Vitamin D drops and preparation method thereof

Abstract

The present invention relates to the field of pharmaceutical preparations, and provides a vitamin D drop and a preparation method thereof, wherein the main components include vitamin D, an antioxidant, an oil phase, a surfactant, and a cosurfactant; wherein the content is a self-microemulsion system made of vitamin D, an oil phase, a surfactant, and a cosurfactant; and the soft capsule shell is made of gelatin, a plasticizer, and purified water. During the preparation, the oil phase, the surfactant, and the cosurfactant are first made into a blank self-microemulsion under stirring conditions, and then vitamin D and an antioxidant are added and stirred to obtain a drug-loaded self-microemulsion; and the drug-loaded self-microemulsion is then filled into a soft capsule as a content to obtain the target product. After the vitamin D drops disintegrate in water, they spontaneously form a microemulsion solution with a particle size not exceeding 100 nm, a clear and uniform appearance, and good stability, which significantly improves the solubility of vitamin D in water, and improves the in vitro dissolution and in vivo bioavailability of vitamin D.

Description

Technical Field

[0001] The invention relates to the field of novel pharmaceutical preparations, and specifically discloses vitamin D drops and a preparation method thereof. Background Art

[0002] The self-microemulsifying drug delivery system (SMEDDS) is a liquid or solid preparation composed of an oil phase, a surfactant and a co-surfactant. After oral administration, it can spontaneously form emulsion droplets less than 100 nm under the action of gastrointestinal peristalsis. As a new technology in the field of pharmaceutical preparations, the self-microemulsifying system is an excellent carrier for poorly soluble drugs. Since the drugs in the self-emulsifying system are in a dissolved state, they can directly skip the dissolution process and present a fast dissolution rate, so that the drugs are distributed in the gastrointestinal tract in the form of microemulsion droplets, increasing the contact area between the drugs in the oil phase and the gastrointestinal tract, making them easier to be absorbed through the lymph, avoiding the first-pass effect of the liver, and helping to improve bioavailability.

[0003] Vitamin D (VD) is a steroid hormone present in the human body, mainly in the form of vitamin D2 and vitamin D3. Related experiments have shown that vitamin D3 is better than vitamin D2 and has a wider clinical application. It is currently mainly used to prevent rickets in children and osteomalacia and joint pain in adults. Vitamin D3 is an essential trace element for the human body. It allows the small intestine to absorb calcium and phosphorus from food, promotes bone growth and calcification, and the main cause of rickets, osteomalacia and osteoporosis is a lack of vitamin D3. Vitamin D3 is hydrophobic and lipophilic. For this type of drug, solubility is the main rate-limiting step for drug absorption. Vitamin D is a fat-soluble vitamin, and its solubility is generally low, which affects the clinical efficacy of this product. In addition, this product is mainly used for children and the elderly, and its taste can also affect the compliance of this product. Currently, marketed preparations of vitamin D include tablets, granules, drops, emulsions, etc. Compared with these preparations, SMEDDS can improve the solubility of the drug and thus enhance the absorption of the drug.

[0004] Chinese patent CN105311037A discloses a vitamin D capsule drop and its preparation method. Its main invention is to add polyethylene glycol to the conventional soft capsule material, which is conducive to the rapid rupture of the soft capsule and improves the solubility of vitamin D. However, the vitamin D is only dissolved in soybean oil for soft capsule filling. After the dosage form disintegrates in the body, the contents cannot be effectively dispersed, and the absorption and utilization of the active ingredients cannot be improved. Chinese patent CN112641752A discloses a soft capsule and its preparation method and use for treating constipation. The patent directly dissolves the active ingredients in an oily solution and then fills the soft capsule. This method cannot improve the solubility of the soft capsule. Chinese patent CN105535979A discloses a self-microemulsifying drug delivery system for improving the bioavailability of poorly soluble drugs and its application. The system is composed of 10-70% of an oil phase, 25-70% of a surfactant and 5-20% of a co-surfactant, and can be used for the administration of pH-dependent and pH-independent poorly soluble drugs. Although the disclosed drug combination contains vitamin D, its prescription composition is not complete, and the final dosage form is not clarified. At the same time, for soft capsule dosage forms, due to the uneven breakage of gelatin molecular chains and its own hydrophilicity, the barrier capacity of a single gelatin film is poor. Stability phenomena such as capsule shell disintegration and delayed dissolution during storage of soft capsules are common problems in soft capsule products.

