Alfacalcidol soft capsule and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly discloses an alfacalcidol soft capsule and a preparation method thereof, and the preparation method is specifically as follows: specific caprylic / capric acid mono / diglyceride with a surfactant effect is added into the content of the alfacalcidol soft capsule, and a certain amount of antioxidant is matched to effectively protect the raw material medicine alfacalcidol. The stability of the alfacalcidol soft capsule is greatly improved, so that the medication effectiveness of a patient is ensured, and the bioavailability of the alfacalcidol is improved. According to the alfacalcidol soft capsule disclosed by the invention, the stability of the raw material medicines can be effectively improved by virtue of a simple content formula composition, the existing formula composition is greatly simplified, the safety problem caused by a complicated formula of medicine auxiliary materials is reduced, the production cost of the medicine is also reduced, and the industrial production is facilitated.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to an alfacalcidol soft capsule and a preparation method thereof. Background Art

[0002] Alfacalcidol, chemically named (1S,3R,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-1,3-diol, has the molecular formula: C 27 H 44 O 2 , with a relative molecular weight of 400.64, and its structure is shown as follows:

[0003] Alfacalcidol is an analogue of calcitriol. Alfacalcidol can increase the reabsorption of calcium in the small intestine and renal tubules, inhibit parathyroid gland hyperplasia, reduce the synthesis and release of parathyroid hormone, inhibit bone resorption, increase the synthesis of transforming growth factor - B (TGF - B) and insulin - like growth factor - I (IGF - I), promote the synthesis of collagen and bone matrix proteins, regulate muscle calcium metabolism, promote myocyte differentiation, enhance muscle strength, increase neuromuscular coordination, and reduce the tendency to fall. Alfacalcidol is used to treat calcium metabolism disorder diseases caused by insufficient production of endogenous 1,25 - dihydroxyvitamin D3. For example, renal osteodystrophy, postoperative or idiopathic hypoparathyroidism, pseudohypoparathyroidism, vitamin D - resistant rickets or osteomalacia, vitamin D - dependent rickets, neonatal hypocalcemia or rickets, calcium malabsorption, osteoporosis, malabsorptive and nutritional rickets and osteomalacia.

[0004] The aging phenomenon in China is becoming more and more serious, and the number of people with osteoporosis is huge. According to the statistics of the International Osteoporosis Foundation, by 2022, there will be nearly 298 million osteoporosis patients in China alone. As the latest and most effective treatment drug at present, alfacalcidol has a promising market prospect.

[0005] The existing alfacalcidol preparations are mainly tablets and soft capsules, and the specifications are relatively small, which are: 0.5 μg. The soft capsule consists of contents and a capsule shell. The contents generally consist of a drug and an oily solvent, and the capsule shell generally consists of a matrix, a plasticizer, a preservative, a light - shielding agent, a colorant and a solvent. The alfacalcidol raw material drug is soluble in fatty oils, so an oily carrier is selected to dissolve the raw material drug when preparing the soft capsule. In the prior art, oily carriers such as sesame oil, medium - chain triglycerides and glycerol are all selected as carriers, and they do not have a solubilizing effect.

[0006] The contents of the alfacalcidol capsules disclosed in CN111214453A include: alfacalcidol, medium-chain triglyceride, ascorbyl palmitate, gliadin, polyethylene glycol, phospholipid, and glycerol monolaurate; the components of the capsule shell include: gelatin, glycerol, water, ethylparaben, sodium alginate, and chitosan. It is obtained by pill pressing and drying. The composition of the contents is complex, the preparation process is cumbersome, and the cost is high.

[0007] CN104800187A discloses an alfacalcidol soft capsule and its preparation method. The content preparation of this method is as follows: 35-50 parts of alfacalcidol, 15-20 parts of glycerol, 20-40 parts of polyethylene glycol 4000, 10-20 parts of polyethylene glycol 6000, 10-20 parts of accelerator, 45-57 parts of thickener, and 30-60 parts of antioxidant. This content preparation adds more thickeners and solidifying agents, which affects the drug absorption of patients after taking.

