CN118161463A - Vitamin D3-embedded core-shell composition and preparation method thereof - Google Patents

Vitamin D3-embedded core-shell composition and preparation method thereof Download PDF

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Publication number
CN118161463A
CN118161463A CN202410416829.3A CN202410416829A CN118161463A CN 118161463 A CN118161463 A CN 118161463A CN 202410416829 A CN202410416829 A CN 202410416829A CN 118161463 A CN118161463 A CN 118161463A
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vitamin
core
shell composition
oil
embedded
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王栋
李杨
李学明
王丹妮
胡子旋
黄凯宇
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Nanjing Bestform Pharmtech Co ltd
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Nanjing Bestform Pharmtech Co ltd
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Abstract

The invention discloses a vitamin D3-embedded core-shell composition and a preparation method thereof. The beneficial effects are that: the process route of the vitamin D3 embedded material with high yield and high stability ensures that the embedded vitamin D3 can be uniformly mixed with other raw materials and further processed into tablets, can withstand the pressure in a higher range of a tabletting process, has good stability of emulsion prepared in the process, has no demulsification, and has the yield of a finished product which is not lower than 90 percent, usually close to 99 percent, through the process of solidifying the emulsion into a shell layer by a fluidized bed drying mode; the core-shell composition embedded with vitamin D3 is further used as a preparation intermediate for developing compound tablets, chewable tablets and granules of calcium carbonate D3 of medicines and health products.

Description

Vitamin D3-embedded core-shell composition and preparation method thereof
Technical Field
The invention relates to the technical field of pharmacy, in particular to a vitamin D3-embedded core-shell composition and a preparation method thereof.
Background
Vitamin D (abbreviated as VD) is a fat-soluble vitamin containing 5 compounds, and is mainly VD3 and VD2, wherein the vitamin D is prepared by irradiating 7-dehydrocholesterol under human skin with ultraviolet rays, and the vitamin D is prepared by irradiating ergosterol contained in plants or yeast with ultraviolet rays. Wherein, VD3 is the most main active form of VD, can prevent or treat rickets, osteomalacia, osteoporosis, parathyroid hypofunction, infantile tetany, bone and muscle pain, etc. caused by calcium deficiency, and the senile people generally have osteoporosis problem, and especially need to supplement a certain amount of VD3.
VD3 is also called cholecalciferol and cholecalciferol, is white needle crystal, is easily dissolved in ethanol, acetone, diethyl ether and chloroform, is insoluble in water, is a nutrient necessary for normal calcification of bones in human and animals, and has the basic functions of promoting the absorption of calcium and phosphorus by intestinal tracts, ensuring the maintenance of normal level of calcium and phosphorus in blood and promoting the calcification of bones. The method is widely applied to the fields of feed additives, food additives, nutritional health products, medicines and the like at present, and the market demand is steadily increased.
Because VD3 is poorly water-soluble, has high physiological activity, and is extremely unstable under light and oxidative conditions, the application of VD3 to pharmaceutical products or nutritional supplements presents a major technical challenge. Mainly in two aspects:
Firstly, VD3 is used as an extremely unstable compound, and in order to ensure the stability of a product under long-term storage conditions, a high polymer material is generally required to be used for embedding raw medicines so as to reduce sensitivity to illumination, oxygen and the like. Secondly, the recommended daily supplementary dose of VD3 is 100-600IU (equivalent to 2.5-15 μg), which is very small and thus it is difficult to ensure even distribution in the final product. It is common practice to reduce this effect as much as possible by overdosing, but this also presents a safety hazard to the audience's health.
Aiming at the instability of VD3, the difficulty that the content uniformity is unqualified and the like in the preparation of a calcium carbonate D3 compound preparation, the vitamin D3 embedding substance which is stable, has proper fluidity and is convenient for tabletting needs to be developed.
