1, 2, 3, and 6 monthsNumber 10²cfu/ml, the total number of mould and yeast is 10cfu/ml, and the requirements of Escherichia coli and salmonella can not be detected.

TABLE 15 test results of comparative example 5

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A method for preparing vitamin oral liquid containing vitamin B₂Vitamin D and vitamin E, characterized in that it comprises:

(4) adding an ethanol solution of vitamin D into the mixed solution IV;

the concentration of the sorbitol in the vitamin oral liquid is 250-350 g/L;

the surfactant is tween 80; the mass ratio of the vitamin E, the sorbitol and the Tween 80 is 1: (250-350): (6-8);

the thickening agent is sodium carboxymethyl cellulose; the molecular weight of the sodium carboxymethyl cellulose is 90000-120000; the mass-volume ratio of the sodium carboxymethylcellulose to the water in the mixed solution III is 17-23 mg/mL;

the mass ratio of the vitamin D to the sodium carboxymethyl cellulose is 1: (10000-14000).

2. The method of claim 1, wherein the concentration of sorbitol in the vitamin oral liquid is 300 g/L.

3. The method according to any one of claims 1-2, wherein in step (1), further comprising the step of adding a first active substance to the aqueous solution of sorbitol; the first active substance is a poorly soluble drug;

and/or, in the step (3), a step of adding a second active substance into the third mixed solution is further included; the second active substance is a freely soluble drug.

4. The method of claim 3, wherein the first active agent is vitamin B₁₂One or more of calcium lactate and calcium glycerophosphate; the second active substance is vitamin B₁Vitamin B₆One or more of vitamin C, lysine hydrochloride, nicotinamide and D-panthenol.

5. The method of claim 1,

the temperature of the aqueous solution of sorbitol is 80-90 ℃; the temperature of the mixed liquid I is 20-30 ℃;

and/or, in the step (3), a step of adding a metal ion complexing agent and a sweetening agent is further included;

and/or, after the step (4), the step of adding a flavoring agent and a pH regulator is further included.

6. A vitamin oral liquid, characterized in that it is prepared by the method according to any one of claims 1 to 5.

7. The vitamin oral liquid according to claim 6, wherein the viscosity of the vitamin oral liquid is 50-220 cp at 30 ℃; the pH value is 3.0-4.5.

8. Use of a method according to any one of claims 1 to 5 for the preparation of a vitamin-containing oral liquid.