CN113350374B - Preparation method of calcium phosphate and vitamin D composite microcapsule - Google Patents
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Abstract
The invention discloses a preparation method of a calcium phosphate and vitamin D composite microcapsule, wherein a hydrogen phosphate aqueous solution is used as an internal water phase, vitamin D is dissolved in an organic solvent, and an emulsifier is added to emulsify to form W/O type colostrum. The calcium salt water solution is used as an external water phase, and an emulsifier is added to emulsify to form W/O/W multiple emulsion. The hydrogen phosphate and calcium salt in the inner and outer water phases react to generate calcium phosphate in different forms, and vitamin D is absorbed in the calcium phosphate to form a core material. Adding the capsule core material into sodium alginate solution, reacting with calcium salt to generate calcium alginate, coating calcium phosphate and vitamin D, solidifying to obtain capsule, settling, washing, and drying. The microcapsule prepared by the invention is obtained by a double emulsification method and calcium alginate sedimentation, and the vitamin D and the calcium phosphate are uniformly mixed, so that the microcapsule has high encapsulation efficiency and good stability. The invention is a microcapsule preparation, which is beneficial to the absorption of a calcium supplement preparation in the gastrointestinal tract.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of a calcium phosphate and vitamin D composite microcapsule.
Background
Calcium is the most abundant mineral element in human body, accounts for 1.5% -2.0% of human body weight, and most of calcium in human body is intensively distributed in bones and teeth in the form of phosphate crystals. The body requires the participation of calcium for all life processes. According to the investigation of Chinese medical society, the number of people with calcium deficiency in China is as high as 9 hundred million, and the number of people with calcium deficiency is 2 hundred million, wherein infants, pregnant and lying-in women and old people are particularly prominent.
When calcium is not ingested sufficiently, oral administration of a calcium-containing preparation is an effective calcium supplement method, and currently commercially available calcium supplements are mainly classified into inorganic calcium and organic calcium. The inorganic calcium comprises calcium carbonate, calcium sulfate and the like, and the calcium preparation has poor solubility, large irritation to stomach, low bioavailability and low bone compatibility. Vitamin D in the calcium supplement is beneficial to the absorption and utilization of calcium and regulates the metabolism of calcium and phosphorus in vivo. However, since vitamin D is used in a small amount (about 1% of calcium content), it is difficult to uniformly mix a calcium-containing compound and an auxiliary material in a solid preparation such as a tablet, and vitamin D is susceptible to a reduction in stability caused by high temperature, oxidation, an acidic medium, and the like.
Based on the analysis, a calcium supplement which is added with vitamin D and has strong vitamin D stability and high calcium utilization degree and can effectively solve the problem that the traditional calcium phosphate and vitamin D are suddenly released in the intestinal tract is urgently needed in the industry at present.
Disclosure of Invention
The invention aims to provide a composite microcapsule preparation with a calcium supplementing function and a preparation method thereof. The calcium phosphate in the composite microcapsule preparation produced according to the invention has good bone compatibility, and the vitamin D promotes the absorption of calcium, can improve the stability of the vitamin D and is beneficial to the absorption of the calcium supplement preparation in intestinal tracts. The invention provides a preparation method of a calcium phosphate and vitamin D composite microcapsule, which is prepared by adsorbing vitamin D in calcium phosphate as a capsule core and taking calcium alginate as a capsule wall material.
The invention is realized by the following technical scheme:
a preparation method of calcium phosphate and vitamin D composite microcapsule comprises raw materials of hydrogen phosphate, calcium salt, vitamin D, emulsifier, sodium hydroxide and sodium alginate.
After the pH of the aqueous solution of the hydrogen phosphate is adjusted, the aqueous solution of the hydrogen phosphate is used as an internal water phase and is mixed with an oil phase for dissolving vitamin D to generate W/O type colostrum under the action of a W/O type emulsifier, and the colostrum and the calcium salt solution form W/O/W type multiple emulsion under the action of the O/W type emulsifier; stirring to make the hydrogen phosphate in internal water phase react with calcium salt in external water phase to generate calcium phosphate, drying, adsorbing vitamin D in calcium phosphate to form capsule core, and solidifying with calcium alginate to obtain the final product.