[0005] In summary, although the existing technology can improve vitamin D drops, it cannot fundamentally solve the solubility of vitamin D in water, thereby improving the bioavailability in vivo. In view of the above problems, preparing a highly stable and highly absorbed vitamin D drop can solve the solubility problem of vitamin D, improve bioavailability and medication compliance. Summary of the invention

[0006] The present invention aims at the many deficiencies of the prior art and provides a vitamin D drop and a preparation method thereof, wherein the main components include vitamin D, an antioxidant, an oil phase, a surfactant, and a cosurfactant; wherein the content is a self-microemulsion system made of vitamin D, an oil phase, a surfactant, and a cosurfactant; and the soft capsule shell is made of gelatin, a plasticizer, and purified water. During the preparation, the oil phase, the surfactant, and the cosurfactant are first made into a blank self-microemulsion under stirring conditions, and then vitamin D and an antioxidant are added and stirred to obtain a drug-loaded self-microemulsion; and the drug-loaded self-microemulsion is then filled into a soft capsule as a content to obtain the target product. After the above vitamin D drops disintegrate in water, they spontaneously form a microemulsion solution with a particle size not exceeding 100nm, a clear and uniform appearance, and good stability, which significantly improves the solubility of vitamin D in water, and improves the in vitro dissolution and in vivo bioavailability of vitamin D.

[0007] The technical solution finally determined by the inventor is as follows:

[0008] The invention provides a vitamin D drop soft capsule, comprising contents and a soft capsule shell, wherein the soft capsule shell accounts for 40%-80% of the weight of the contents; more preferably 48%-75%.

[0009] The weight percentages of its contents are as follows:

[0010] Vitamin D 0.006%-0.16%

[0011] Antioxidant 0.1%-0.5%

[0012] Oil phase 10%-35%

[0013] Co-surfactant 15%-30%

[0014] Surfactant residue,

[0015] The oil phase, surfactant and co-surfactant constitute a self-microemulsification system;

[0016] The weight percentage of the soft capsule shell is as follows:

[0017] Gelatin 38%-55%

[0018] Plasticizer 2%-30%

[0019] Purified water balance;

[0020] The plasticizer is one or more of glycerol, trehalose, maltitol, xylitol and sorbitol;

[0021] The vitamin D is at least one of vitamin D2 and vitamin D3.

[0022] Correspondingly, each dosage unit of the drops contains 400 international units, 800 international units, 1200 international units, 2000 international units, 5000 international units, 10,000 international units and 100,000 international units of vitamin D.

[0023] As for other components, the antioxidant is selected from α-tocopherol; the oil phase is selected from at least one of monoolein glyceryl, monolinolein glyceryl, propylene glycol dicaprylate caprate, and caprylic capric mono- and diglycerides; the surfactant is selected from at least one of oleoyl polyoxyethylene glyceride, caprylic capric polyethylene glycol glyceride, and oleic acid polyethylene glycol glyceride; the co-surfactant is selected from at least one of diethylene glycol monoethyl ether and propylene glycol monocaprylate; and it is further preferred that the amount of surfactant to co-surfactant is 2:1.

[0024] In addition, the inventors analyzed the main reasons for the shell disintegration and delayed dissolution of the soft capsules during the storage period and found that the main reason was the cross-linking and aging of the gelatin in the soft capsule shell. In order to alleviate or solve the common problem of cross-linking and aging, the inventors found that a new plasticizer can be added to the gelatin film to cross-link with the gelatin to form a film, while further reducing the hygroscopicity of the shell and cross-linking aging, thereby ensuring the in vitro / in vivo release of the soft capsule. This is another important feature that distinguishes the present application from existing vitamin D drops.

[0025] The plasticizer used is one or more of glycerol, trehalose, maltitol, xylitol and sorbitol.

[0026] It is further preferred to use a glycerol and trehalose composition with a mass ratio of (2-40): (2-30); the most preferred mass ratio is 13:11. Using trehalose as a plasticizer can not only effectively promote gelatin cross-linking film formation, but also reduce the cross-linking aging that occurs during the late stability of the capsule shell. Trehalose is a non-reducing disaccharide formed by two glucose molecules connected by α, α-1, 1 bonds. Its physical and chemical properties are particularly stable to heat, acid and alkali. When coexisting with amino acids and proteins in gelatin, it can form strong hydrogen bonds to improve the wettability, ductility and stability of gelatin. Even if heated, the Maillard reaction will not occur, and the loss of water in the soft capsule content or capsule shell can be prevented; while glycerol, as a traditional soft capsule rubber plasticizer, has the characteristics of good moldability and improved glue viscosity, but glycerol has a poor effect in preventing oxygen in the air from oxidizing gelatin, and as the proportion of glycerol increases, the disintegration time of the rubber is also prolonged. The combination of the two can utilize the plasticizing effect of glycerol to ensure the toughness of the capsule shell and facilitate molding; and the moisturizing and stabilizing functions of trehalose can be utilized to prevent cross-linking aging of the soft capsule and increase stability, achieving unexpected technical effects.

