Calcitriol capsule and preparation method thereof

Abstract

The invention belongs to the field of calcitriol capsules, and particularly relates to a calcitriol capsule and a preparation method thereof. In order to avoid the use of a cosolvent, increase the safety of a calcitriol soft capsule, simplify the production process and assist dissolution with room-temperature ultrasound in the liquid preparation process, the invention provides a calcitriol capsule, the content of the calcitriol capsule comprises calcitriol, an antioxidant and a solvent, the solvent is medium-chain triglyceride, the content does not contain ethanol, and the antioxidant is a calcium stearate. The antioxidant is selected from one or a combination of hydroxyanisole and butylated hydroxytoluene. Compared with a commercially available preparation, the preparation has the technical effects that a cosolvent-ethanol in a prescription is removed, and the safety of a product is improved; the production process is optimized, the preparation loss is reduced, and the product quality and stability are improved.

Description

Technical Field

[0001] The invention belongs to the field of calcitriol capsules, and particularly relates to calcitriol capsules and a preparation method thereof. Background Art

[0002] Calcitriol capsules were developed by Roche Pharmaceuticals as a reference preparation. The prescription composition of its contents is: butylated hydroxytoluene, butylated hydroxyanisole, medium-chain triglycerides, calcitriol, and the composition of the rubber excipients is: gelatin, glycerin, Karion 83, yellow iron oxide, red iron oxide, and titanium dioxide.

[0003] Usually, soft capsules are prepared in two parts: calcitriol, butylated hydroxytoluene, butylated hydroxyanisole and medium-chain triglycerides are mixed and dissolved to form the contents; gelatin, glycerin, Karion 83, yellow iron oxide, red iron oxide, titanium dioxide and an appropriate amount of purified water are mixed evenly and heated to form a gelatin solution; the contents and the gelatin solution are added to a soft capsule machine respectively, and the soft capsules are pressed, shaped and dried.

[0004] The inventors found that when preparing the contents of this product, calcitriol dissolves slowly in the oil solution. For example, in patent CN107362151, it takes 120 minutes to dissolve under room temperature stirring. Therefore, some dissolution methods are usually used, such as heating dissolution in patents CN103202821 and CN109260209, cosolvent polyethylene glycol ether in patent CN109276556, and cosolvent ethanol in patents CN111773196 and CN106265586. The study found that the reference preparation detected about 0.10% ethanol, which was not reflected in the instructions. It is speculated that ethanol was also added to the reference preparation during the preparation process to aid dissolution and was removed in the subsequent process.

[0005] The reference preparation uses organic solvent ethanol as a solubilizer, which adds additional excipients. The organic solvent is also irritating, which poses certain safety risks to manufacturers and users. If ethanol is not used as a solubilizer during the preparation process, the dissolution time is relatively long. If ethanol is used as a solubilizer, the solubilizer needs to be removed in the subsequent production process. Generally, it is considered to evaporate by heating after the preparation is completed, or to evaporate naturally by extending the drying time. The process is complicated and not conducive to production control. Summary of the invention

[0006] In order to avoid the use of co-solvents, increase the safety of calcitriol soft capsules and simplify the production process, room temperature ultrasound is used to assist dissolution during the liquid preparation process. The present invention provides a calcitriol soft capsule and a preparation method thereof.

[0007] Technical solution: A calcitriol capsule comprises calcitriol, an antioxidant and a solvent, wherein the solvent is a medium-chain triglyceride, and the content does not contain ethanol. The antioxidant is selected from butyl hydroxyanisole, butylated hydroxytoluene or a combination thereof.

[0008] Preferably, by weight, the medium-chain triglycerides account for ≥ 99% of the contents.

[0009] Preferably, in the preparation process, ≥0.5% of the prescribed amount of medium-chain triglycerides is first used to dissolve butylated hydroxyanisole, dibutyl hydroxytoluene, and calcitriol, and then the remaining amount of medium-chain triglycerides is added as the content, and the content and the preparation process do not contain / do not use ethanol.

[0010] Preferably, the medium chain triglycerides in the process of dissolving the contents are 0.5-2% of the prescribed amount.