Further, the hydrogen phosphate may be Na2HPO4、K2 HPO4、(NH4)2HPO4The concentration of the soluble phosphate is 0.2-2.0 mol/L; the calcium salt is CaCl2、Ca(NO3)2And soluble calcium salts such as calcium acetate, the concentration of which is 0.05-0.5 mol/L. The molar ratio of the calcium salt to the hydrogen phosphate is 0.5-2.0.
Further, the calcium salt is CaCl2The molar ratio of the calcium salt to the hydrogen phosphate is 1.5-2.0.
Further, the vitamin D is selected from one or more of vitamin D2 and vitamin D3.
Further, the vitamin D is vitamin D3 or a mixture with vitamin D2.
Further, the organic solvent is one or a mixed solvent of dichloromethane, ethyl acetate, acetone and diethyl ether which are insoluble with water and have low boiling point.
Further, the organic solvent is dichloromethane or a mixed solvent of dichloromethane and ethanol.
Further, sodium alginate with the concentration of 1-3% and calcium salt are used for the curing microcapsule, and insoluble calcium alginate is generated through reaction and attached to the surface of the capsule core and is obtained through curing.
Further, the concentration of the sodium alginate solution is 1.5 percent, and CaCl is dripped2The concentration of the solution is 2.0%, and the reaction time is 30-60 minutes after stirring.
By adjusting the HPO in the internal aqueous phase4 2-With Ca in the external aqueous phase2+To form different forms of calcium phosphate, including: calcium dihydrogen phosphate, calcium hydrogen phosphate, octacalcium phosphate, tricalcium phosphate, hydroxyapatite and tetracalcium phosphate.
Further, the calcium phosphate is hydroxyapatite or a mixture of the calcium phosphate and tetracalcium phosphate.
The invention has the beneficial effects that:
the composite microcapsule of calcium phosphate and vitamin D is prepared and used as a calcium supplement, the vitamin D can promote the absorption of calcium, the calcium phosphate and the calcium phosphate in bones have good compatibility, the microcapsule has smaller grain diameter, swells, adheres and stays at the absorption part to prolong the absorption time, and the utilization rate of calcium is improved; the microcapsule prepared by the method can ensure that the vitamin D is adsorbed on the surface of the calcium phosphate, the vitamin D and the calcium phosphate are uniformly mixed, burst release is avoided, and the drug effect is mild and reliable; in addition, the prepared microcapsule can isolate external influence factors and improve the stability of vitamin D.
The capsule core material is prepared by a multiple emulsion-desolventizing method, and the form of calcium phosphate can be controlled; because the dosage of the vitamin D is small, the calcium phosphate and the vitamin D can be uniformly mixed by the method; after the microcapsule is prepared, the stability of vitamin D is improved. The calcium alginate is the capsule membrane of the microcapsule, is natural polymer material, can increase calcium content of the preparation, and can reduce introduction of other components.
Drawings
Figure 1 is a composite calcium phosphate and vitamin D microcapsule;
FIG. 2 is a composite microcapsule observed under an optical microscope;
FIG. 3 is a composite microcapsule observed under a scanning electron microscope;
FIG. 4 shows the results of differential scanning calorimetry of the obtained composite microcapsules;
fig. 5 is a schematic diagram of the preparation process of the composite microcapsule.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. The following detailed description is intended to be illustrative rather than restrictive, and is not intended to limit the scope of the invention.
