Water-soluble vitamin d 3 composition and preparation method therefor

Abstract

A water-soluble vitamin D3 composition. The composition consists of vitamin D3, β-CD (β-cyclodextrin), and PEG (polyethylene glycol) in a ratio of 30-1500 units:1-10 g:10-100 g. Further provided is a formulation, preferably a granule formulation, comprising the vitamin D3 pharmaceutical composition. The prepared composition can effectively improve the bioavailability of vitamin D3 and has the characteristics of stability and high-temperature resistance, thereby being suitable for clinical and healthcare applications.

Description

A water-soluble vitamin D3 composition and preparation method thereof Technical Field

[0001] The invention provides a water-soluble vitamin D3 composition, belonging to the field of medicines and dietary supplements. Background Art

[0002] It is known that vitamin D3 (VD3) is correlated with calcium absorption in the human body. In recent years, some people have found that when vitamin D is deficient, the calcium content in the mitochondria decreases, but increases after vitamin D is given. Therefore, it is believed that the main function of vitamin D is to concentrate calcium in the mitochondria, reduce the calcium concentration in the cytoplasm, and facilitate the passive absorption of calcium by intestinal mucosal cells.

[0003] Vitamin D3 is unstable to light and heat. It loses its activity after oxidation and photochemical decomposition in the air into various products such as provitamin D3, trans-vitamin D3, tachysterol D3, isostachyl D3, lumisterol D3, and 7-dehydrocholesterol. It is also unstable under acidic conditions (a key factor for clinical effectiveness). Vitamin D3 is a fat-soluble vitamin and is insoluble in water. Currently, the VD3 preparations on the market are drops and injections. There are two types of drops: capsules and oral solutions. They all dissolve VD3 in vegetable oil and wrap it in a gelatin layer, but the excipients and production processes used are slightly different. There are also two specifications: 400 IU and 800 IU. The specifications of the injections are relatively large, respectively 150,000 IU, 300,000 IU, and 600,000 IU. Because individual drops are relatively large, children and young children often break the outer gelatin layer and squeeze the solution directly into their mouths. This method of administration first results in inaccurate VD3 dosage and inestimable loss. Furthermore, the VD3 oil solution is directly broken down by digestive enzymes in the mouth and further affected by gastric acid in the stomach, resulting in significant VD3 loss. This further inaccurately determines the amount of VD3 that can be absorbed and utilized, resulting in a significant waste of resources and failing to achieve the goal of safe and effective treatment and prevention of disease. Injections, due to their large dosage, cannot be used for prevention or low-dose applications.

[0004] The usual technology is to modify it or embed drugs to make it water-soluble (see patent ZL201110139889.8) to facilitate the preparation of granules or tablets. At the same time, VD3 needs to be absorbed by the intestine. Existing VD3 inclusion compounds are sensitive to temperature and require low-temperature drying. The drying temperature is around 35 degrees, which has low drying efficiency and low production efficiency. The VD3 composition needs to be heat-resistant, stable, and easy to absorb by the intestine during the digestion process. At present, no such product has been launched.

[0005] Summary of the Invention

[0006] In order to solve the technical problems in the above-mentioned prior art that VD3 inclusion compounds are temperature sensitive, require low-temperature drying, and have low production efficiency, the applicant proposes a water-soluble vitamin D3 composition consisting of vitamin D3, inclusion compound 1 and inclusion compound 2, with a dosage ratio of 30-1500 units: 1-10 mg: 10-100 mg.

[0007] The inventors of the present invention included VD3 twice for the first time, breaking the conventional practice in the field and subjecting the inclusion compound prepared with the above-mentioned β-cyclodextrin to PEG inclusion again, thereby greatly improving the solubility of the preparation and further optimizing the stability of the VD3 preparation, which is conducive to reducing losses during further absorption in the body.

[0008] Preferably, in the above water-soluble vitamin D3 composition, the dosage ratio of the vitamin D3, inclusion complex 1 and inclusion complex 2 is 100-1000 units: 1-5 mg: 10-50 mg.

[0009] Preferably, in the above water-soluble vitamin D3 composition, the dosage ratio of the vitamin D3, inclusion complex 1 and inclusion complex 2 is 200-1000 units: 1-5 mg: 10-50 mg.

[0010] Preferably, in the above water-soluble vitamin D3 composition, the vitamin D3 is included in inclusion complex 1 and inclusion complex 2 in sequence.

[0011] Preferably, in the above water-soluble vitamin D3 composition, the inclusion compound 1 is β-cyclodextrin, and the inclusion compound 2 is PEG.

[0012] Preferably, in the above water-soluble vitamin D3 composition, the PEG is PEG400-8000, preferably PEG4000-PEG6000, more preferably PEG6000.

