Titanium dioxide-free vitamin D3 soft capsule and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a titanium dioxide-free vitamin D3 soft capsule and a preparation method thereof. The vitamin D3 soft capsule is composed of a liquid medicine and a soft capsule wall material, the liquid medicine comprises vitamin D3 and medium chain triglyceride, the soft capsule wall material comprises gelatin, glycerin, calcium carbonate and zinc oxide, and the soft capsule wall material does not contain titanium dioxide; the mass ratio of the gelatin to the calcium carbonate is 1: (0.015-0.025); the mass ratio of the calcium carbonate to the zinc oxide is 1: (0.2-0.3). The vitamin D3 soft capsule does not contain titanium dioxide, is high in safety, high in stability of effective components and free of rancidity smell after being stored for a long time.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a vitamin D3 soft capsule without titanium dioxide and a preparation method thereof. Background Art

[0002] Vitamin D is related to the calcification of animal bones, so it is also called calciferol. The physiological function of vitamin D is to help the human body absorb phosphorus and calcium, and it is an essential raw material for bone formation. Therefore, long-term deficiency of vitamin D may cause rickets. Vitamin D is the engine for forming bones and cartilage and can make teeth hard. In bones, it not only helps the calcification of new bones, but also promotes the release of calcium from aging bone marrow, so as to continuously update bone mass and maintain the balance of blood calcium. In particular, the demand for vitamin D is relatively large in pregnant women, infants and teenagers.

[0003] Vitamin D3 is a kind of vitamin D. Since vitamin D3 is sensitive to light, a light-shielding agent needs to be added to the soft capsule shell in vitamin D3 soft capsules to avoid the photodegradation of vitamin D3.

[0004] The prior art (Xiao Liansheng, Ge Ying. Application of coloring agents and light-shielding agents in oral soft capsules [J]. Tianjin Pharmacy, 1997, 9(1):3.) discloses that common light-shielding agents in oral soft capsules include red, yellow or brown iron oxide, carbon black, titanium white (titanium dioxide), etc. At present, almost all vitamin D3 soft capsules use titanium dioxide as the light-shielding agent.

[0005] For example, Chinese Patent Publication No. CN109662953A discloses a vitamin D soft capsule, which is composed of the following substances in parts by mass: 400-625 parts of calcium carbonate; 0.001-0.005 parts of vitamin D3; 225-550 parts of soybean oil; 425-650 parts of gelatin; 450-700 parts of purified water; 110-325 parts of glycerol; 100-400 parts of glyceryl monostearate; 0.01-0.02 parts of titanium dioxide; 100-200 parts of corn oil; 0.05-0.2 parts of dibutylhydroxytoluene.

[0006] Chinese Patent Publication No. CN115282237A discloses a calcium soft capsule, which includes a capsule skin and a calcium material liquid encapsulated in the capsule skin. The calcium material liquid includes 625-875 parts of calcium carbonate, 100-150 parts of walnut oil, 68.4-437.92 parts of corn oil, 30-40 parts of mono- and diglycerol fatty acid esters, 0.08-0.6 parts of vitamin D3 oil, 7-66 parts of vitamin K2 oil; the capsule skin includes 240-375 parts of gelatin, 240-375 parts of purified water, 96-150 parts of glycerol, and 1.2-22 parts of titanium dioxide.

[0007] However, current research has found that titanium dioxide has safety issues and a potential carcinogenic risk. Existing technologies (Zhao Lin, Shen Zhenlin, Jia Guang. Epidemiological research progress on the carcinogenic effect of occupational exposure to titanium dioxide [J]. China Occupational Medicine, 2015, 000(001):89-92.) have disclosed that the International Agency for Research on Cancer has classified TiO2 as a suspected human carcinogen.

[0008] Therefore, developing a highly stable vitamin D3 soft capsule preparation without titanium dioxide has become an urgent problem to be solved. Summary of the Invention

[0009] The objective of the present invention is to overcome the deficiencies of the prior art and provide a vitamin D3 soft capsule without titanium dioxide, with high safety, high stability of the active ingredient, and no rancid odor after long-term storage, and a preparation method thereof.