Example 1
Taking 20mg/L vitamin D3 dichloromethane solution, adding span 801.5 mL for dissolving, stirring and adding 5mL Na with concentration of 0.50mol/L2HPO4Adding the solution (pH adjusted to 10.0 with NaOH solution), mixing, and high-speed shearing to obtain W/O type colostrum. Adding the colostrum into 40mL CaCl with the concentration of 0.10mol/L2And 4mL of Tween-80 is added into the solution, and W/O/W type multiple emulsion is formed after ultrasonic treatment. Stirring at 30 deg.C for 5 hr, using multiple emulsion system as microreactor, and adding Na in internal and external water phases2HPO4With CaCl2The reaction takes place to form calcium phosphate, in which vitamin D3 is adsorbed. Rotary evaporating to remove dichloromethane, washing with water, centrifuging, and drying to obtain capsule core material. Adding the capsule core material into 100mL of 1.5% sodium alginate solution, stirring, and adding 2.0% CaCl dropwise2And (3) continuing stirring for 45min in the solution, standing, washing twice after precipitation, and drying to obtain the product. The calcium content was measured by atomic absorption spectrophotometry, the phosphorus content was measured by molybdenum blue colorimetry (phosphorus assay 3103 in the four-part general rule of the chinese pharmacopoeia 2020 edition), the vitamin D content was measured by high performance liquid chromatography, and the particle size of the microcapsules was measured by dynamic laser scattering method, the results are shown in table 1.
Example 2
Collecting vitamin D3 dichloromethane solution with concentration of 30mg/L, adding span 801.5 mL for dissolving, stirring, adding 5mL Na with concentration of 1.0mol/L2HPO4Adding the solution (pH adjusted to 8.5 with NaOH solution), mixing, and high-speed shearing to obtain W/O type colostrum. Adding 40mL of 0.20mol/L Ca (NO) into the colostrum3)2Adding 4mL of Tween-80 into the solution, and performing ultrafiltrationForming W/O/W type multiple emulsion after sounding. Stirring at 30 deg.C for 6 hr, using multiple emulsion system as microreactor, and adding Na in internal and external water phases2HPO4With Ca (NO)3)2The reaction takes place to form calcium phosphate, in which vitamin D3 is adsorbed. Adding the capsule core material into 100mL of 1.0% sodium alginate solution, stirring, and adding 2.0% CaCl dropwise2And (4) continuing stirring for 45min in the solution, standing, washing twice after precipitation, and drying to obtain the product. The calcium content was measured by atomic absorption spectrophotometry, the phosphorus content was measured by molybdenum blue colorimetry (phosphorus assay 3103 in the four-part general rule of the chinese pharmacopoeia 2020), the vitamin D content was measured by high performance liquid chromatography, and the particle size of the microcapsules was measured by dynamic laser scattering, the results of which are shown in table 1.
Example 3
Collecting 40mg/L vitamin D (containing vitamin D2 and vitamin D3) dichloromethane solution, adding span 801.5 mL to dissolve, stirring, adding 5mL Na with 2.0mol/L molar concentration2HPO4Adding the solution (pH adjusted to 8.5 with NaOH solution), mixing, and high-speed shearing to obtain W/O type colostrum. Adding the colostrum into 40mL CaCl with concentration of 0.50mol/L2And 4mL of Tween-80 is added into the solution, and W/O/W type multiple emulsion is formed after ultrasonic treatment. Stirring at 30 deg.C for 4 hr, using multiple emulsion system as microreactor, and adding Na in internal and external water phases2HPO4With CaCl2The reaction takes place to form calcium phosphate, in which vitamin D is adsorbed. Rotary evaporating to remove dichloromethane, washing with water, centrifuging, and drying to obtain capsule core material. Adding the capsule core material into 100mL of 2.0% sodium alginate solution, stirring, and adding 2.0% CaCl dropwise2And (4) continuing stirring for 45min in the solution, standing, washing twice after precipitation, and drying to obtain the product. The calcium content was measured by atomic absorption spectrophotometry, the phosphorus content was measured by molybdenum blue colorimetry (phosphorus assay 3103 in the four-part general rule of the chinese pharmacopoeia 2020), the vitamin D content was measured by high performance liquid chromatography, and the particle size of the microcapsules was measured by dynamic laser scattering, the results of which are shown in table 1.