[0013] Preferably, in the above water-soluble vitamin D3 composition, the dosage ratio of inclusion compound 1 to inclusion compound 2 is 1:1-1:20, preferably 1:1-1:10.

[0014] Preferably, the present invention further provides a preparation containing the above composition, which includes pharmaceutically acceptable excipients.

[0015] Preferably, in the above preparations, the preparations include granules, tablets, and pills.

[0016] The granules include capsules. The tablets include sustained-release tablets, ordinary tablets, etc.

[0017] The present invention further provides a method for preparing the above vitamin D3 composition, wherein:

[0018] It consists of the following steps:

[0019] 1) Weighing a prescribed amount of inclusion compound 1 to prepare a saturated aqueous solution, weighing a prescribed amount of vitamin D3, adding vitamin D3 to the saturated aqueous solution of inclusion compound 1, cooling, filtering, drying, and pulverizing to obtain vitamin D3-inclusion compound 1;

[0020] 2) The vitamin D3 inclusion compound 1 of step 1) is mixed with the melted inclusion compound 2 of the prescribed amount, cooled, filtered, dried, and crushed to obtain the vitamin D3 composition.

[0021] The mixing temperature of the saturated aqueous solution of vitamin D3 and inclusion complex 1 can be in the range of 40°C to 80°C.

[0022] More preferably, the temperature range of the inclusion compound 2, i.e., PEG, is 50-100°C.

[0023] The purpose of cooling is to cool quickly, so the temperature difference should be large, preferably -20 to 10℃.

[0024] The present invention further provides a use of the water-soluble vitamin D3 composition in the preparation of a medicine for preventing and treating osteoporosis and rickets in children.

[0025] The PEG is polyethylene glycol. The present invention is the first to prepare a highly water-soluble oral VD3 preparation, which is superior to the preparation of VD3 and β-cyclodextrin, that is, the prior art.

[0026] The specific preparation method is as follows: vitamin D3 (solid or solution state) is prepared into a mixed solution of inclusion complex using a saturated β-cyclodextrin aqueous solution at 50°C, which is then placed in a 0°C freezer for crystallization, filtered, dried, and crushed to obtain a vitamin D3 / β-cyclodextrin inclusion complex (hereinafter referred to as the old VD3 inclusion complex). PEG6000 is then melted in a 60°C water bath, the inclusion complex is added to the PEG6000 solution, stirred evenly, cooled in a freezer, and crushed to obtain a new VD3 inclusion complex.

[0027] Vitamin D3 can be dissolved in an ethanol solution and added dropwise, which is beneficial to the formation of an inclusion complex and belongs to the existing technology in this field.

[0028] The inventors compared the new VD3 inclusion compound of the present invention with the old VD3 (single inclusion) inclusion compound and found that the new VD3 inclusion compound has better solubility and better stability.

[0029] Technical effect 1 of the present invention:

[0030] In an embodiment of the present invention, PEG6000 was added, and it was found that the solubility of the obtained new VD3 inclusion compound was improved. The specific method was as follows:

[0031] Take appropriate amounts of vitamin D3, old VD3 inclusion compound, and new VD3 inclusion compound (Example 1) and place them in 50 ml stoppered test tubes, respectively. Prepare saturated aqueous solutions at 35 and 40°C. After dissolution reaches equilibrium, take the supernatant and filter it with a 0.8 μm microporous filter membrane. The absorbance of the filtrate is measured at 265 nm using a UV-visible spectrophotometer. Substitute the absorbance into the standard curve equation (established in advance) to calculate the solubility. The results are as follows:

[0032] Table 1. Solubility in water at different temperatures (μg / ml)

[0033] 35°C to 40°C is a comfortable temperature for human consumption of pharmaceuticals, so the solubility of the new VD3 inclusion complex was determined at these temperatures. The results showed that at 35°C, dissolving 800 IU of the new VD3 inclusion complex required only 22 ml of water, while dissolving 800 IU of the old VD3 inclusion complex required 44.5 ml of water. Dissolving 800 IU of the original VD3 requires at least 200 ml of water.

[0034] The inventors used different types of PEG, such as PEG6000 and PEG4000, for encapsulation treatment, and then conducted accelerated comparisons to select PEG6000 with a smaller dosage and better stability.

[0035] Table 2, accelerated comparative test is as follows:

[0036] It can be seen that the new VD3 inclusion complex has better stability than the old VD3 inclusion complex.

[0037] Advantage 2 of the present invention:

[0038] Existing VD3 inclusion compounds are sensitive to temperature and require low-temperature drying. The drying temperature is around 35 degrees, which has low production efficiency.

[0039] The new inclusion compound material developed by the inventors can increase the drying temperature to around 60 degrees Celsius, shortening the drying time and improving production efficiency. See Table 3.