[0008] The characteristics of the soft capsule dosage form determine that the drug in the contents is isolated from the outside world. At the same time, the capsule shell has plasticity and elasticity, and has the functions of antioxidation, light protection, moisture protection, and beautiful appearance, improving the medication compliance of patients. Since alfacalcidol is sensitive to light and air, the long-term storage of the preparation poses a great challenge to its stability. Although the preparation into soft capsules has improved the stability to a certain extent, the alfacalcidol soft capsules produced in China at present generally have the defects of long disintegration time when taken, the capsule skin is easily affected by the environment and becomes soft or hard, and poor stability. Therefore, how to improve the stability of alfacalcidol soft capsules, shorten the disintegration time limit, avoid the use of thickeners, and meet the demand for solubilization of the oily carrier in the contents has become an urgent problem to be solved in the preparation of alfacalcidol soft capsules. Summary of the Invention

[0009] In order to overcome the above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide an alfacalcidol soft capsule with simple content composition and process, short disintegration time, fast drug absorption, high drug dissolution rate, and avoiding the use of thickeners, and its preparation method.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is: The present invention provides an alfacalcidol soft capsule, which is prepared from contents and a capsule shell.

[0011] Among them, the contents include: alfacalcidol, an oily carrier, and an antioxidant; the capsule shell includes: capsule gelatin, a plasticizer, a light-shielding agent, a coloring agent, a preservative, and a solvent.

[0012] According to an embodiment of the present invention, the oily carrier in the alfacalcidol pharmaceutical composition disclosed by the present invention is selected from one or more of soybean oil, medium-chain triglycerides, sesame oil, glycerol, and caprylic / capric monoglyceride and diglyceride; through multiple experimental studies, the inventor surprisingly found that when caprylic / capric monoglyceride and diglyceride with surface-active effects is added in an amount of 90,000 to 110,000 parts by weight, the dissolution effect of the stability sample can be significantly improved. The oily carrier is preferably caprylic / capric monoglyceride and diglyceride, and the parts by weight are selected from 90,000 to 110,000 parts.

[0013] Further preferably, the parts by weight of the oily carrier caprylic / capric monoglyceride and diglyceride are selected from 99,900 parts.

[0014] According to an embodiment of the present invention, the antioxidant in the alfacalcidol pharmaceutical composition disclosed by the present invention is selected from one or more of all-rac-α-tocopherol, butylated hydroxyanisole, ascorbyl palmitate, and propyl gallate; Preferably, the antioxidant is selected from butylated hydroxyanisole, and the parts by weight are selected from 30 to 200 parts, having better stability than the prior art; More preferably, the parts by weight of the antioxidant butylated hydroxyanisole are selected from 100 parts.

[0015] According to an embodiment of the present invention, the plasticizer in the alfacalcidol pharmaceutical composition disclosed by the present invention is selected from one or more of sorbitol, glycerol, and sorbitan solution; Preferably, the plasticizer is selected from sorbitan solution, and the parts by weight are selected from 20,000 to 30,000 parts.

[0016] According to an embodiment of the present invention, the colorant in the alfacalcidol pharmaceutical composition disclosed by the present invention is selected from one or more of red iron oxide, brilliant blue, manganese dioxide, amaranth, and yellow iron oxide; Preferably, the colorant is selected from red iron oxide and yellow iron oxide, and the total parts by weight are selected from 200 to 500 parts.

[0017] According to an embodiment of the present invention, the preservative in the alfacalcidol pharmaceutical composition disclosed by the present invention is selected from one or more of p-hydroxybenzyl acetate, p-hydroxycinnamate, p-hydroxybutyrate, potassium sorbate, and benzoic acid and its salts; Preferably, the preservative is selected from potassium sorbate, and the parts by weight are selected from 200 to 400 parts.