[0010] The present invention is achieved through the following technical solutions: In a first aspect of the present invention, a vitamin D3 soft capsule without titanium dioxide is provided, which is composed of a liquid medicine and a soft capsule material. The liquid medicine includes vitamin D3 and medium-chain triglyceride, and the soft capsule material includes the following components: gelatin, glycerin, calcium carbonate, and zinc oxide, and the soft capsule material does not contain titanium dioxide; The mass ratio of the gelatin to the calcium carbonate is 1:0.015-0.025; the mass ratio of the calcium carbonate to the zinc oxide is 1:0.2-0.3.

[0011] Preferably, the particle size distribution of the calcium carbonate is D90≤5μm. Within this range, the vitamin D3 soft capsule of the present invention has relatively high stability.

[0012] The present invention uses calcium carbonate and zinc oxide as light-shielding agents, avoiding the use of titanium dioxide, reducing the safety risk, and through optimizing the dosage ratio of the two, making the light-shielding effect equivalent to that of titanium dioxide, ensuring relatively high stability.

[0013] The present invention reduces the adverse effect of light on vitamin D3 and improves the stability of the soft capsule by optimizing the dosage ratio of gelatin to calcium carbonate and the dosage ratio of calcium carbonate to zinc oxide.

[0014] The present invention uses medium-chain triglyceride as the solvent in the liquid medicine, avoiding the rancidity problem existing during the storage of the drug.

[0015] As an implementation manner of the present invention, the mass ratio of the vitamin D3 to the medium-chain triglyceride is 1:10000-14000 or 1:20000-28000.

[0016] Preferably, the mass ratio of vitamin D3 to medium-chain triglyceride is 1:12000 (preparation specification: 800 IU) or 1:24000 (preparation specification: 400 IU).

[0017] The excipient formula of the present invention is applicable to the vitamin D3 formulas of the above two specifications at the same time, without specific limitation.

[0018] As an embodiment of the present invention, the mass ratio of gelatin to glycerol is 1:0.4 - 1:0.5.

[0019] As an embodiment of the present invention, the mass ratio of the liquid medicine to the soft capsule material is 1:1 - 1:1.5.

[0020] As an embodiment of the present invention, the soft capsule material further includes pigment.

[0021] Preferably, the pigment includes but is not limited to erythrosine.

[0022] Preferably, the mass ratio of gelatin to pigment is 1:0.0004 - 1:0.0006.

[0023] As an embodiment of the present invention, the soft capsule material further includes water.

[0024] The second aspect of the present invention provides a preparation method of vitamin D3 soft capsules, including the following steps: (1) Mix vitamin D3 and medium-chain triglyceride and then stir to obtain the liquid medicine; (2) First, stir and mix glycerol and water, then add gelatin, calcium carbonate, zinc oxide and pigment, and homogenize to obtain the colloidal solution of the soft capsule material; (3) Use a soft capsule machine to press the liquid medicine and the colloidal solution of the soft capsule material into pills, and obtain the product after drying.

[0025] Or a preparation method of vitamin D3 soft capsules, including the following steps: (1) Mix vitamin D3 and medium-chain triglyceride and then stir to obtain the liquid medicine; (2) First, stir and mix glycerol and water, then add gelatin, calcium carbonate and zinc oxide, and homogenize to obtain the colloidal solution of the soft capsule material; (3) Use a soft capsule machine to press the liquid medicine and the colloidal solution of the soft capsule material into pills, and obtain the product after drying.

[0026] As an embodiment of the present invention, in step (2), the mass ratio of water to gelatin is 1:0.8 - 1:1.2.

[0027] As an embodiment of the present invention, in step (1), after mixing vitamin D3 and medium-chain triglyceride, vacuum is pumped to -0.06 ± 0.01 MPa, the stirring speed is 200 - 400 rpm, and the stirring time is 0.5 - 1.5 h.

[0028] As an embodiment of the present invention, in step (2), glycerol and water are stirred and mixed at a speed of 40 - 60 rpm, the temperature is raised to 75 ± 5 °C, gelatin, calcium carbonate, zinc oxide and pigment (pigment does not need to be added in the case of no pigment) are added, homogenization is started, the speed is 800 - 1200 rpm, after homogenizing for 15 - 25 min, the temperature is controlled at 75 ± 5 °C, the vacuum degree is -0.1 ~ -0.05 MPa, the viscosity of the glue solution is 20000 - 40000 MPa·s, and it is ground evenly and kept warm at 60 ± 5 °C to obtain the glue solution of the soft capsule material.