[0011] Preferably, 0.5-2% of the prescribed amount of medium chain triglycerides may be used to rinse the container.

[0012] Preferably, during the process of preparing the contents, ultrasound is used to assist dissolution.

[0013] Preferably, the ultrasonic process has a duration of ≤60 min and an ultrasonic temperature of ≤25°C.

[0014] The advantages and positive effects of the present invention are: (1) Compared with commercially available preparations, the cosolvent - ethanol - is removed from the formulation to improve product safety; (2) Optimize production processes, reduce preparation losses, and improve product quality and stability. DETAILED DESCRIPTION

[0015] While the invention may be described with respect to a particular application or industry, those skilled in the art will recognize the broader applicability of the invention.

[0016] A calcitriol capsule comprises calcitriol, an antioxidant and a solvent, wherein the solvent is a medium-chain triglyceride, and the content does not contain ethanol. The antioxidant is selected from butyl hydroxyanisole, butylated hydroxytoluene or a combination thereof.

[0017] Preferably, by weight, the medium-chain triglycerides account for ≥ 99% of the contents.

[0018] Preferably, in the preparation process, ≥0.5% of the prescribed amount of medium-chain triglycerides is first used to dissolve butylated hydroxyanisole, dibutyl hydroxytoluene, and calcitriol, and then the remaining amount of medium-chain triglycerides is added as the content, and the content and the preparation process do not contain / do not use ethanol.

[0019] Preferably, the medium chain triglycerides in the process of dissolving the contents are 0.5-2% of the prescribed amount.

[0020] Preferably, 0.5-2% of the prescribed amount of medium chain triglycerides may be used to rinse the container.

[0021] Preferably, during the process of preparing the contents, ultrasound is used to assist dissolution.

[0022] Preferably, the ultrasonic process has a duration of ≤60 min and an ultrasonic temperature of ≤25°C.

[0023] Comparative Example 1

[0024] Preparation process: According to the prescription table, prepare 12,000 unit doses, weigh about 50% of the prescribed amount of ethanol and add it to container 1, weigh the prescribed amount of butylated hydroxyanisole, dibutyl hydroxytoluene, and calcitriol and add them to container 1 and mix evenly, add the solution in container 1 to container 2 with the prescribed amount of medium-chain triglycerides, take the remaining prescribed amount (about 50%) of ethanol to rinse container 1, add the rinse solution to container 2 and mix evenly, stir at 40°C for 40 minutes to remove ethanol, fill the sample into a vial and seal it for storage.

[0025] Embodiment 1:

[0026] Preparation process: Weigh 1% of the prescribed amount of medium-chain triglycerides and add them to container 1, weigh the prescribed amount of butylated hydroxyanisole, dibutyl hydroxytoluene, and calcitriol and add them to container 1, ultrasonicate at room temperature until dissolved, stir and mix, add the solution in container 1 to container 2 containing 98% of the prescribed amount of medium-chain triglycerides, take another 1% of the prescribed amount of medium-chain triglycerides to rinse container 1, add the rinse solution to container 2 and mix evenly, fill the sample into a vial and seal it for storage.

[0027]

[0028] Note: The determination method of calcitriol precursor refers to the Luogequan imported registered standard (JX20110084), using the test solution under the content determination item and the same content determination chromatographic conditions for sampling and detection.

[0029] The calcitriol precursor is a conversion impurity of calcitriol. Under the premise of no preparation loss, the sum of the calcitriol precursor and calcitriol should be equivalent to the feed amount. The results show that there is no significant difference between the sum of the 0d precursor and the content of Example 1 and Example 2 and are close to 100%, indicating that both room temperature ultrasonic dissolution and the addition of ethanol to assist dissolution can completely dissolve the API; but the 0d and 50℃10d calcitriol precursors of Example 1 are higher, indicating that the sample dissolved by ultrasonic treatment at room temperature has better stability. In summary, compared with the sample dissolved by ethanol to assist dissolution, the sample dissolved by ultrasonic treatment at room temperature has obvious advantages in preparation process and stability, and no additional ethanol is introduced, which improves the safety of the product.

[0030] Example 2: 0.5% solvent concentration The prescription is the same as that in Example 1.

