Edecalciferol capsule with proper and stable hardness and preparation method thereof

Abstract

The invention provides an idedecalciferol capsule with proper and stable hardness, raw materials for preparing the idedecalciferol capsule comprise a liquid medicine raw material and a glue solution raw material for preparing a soft capsule material, and the viscosity of the glue solution is 15000-20000 mPa.s. The invention further provides a preparation method of the idedecalciferol capsule. According to the eldecalciferol capsule disclosed by the invention, the viscosity of a glue solution in the process of preparing a soft capsule material is controlled, specific components are added, the hardness of the capsule is proper, the stability of a liquid medicine in the capsule is good, and few impurities are generated by degradation.

Description

Technical Field

[0001] The invention relates to the technical field of idecalcitol drugs, and in particular to idecalcitol capsules with suitable and stable hardness and a preparation method thereof. Background Art

[0002] Idecalcitol is a new type of active vitamin D analogue, mainly used to treat osteoporosis in postmenopausal women. It inhibits osteoclast differentiation and maturation, reduces bone resorption, and promotes intestinal calcium absorption to increase bone density.

[0003] Under high temperature, high humidity or light conditions, idecalcitol is easily degraded, resulting in a decrease in the content of active ingredients. Summary of the invention

[0004] The researchers of the present invention found in the study of the glue solution for preparing soft capsule materials of idecalcitol capsules that too low glue viscosity will lead to too low hardness and thus rupture of the capsules. The present invention is based on a series of studies on the glue solution components for preparing soft capsule materials.

[0005] In a first aspect, the present invention provides an idecalcitol capsule with suitable and stable hardness, wherein the raw materials for preparing the capsule include a drug solution raw material and a gelatin raw material for preparing a soft capsule material, and the viscosity of the gelatin is 15000-20000 mPa·s.

[0006] According to the stable idecalcitol capsules provided by the present invention, the raw materials for preparing the gelatin solution include: Gelatin 50-100 parts by weight; Glycerin 15-25 parts by weight; Sorbitol 1-5 parts by weight; Yellow iron oxide 0.1-0.5 parts by weight; Titanium dioxide 0.1-0.5 parts by weight; Purified water is added to make the viscosity of the glue solution 15000-20000 mPa·s.

[0007] According to the stable idecalcitol capsules provided by the present invention, the raw materials for preparing each 100 mg of the drug solution include: Idecalcitol 0.5-2 μg; Butylated hydroxyanisole 15-25 μg; Racemic α-tocopherol 0.5-2 mg; Soybean oil was added to make the total weight of the drug solution 100 mg.

[0008] According to the stable idecalcitol capsules provided by the present invention, the raw materials for preparing the gelatin solution also include: Caffeic acid 1-5 parts by weight and / or caffeic acid 1-5 parts by weight.

[0009] The study also found that adding some components of phenolic acid antioxidants can affect the production of impurities in the idecalciferol in the capsule solution. On the other hand, the present invention also provides a method for preparing the stable idecalcitol capsules according to the first aspect, comprising the following steps: S01, preparing a drug solution; S02, preparing glue solution; S03, using the drug solution obtained in S01 and the gelatin solution obtained in S02, to prepare pills by a dripping method, so as to obtain the stable idecalciferol capsules.

[0010] According to the method for preparing stable idecalcitol capsules provided by the present invention, S01 comprises the following steps: S11, weighing the prescribed amount of idecalcitol, racemic α-tocopherol and soybean oil into a beaker, stirring and homogenizing to prepare a mixed solution A; S12, weighing a prescribed amount of butylated hydroxyanisole, adding it to the mixture A, and stirring to homogenize.

[0011] According to the method for preparing stable idecalciferol capsules provided by the present invention, in S01, the stirring and homogenizing is carried out at a speed of 2500-3500 rpm for 10-25 min. According to the method for preparing stable idecalcitol capsules provided by the present invention, S02 comprises the following steps: S21, adding a portion of the prescribed amount of purified water to the prescribed amount of yellow iron oxide and titanium dioxide, stirring and mixing to prepare a suspension for standby use; reserving a portion of the prescribed amount of purified water; S22, put sorbitol, glycerol or sorbitol, glycerol, caffeic acid, chlorogenic acid and part of the prescribed amount of purified water into a gelatin preparation container, heat while stirring, stop stirring, add gelatin, add purified water to the prescribed amount, continue stirring until the gelatin is dissolved, add the suspension of S21, and wash the container containing the suspension with the reserved purified water, transfer it to the gelatin solution, stir, vacuum degas, and set aside.