[0029] The vitamin D3 soft capsule of the present invention is used for preventing and treating vitamin D deficiency diseases such as rickets.

[0030] The beneficial effects of the present invention are as follows: The present invention uses calcium carbonate and zinc oxide as light-shielding agents, avoiding the use of titanium dioxide, reducing the safety risk of patients who need to take medicine for a long time, and by optimizing the dosage ratio of the two, the light-shielding effect is equivalent to that of titanium dioxide, ensuring high stability.

[0031] The present invention reduces the adverse effects of light on vitamin D3 and improves the stability of the soft capsule by optimizing the dosage ratio of gelatin and calcium carbonate and the dosage ratio of calcium carbonate and zinc oxide.

[0032] Currently, commercially available vitamin D3 soft capsule preparations usually use vegetable oil as the solvent in the medicinal liquid, which is prone to rancidity during long-term storage. The present invention uses medium-chain triglyceride to replace vegetable oil, avoiding the rancidity problem existing during the drug storage process. Specific Embodiments

[0033] The following specific examples are used to further describe the present invention, and the advantages and characteristics of the present invention will become clearer as the description progresses. However, these examples are only exemplary and do not constitute any limitation to the scope of the present invention. Those skilled in the art should understand that the details and forms of the technical solutions of the present invention can be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the protection scope of the present invention.

[0034] The commercially available information of raw materials and auxiliary materials used in the following examples and comparative examples is shown in Table 1.

[0035] Table 1 Commercially Available Information of Raw Materials and Auxiliary Materials

[0036] Example 1 The prescription composition of the vitamin D3 soft capsules in this example is shown in Table 2.

[0037] Table 2 Prescription composition of Example 1

[0038] The preparation method of the vitamin D3 soft capsules in this example is as follows: Liquid preparation: ① Put medium-chain triglyceride and vitamin D3 into the liquid preparation tank.

[0039] ② Evacuate to a pressure of -0.06 MPa in the tank, set the stirring speed at 300 rpm, and stir for 1 h to obtain the liquid medicine.

[0040] Gelatinization: ① Turn on the heating of the gelatinization tank, set the stirring speed at 50 rpm, suck the prescribed amount of glycerol and purified water (the mass ratio of purified water to gelatin is 1:1) into the gelatinization tank, and stir and mix.

[0041] ② When the temperature in the tank rises to 75 °C, set the homogenization speed at 1000 rpm, turn on the homogenization and add the prescribed amount of gelatin, calcium carbonate, zinc oxide, and pigment, and homogenize and stir for 20 minutes.

[0042] ③ When the temperature of the glue solution rises to 75 °C, turn on the vacuum pump, control the vacuum degree at -0.1 MPa, evacuate until the viscosity of the glue solution reaches 30000 MPa·s, and grind evenly through a colloid mill.

[0043] ④ Keep the ground glue solution at 60 °C, seal it for storage and use to obtain the glue solution of the soft capsule material.

[0044] Tabletting: Use a soft capsule machine, install a suitable mold, tablet the liquid medicine and the glue solution of the soft capsule material, place the soft capsules in a rotating cage after tabletting, dry for 12 h, and discharge the product.

[0045] Example 2 The prescription composition of the vitamin D3 soft capsules in this example is shown in Table 3.

[0046] Table 3 Prescription composition of Example 2

[0047] The preparation method of the vitamin D3 soft capsules in this example is as follows: Liquid preparation: ① Put medium-chain triglyceride and vitamin D3 into the liquid preparation tank.

[0048] ② Evacuate to a pressure of -0.07 MPa in the tank, set the stirring speed at 200 rpm, and stir for 0.5 h to obtain the liquid medicine.

[0049] Gelatinization: ① Turn on the heating of the gelatinization tank, set the stirring speed at 40 rpm, suck the prescribed amount of glycerol and purified water (the mass ratio of purified water to gelatin is 1:0.8) into the gelatinization tank, and stir and mix.

[0050] ② When the temperature in the tank rises to 70 °C, set the homogenization speed at 800 rpm, turn on the homogenization and add the prescribed amount of gelatin, calcium carbonate, zinc oxide, and pigment, and homogenize and stir for 15 minutes.