[0018] According to an embodiment of the present invention, the light-shielding agent in the alfacalcidol pharmaceutical composition disclosed by the present invention is selected from titanium dioxide, and the parts by weight are selected from 800 to 1500 parts.

[0019] According to an embodiment of the present invention, the solvent in the alfacalcidol pharmaceutical composition disclosed by the present invention is selected from water, and the weight portion is selected from 45,000 to 60,000 portions.

[0020] The present invention also provides a preparation method of alfacalcidol soft capsules, comprising: ① Preparation of the content: Weigh a part of the oily carrier, add the prescribed amount of antioxidant, and stir until completely dissolved; Weigh the prescribed amount of alfacalcidol and add it to a part of the oily carrier, and stir until completely dissolved; Under light avoidance, take the remaining oily carrier to rinse the alfacalcidol container, and completely transfer it. Rinse 6 times, evacuate to -0.05 MPa and maintain for 3 min, fill nitrogen to a positive pressure of 0.03 MPa, repeat 3 times, fill nitrogen to 0.03 MPa and continue to stir for 1 - 1.5 h until completely dissolved; ② Preparation of the gelatin solution: Take a part of the solvent, plasticizer, light-shielding agent, and coloring agent, stir evenly, and pass through a colloid mill for 30 min to obtain a coloring solution; Dissolve the preservative and gelatin for capsules in hot water at 75°C ± 5°C, add the coloring solution, stir for 30 min, evacuate under -0.08 MPa for 60 min, and let stand overnight to prepare the gelatin solution of the present invention.

[0021] ③ Press the soft capsules with a soft capsule machine and rotate and dry them in a rotary cage dryer to obtain alfacalcidol soft capsules.

[0022] According to an embodiment of the present invention, a part of the oily carrier in the above preparation method is 40% of the oily carrier.

[0023] Compared with the prior art, the beneficial effects of the present invention are: The present invention provides an alfacalcidol soft capsule and its preparation method with a simple content composition, short disintegration time limit, and improved stability of alfacalcidol soft capsules. By adding a specific caprylic / capric monoglyceride with a surfactant effect to the content of the alfacalcidol soft capsule and cooperating with a certain amount of antioxidant, the raw material drug alfacalcidol can be effectively protected, greatly improving the stability of the alfacalcidol soft capsule, thereby ensuring the effectiveness of patients' medication and improving the bioavailability of alfacalcidol. The alfacalcidol soft capsule of the present invention can very effectively improve the stability of the raw material drug with a simple content formula composition, greatly simplifying the existing formula composition, reducing the safety problems caused by the complexity of the drug excipient formula, and also reducing the production cost of the drug, which is convenient for industrial production. Description of the Drawings

[0024] Figure 1For the comparison of the dissolution of alfacalcidol soft capsules accelerated for 6 months with different oily carriers, from top to bottom are the oily carriers caprylic / capric mono- and diglycerides, glycerol, and medium-chain triglycerides.

[0025] Figure 2 For the comparison of the dissolution of alfacalcidol soft capsules accelerated for 6 months with different dosages of caprylic / capric mono- and diglycerides, from top to bottom are Example 12, Example 1, and Example 11.

[0026] Figure 3 For the comparison of the dissolution of alfacalcidol soft capsules accelerated for 6 months with different dosages of caprylic / capric mono- and diglycerides, from top to bottom are Example 1 and the comparative example. Detailed implementation manners

[0027] Experimental materials: Alfacalcidol (Société Industrielle des Oléagineux), caprylic / capric mono- and diglycerides, butylated hydroxyanisole, gelatin for capsules, sorbitan solution, titanium dioxide, red iron oxide, yellow iron oxide, potassium sorbate.