[0027] Based on the above technical solution, the inventors prefer the following weight percentages of the contents:

[0028]

[0029] The most preferred and feasible technical solutions are as follows:

[0030] The weight percentages of the contents are as follows:

[0031]

[0032] Or the weight percentage of the contents is as follows:

[0033]

[0034] Or the weight percentage of the contents is as follows:

[0035]

[0036] Or the weight percentage of the contents is as follows:

[0037]

[0038] On the basis of the above technical solutions, the inventors preferred the following feasible technical solutions for the soft capsule shell:

[0039] The weight percentages of the soft capsule shell are as follows:

[0040]

[0041] Or the weight percentage of the soft capsule shell is as follows:

[0042]

[0043] Or the weight percentage of the soft capsule shell is as follows:

[0044]

[0045]

[0046] Regardless of the composition used, the preparation method of the above-mentioned vitamin D drop soft capsules comprises the following specific steps:

[0047] a. The oil phase, surfactant and co-surfactant were stirred and mixed in a water bath at 35-40°C to obtain a blank self-microemulsion system having a particle size not exceeding 100 nm;

[0048] b. Adding vitamin D and an antioxidant to the self-microemulsification system obtained in step a, stirring until they are dissolved in the self-microemulsification system, and finally diluting with 50 times the weight of purified water to prepare a drug-containing self-microemulsion, that is, obtaining a white uniform content of vitamin D drops;

[0049] c. Fill the soft capsule contents obtained in step b into soft capsules to prepare vitamin D drops.

[0050] The specific process of step c is as follows:

[0051] ① Material preparation: According to the material table, weigh and prepare gelatin, glycerol, trehalose and purified water for capsules.

[0052] ② Gelatinization: Add the prepared gelatin, glycerin, trehalose and purified water into the gelatinization tank, heat to 80℃, stir for 90 minutes and then start vacuuming with a vacuum degree of -0.06~-0.09Mpa. Keep the gelatin solution boiling without overflowing, stop stirring and turn off the vacuum until there are no obvious bubbles in the gelatin solution, and keep it warm at 65℃ for later use.

[0053] ③Pellet pressing: Control the temperature of the preparation room at 18-22℃ and the humidity below 50%; the temperature of the glue box is 55℃, and the temperature of the spray body is 39℃; adjust and control the thickness of the rubber to maintain at 0.7-0.8mm, and the contents are automatically filled for pill pressing.

[0054] ④ Shaping: After being pressed into pills, the soft capsules are conveyed through a conveyor belt into a roller cage dryer for shaping, and the shaping time is 2-3 hours.

[0055] ⑤ Drying: Continue drying the shaped soft capsules. Keep the temperature at about 22-28°C and the humidity at below 40%, and dry for 14-16 hours to obtain the vitamin D drop soft capsules of the present invention.

[0056] The vitamin D drop soft capsule provided by the present invention selects materials with high safety, non-toxicity and low gastrointestinal irritation. These materials are preferably combined according to the present invention to obtain various preferred embodiments of the present invention. The self-microemulsion particle size in the present invention is nanometer-level, which can effectively solve the defects of large particle size and thermodynamic instability of traditional emulsions; small particle size is conducive to the stability of self-microemulsion and prolongs the storage time, improves the dispersibility and dissolution rate of vitamin D in water, is conducive to increasing the absorption degree of drugs in the body, improves the bioavailability of vitamin D, and reduces the irritation caused by contact between drugs and the gastrointestinal tract; while using a new plasticizer to cross-link and form a film with gelatin, the hygroscopicity of the capsule shell and cross-linking aging are further reduced to ensure the in vitro / in vivo release of the soft capsule. The self-microemulsion and soft capsule combination preparation method of the present invention is simple and feasible, low in cost, and easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 The standard curve for determining the content of vitamin D3 in the vitamin D3 self-microemulsion of the present invention;

[0058] Figure 2 The ternary phase diagram of the effective region of the blank self-microemulsion of the present invention;

[0059] Figure 3 This is a schematic diagram of the appearance of the soft capsule rubber of the present invention;

[0060] Figure 4 is a particle size distribution diagram of the self-microemulsion of the present invention;

[0061] Figure 5 This is the appearance diagram of the self-microemulsion of the present invention;

[0062] Figure 6 This is a schematic diagram of the dissolution test results of vitamin D3, an active ingredient of the products prepared in Examples 1 and 3 of the present invention;

[0063] Figure 7This is a schematic diagram of the dissolution test results of the active ingredient vitamin D2 of the products prepared in Examples 2 and 4 of the present invention;

[0064] Figure 8 Schematic diagram of the cross-linking phenomenon of the soft capsule of commercially available product S1 under accelerated conditions in Experimental Example 2 of the present invention. DETAILED DESCRIPTION

[0065] In order to better understand the present invention, the content of the present invention is further explained below in conjunction with examples, but the content of the present invention is not limited to the following embodiments.