Patent CN112569197a discloses a vitamin D3 composition, wherein a solution containing vitamin D3 is sprayed onto a sugar core by using a bottom spraying technique, and hydroxypropyl methylcellulose suspension is further sprayed as a protective layer, so that the stability and granularity of vitamin D3 are improved. However, the uniformity of mixing of the preparation described in the examples is inferior to that of the preparation of the present invention, and the stability of the calcium carbonate D3 tablet prepared in the examples is examined under long-term conditions (the temperature is 25 ℃), the addition amount of vitamin D3 in the preparation is very low, and the process of mixing with a large amount of auxiliary materials in the preparation can provide a certain protection effect, so that the protection effect of the technical process described in patent CN112569197a on vitamin D3 cannot be shown at 25 ℃.
Patent US20100158998 A1 discloses a stable formulation containing vitamin D3, which is prepared by spraying an emulsion containing vitamin D3 as an active layer onto the surface of inert pellets, spheres or beads, and further spraying a protective layer comprising hydroxypropyl methylcellulose, lactose and the like outside the active layer, wherein the components and types of solvents, antioxidants, emulsifiers, film forming agents and the like in the prescription are disclosed. However, the vitamin D3 formulation investigated in this patent was only stable for 3 months at 40 ℃ and 75% rh in a nitrogen filled container, which is not only not representative of the temperature of 40 ℃ but the nitrogen filled container has completely excluded vitamin D3 sensitive oxygen, the result obtained being practically unable to demonstrate the protective effect of the process on vitamin D3.
Conventionally, when vitamin D3 is subjected to a tabletting process during further formulation after its stability is improved by a protection strategy, the protection structure of vitamin D3 is broken if a tabletting pressure is applied higher, and there is a risk of stability decrease. While patent CN112569197 a and patent US 20100158998A1 both disclose tablets containing vitamin D3 and have good stability under long-term or accelerated conditions, the premise is that antioxidants are added in both patent technologies, providing additional antioxidant effect for vitamin D3; furthermore, neither of the two patent techniques describes the pressure range of the tabletting process when preparing tablets, nor does it guarantee that the solution is able to withstand the higher pressures of vitamin D3 without affecting the stability.
For the problems in the related art, no effective solution has been proposed at present.
Disclosure of Invention
Aiming at the problems in the related art, the invention provides a core-shell composition for embedding vitamin D3 and a preparation method thereof, so as to overcome the technical problems in the prior art.
For this purpose, the invention adopts the following specific technical scheme:
A vitamin D3-embedded core-shell composition and a preparation method thereof comprise a spherical particle core and an oil-in-water system, wherein a shell layer formed by solidifying the oil-in-water system is distributed on the surface of the spherical particle core.
Preferably, the oil-in-water system consists of a wall material and vitamin D3, and the particle size D50 of the core is 100-200 mu m.
Preferably, the vitamin D3 content of the core-shell composition is maintained at 90% or more after thirty days of exposure to 60 ℃;
the core-shell composition is further used for preparing tablets containing vitamin D3, wherein the mixing uniformity RSD of the vitamin D3 in the tablets is less than or equal to 5, and the stability of the vitamin D3 is not affected after the tablets are compressed under the pressure of 100-300N.
Preferably, the spherical particles have a core 100% particle size of less than 350 μm,90% particle size of less than 300 μm,50% particle size of less than 200 μm and greater than 100 μm.
Preferably, the wall polysaccharide or protein is one or two of alginate, chitosan, sodium caseinate, acacia, sucrose, maltodextrin, glucose, corn syrup, etc.