Example 4
Taking 20mg/L vitamin D3 dichloromethane solution, adding span 801.5 mL solutionThen, 5mL of (NH) with a concentration of 1.0mol/L was added with stirring4)2HPO4The solution (NaOH solution is adjusted to pH 6.5), mixed evenly and sheared at high speed to form W/O type colostrum. Adding 40mL CaCl with concentration of 0.06mol/L into the primary emulsion2And 4mL of Tween-80 is added into the solution, and W/O/W type multiple emulsion is formed after ultrasonic treatment. Stirring for 1 hour at 30 deg.C, using multiple emulsion system as microreactor, and adding (NH) in internal and external water phases4)2HPO4With CaCl2The reaction takes place to form calcium phosphate, in which vitamin D3 is adsorbed. Rotary evaporating to remove dichloromethane, washing with water, centrifuging, and drying to obtain capsule core material. Adding the capsule core material into 100mL of 3.0% sodium alginate solution, stirring, and adding 2.0% CaCl dropwise2And (4) continuing stirring for 45min in the solution, standing, washing twice after precipitation, and drying to obtain the product. The calcium content was measured by atomic absorption spectrophotometry, the phosphorus content was measured by molybdenum blue colorimetry (phosphorus assay 3103 in the four-part general rule of the chinese pharmacopoeia 2020 edition), the vitamin D content was measured by high performance liquid chromatography, and the particle size of the microcapsules was measured by dynamic laser scattering method, the results are shown in table 1.
Example 5
Collecting 30mg/L vitamin D (mixture of vitamin D2 and vitamin D3) dichloromethane solution, adding span 801.5 mL to dissolve, stirring, adding 5mL (NH) with concentration of 0.50mol/L4)2HPO4The solution (NaOH solution is adjusted to pH 12.0), mixed evenly and sheared at high speed to form W/O type colostrum. Adding 40mL of 0.10mol/L Ca (NO) into the colostrum3)2And 4mL of Tween-80 is added into the solution, and W/O/W type multiple emulsion is formed after ultrasonic treatment. Stirring at 30 deg.C for 5 hr, using multiple emulsion system as microreactor, and adding (NH) in internal and external water phases4)2HPO4With Ca (NO)3)2The reaction takes place to form calcium phosphate, in which vitamin D is adsorbed. The dichloromethane was removed by rotary evaporation, washed with water, centrifuged and dried to give the core. Adding the capsule core material into 100mL of 1.5% sodium alginate solution, stirring, and adding 2.0% CaCl dropwise2And (4) continuing stirring for 45min in the solution, standing, washing twice after precipitation, and drying to obtain the product. By usingThe calcium content was measured by atomic absorption spectrophotometry, the phosphorus content was measured by molybdenum blue colorimetry (phosphorus assay 3103 in the four-part general rule of the chinese pharmacopoeia 2020 edition), the vitamin D content was measured by high performance liquid chromatography, and the particle size of the microcapsules was measured by dynamic laser scattering method, the results are shown in table 1.
Example 6
Taking 20mg/L vitamin D3 dichloromethane solution, adding span 801.5 mL for dissolving, stirring and adding 5mL K with concentration of 0.20mol/L2HPO4Adding the solution (pH adjusted to 10.0 with NaOH solution), mixing, and high-speed shearing to obtain W/O type colostrum. Adding 40mL CaCl with concentration of 0.05mol/L into the primary emulsion2And 4mL of Tween-80 is added into the solution, and W/O/W type multiple emulsion is formed after ultrasonic treatment. At 30 ℃, continuously stirring for 3 hours, taking a multiple emulsion system as a micro-reactor, and taking K in the internal and external water phases2HPO4With CaCl2The reaction takes place to form calcium phosphate, in which vitamin D3 is adsorbed. The dichloromethane was removed by rotary evaporation, washed with water, centrifuged and dried to give the core. Adding the capsule core material into 100mL of 1.5% sodium alginate solution, stirring, and adding 2.0% CaCl dropwise2And (3) continuing stirring for 45min in the solution, standing, washing twice after precipitation, and drying to obtain the product. The calcium content was measured by atomic absorption spectrophotometry, the phosphorus content was measured by molybdenum blue colorimetry (phosphorus assay 3103 in the four-part general rule of the chinese pharmacopoeia 2020 edition), the vitamin D content was measured by high performance liquid chromatography, and the particle size of the microcapsules was measured by dynamic laser scattering method, the results are shown in table 1.