[0066] The materials used in the following embodiments may be selected but are not limited to:

[0067] Ethyl oleate (lot number 0001778173) was purchased from Croda Inc.; monoolein (lot number 193840), monolinolein (lot number 183103), propylene glycol dicaprylate (lot number 187377), oleoyl polyoxyethylene glyceride (lot number 189637), propylene glycol monocaprylate (lot number 193839), diethylene glycol monoethyl ether (lot number 176615) were purchased from Jiafashi China Co., Ltd., caprylic capric acid polyethylene glycol glyceride (lot number C12880792) was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; anhydrous ethanol (lot number 2304041) was purchased from Shanghai MacLean Biochemical Technology Co., Ltd. 42B) was purchased from Nanjing Chemical Reagent Co., Ltd., vitamin D3 (batch number UT21020134) was purchased from DSM; n-hexane (HPLC, batch number FT369121B05) was purchased from Hubei Futon Biochemical Technology Co., Ltd.; n-pentanol (HPLC, batch number 20200325) was purchased from Tianjin Komiou Chemical Reagent Co., Ltd.; gelatin for capsules (batch number 202304011) was purchased from Baotou Dongbao Biotechnology Co., Ltd.; glycerol (batch number 202301002) was purchased from Nanchang Baiyun Pharmaceutical Co., Ltd.

[0068] The equipment used in the experiment is:

[0069] Agilent 1260 high performance liquid chromatograph (Agilent Technologies, Inc., USA); MS16001LE electronic balance (METTLER TOLEDO); EU50 electric stirrer (Shanghai Fluke Technology Development Co., Ltd.); TG16 high-speed centrifuge (Shanghai Lu Xiangyi Centrifuge Instrument Co., Ltd.); laser particle size tester (Symptech, Germany); electron microscope (LEICA); YWJ100-Ⅱ fully automatic soft capsule machine (Xinhang Chengshangjie (Langfang) Technology Development Co., Ltd.); FADT-1202 automatic dissolution apparatus (Shanghai Fucox Analytical Instrument Co., Ltd.).

[0070] Content determination method:

[0071] The method was carried out with reference to the first method of Part 4 General Rules 0722 of the 2020 edition of the Pharmacopoeia of the People's Republic of China. The chromatographic conditions were as follows: the chromatographic column was a Yuexu Technology normal phase silica gel column (4.6mm×200mm, 5μm); the mobile phase was n-hexane: n-pentanol (997:3); the detection wavelength was 254nm; the flow rate was 2ml / min; the column temperature was 30℃; the injection volume was 100μl. The method was validated by the method, and the theoretical plate number of the method was greater than 10,000. The vitamin D3 concentration (c) had a good linear relationship with the peak area (y) in the range of 1.5516-6.2064μg / ml, and the standard curve equation was y=134x+0.8543(R 2 =1.0000)( Figure 1 The precision and accuracy of this method meet the requirements, and the established detection method is accurate and reliable.

[0072] Solubility test:

[0073] Excess vitamin D3 was added to different types of oil phase, surfactant and co-surfactant, placed in a 37°C water bath at a speed of 75 rpm for 30 minutes, centrifuged (10000 rpm) for 8 minutes, the supernatant was removed, filtered through a 0.45 μm filter membrane and diluted with n-hexane to an appropriate concentration, and the solubility of vitamin D3 in different excipients was determined. The results (Table 1) show that vitamin D3 has the highest solubility in oil phase monoolein, surfactant oleoyl polyoxyethylene glyceride, and co-surfactant anhydrous ethanol, but anhydrous ethanol is volatile and has a certain effect on the capsule shell and preparation stability. Therefore, monoolein is finally preferred as the oil phase, oleoyl polyoxyethylene glyceride as the surfactant, and diethylene glycol monoethyl ether as the co-surfactant, but the selection of surfactant and co-surfactant is not limited to a single selection, and a combination selection can also be made; the inventor further screened the dosage of each component in the vitamin D3 self-microemulsion prescription.

[0074] Table 1 Solubility of vitamin D3 in different excipients ( n=3)

[0075]

[0076] Self-microemulsification prescription dosage screening:

[0077] Monoolein was selected as the oil phase, oleoyl polyoxyethylene glyceride as the surfactant, and diethylene glycol monoethyl ether as the cosurfactant. The surfactant and the cosurfactant were respectively in a mass ratio of 3:1, 2:1, 1:1, 1:2, and 1:3 (K m) were mixed evenly, and then the oil phase and the mixed surfactant were mixed evenly in a mass ratio of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, and 9:1. After that, it was placed in a 37°C water bath and stirred at 75 rpm for 30 minutes to prepare a blank self-microemulsion, and the self-microemulsion state was observed; then, 50 times the weight of purified water was added to the self-microemulsion until a white, uniform emulsion appeared, and the amount of water added was recorded at this time. The oil phase, mixed surfactant, and purified water were respectively the three vertices of the phase diagram, and a pseudo-ternary phase diagram was drawn using Origin Pro8.0 software. According to the size of the microemulsion area formed, K was screened. m The specific results are shown in Figure 2 .