[0051] ③ When the temperature of the glue solution rises to 70 °C, turn on the vacuum pump, control the vacuum degree at -0.05 MPa, evacuate until the viscosity of the glue solution reaches 20000 MPa·s, and grind evenly through a colloid mill.

[0052] ④ Keep the ground glue solution at 55 °C, seal and store for later use to obtain the glue solution of the soft capsule shell material.

[0053] Pill pressing: Use a soft capsule machine, install a suitable mold, press the liquid medicine and the glue solution of the soft capsule shell material into pills. After pill pressing, place the soft capsules in a rotating cage, dry for 10 h, and discharge the material.

[0054] Example 3 The prescription composition of the vitamin D3 soft capsules in this example is shown in Table 4.

[0055] Table 4 Prescription Composition of Example 3

[0056] The preparation method of the vitamin D3 soft capsules in this example is as follows: Liquid preparation: ① Put medium-chain triglyceride and vitamin D3 into the liquid preparation tank.

[0057] ② Evacuate to a pressure of -0.05 MPa in the tank, set the stirring speed at 400 rpm, and stir for 1.5 h to obtain the liquid medicine.

[0058] Gelatinization: ① Turn on the heating of the gelatinization tank, set the stirring speed at 60 rpm, suck the prescribed amount of glycerol and purified water (the mass ratio of purified water to gelatin is 1:1.2) into the gelatinization tank, and stir and mix.

[0059] ② When the temperature in the tank rises to 80 °C, set the homogenization speed at 1200 rpm, turn on the homogenization and add the prescribed amount of gelatin, calcium carbonate, zinc oxide, and pigment, and homogenize and stir for 25 minutes.

[0060] ③ When the temperature of the glue solution rises to 80 °C, turn on the vacuum pump, control the vacuum degree at -0.1 MPa, evacuate until the viscosity of the glue solution reaches 40000 MPa·s, and grind evenly through a colloid mill.

[0061] ④ Keep the ground glue solution at 65 °C for heat preservation, seal it for storage for later use to obtain the glue solution for the soft capsule shell material.

[0062] Pelletizing: Use a soft capsule machine, install a suitable mold, pelletize the liquid medicine and the glue solution of the soft capsule shell material. After pelletizing, place the soft capsules in a rotating cage, dry for 15 h, and discharge the products.

[0063] Example 4 Compared with Example 1, the only difference is that the mass ratio of calcium carbonate to zinc oxide is 1:0.2.

[0064] Example 5 Compared with Example 1, the only difference is that the mass ratio of calcium carbonate to zinc oxide is 1:0.3.

[0065] Comparative Example 1 Compared with Example 1, the only difference is that the mass ratio of gelatin to calcium carbonate is 1:0.005.

[0066] Comparative Example 2 Compared with Example 1, the only difference is that the mass ratio of calcium carbonate to zinc oxide is 1:0.1.

[0067] Comparative Example 3 Compared with Example 1, the only difference is that the mass ratio of calcium carbonate to zinc oxide is 1:0.4.

[0068] Comparative Example 4 Compared with Example 1, the only difference is that the triglyceride in the liquid medicine solvent is replaced with soybean oil of equal mass.

[0069] Comparative Example 5 A commercially available product using vegetable oil as the liquid medicine solvent and titanium dioxide as the opacifier.

[0070] Comparative Example 6 Compared with Example 1, the only difference is that the total dosage of the opacifier remains unchanged, the composition is different, and calcium carbonate and zinc oxide are replaced with titanium dioxide of equal mass.

[0071] Comparative Example 7 Compared with Example 1, the only difference is that the particle size of calcium carbonate is different, and D90 is 17 μm.

[0072] Effect test Test 1 Influence factor light experiment Experimental method: Place 10 vitamin D3 soft capsules (preparation specification: 800 IU) prepared in each example and comparative example in a light box for 10 days (total illuminance is 1.2×10 6 Lux•hr, near-ultraviolet energy is 200 w•hr / m).

[0073] Detect the content of vitamin D3 before and after light exposure: Determine according to the fourth method of the vitamin D assay (General Chapter 0722, Volume IV, Chinese Pharmacopoeia 2020 Edition). Take the average value of the test results of 10 capsules.

[0074] Evaluation index: The content of vitamin D3 is between 90.0% and 110.0%.