[0028] Experimental equipment: Electronic balance (Mettler-Toledo International Trade (Shanghai) Co., Ltd.), glue melting tank (TMHJ-30), rotary die soft capsule machine (Beijing Changzheng Tianmin High-Tech Co., Ltd.), cage dryer (Beijing Changzheng Tianmin High-Tech Co., Ltd.), colloid mill (Langfang General Machinery Manufacturing Co., Ltd.), flow-through cell (Logan SYSTEM 4000), intelligent disintegration tester (Tianjin Tianda Tianfa Technology Co., Ltd.). Example 1

[0029] Prescription

[0030] Preparation method ① Preparation of the content: Weigh 40% of caprylic / capric mono- and diglycerides, add the prescribed amount of butylated hydroxyanisole, and stir for 30 - 60 min until completely dissolved; Weigh the prescribed amount of alfacalcidol and add it to 40% of the oily carrier, and stir until completely dissolved; Under light protection, take the remaining caprylic / capric mono- and diglycerides to rinse the alfacalcidol container, and completely transfer it. Rinse 6 times. Evacuate to -0.05 MPa and maintain for 3 min, fill with nitrogen to a positive pressure of 0.03 MPa, repeat 3 times, fill with nitrogen to 0.03 MPa and continue to stir for 1 - 1.5 h until completely dissolved; ② Preparation of the glue solution: Take a part of purified water, sorbitan solution, titanium dioxide, red iron oxide, and yellow iron oxide, stir evenly, and pass through the colloid mill for 30 min to obtain the coloring solution; Dissolve potassium sorbate and gelatin for capsules in hot water at 75°C ± 5°C, add the coloring solution, stir for 30 min, evacuate under -0.08 MPa for 60 min, and let stand overnight to prepare the glue solution of the present invention; ③Press the soft capsules with a soft capsule machine and rotate and dry them in a rotary dryer to obtain alfacalcidol soft capsules.

[0031] Example 2 Prescription

[0032] The preparation method is the same as that of Example 1.

[0033] Example 3 Prescription

[0034] The preparation method is the same as that of Example 1.

[0035] Example 4 Prescription

[0036] The preparation method is the same as that of Example 1.

[0037] Example 5 Prescription

[0038] The preparation method is the same as that of Example 1.

[0039] Example 6 Prescription

[0040] The preparation method is the same as that of Example 1.

[0041] Example 7 Prescription

[0042] The preparation method is the same as that of Example 1.

[0043] Example 8 Prescription

[0044] The preparation method is the same as that of Example 1. Example 9

[0045] Prescription

[0046] Preparation method ① Preparation of the content: Weigh 40% of caprylic / capric monoglyceride and diglyceride, add the prescribed amount of butylated hydroxyanisole, and stir for 30 - 60 min until completely dissolved; Weigh the prescribed amount of alfacalcidol and add it to 40% oily carrier, stir until completely dissolved; Under light protection, take the remaining caprylic / capric monoglyceride and diglyceride to rinse the alfacalcidol container, and transfer completely. Rinse 6 times. Continue to stir for 1 - 1.5 h until completely dissolved; ② Preparation of gelatin solution: Take a part of purified water, sorbitan solution, titanium dioxide, red iron oxide and yellow iron oxide, stir evenly, and pass through a colloid mill for 30 min to obtain a coloring solution; Dissolve potassium sorbate and gelatin for capsules in hot water at 75℃ ± 5℃, add the coloring solution, stir for 30 min, and evacuate under -0.08 MPa for 60 min to prepare the gelatin solution of the present invention; ③ Press soft capsules with a soft capsule machine and rotate and dry under a rotary cage dryer to obtain alfacalcidol soft capsules.

[0047] Example 10 Prescription

[0048] The preparation method is the same as that of Example 1. Example 11

[0049] Prescription

[0050] The preparation method is the same as that of Example 1. Example 12

[0051] Prescription

[0052] The preparation method is the same as that of Example 1.

[0053] Comparative example Reference preparation of alfacalcidol soft capsules, trade name EinsAlpha ® with a specification of 0.5 μg, the license holder is LEOLaboratories Limited, an EU - listed drug (manufactured in Denmark).