[0078] It can be seen from the pseudo-ternary phase diagram that when the Km value is greater than 2:1 (surfactant: cosurfactant), the emulsification effect is too strong, which increases the gel area, but affects the self-microemulsification effect and reduces the area of ​​the microemulsion area; when the Km value is 2:1 (surfactant: cosurfactant), the area of ​​the microemulsion area is the largest, indicating that the emulsification effect is the best; when the Km value is less than 2:1 (surfactant: cosurfactant), the area of ​​the microemulsion area gradually decreases, indicating that as the amount of surfactant decreases, the emulsification ability of the system also decreases. Therefore, the final surfactant: cosurfactant dosage is 2:1. Since the self-microemulsion is to be filled in the soft capsule as the content, a prescription ratio with better dilution ability is selected, that is, a prescription with an oil phase ratio of 10%-32% is selected.

[0079] Screening of the ratio of plasticizer glycerol and trehalose

[0080] While keeping the ratio of gelatin and purified water for capsules unchanged, the ratio of glycerol and trehalose in the plasticizer composition was screened based on indicators such as appearance elasticity, viscosity, moisture, and disintegration time, as shown in Table 2; the results are shown in Tables 3 and 4.

[0081] Table 2 Screening of glycerol and trehalose dosage

[0082]

[0083] Table 3 Screening results of glycerol and trehalose dosage ratio (1)

[0084]

[0085] Table 4 Screening results of glycerol and trehalose dosage ratio (2)

[0086]

[0087] As shown in Table 3, there is no significant difference in viscosity, moisture content and disintegration time during the screening of glycerol and trehalose dosage, except for a slight difference in appearance elasticity. Figure 3 As shown in Table 4, after one month of accelerated soft capsule disintegration, it can be determined that No. 2 has the shortest disintegration time and No. 3 has the longest disintegration time. Therefore, the final ratio of glycerol to trehalose is 13:11.

[0088] Preparation of Vitamin D3 Drops

[0089] Table 5 Vitamin D3 drops prescription

[0090]

[0091]

[0092] The specification of the prescription is that each capsule contains 400 IU of vitamin D3, a total of 10,000 capsules are made, and the weight of the contents is 3.1 kg. The formula for calculating the amount of vitamin D3 is: dosage (g) = prescription dosage (IU) / vitamin D3 content (IU / g). In the rubber skin prescription, gelatin for capsules accounts for 40% of the prescription dosage of the capsule shell, glycerol accounts for 10.4% of the prescription dosage of the capsule shell, trehalose accounts for 8.8% of the prescription dosage of the capsule shell, and the balance is the amount of purified water. During the soft capsule pressing process, the capsule shell thickness is controlled to be 0.75±0.05mm, and the weight gain of each soft capsule is about 48%-75% of the contents (that is, the soft capsule shell accounts for 48%-75% of the weight of the contents). Taking into account the loss of debugging machines and mesh glue, the amount of chemical glue needs to be appropriately increased during production.

[0093] The dosage of the self-microemulsification prescription screened above was verified.

[0094] First, weigh 1488g of oleoyl polyoxyethylene glyceride and 744g of diethylene glycol monoethyl ether and mix them evenly. Then, add 858g of monoolein glyceride and mix them. Then, place them in a 37°C water bath and stir at 75rpm for 30 minutes to prepare a blank self-microemulsion. Then, slowly add 9.752g of α-tocopherol and 0.248g of vitamin D3 to the blank self-microemulsion, stir for 15 minutes, observe the self-microemulsion, and finally dilute with 50 times the weight of purified water until a white, uniform emulsion appears. Take a small amount of the self-microemulsion and determine the content according to the above-mentioned content determination method. The result is 99.45%; the particle size is measured by a laser particle size analyzer, and the average particle size is 9.7nm. Figure 4 Another 100 ml of microemulsion was taken and kept at room temperature for 8 hours. The result was that the emulsion was stable and no crystals were precipitated. Figure 5 .

[0095] The prepared vitamin D3 self-microemulsion is used as the content to prepare soft capsules by a soft capsule machine. The specific preparation process is as follows:

[0096] ① Material preparation: According to the material table, weigh and prepare gelatin, glycerol, trehalose and purified water for capsules.

[0097] ② Gelatinization: Add the prepared gelatin, glycerin, trehalose and purified water into the gelatinization tank, heat to 80℃, stir for 90 minutes and then start vacuuming with a vacuum degree of -0.06~-0.09Mpa. Keep the gelatin solution boiling without overflowing, stop stirring and turn off the vacuum until there are no obvious bubbles in the gelatin solution, and keep it warm at 65℃ for later use.