[0040] Table 3

[0041] Note: Through HPLC detection, the peak area of ​​the new VD3 inclusion complex has basically not changed. According to the provisions of the allowable error of HPLC, the change in peak area is negligible, so the decrease is 0.

[0042] In the inclusion compound of the present invention, the molar ratio of the β-cyclodextrin to vitamin D3 is 3:1-6:1.

[0043] The molar ratio of 3:1-6:1 herein refers to the ratio of molar concentrations, a specialized term in this field, and refers to the molar concentration ratio of the β-cyclodextrin solution (aqueous solution) to the vitamin D3 solution (preferably a saturated solution) of 3:1-6:1. Because the optimal encapsulation efficiency is achieved by adding the vitamin D3 solution dropwise before encapsulation, previous research (ZL 201110139889.8), based on experimental results of vitamin D3 encapsulated in β-cyclodextrin, found that the best encapsulation efficiency was achieved when the molar concentration ratio was 3:1-6:1. DETAILED DESCRIPTION

[0044] The following examples are used to further illustrate the present invention but are not intended to limit the present invention.

[0045] In the present invention, vitamin D3 can be represented by VD3 or VD3.

[0046] Example 1

[0047] A water-soluble vitamin D3 composition, wherein the dosage ratio of vitamin D3: beta-cyclodextrin: PEG6000 is 800 units: 0.0027 g: 0.027 g, and 3000 g of a new VD3 compound is obtained.

[0048] Preparation method:

[0049] Vitamin D3 is prepared into an inclusion complex mixed solution using a saturated β-cyclodextrin aqueous solution at 50°C, which is then placed in a 0°C freezer for crystallization, filtered, dried, and crushed to obtain a vitamin D3 / β-cyclodextrin inclusion complex (hereinafter referred to as the old VD3 inclusion complex). 2700g of PEG6000 is then melted in a 60°C water bath, and the inclusion complex is added to the PEG6000 solution. The mixture is stirred evenly, cooled in a freezer, and crushed to obtain 3000g of a new VD3 inclusion complex (enough for 100,000 bags).

[0050] The weight to unit conversion ratio of the VD3 raw material in the embodiment of the present invention is 1 μg = 40 units. Based on this calculation, 800 IU of VD3 raw material is approximately 20 μg.

[0051] See Table 1 for solubility experiments.

[0052] Example 2

[0053] A water-soluble vitamin D3 composition, wherein the dosage ratio of vitamin D3: beta-cyclodextrin: PEG6000 is 800 units: 0.0027 g: 0.0027 g, and 550 g of a new VD3 inclusion compound (amount for 100,000 bags) is obtained.

[0054] The preparation method is the same as that of Example 1.

[0055] Table 4. Solubility in water at different temperatures (μg / ml)

[0056] Example 3

[0057] A water-soluble vitamin D3 composition, wherein the dosage ratio of vitamin D3: beta-cyclodextrin: PEG6000 is 800 units: 0.0027g: 0.0135g, and 1600g of a new VD3 inclusion compound (amount for 100,000 bags) is obtained.

[0058] The preparation method is the same as that of Example 1.

[0059] Table 5. Solubility in water at different temperatures (μg / ml)

[0060] Example 4

[0061] A water-soluble vitamin D3 composition, wherein the dosage ratio of vitamin D3: beta-cyclodextrin: PEG6000 is 800 units: 0.0027g: 0.054g, and 5700g of a new VD3 inclusion compound (amount for 100,000 bags) is obtained.

[0062] The preparation method is the same as that of Example 1.

[0063] Table 6. Solubility in water at different temperatures (μg / ml)

[0064] From Example 4 above, it was found that when the ratio of PEG6000 to β-cyclodextrin was 20:1, the solubility-enhancing function of PEG6000 was lost.

[0065] The weight to weight unit conversion ratio of the raw material drug of Example VD3 of the present invention is 1 μg = 40 units. The raw material drug of VD3 is solid, which is common knowledge in the art.

[0066] Example 5

[0067] Referring to Example 1, the granule formulation was prepared

[0068] Table 7. Granule formulations

[0069] The preparation method of the above formula is:

[0070] After adding the prescribed amount of flavoring agent, diluent and binder to the composition obtained in Example 1, the preparation is prepared and packaged to obtain VD3 preparations, such as granules, capsules or tablets.

[0071] The dry or wet granulation is a conventional technique in the art.

[0072] In summary, the inventors prepared β-cyclodextrin inclusion complexes in the prior art patent ZL 201110139889.8 and found that the VD-β-cyclodextrin inclusion complex was soluble in water and easy to prepare various preparations. However, they still found that even such encapsulated products were unstable to light, heat, etc. Therefore, the inventors used the re-inclusion technology for the first time, using both PEG4000 and PEG6000. The experimental data are as follows:

[0073] 1. Use different types of PEG for encapsulation treatment, then conduct accelerated comparison, and select PEG6000 with less dosage and better stability improvement, based on Example 1.