[0054] Experimental example 1 Inspection of samples in accelerated test

[0055] The samples were taken for inspection of content, total impurities and disintegration time limit at 3 and 6 months under accelerated conditions (temperature 40°C, humidity 75%). The inspection method was in accordance with the provisions of the Chinese Pharmacopoeia 2020 edition. The dissolution of the samples was determined using USP Apparatus 4 (flow-through cell method), and the medium was 0.5% Triton X-100. The results of content, total impurities, disintegration time limit and dissolution of Test Examples 1-12 are as follows: Table 1 Inspection Results of Example Samples

[0056] Comparing Comparative Examples 1, 2, 3 and the control example, it can be seen that under the condition of the same prescription dosage of the oily carrier, when different types of oily carriers were used for prescription preparation, the samples prepared with caprylic / capric monoglyceride and diglyceride had faster dissolution, which was also faster than that of the control example. This trend was consistent with the disintegration time limit. From Figure 1 it can be known that different oily carriers have a significant impact on the dissolution of alfacalcidol soft capsules accelerated for 6 months. Caprylic / capric monoglyceride and diglyceride as the oily carrier are more conducive to the dissolution of the drug.

[0057] Comparing Comparative Examples 1, 11, 12 and the control example, it can be seen that on the basis of selecting the specific oily carrier caprylic / capric monoglyceride and diglyceride, when different dosages of the oily carrier were used for prescription preparation, the dissolution of Example 1 was faster. This trend was consistent with the disintegration time limit. From Figure 2 it can be known that different dosages of caprylic / capric monoglyceride and diglyceride have a significant impact on the dissolution of alfacalcidol soft capsules accelerated for 6 months. With the increase of the dosage, the dissolution rate increases.

[0058] Comparing Comparative Examples 1, 6, 7, 8, it can be seen that when selecting the specific oily carrier caprylic / capric monoglyceride and diglyceride and combining with different types of antioxidants, the stability of alfacalcidol soft capsules is the best when butylated hydroxyanisole is selected as the antioxidant.

[0059] Comparing Comparative Examples 1, 4, 5, 10, it can be seen that when selecting the specific oily carrier caprylic / capric monoglyceride and diglyceride and combining with different dosages of antioxidants, the stability of alfacalcidol soft capsules can be greatly improved. The preferred weight parts of caprylic / capric monoglyceride and diglyceride are 99,900 parts, and the preferred weight parts of the antioxidant butylated hydroxyanisole are 100 parts.

[0060] Comparing Comparative Examples 1-10, it can be seen that on the basis of selecting the specific oily carrier caprylic / capric monoglyceride and diglyceride and a certain amount of antioxidant, when preparing the content, nitrogen protection can reduce the oxygen content in the content and further improve the stability of alfacalcidol soft capsules.

[0061] It can be seen that the types and ratios of the raw and auxiliary materials in Example 1 are the most reasonable, which improves the dissolution of alfacalcidol soft capsules.

[0062] Conclusion: The types and ratios of the raw and auxiliary materials in Example 1 are the most reasonable. The prepared samples are the most stable under accelerated conditions, and the increasing trend of the degradation impurities is consistent with that of the comparative example. At the same time, Example 1 shortens the disintegration time limit and improves the dissolution of alfacalcidol soft capsules. It can be Figure 3 seen that the dissolution of Example 1 is better than that of the original research comparative example. Experimental Example 2 Bioavailability Detection

[0063] Six beagle dogs (all male) were orally administered. They were respectively fed with the alfacalcidol soft capsules prepared in Examples 1-12 of the present invention and the comparative example, with a dose of 10 μg / animal (calculated as alfacalcidol), and the dosing interval was 7 days. After administration, blood samples were collected at different times, and the maximum blood concentration (C max ) and bioavailability (AUC o→48 ) of alfacalcidol were calculated. The sampling time points were 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 32 h, 48 h, and the calculation results are as follows: Table 2 Comparison of Bioavailability

[0064] It can be seen from the above table that generally speaking, the blood drug concentration of the alfacalcidol soft capsules prepared in Example 1 of the present invention is relatively high, and the bioavailability is higher than that of the original research comparative example, indicating that the specific components and component ratios of the content of the alfacalcidol soft capsules have a greater impact on its bioavailability.