[0098] ③Pellet pressing: Control the temperature of the preparation room at 18-22℃ and the humidity below 50%; the temperature of the glue box is 55℃, and the temperature of the spray body is 39℃; adjust and control the thickness of the rubber to maintain at 0.7-0.8mm, and the contents are automatically filled for pill pressing.

[0099] ④ Shaping: After being pressed into pills, the soft capsules are conveyed through a conveyor belt into a roller cage dryer for shaping, and the shaping time is 2-3 hours.

[0100] ⑤ Drying: Continue drying the shaped soft capsules. Keep the temperature at about 22-28°C and the humidity at below 40%, and dry for 14-16 hours to obtain the vitamin D drop soft capsules of the present invention.

[0101] Example 1

[0102] A vitamin D drop, the composition of which is calculated by weight percentage:

[0103]

[0104]

[0105] The specification of this prescription is that each capsule contains 400 IU of vitamin D3. In the rubber skin prescription, gelatin for capsules accounts for 40% of the capsule shell prescription, glycerin accounts for 10.4% of the capsule shell prescription, trehalose accounts for 8.8% of the capsule shell prescription, and the balance is the amount of purified water. During the soft capsule pressing process, the capsule shell thickness is controlled to be 0.75±0.05mm, and the weight gain of each soft capsule is about 48%-75% of the content. Considering the loss of debugging machine and mesh glue, the amount of glue needs to be appropriately increased during production.

[0106] The preparation method is as follows:

[0107] 1) Preparation of a blank self-microemulsion: The prescribed amount of monoolein, oleoyl polyoxyethylene glyceride and diethylene glycol monoethyl ether were mixed with an electric stirrer in a water bath at 37° C. to obtain a blank self-microemulsion with a particle size not exceeding 100 nm.

[0108] 2) Preparing the contents: adding vitamin D and antioxidants to the self-microemulsification system obtained in step a, mixing evenly, and finally diluting with 50 times the weight of purified water to prepare a drug-containing self-microemulsion, that is, obtaining white and uniform vitamin D drops.

[0109] 3) Preparation of soft capsules: The preparation process is the same as the above-mentioned “Preparation of vitamin D3 drops”.

[0110] Example 2

[0111] A vitamin D drop, the composition of which is calculated by weight percentage:

[0112]

[0113] The specification of this prescription is that each capsule contains 5000IU of vitamin D3. In the rubber skin prescription, gelatin for capsules accounts for 45% of the capsule shell prescription, glycerin accounts for 9.1% of the capsule shell prescription, trehalose accounts for 7.7% of the capsule shell prescription, and the balance is the amount of purified water. During the soft capsule pressing process, the capsule shell thickness is controlled to be 0.75±0.05mm, and the weight gain of each soft capsule is about 48%-75% of the content. Considering the loss of debugging machine and mesh glue, the amount of glue needs to be appropriately increased during production.

[0114] The preparation method is as follows:

[0115] 1) Preparation of a blank self-microemulsion: The prescribed amount of monoolein, caprylic capric macrogol glyceride and oleic macrogol glyceride were mixed with an electric stirrer in a water bath at 35° C. to obtain a blank self-microemulsion with a particle size not exceeding 100 nm.

[0116] 2) Preparation of contents: Add the prescribed amount of vitamin D2 and α-tocopherol to the blank self-microemulsion, mix well, and finally dilute with 50 times purified water to prepare the drug-containing self-microemulsion, that is, obtain white and uniform vitamin D drops.

[0117] 3) Preparation of soft capsules: The preparation process is the same as “Preparation of vitamin D3 drops”.

[0118] Example 3

[0119] A vitamin D drop, the composition of which is calculated by weight percentage:

[0120]

[0121] The specification of this prescription is that each capsule contains 400 IU of vitamin D3. In the rubber skin prescription, gelatin for capsules accounts for 42% of the capsule shell prescription, glycerin accounts for 11.375% of the capsule shell prescription, trehalose accounts for 9.625% of the capsule shell prescription, and the balance is the amount of purified water. During the soft capsule pressing process, the capsule shell thickness is controlled to be 0.75±0.05mm, and the weight gain of each soft capsule is about 48%-75% of the content. Considering the loss of debugging machine and mesh glue, the amount of glue needs to be appropriately increased during production.

[0122] The preparation method is as follows:

[0123] 1) Preparation of a blank self-microemulsion: The prescribed amount of glyceryl monooleate, caprylic capric macrogol glyceride, oleic acid macrogol glyceride, propylene glycol monocaprylate and diethylene glycol monoethyl ether were mixed with an electric stirrer in a water bath at 38° C. to obtain a blank self-microemulsion with a particle size not exceeding 100 nm.