According to another aspect of the present invention, there is provided a method for preparing a vitamin D3-embedded core-shell composition, characterized by comprising the steps of;
s1, adding a wall material into purified water, stirring and dissolving to prepare a wall material aqueous solution with the mass percent concentration of 5-30% as a water phase;
s2, under continuous stirring, slowly adding the obtained water phase into an oil phase consisting of vitamin D3 until phase transition occurs, so as to form an oil-in-water system;
S3, shearing and homogenizing the obtained oil-in-water system at the rotating speed of 5000-10000 rpm to obtain emulsion;
S4, solidifying the obtained emulsion on the cores of the spherical particles in a bottom spraying or side spraying mode of fluidized bed equipment, and drying to obtain the vitamin D3-embedded core-shell composition, wherein the mass percentage of the wall material to the vitamin D3 is 1:1-1:10
Preferably, the oil phase composed of vitamin D3 in the step S2 further includes a solvent for vitamin D3, wherein the mass ratio of the solvent to the vitamin D3 is 10:1-20:1, and the solvent is specifically a low-viscosity liquid including one of grease, vitamin oil and vegetable oil;
the emulsion in the step S3 has a particle size D50 of not more than 200nm.
Preferably, the core-shell composition prepared in step S4 is further coated with a coating consisting of a wall material, so as to obtain a secondary-embedded core-shell composition, the loss of vitamin D3 content of which is not more than 10% after 30 days of exposure to 60 ℃.
Preferably, the embedding rate of the vitamin D3 is 99%, the yield of the finished product is not lower than 90%, and the vitamin D3 is further used for preparing calcium carbonate D3 compound tablets, chewable tablets and granules of medicines and health products.
Preferably, the method can also be used for embedding unstable or fat-soluble nutrients, and specifically comprises the following steps: vitamin A, vitamin E, vitamin K, omega-3 fatty acid, lycopene, and coenzyme Q10.
The beneficial effects of the invention are as follows: the process route of the vitamin D3 embedded material with high yield and high stability ensures that the embedded vitamin D3 can be uniformly mixed with other raw materials and further processed into tablets, can withstand the pressure in a higher range of a tabletting process, has good stability of emulsion prepared in the process, has no demulsification, and has the yield of a finished product which is not lower than 90 percent, usually close to 99 percent, through the process of solidifying the emulsion into a shell layer by a fluidized bed drying mode; the core-shell composition embedded with vitamin D3 is used as a preparation intermediate for further developing compound tablets, chewable tablets and granules of calcium carbonate D3 of medicines and health products;
the same composition and preparation process can also be used for embedding other types of unstable or fat-soluble nutrients, including but not limited to vitamin A, vitamin E, vitamin K, omega-3 fatty acids, lycopene, coenzyme Q10, etc. In practical application, the nutrients are often unstable or poor in water solubility, so that a plurality of technical barriers exist in developing a more stable and more convenient solid oral dosage form, the soft capsules or drops are inconvenient to swallow or administer when taken, and the appearance and quality of the product are easily influenced by environmental and climate change. By encapsulating and solidifying such nutrients, stability is improved, while the development of solid formulations is facilitated.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph of droplet size in an oil-in-water emulsion according to an embodiment of the invention;
FIG. 2 is a graph of droplet size in an oil-in-water emulsion according to example 3-1 of the present invention;
FIG. 3 is a graph of emulsion droplet size in an oil-in-water emulsion according to example 3-2 of the present invention;
Fig. 4 is a microscopic morphology of vitamin D3 powder after dissolution in water according to an embodiment of the present invention.
Detailed Description
For the purpose of further illustrating the various embodiments, the present invention provides the accompanying drawings, which are a part of the disclosure of the present invention, and which are mainly used to illustrate the embodiments and, together with the description, serve to explain the principles of the embodiments, and with reference to these descriptions, one skilled in the art will recognize other possible implementations and advantages of the present invention, wherein elements are not drawn to scale, and like reference numerals are generally used to designate like elements.
According to an embodiment of the invention, a core-shell composition embedding vitamin D3 and a preparation method thereof are provided.