Example 7
Taking 30mg/L vitamin D3 dichloromethane solution, adding span 801.5 mL for dissolving, stirring and adding 5mL K with concentration of 0.50mol/L2HPO4Adding the solution (pH adjusted to 8.5 with NaOH solution), mixing, and high-speed shearing to obtain W/O type colostrum. Adding 40mL of 0.40mol/L Ca (NO) into the colostrum3)2Adding 4mL of Tween-80 into the solution, and performing ultrasonic treatment to form W/O/W type multiple emulsion. At 30 ℃, continuously stirring for 5 hours, taking a multiple emulsion system as a micro-reactor, and taking K in the internal and external water phases2HPO4With Ca (NO)3)2The reaction is carried out to generate calcium phosphate, vitamin D3 is absorbedAttached to calcium phosphate. The dichloromethane was removed by rotary evaporation, washed with water, centrifuged and dried to give the core. Adding the capsule core material into 100mL of 2.0% sodium alginate solution, stirring, and adding 2.0% CaCl dropwise2And (4) continuing stirring for 45min in the solution, standing, washing twice after precipitation, and drying to obtain the product. The calcium content was measured by atomic absorption spectrophotometry, the phosphorus content was measured by molybdenum blue colorimetry (phosphorus assay 3103 in the four-part general rule of the chinese pharmacopoeia 2020 edition), the vitamin D content was measured by high performance liquid chromatography, and the particle size of the microcapsules was measured by dynamic laser scattering method, the results are shown in table 1.
Example 8
Collecting 40mg/L vitamin D (containing vitamin D2 and vitamin D3) dichloromethane solution, adding span 801.5 mL to dissolve, stirring, adding 5mL 2.00mol/L K2HPO4Adding the solution (pH adjusted to 10.0 with NaOH solution), mixing, and high-speed shearing to obtain W/O type colostrum. Adding 40mL CaCl with concentration of 0.40mol/L into the primary emulsion2Adding 4mL of Tween-80 into the solution, and performing ultrasonic treatment to form W/O/W type multiple emulsion. At 30 ℃, continuously stirring for 5 hours, taking a multiple emulsion system as a micro-reactor, and taking K in the internal and external water phases2HPO4With CaCl2The reaction takes place to form calcium phosphate, in which vitamin D is adsorbed. The dichloromethane was removed by rotary evaporation, washed with water, centrifuged and dried to give the core. Adding the capsule core material into 100mL of 1.5% sodium alginate solution, stirring, and adding 2.0% CaCl dropwise2And (4) continuing stirring the solution for 60min, standing the solution, washing the solution twice after precipitation, and drying the solution to obtain the product. The calcium content was measured by atomic absorption spectrophotometry, the phosphorus content was measured by molybdenum blue colorimetry (phosphorus assay 3103 in the four-part general rule of the chinese pharmacopoeia 2020 edition), the vitamin D content was measured by high performance liquid chromatography, and the particle size of the microcapsules was measured by dynamic laser scattering method, the results are shown in table 1.