[0124] 2) Preparation of contents: Add the prescribed amount of vitamin D3 and α-tocopherol to a blank self-microemulsion, mix well, and finally dilute with 50 times the weight of purified water to prepare a drug-containing self-microemulsion, that is, obtain a white and uniform vitamin D drop content.

[0125] 3) Preparation of soft capsules: The preparation process is the same as “Preparation of vitamin D3 drops”.

[0126] Example 4

[0127] A vitamin D drop, the composition of which is calculated by weight percentage:

[0128]

[0129]

[0130] The specification of this prescription is that each capsule contains 10000 IU of vitamin D2. In the rubber skin prescription, gelatin for capsules accounts for 40% of the capsule shell prescription, glycerin accounts for 10.4% of the capsule shell prescription, trehalose accounts for 8.8% of the capsule shell prescription, and the balance is the amount of purified water. During the soft capsule pressing process, the capsule shell thickness is controlled to be 0.75±0.05mm, and the weight gain of each soft capsule is about 48%-75% of the content. Considering the loss of debugging machine and mesh glue, the amount of glue needs to be appropriately increased during production.

[0131] The preparation method is as follows:

[0132] 1) Preparation of a blank self-microemulsion: The prescribed amount of monolinoleyl glyceryl, caprylic capric macrogol glyceride, oleic acid macrogol glyceride, propylene glycol monocaprylate and diethylene glycol monoethyl ether were mixed with an electric stirrer in a water bath at 40° C. to obtain a blank self-microemulsion with a particle size not exceeding 100 nm.

[0133] 2) Preparation of contents: Add the prescribed amount of vitamin D2 and α-tocopherol to a blank self-microemulsion, mix well, and finally dilute with 50 times the weight of purified water to prepare a drug-containing self-microemulsion, that is, obtain a white and uniform vitamin D drop content.

[0134] 3) Preparation of soft capsules: The preparation process is the same as “Preparation of vitamin D3 drops”.

[0135] Experimental Example 1

[0136] This experimental example involves a study on the dissolution performance of vitamin D in the vitamin D drops prepared in Examples 1-4. Commercially available vitamin D3 soft capsules (hereinafter referred to as S1) and vitamin D2 soft capsules (S2) were selected as control drugs, wherein the contents of commercial products S1 and S2 are mostly composed of a mixed solution of soybean oil or peanut oil containing vitamin D, and the capsule shell of the commercial soft capsule is composed of gelatin, glycerol, and water. A comparative study of the dissolution curves simulating in vivo absorption was conducted with the products prepared in Examples 1 to 4 of the present invention.

[0137] The experimental method is: the second method of the paddle method in the dissolution and release determination method of the Chinese Pharmacopoeia 0931 is adopted, the speed is 75 rpm, and the concentration is 0.1 mol·L -1 Sodium hydroxide-5% Triton X-100 solution was used as the dissolution medium. The dissolution was investigated within 60 minutes, the cumulative dissolution was calculated, and the dissolution curve was drawn.

[0138] The particle size of the vitamin D self-microemulsion prepared in Examples 1-4 was measured using a laser particle size analyzer. The results are shown in Table 6.

[0139] The dissolution experiment of vitamin D3 was compared with Example 1, Example 3 and commercial product S1. The results are shown in Table 7 and Figure 6 shown.

[0140] The dissolution experiment of vitamin D2 selected Example 2, Example 4 and commercial product S2 for comparison. The results are shown in Table 8 and Figure 7 shown.

[0141] Table 6 Particle size test results of vitamin D self-microemulsion prepared in Examples 1-4

[0142]

[0143] It can be seen from Table 6 that the particle size distribution of the vitamin D self-microemulsions prepared in Examples 1-4 is basically the same, and the D50 particle size is basically around 10 nm.

[0144] Table 7 Vitamin D3 dissolution curve study results

[0145]

[0146] As can be seen from Table 7, the dissolution rates of Examples 1 and 3 are relatively fast, with the dissolution rate being above 90% in 20 minutes, while the commercial product reaches 91.72% in 60 minutes, indicating that the active ingredient dissolution rates of Examples 1 and 3 of the present invention are faster than that of the commercial product 1.

[0147] Table 8 Vitamin D2 dissolution curve study results

[0148]

[0149] As can be seen from Table 8, the dissolution rates of Examples 2 and 4 are relatively fast, with the dissolution rates both being above 85% in 20 minutes, while the commercial product reaches 88.77% in 45 minutes, indicating that the active ingredients of Examples 2 and 4 of the present invention dissolve faster than those of the commercial product 2.