Embodiment one;
As shown in fig. 1 to 4, the vitamin D3-embedded core-shell composition and the preparation method thereof according to the embodiments of the present invention is composed of two parts, one of which is a core of spherical particles having a specific particle size (d50:100-200 μm), and after the core within the particle size range is overlapped with the shell thickness of the outer layer, it can be uniformly mixed with other components and is not layered due to the excessively large particle size, and the mixing uniformity index of the vitamin D3 can be controlled to be less than or equal to 5 (the limit in the related technical requirements is RSD less than or equal to 15). Secondly, experiments find that spherical particles have higher pressure resistance than irregularly shaped particles (e.g. example 3), especially when preparing compound tablets of calcium carbonate and vitamin D3, the stability of vitamin D3 is unaffected at pressures of 100-300N.
And secondly, a shell layer formed by solidifying an oil-in-water system attached to the surface of the core. The specific forming process of the shell layer is as follows: and (3) emulsifying an oil phase formed by the wall material aqueous solution, vitamin D3 and a solvent thereof to form an oil-in-water system, spraying the oil-in-water system on the surface of the core through a fluidized bed, and drying and solidifying the oil-in-water system to form a shell layer. The proportion of the wall material and the vitamin D3 is controlled so that the vitamin D3 is completely wrapped by the wall material with enough thickness, and the obtained oil-in-water system is relatively stable. Therefore, the stability of the oil-in-water system is controlled, the effective embedding amount of the vitamin D3 in the core-shell composition can reach 99 percent by combining the relatively low-temperature and high-efficiency process of the fluidized bed, and the content loss of the vitamin D3 is lower than 10 percent after the vitamin D3 is placed for 30 days in the environment of high temperature and 60 ℃ which is most sensitive.
The particle diameter of the core of the spherical particles is not a single or narrow range in practical cases, and commercially available spherical particles (such as trade nameThe commercialized pellet core) has a plurality of products with different particle size ranges, and the particle size distribution of the invention is obtained through experimental screening, specifically, 100% of the particle size distribution is smaller than 350 mu m,90% of the particle size distribution is smaller than 300 mu m, and 50% of the particle size distribution is smaller than 200 mu m and larger than 100 mu m.
The spherical particle is a core, and the outer layer is sprayed with a shell layer which is formed by drying and solidifying an oil-in-water system in a fluidized bed, and particularly mainly comprises wall materials and vitamin D3. Wherein the wall material is a protective material for wrapping vitamin D3, and mainly comprises acacia, or one or two of alginate, chitosan, sodium caseinate, sucrose, maltodextrin, glucose and corn syrup are compounded in acacia. The acacia has a larger molecular structure than other components, can be dissolved in water at normal temperature, has the concentration of 30% or more in water, and has the characteristics of being particularly suitable for embedding vitamin D3.
The preparation process of the core-shell composition specifically comprises the following steps:
S1, adding a wall material into a proper amount of purified water, stirring and dissolving to prepare a wall material aqueous solution with the mass percent concentration of 5-30% as a water phase;
S2, slowly adding the water phase obtained in the step S1 into an oil phase composed of vitamin D3 under continuous stirring until phase transition occurs, so as to form an oil-in-water system;
s3, shearing and homogenizing the oil-in-water system obtained in the step S3 at a rotating speed of 5000-10000 rpm to obtain emulsion;
S4, solidifying the emulsion obtained in the step S4 on the cores of the spherical particles in a bottom spraying or side spraying mode of fluidized bed equipment, and drying to obtain the core-shell composition embedded with the vitamin D3, wherein the mass percentage of the wall material to the vitamin D3 is 1:1-1:10.
Steps S1 and S2 are respectively to prepare an aqueous phase and an oil phase, and to prepare an oil-in-water system through a phase transition process. The conventional oil-in-water system is to add the oil phase into the water phase to form emulsion in a 'top-down' assembly mode, high energy (such as ultrasonic, high-pressure homogenization, micro-jet homogenization and the like) is required to be input to enable the particle size of emulsion droplets to be smaller, while the phase transformation method is a 'bottom-up' assembly process, and the water phase is continuously added into the oil phase to form water-in-oil emulsion firstly, and gradually coalesces together with the addition of the water phase: the surface tension is minimal when the aqueous phase is added to a certain proportion, and as the aqueous phase increases further, an oil-in-water emulsion is formed. The emulsion prepared by the phase transition method does not need input with higher capacity, and is simple to operate and does not need high-precision equipment.