TABLE 1 calcium phosphate and vitamin D composite microcapsule composition Table
From DSC, the core material composed of calcium phosphate and vitamin D is aggregated in a powder state, and vitamin D is uniformly dispersed. From the results in table 1, it can be seen that: the calcium phosphate in the composite microcapsule prepared by the embodiment can be monocalcium phosphate, tricalcium phosphate, tetracalcium phosphate, hydroxyapatite or a mixture of the two, the calcium-phosphorus ratio is 0.69-2.02, and the composite microcapsule can have good compatibility with calcium phosphate in bones; the vitamin D is vitamin D3 or a mixture of vitamin D2, can promote absorption of calcium, and the stability of the vitamin D is improved by wrapping the capsule wall material; except for example 4, the calcium content of the other examples is about 40%, and the calcium content is higher. The particle size of the microcapsule is more than 1-3 mu m, the size is proper, and in addition, the capsule material calcium alginate can induce viscosity in digestive juice and is retained at an absorption part, so that the absorption of the microcapsule is facilitated.
The above description is only a preferred embodiment of the present invention, and for those skilled in the art, the present invention should not be limited by the description of the present invention, which should be interpreted as a limitation.
Claims (10)
1. A preparation method of calcium phosphate and vitamin D composite microcapsules comprises the following steps:
(1) preparing compound milk: taking a hydrogen phosphate solution as an internal water phase, adjusting the pH value to 6.5-12.0, dissolving vitamin D in an organic solvent, adding a water-in-oil type emulsifier as an oil phase, uniformly mixing the internal water phase and the oil phase, shearing at high speed to form W/O type colostrum, adding the colostrum into a calcium salt solution containing an oil-in-water type emulsifier, and performing ultrasonic treatment to obtain W/O/W type multiple emulsion;
(2) preparing a capsule core material: reacting the hydrogen phosphate with the calcium salt for 1-6 hours under stirring at 10-30 r/min, fully reacting, removing the organic solvent by rotary evaporation, centrifuging, washing and drying to obtain a calcium phosphate core material adsorbing vitamin D;
(3) formation of composite microcapsules: and adding the capsule core material into a sodium alginate solution with the concentration of 1-3% after swelling, dropwise adding a proper amount of a calcium salt solution while stirring, continuously stirring for 30-60 min, standing and curing to form a capsule, washing the precipitate twice, and drying to obtain the calcium phosphate and vitamin D composite microcapsule.
2. The production method according to claim 1, wherein:
the molar ratio of the calcium salt to the hydrogen phosphate is 0.5-2.0.
3. The production method according to claim 1, wherein:
the concentration of the hydrogen phosphate in the step (1) is 0.2-2 mol/L, and the hydrogen phosphate is selected from: na (Na)2HPO4、K2HPO4、(NH4)2HPO4。
4. The production method according to claim 1, wherein:
the concentration of the calcium salt in the step (1) is 0.05-0.5 mol/L, and the calcium salt is selected from the following components: CaCl2、Ca(NO3)2And calcium acetate.
5. The production method according to claim 1, wherein:
the vitamin D in the step (1) is selected from one or two of vitamin D2 and vitamin D3.
6. The method of claim 1, wherein:
the organic solvent in the step (1) is: one or more mixed solvents of dichloromethane, ethyl acetate, acetone and diethyl ether.
7. The method of claim 1, wherein:
the emulsifier is span in a W/O type surfactant acceptable in pharmacy, and one of Tween, British or poloxamer in an O/W type nonionic surfactant.
8. A calcium phosphate and vitamin D composite microcapsule prepared by the preparation method according to any one of claims 1 to 7.
9. The calcium phosphate and vitamin D composite microcapsule according to claim 8, wherein:
the composite microcapsule contains 25-45% of calcium and 2-50 ppm of vitamin D;
the average particle size of the composite microcapsule is 1-5 μm.
10. A method for preparing a calcium supplement using the calcium phosphate and vitamin D composite microcapsules of claim 8, comprising:
the compound microcapsule is used as an intermediate, and pharmaceutically acceptable auxiliary materials are further added to prepare granules, capsules and tablets.
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