[0150] Experimental Example 2

[0151] This experimental example involves the stability study of the vitamin D drops prepared in Example 1 and Example 3, mainly an accelerated experiment. The commercially available product S1 in Experimental Example 1 was selected as the control drug and examined under accelerated conditions for 3 months. The stability test refers to the "9001 Guidelines for Stability Testing of Raw Materials and Preparations" in Part IV of the 2020 Edition of the "Chinese Pharmacopoeia". The accelerated conditions are 40°C ± 2°C and 75% ± 5% relative humidity. Samples are taken at 0, 1, 2, and 3 months, respectively, and the active ingredients and disintegration time are tested.

[0152] Vitamin D3 content determination method: see the method in the examples.

[0153] Dissolution test method: The second paddle method in the dissolution and release test method of the Chinese Pharmacopoeia 0931 was used, with a rotation speed of 75 rpm and a concentration of 0.1 mol·L -1 Sodium hydroxide-5% Triton X-100 solution was used as the dissolution medium, and the dissolution rate was investigated for 30 minutes.

[0154] The vitamin D stability experiment selected Example 1, Example 3 and commercially available product S1 for comparison. The results are shown in Table 9 and Figure 8 .

[0155] Table 9 Results of vitamin D stability test

[0156]

[0157] As can be seen from Table 9, after 3 months of acceleration, the content and solubility of Example 1 and Example 3 remained basically unchanged; however, the content of the commercial product S1 showed a slight downward trend, and the solubility was obviously not dissolved after 3 months of acceleration. Figure 8), it was found that there was a thin film on the surface of the capsule shell that hindered the release of the drug, indicating that the commercial product was cross-linked. Because the plasticizer in the capsule shell of the commercial product is glycerol, glycerol only plays a plasticizing role in the capsule shell and cannot hinder the oxidation of gelatin by oxygen, so the soft capsule is prone to cross-linking after being placed for a certain period of time; while the plasticizer of the soft capsule of the present invention is glycerol and trehalose, trehalose has moisturizing and stability functions, and can prevent the capsule shell from being cross-linked. It shows that the product stability of Examples 1 and 3 of the present invention is better than that of the commercial product S1.

[0158] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A vitamin D drop, comprising contents and a soft capsule shell, characterized in that: The weight percentages of its contents are as follows: Vitamin D 0.006%-0.16% Antioxidant 0.1%-0.5% Oil phase 10%-35% Co-surfactant 15%-30% Surfactant residue, The oil phase, surfactant and co-surfactant constitute a self-microemulsification system; The weight percentage of the soft capsule shell is as follows: Gelatin 38%-55% Plasticizer 2%-30% Purified water balance; The plasticizer is a composition of glycerol and trehalose in a weight ratio of (2-40):(2-30); The drops are composed of contents and soft capsule shells, wherein the soft capsule shell accounts for 40%-80% of the weight of the contents; The surfactant is selected from at least one of oleoyl polyoxyethylene glyceride, caprylic capric polyethylene glycol glyceride, and oleic acid polyethylene glycol glyceride; the co-surfactant is selected from at least one of diethylene glycol monoethyl ether and propylene glycol monocaprylate, and the dosage of the surfactant and the co-surfactant is 2:

1.

2. The vitamin D drops according to claim 1, characterized in that The vitamin D is at least one of vitamin D2 and vitamin D3.

3. The vitamin D drops according to claim 1, characterized in that The antioxidant is selected from α-tocopherol; the oil phase is selected from at least one of monoolein, monolinolein, propylene glycol dicaprylate, caprylic capric mono- and diglycerides, and medium chain triglycerides.

4. The vitamin D drops according to claim 1, characterized in that The plasticizer in the soft capsule shell is a composition of glycerol and trehalose in a weight ratio of 13:

11.

5. The vitamin D drops according to claim 1, characterized in that The weight percentages of its contents are as follows: Vitamin D 0.006%-0.16% Antioxidant 0.2%-0.5% Oil phase 10%-32% Surfactant 30%-56% Co-surfactant 15%-28%.

6. The vitamin D drops according to claim 1, characterized in that Each dosage unit of the drops contains 400 international units, 800 international units, 1200 international units, 2000 international units, 5000 international units, 10,000 international units and 100,000 international units of vitamin D.

7. The vitamin D drops according to claim 1, characterized in that The soft capsule shell accounts for 48%-75% of the weight of the contents.

8. The method for preparing the vitamin D drops according to claim 1, characterized in that: The specific steps are as follows: a. The oil phase, surfactant and co-surfactant were stirred and mixed in a water bath at 35-40°C to obtain a blank self-microemulsion system having a particle size not exceeding 100 nm; b. Adding vitamin D and an antioxidant to the self-microemulsification system obtained in step a, stirring until they are dissolved in the self-microemulsification system, and finally diluting with 50 times the weight of purified water to prepare a drug-containing self-microemulsion, that is, obtaining a white uniform content of vitamin D drops; c. Fill the soft capsule contents obtained in step b into soft capsules to prepare vitamin D drops.

Images