Vitamin D3 is a crystalline solid, and is dissolved in a suitable solvent before being made into an emulsion, and has a low viscosity after dissolution to facilitate emulsification, so that the suitable solvent can dissolve vitamin D3 and has a low viscosity, and the specific solvent includes one of grease, vitamin oil, and vegetable oil.
The shell layer of the core-shell composition is sprayed with a coating layer consisting of wall materials, so that the stability of vitamin D3 at high temperature of 60 ℃ can be obviously improved, the further process of the secondary embedding can be used for developing vitamin D3 medicines with stricter requirements on products, and the content loss of the vitamin D3 after the secondary embedding is exposed at 60 ℃ for 30 days is not more than 10 percent and is obviously superior to the commercial similar products.
Embodiment two;
As shown in FIGS. 1-4, the vitamin D3-embedded core-shell composition comprises
And volatilizes during the fluidized bed drying process.
The technical process comprises the following steps:
1) Adding acacia and maltodextrin into a proper amount of purified water, stirring and dissolving to obtain a water phase; adding vitamin D3 into soybean vegetable oil, stirring to dissolve vitamin D3, and taking as oil phase;
2) Slowly adding the water phase obtained in the step 1) into an oil phase composed of vitamin D3 under continuous stirring until phase transition occurs to form colostrum;
3) Shearing and homogenizing the primary emulsion obtained in the step 2) at 8000rpm to obtain vitamin D3 emulsion;
4) Will be Putting the pill core into a fluidized bed, starting a fan and heating, atomizing the emulsion obtained in the step 3) to the surface of the pill core in a side spraying mode, and drying to obtain the vitamin D3-embedded core-shell composition.
Stability investigation results:
The stability of example 1 and commercial vitamin D3 powder was examined at 40 ℃ and 60 ℃.
Embodiment three;
as shown in FIGS. 1-4, the effect of the appearance shape of the core on the properties of the composition was examined, including
The technical process comprises the following steps: the process of the core-shell composition embedding vitamin D3 is the same as that of the second embodiment, and the prepared core-shell composition is further mixed with auxiliary materials such as sorbitol, silicon dioxide, magnesium stearate and the like, and tabletting is carried out.
Tablet content uniformity and hardness test results:
tablet stability results:
Fourth embodiment;
As shown in figures 1-4, the vitamin D3 content uniformity and stability are checked for different particle size distribution ranges
Prescription: consistent with the formulation and amounts in example three, only cores of different particle size ranges were selected. The cores shown in the following table are derived from commercial products (brands: ) Wherein the particle sizes of the cores used in different batches are obtained by mixing different specifications of commercial products according to the experimental purposes.
Batch of Pellet core particle diameter D50
Example 4-1 50-106μm
Example 4-2 150-200μm
Examples 4 to 3 250-400μm
The technical process comprises the following steps: as in the examples;
tablet content uniformity and hardness test results:
Sample numbering Average content of 10 tablets RSD Average hardness of tablet
Example 4-1 115.4％ 11.0％ 276N
Example 4-2 110.3％ 3.9％ 298N
Examples 4 to 3 108.7％ 6.9％ 288N
Tablet stability results:
in summary, by means of the technical scheme, the emulsion prepared in the process has good stability and no demulsification, and the yield of the finished product obtained by the process of solidifying the emulsion into a shell layer by a fluidized bed drying mode is not less than 90%, and is generally close to 99%; the core-shell composition embedded with vitamin D3 is used as a preparation intermediate for further developing compound tablets, chewable tablets and granules of calcium carbonate D3 of medicines and health products;
the same composition and preparation process can also be used for embedding other types of unstable or fat-soluble nutrients, including but not limited to vitamin A, vitamin E, vitamin K, omega-3 fatty acids, lycopene, coenzyme Q10, etc. In practical application, the nutrients are often unstable or poor in water solubility, so that a plurality of technical barriers exist in developing a more stable and more convenient solid oral dosage form, the soft capsules or drops are inconvenient to swallow or administer when taken, and the appearance and quality of the product are easily influenced by environmental and climate change. By encapsulating and solidifying such nutrients, stability is improved, while the development of solid formulations is facilitated.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (10)

1. A vitamin D3-embedded core-shell composition comprising a core of spherical particles and an oil-in-water system, wherein the shell formed upon solidification of the oil-in-water system is distributed on the surface of the core of the spherical particles.