[0012] According to the method for preparing stable idecalcitol capsules provided by the present invention, in S03, the temperature of the gel solution obtained in S02 is maintained, and a pill dropping machine is used, and liquid paraffin or medium-chain triglycerides are used as a coolant to drip to obtain the stable idecalcitol capsules.

[0013] According to the method for preparing stable idecalcitol capsules provided by the present invention, in S03, the temperature of the gel is 60° C., the temperature of the dripper is 55° C., the amount of the drug solution is controlled at 100 mg, and the weight of the gel is controlled at 165 mg.

[0014] The idecalcitol capsule of the present invention controls the viscosity of the glue solution in the process of preparing the soft capsule material, and has an appropriate hardness. The idecalcitol capsule of the present invention adds a specific component to the glue solution in the process of preparing the soft capsule material, wherein the drug solution has good stability and less impurities generated by degradation. DETAILED DESCRIPTION

[0015] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in combination with the embodiments and comparative examples of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0016] In the following examples and comparative examples, the reagents used are all commercially available products, among which the model of gelatin is 180.

[0017] In the following examples and comparative examples, unless otherwise specified, the examples and comparative examples are parallel tests with the same components, component contents, preparation steps and preparation parameters.

[0018] Example 1 A method for preparing idecalcitol capsules with suitable and stable hardness A prescription

[0019] Two-prescription process 1. Preparation of drug solution ① Weigh the prescribed amount of idecalcitol, racemic α-tocopherol and a certain amount of soybean oil into a beaker, and homogenize at 3000 rpm for 15 min to prepare a mixed solution A.

[0020] ② Weigh the prescribed amount of butylated hydroxyanisole, add it to the above mixture A, and homogenize at 3000 rpm for 20 minutes.

[0021] 2. Preparation of glue Add about 10% of the prescribed amount of purified water to the prescribed amount of yellow iron oxide and titanium dioxide, stir and mix evenly to form a suspension for later use. Reserve about 10% of the prescribed amount of purified water for rinsing the container.

[0022] Put sorbitol, glycerol and 40% of the prescription amount of purified water into the gelatin preparation container, and heat to 70°C while stirring. Stop stirring, add gelatin, add purified water to the prescription amount, continue stirring until the gelatin is dissolved, add the mixed suspension, and use the reserved 10% prescription amount of purified water to wash the container containing the suspension solution three times, transfer it to the gelatin solution, and stir evenly. Vacuum degassing, set aside, and test the viscosity of the gelatin solution.

[0023] Glue viscosity: 18529 mPa·s.

[0024] Test method: Take an appropriate amount of glue and measure it according to the law (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0633 Method 3 (3)), the viscosity should be 15000-20000 mPa·s.

[0025] 3. Pill making by dripping method Keep the glue solution at 60℃, use a suitable dripper for the pill machine, the dripper temperature is 55℃, the liquid dosage is controlled at around 100mg, the rubber weight is controlled at around 165mg, use liquid paraffin or medium-chain triglycerides as coolant, and start dripping.

[0026] Quality requirements: Finished product disintegration time limit: Should be completely disintegrated within 50 minutes.

[0027] Test method: Take this product and measure it according to the disintegration time test method (Chinese Pharmacopoeia 2020 Edition Part 4 General Rules 0921). It should be completely disintegrated within 40 minutes.

[0028] Filling volume difference: ±6% Test method: Take 20 capsules of this product, accurately weigh them respectively, take out the contents (the capsule shell must not be lost), wash the capsule shell with ethanol, place it in a ventilated place to allow the solvent to evaporate naturally, and check according to the filling difference inspection method under the capsule (General Rules 0103 of Part IV of the Chinese Pharmacopoeia 2020 Edition), which should comply with the regulations.

[0029] Content: 90-110%. Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512).

[0030] The quality of Example 1 meets all the above requirements.

[0031] Example 2 A method for preparing idecalcitol capsules with suitable and stable hardness A prescription

[0032] Two prescription processes, Example 1.

[0033] Glue viscosity: 19898 mPa·s.