[0074] Table 8. Accelerated test data are summarized as follows:

[0075] The VD3 content in the new VD3 inclusion complex remains basically unchanged.

[0076] Compared with the old VD3 inclusion compound, the new VD3 inclusion compound is more stable.

[0077] When PEG6000 was added, the solubility of VD3 was found to be improved.

[0078] 2. Take appropriate amounts of vitamin D3, old VD3 inclusion complex, and new VD3 inclusion complex and place them in 50 ml stoppered test tubes respectively. Prepare saturated aqueous solutions at 35 and 40°C. After dissolution reaches equilibrium, take the supernatant and filter it through a 0.8 μm microporous filter membrane. Measure the absorbance of the filtrate at 265 nm using a UV-visible spectrophotometer and substitute it into the standard curve equation to calculate the solubility. The results are shown in Table 9:

[0079] Table 9. Solubility in water at different temperatures (μg / ml)

[0080] 35°C to 40°C is a comfortable temperature for human consumption of pharmaceuticals, so the solubility of the new VD3 inclusion complex was determined at these temperatures. The results showed that at 35°C, dissolving 800 IU of the new VD3 inclusion complex required only 22 ml of water, while dissolving 800 IU of the old VD3 inclusion complex required 44.5 ml of water. Dissolving 800 IU of the original VD3 requires at least 200 ml of water.

[0081] 3. The new VD3 inclusion complex shows improved stability compared to the old VD3 inclusion complex. Tested under the Chinese Pharmacopoeia accelerated test conditions of 30°C ± 2°C, the results showed that the new VD3 inclusion complex remained stable over the four-month accelerated test period, with minimal change in content. Comparisons were performed using different PEG dosage groups, different PEG materials, and different PEG weights.

[0082] The accelerated comparison test is as follows:

[0083] Table 10

[0084] 5 g and 10 g correspond to Example 3 and Example 1, respectively, that is, the weight ratio of PEG:β-cyclodextrin is 5:1 and 10:1.

[0085] Both PEG4000 and 6000 can maintain high stability of the product.

[0086] Conclusion: The present invention provides a water-soluble vitamin D3 composition, which can improve the stability of vitamin preparations while not affecting the absorption stability of vitamin D3, thereby improving the solubility in the body and further improving the in vivo absorbability of vitamin D3. Moreover, the improvement of the present invention also improves the preparation process.

Claims

1. A water-soluble vitamin D3 composition, characterized in that, It consists of vitamin D3, inclusion compound 1 and inclusion compound 2, and the dosage ratio is 30 - 1500 units : 1 - 10 mg : 10 - 100 mg.

2. The water-soluble vitamin D3 composition according to claim 1, characterized in that, The dosage ratio of the said vitamin D3, inclusion compound 1 and inclusion compound 2 is 100 - 1000 units : 1 - 5 mg : 10 - 50 mg.

3. The water-soluble vitamin D3 composition according to claim 2, wherein The dosage ratio of the said vitamin D3, inclusion compound 1 and inclusion compound 2 is 200 - 1000 units : 1 - 5 mg : 10 - 50 mg.

4. The water-soluble vitamin D3 composition according to claim 1, wherein, The said vitamin D3 is sequentially included by inclusion compound 1 and inclusion compound 2.

5. The water-soluble vitamin D3 composition according to claim 1, wherein The said inclusion compound 1 is β - cyclodextrin, and inclusion compound 2 is PEG.

6. The water-soluble vitamin D3 composition according to claim 5, wherein, The said PEG is PEG400 - 8000, preferably PEG - 6000.

7. The water-soluble vitamin D3 composition according to claim 1, characterized in that, The dosage ratio of the said inclusion compound 1 and inclusion compound 2 is 1:1 - 1:20, preferably 1:1 - 1:

10.

8. A preparation containing the vitamin D3 composition described in claim 1, which contains pharmaceutically acceptable excipients.

9. The preparation method of the vitamin D3 composition according to claim 1, characterized in that It consists of the following steps: 1) Weigh the prescription amount of inclusion compound 1, prepare a saturated aqueous solution, weigh the prescription amount of vitamin D3, add vitamin D3 to the saturated aqueous solution of inclusion compound 1, cool down, filter, dry, and pulverize to obtain vitamin D3 - inclusion compound 1; 2) Mix the vitamin D3 - inclusion compound 1 obtained in step 1) with the prescription amount of melted inclusion compound 2, cool down, filter, dry, and pulverize to obtain the said vitamin D3 composition.

10. The application of the water - soluble vitamin D3 composition described in claim 1 in the preparation of drugs for preventing and treating osteoporosis and infantile rickets.

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