2. A vitamin D3-embedded core-shell composition according to claim 1, wherein the oil-in-water system consists of wall material and vitamin D3, and the particle size D50 of the core is 100-200 μm.
3. A vitamin D3-embedded core-shell composition according to claim 2, wherein the vitamin D3 content remains above 90% after thirty days of exposure of the core-shell composition to 60 ℃;
the core-shell composition is further used for preparing tablets containing vitamin D3, wherein the mixing uniformity RSD of the vitamin D3 in the tablets is less than or equal to 5, and the stability of the vitamin D3 is not affected after the tablets are compressed under the pressure of 100-300N.
4. A vitamin D3 entrapped core-shell composition according to claim 3 wherein the spherical particles have a core 100% particle size of less than 350 μm,90% particle size of less than 300 μm,50% particle size of less than 200 μm and greater than 100 μm.
5. The vitamin D3-embedded core-shell composition of claim 4, wherein the wall material is a polysaccharide or a protein, and specifically is one or a combination of two of alginate, chitosan, sodium caseinate, acacia, sucrose, maltodextrin, glucose, corn syrup and the like.
6. A method for preparing a vitamin D3-embedded core-shell composition, comprising the steps of;
s1, adding a wall material into purified water, stirring and dissolving to prepare a wall material aqueous solution with the mass percent concentration of 5-30% as a water phase;
s2, under continuous stirring, slowly adding the obtained water phase into an oil phase consisting of vitamin D3 until phase transition occurs, so as to form an oil-in-water system;
S3, shearing and homogenizing the obtained oil-in-water system at the rotating speed of 5000-10000 rpm to obtain emulsion;
S4, solidifying the obtained emulsion on the cores of the spherical particles in a bottom spraying or side spraying mode of fluidized bed equipment, and drying to obtain the core-shell composition embedding the vitamin D3, wherein the mass percentage of the wall material to the vitamin D3 is 1:1-1:10.
7. The method for preparing the vitamin D3-embedded core-shell composition according to claim 1, wherein the oil phase composed of the vitamin D3 in the step S2 further comprises a solvent of the vitamin D3, the mass ratio of the solvent to the vitamin D3 is 10:1-20:1, and the solvent is specifically a low-viscosity liquid comprising one of grease, vitamin oil and vegetable oil;
the emulsion in the step S3 has a particle size D50 of not more than 200nm.
8. The method of claim 1, wherein the core-shell composition obtained in step S4 is further coated with a coating consisting of a wall material to obtain a secondary-embedded core-shell composition, wherein the loss of vitamin D3 content is not more than 10% after 30 days of exposure to 60 ℃.
9. The method for preparing a vitamin D3-embedded core-shell composition according to any one of claims 1 to 7, wherein the embedding rate of the vitamin D3 is 99%, the yield of the finished product is not less than 90%, and the vitamin D3-embedded core-shell composition is further used for preparing calcium carbonate D3 compound tablets, chewable tablets and granules of medicines and health products.
10. A vitamin D3-embedded core-shell composition and a method for preparing the same according to any of claims 1-8, which can also be used for embedding labile or fat-soluble nutrients, comprising in particular: vitamin A, vitamin E, vitamin K, omega-3 fatty acid, lycopene, and coenzyme Q10.
CN202410416829.3A 2024-04-08 2024-04-08 Vitamin D3-embedded core-shell composition and preparation method thereof Pending CN118161463A (en)

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