[0034] The disintegration time limit, filling amount difference and content of the finished product are the same as those in Example 1, and all meet the quality requirements.

[0035] Example 3 A method for preparing idecalcitol capsules with suitable and stable hardness A prescription

[0036] The second prescription process is the same as that of Example 1.

[0037] Glue viscosity: 16109 mPa·s.

[0038] The disintegration time limit, filling amount difference and content of the finished product are the same as those in Example 1, and all meet the quality requirements.

[0039] Example 4 A method for preparing idecalcitol capsules with suitable and stable hardness A prescription

[0040] The second formulation process is similar to Example 1. In the preparation of the glue, after adding the plasticizer sorbitol, the stabilizers caffeic acid and chlorogenic acid are added in sequence.

[0041] Glue viscosity: 17657 mPa·s.

[0042] The disintegration time limit, filling amount difference and content of the finished product are the same as those in Example 1, and all meet the quality requirements.

[0043] Example 5 A method for preparing idecalcitol capsules with suitable and stable hardness A prescription

[0044] The second formulation process is similar to Example 1. In the preparation of the glue, after adding the plasticizer sorbitol, the stabilizers caffeic acid and chlorogenic acid are added in sequence.

[0045] Glue viscosity: 17655 mPa·s.

[0046] The disintegration time limit, filling amount difference and content of the finished product are the same as those in Example 1, and all meet the quality requirements.

[0047] Comparative Example 1 A method for preparing idecalcitol soft capsules with suitable and stable hardness is different from that of Example 1 in that the amount of purified water added to the soft capsule material is 106.6 mg, and the viscosity of the obtained colloid is 13658 mPa·s, which is lower than 15000 mPa·s.

[0048] Comparative Example 2 A method for preparing idecalcitol soft capsules with suitable and stable hardness is different from that of Example 1 in that the amount of purified water added to the soft capsule material is 74.6 mg, and the viscosity of the obtained colloid is 23729 mPa·s, which is higher than 20000 mPa·s.

[0049] Comparative Example 3 A method for preparing idecalcitol soft capsules with suitable and stable hardness is different from that of Example 4 in that the soft capsule material only includes 7 mg of caffeic acid, and the viscosity of the obtained jelly is 17697 mPa·s.

[0050] Comparative Example 4 A method for preparing idecalcitol soft capsules with suitable and stable hardness is different from that of Example 4 in that the soft capsule material only includes 7 mg of chlorogenic acid, and the viscosity of the obtained colloid is 17642 mPa·s.

[0051] Performance Testing: 1. Hardness of capsule: Testing method: Take 6 capsules of this product and test them using the German bareiss soft capsule hardness tester. The result is the average value.

[0052] 2 Stability of the content of specific degradation impurities (Impurity A) in capsules A impurity is (1 R ,2 R ,3 R ,5 E ,6 E ,8 Z )-2-(3-hydroxypropoxy)-9,10-opened cholesteryl-5(10),6,8(9)-triene-1,3,25-triol, molecular formula C30H50O5, molecular weight 490.72. This impurity is produced by the degradation of idecalcitol in the capsule at high temperature, and will not be produced under light, high humidity, acid and alkali damage conditions.

[0053] Detection method: The capsules were packaged in aluminum-plastic blisters + polyester / aluminum / polyethylene pharmaceutical composite bags, placed at a temperature and humidity of 40°C ± 2°C and RH75% ± 5% for 1 month, and determined according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). The idecalciferol capsules of the embodiment and the comparative example were tested on day 0, and the A impurity content was 0.

[0054] Test solution: Take an appropriate amount of the above-mentioned capsule contents, dissolve it, perform sample pretreatment using an amino solid phase extraction column, and appropriately concentrate it to prepare a solution containing about 60 μg of idecalciferol per 1 ml.

[0055] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler and water and acetonitrile were used as mobile phases for gradient elution.

[0056] Limit: Calculated by the area normalization method with correction factor, the specific degradation impurity (relative retention time of about 0.72) shall not exceed 1.0%.