[0075] Experiment 2: Accelerated experiment Detection method: Place the vitamin D3 soft capsules (preparation specification: 800 IU) prepared in each example and comparative example in an accelerated chamber (temperature 40 °C, humidity 75%) for 9 months, and take out to check the odor of the product.

[0076] Evaluation index: No rancid smell.

[0077] The test results of the influencing factor light experiment of the vitamin D3 soft capsules in each example and comparative example are shown in Table 5, and the test results of the accelerated experiment are shown in Table 6.

[0078] Table 5 Test results of the influencing factor light experiment of each example and comparative example

[0079] Table 6 Test results of the accelerated experiment of each example and comparative example

[0080] As can be seen from Table 5, the present invention uses calcium carbonate and zinc oxide as light-shielding agents. By optimizing the dosage ratio of calcium carbonate and zinc oxide and the dosage ratio of gelatin and calcium carbonate, the light-shielding effect is equivalent to or even better than that of commercially available products using titanium dioxide as a light-shielding agent, ensuring that the vitamin D3 soft capsules have high stability.

[0081] As can be seen from Table 6, it is easy to go rancid when using soybean oil as the liquid medicine solvent for long-term storage. The present invention uses medium-chain triglycerides to replace soybean oil, avoiding the rancidity problem existing in the drug storage process.

[0082] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification without departing from the present invention shall be included within the scope of the technical solution of the present invention.

Claims

1. A vitamin D3 soft capsule without titanium dioxide, characterized in that: The invention is composed of a medicine liquid and a soft capsule material, wherein the medicine liquid includes vitamin D3 and medium-chain triglycerides, and the soft capsule material includes the following ingredients: gelatin, glycerin, calcium carbonate and zinc oxide, and the soft capsule material does not contain titanium dioxide; The mass ratio of the gelatin to calcium carbonate is 1:0.015-0.025; the mass ratio of the calcium carbonate to zinc oxide is 1:0.2-0.

3.

2. The vitamin D3 soft capsule according to claim 1, characterized in that The particle size distribution of the calcium carbonate is D90≤5 μm; and / or the mass ratio of the vitamin D3 to the medium-chain triglyceride is 1:10000-14000 or 1:20000-28000.

3. The vitamin D3 soft capsule according to claim 2, characterized in that The mass ratio of the vitamin D3 to medium-chain triglycerides is 1:12000 or 1:24000.

4. The vitamin D3 soft capsule according to claim 1, characterized in that The mass ratio of the gelatin to glycerol is 1:0.4-0.5; and / or the mass ratio of the drug solution to the soft capsule material is 1:1-1:1.

5.

5. The vitamin D3 soft capsule according to claim 1, characterized in that The soft capsule material further comprises a pigment.

6. The vitamin D3 soft capsule according to claim 5, characterized in that The pigment is erythrosine.

7. The vitamin D3 soft capsule according to claim 5, characterized in that The mass ratio of the gelatin to the pigment is 1:0.0004-1:0.0006.

8. The method for preparing the vitamin D3 soft capsule according to any one of claims 5 to 7, characterized in that: The steps include: (1) mixing vitamin D3 and medium chain triglycerides and stirring to obtain a medicinal solution; (2) First, stir and mix glycerin and water, then add gelatin, calcium carbonate, zinc oxide and pigment, and homogenize to obtain a soft capsule material glue solution; (3) The drug solution and the gelatin solution of the soft capsule material are pressed into pills using a soft capsule machine and dried to obtain the pills.

9. The preparation method according to claim 8, characterized in that: The mass ratio of water to gelatin in step (2) is 1:0.8-1:1.

2.

10. The preparation method according to claim 8, characterized in that: In step (1), after the vitamin D3 and medium-chain triglycerides are mixed, the mixture is evacuated to -0.06±0.01 MPa, the stirring speed is 200-400 rpm, and the stirring time is 0.5-1.5 h; And / or in step (2), glycerol and water are stirred and mixed at a speed of 40-60 rpm, the temperature is raised to 75±5°C, gelatin, calcium carbonate, zinc oxide and pigment are added, homogenization is started, the speed is 800-1200 rpm, and after homogenization for 15-25 minutes, the temperature is controlled to 75±5°C, the vacuum degree is -0.1~-0.05MPa, the viscosity of the glue is 20000-40000MPa·s, the mixture is ground evenly, and kept warm at 60±5°C to obtain a glue for soft capsule material.

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