[0065] The above-described embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. An alfacalcidol soft capsule, characterized in that, the soft capsule is prepared from a content and a capsule shell, wherein the content includes: alfacalcidol, an oily carrier, and an antioxidant; the capsule shell includes: gelatin for capsules, a plasticizer, a light-shielding agent, a coloring agent, a preservative, and a solvent.

2. The alfacalcidol soft capsule according to claim 1, characterized in that, the oily carrier is selected from one or more of soybean oil, medium-chain triglycerides, sesame oil, glycerol, and caprylic / capric acid monoglyceride and diglyceride, preferably caprylic / capric acid monoglyceride and diglyceride, and the weight portion is selected from 90,000 to 110,000 parts.

3. The alfacalcidol soft capsule according to claim 1, characterized in that, the antioxidant is selected from one or more of all-rac-α-tocopherol, butylated hydroxyanisole, ascorbyl palmitate, and propyl gallate, preferably butylated hydroxyanisole, and the weight portion is selected from 30 to 200 parts.

4. The alfacalcidol soft capsule according to claim 1, characterized in that, the plasticizer is selected from one or more of sorbitol, glycerol, and sorbitan solution, preferably sorbitan solution, and the weight portion is selected from 20,000 to 30,000 parts.

5. The alfacalcidol soft capsule according to claim 1, characterized in that, the coloring agent is selected from one or more of red iron oxide, brilliant blue, manganese dioxide, amaranth, and yellow iron oxide, preferably red iron oxide and yellow iron oxide, and the total weight portion is selected from 200 to 500 parts.

6. The alfacalcidol soft capsule according to claim 1, characterized in that, the preservative is selected from one or more of p-hydroxyphenyl acetate, p-hydroxyphenyl propionate, p-hydroxyphenyl butyrate, potassium sorbate, and benzoic acid and its salts, preferably potassium sorbate, and the weight portion is selected from 200 to 400 parts.

7. The alfacalcidol soft capsule according to claim 1, characterized in that, the light-shielding agent is selected from titanium dioxide, and the weight portion is selected from 800 to 1500 parts.

8. The alfacalcidol soft capsule according to claim 1, characterized in that, the solvent is selected from water, and the weight portion is selected from 45,000 to 60,000 parts.

9. A preparation method of the alfacalcidol soft capsule according to any one of claims 1-8, comprising: ① Preparation of the content: Weigh 40% of the oily carrier, add the antioxidant in the prescribed amount, and stir until completely dissolved; Weigh the prescribed amount of alfacalcidol and add it to 40% of the oily carrier, and stir until completely dissolved; Under light protection, take the remaining oily carrier to rinse the alfacalcidol container, and completely transfer it. Rinse 6 times, evacuate to -0.05 MPa and maintain for 3 min, fill with nitrogen to a positive pressure of 0.03 MPa, repeat 3 times, fill with nitrogen to 0.03 MPa and continue to stir for 1-1.5 h until completely dissolved; ② Preparation of the gelatin solution: Take a part of the solvent, plasticizer, light-shielding agent, and coloring agent, stir evenly, and pass through a colloid mill for 30 min to obtain a coloring solution; Dissolve the preservative and gelatin for capsules in hot water at 75°C ± 5°C, add the coloring solution, stir for 30 min, evacuate under -0.08 MPa for 60 min, and let stand overnight to prepare the glue solution of the present invention; ③Press the soft capsules with a soft capsule machine and rotate and dry them under a rotary cage dryer to obtain alfacalcidol soft capsules.

10. The preparation method of the alfacalcidol soft capsules according to claim 9, characterized in that the partial oily carrier described is 40% oily carrier.

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