[0057] Table 1 Test results

[0058] The results show that the viscosity of the glue in Examples 1-3 is within the range of 15000-20000 mPa·s, the hardness of the obtained capsules is moderate, it is not easy to break during storage, and it is convenient for process operation, but the stability of the liquid medicine is not good. In the preparation of the soft capsule material of Comparative Example 1, the amount of purified water added is large, the viscosity of the obtained glue is lower than 15000 mPa·s, the capsules obtained have low hardness of the capsule shell, and are easy to crack, which is not conducive to product storage. In the preparation of the soft capsule material of Comparative Example 2, the amount of purified water added is small, the viscosity of the obtained glue is higher than 20000 mPa·s, the capsules obtained have high hardness of the capsule shell, are easy to crack, and are not conducive to product storage.

[0059] The results show that in Examples 4 and 5, the phenolic acid antioxidant mixture is added to the soft capsule material, which indirectly improves the stability of the drug solution. Comparative Examples 3 and 4, which add a single phenolic acid antioxidant, have a certain improvement in the stability of the drug solution compared to Examples 1-3, but are significantly lower than Examples 4 and 5.

[0060] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An idecalcitol capsule with suitable and stable hardness, characterized in that: The prepared raw materials include liquid medicine raw materials and glue liquid raw materials for preparing soft capsule materials, and the viscosity of the glue liquid is 15000-20000 mPa·s.

2. The stable idecalcitol capsule according to claim 1, characterized in that: The raw materials for preparing the glue solution include: Gelatin 50-100 parts by weight; Glycerin 15-25 parts by weight; Sorbitol 1-5 parts by weight; Yellow iron oxide 0.1-0.5 parts by weight; Titanium dioxide 0.1-0.5 parts by weight; Purified water is added to make the viscosity of the glue solution 15000-20000 mPa·s.

3. The stable idecalcitol capsule according to claim 1 or 2, characterized in that: The raw materials for preparing each 100 mg of the medicinal solution include: Idecalcitol 0.5-2 μg; Butylated hydroxyanisole 15-25 μg; Racemic α-tocopherol 0.5-2 mg; Soybean oil was added to make the total weight of the drug solution 100 mg.

4. The stable idecalcitol capsule according to any one of claims 1 to 3, characterized in that: The raw materials for preparing the glue solution also include: Caffeic acid 1-5 parts by weight and / or caffeic acid 1-5 parts by weight.

5. A method for preparing the stable idecalcitol capsules according to any one of claims 1 to 4, characterized in that: The following steps are involved: S01, preparing a drug solution; S02, preparing glue solution; S03, using the drug solution obtained in S01 and the gelatin solution obtained in S02, to prepare pills by a dripping method, so as to obtain the stable idecalciferol capsules.

6. The method for preparing stable idecalcitol capsules according to claim 5, characterized in that: S01 includes the following steps: S11, weighing the prescribed amount of idecalcitol, racemic α-tocopherol and soybean oil into a beaker, stirring and homogenizing to prepare a mixed solution A; S12, weighing a prescribed amount of butylated hydroxyanisole, adding it to the mixture A, and stirring to homogenize.

7. The method for preparing stable idecalcitol capsules according to claim 6, characterized in that: In S01, the stirring and homogenizing is carried out at a rotation speed of 2500-3500 rpm for 10-25 min.

8. The method for preparing stable idecalcitol capsules according to claim 6 or 7, characterized in that: S02 includes the following steps: S21, adding a portion of the prescribed amount of purified water to the prescribed amount of yellow iron oxide and titanium dioxide, stirring and mixing to prepare a suspension for standby use; reserving a portion of the prescribed amount of purified water; S22, put sorbitol, glycerol or sorbitol, glycerol, caffeic acid, chlorogenic acid and part of the prescribed amount of purified water into a gelatin preparation container, heat while stirring, stop stirring, add gelatin, add purified water to the prescribed amount, continue stirring until the gelatin is dissolved, add the suspension of S21, and wash the container containing the suspension with the reserved purified water, transfer it to the gelatin solution, stir, vacuum degas, and set aside.

9. The method for preparing the stable idecalcitol capsules according to any one of claims 6 to 8, characterized in that: In S03, the temperature of the gel solution obtained in S02 is maintained, and a pill dropping machine is used, and liquid paraffin or medium-chain triglycerides are used as a coolant to obtain the stable idecalciferol capsules.

10. The method for preparing the stable idecalcitol capsules according to any one of claims 6 to 9, characterized in that: In S03, the temperature of the glue solution is 60°C, the temperature of the dripper is 55°C, the amount of the liquid medicine is controlled at 100 mg, and the weight of the glue solution is controlled at 165 mg.

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