[0031] Preparation process: Weigh 0.5% of the prescribed amount of medium-chain triglycerides and add them to container 1, weigh the prescribed amount of butylated hydroxyanisole, dibutyl hydroxytoluene, and calcitriol and add them to container 1, ultrasonicate at room temperature until dissolved, stir and mix, add the solution in container 1 to container 2 with the remaining medium-chain triglycerides, take another 0.5% of the prescribed amount of medium-chain triglycerides to rinse container 1, and add the rinse solution to container 2 and mix evenly.

[0032] Example 3: 2% solvent concentration The prescription is the same as that in Example 1.

[0033] Preparation process: Weigh 2% of the prescribed amount of medium-chain triglycerides and add them to container 1, weigh the prescribed amount of butylated hydroxyanisole, dibutyl hydroxytoluene, and calcitriol and add them to container 1, ultrasonicate at room temperature until dissolved, stir and mix, add the solution in container 1 to container 2 with the remaining medium-chain triglycerides, take another 2% of the prescribed amount of medium-chain triglycerides to rinse container 1, and add the rinse solution to container 2 to mix evenly.

[0034] Survey results:

[0035] The research results show that there is no significant difference in the content and calcitriol precursor of Examples 1, 2, and 3, indicating that the API can be completely dissolved using a 0.5-2% medium-chain triglyceride concentration without affecting the sample quality.

[0036] Example 4: Ultrasonic parameter investigation Since ultrasound was used in the liquid preparation process, the ultrasound time and temperature were investigated considering the effect of ultrasound on the content.

[0037] The prescription is the same as that in Example 1.

[0038] Preparation process: Weigh the prescribed amount of butylated hydroxyanisole and dibutylated hydroxytoluene in a container and dissolve them in 2% of the prescribed amount of medium-chain triglycerides, and stir until dissolved. Weigh the prescribed amount of calcitriol and add it, mix and stir for 10 minutes at room temperature, then ultrasonicate for 7 minutes (temperature: 20.8°C) until the API is dissolved, stir for 10 minutes to mix evenly, take part of the drug solution to make it equal to the prescribed amount, stir for 20 minutes, and record it as Example 4-1 sample; The remaining liquid was ultrasonicated for 30 minutes, and a portion of the liquid was separated and fixed to the prescribed amount, and stirred for 20 minutes, which was recorded as Example 4-2 sample; The remaining liquid was ultrasonicated for 60 minutes, and a portion of the liquid was separated and fixed to the prescribed amount, and stirred for 20 minutes, which was recorded as the sample of Example 4-3.

[0039] The results of testing the contents of the above three batches of samples are as follows:

[0040] As can be seen from the above table, there is no significant effect on the content when ultrasound is applied for 60 minutes and 7 minutes, which means that the active ingredient has been completely dissolved after 7 minutes of ultrasound, and the content of the active ingredient is still stable after ultrasound for 60 minutes, but the calcitriol precursor shows an increasing trend. Therefore, the ultrasound time should be controlled within 60 minutes and the temperature should be controlled at 25°C or below.

[0041] In summary, the preparation method of this product is determined as follows: using 0.5-2% medium-chain triglyceride concentration (ultrasound-assisted dissolution, ultrasonic time ≤ 60min, ultrasonic temperature ≤ 25°C). The above-mentioned preparation process can minimize the adhesion loss of active ingredients during the preparation process and completely avoid the addition of ethanol, which improves safety while simplifying the process to ensure the quality of the sample.

[0042] While the present invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments.The scope of the following claims is to be accorded the broadest interpretation so as to encompass all such modifications and equivalent structures and functions.

Claims

1. A calcitriol capsule, characterized in that: The contents include calcitriol, an antioxidant, and a solvent, wherein the solvent is a medium-chain triglyceride, and the contents do not contain ethanol. The antioxidant is selected from hydroxyanisole, butylated hydroxytoluene, or a combination thereof.

2. The calcitriol capsule according to claim 1, characterized in that: By weight, the medium-chain triglycerides account for ≥99% of the contents.

3. The method for preparing the calcitriol capsules according to claim 1 or 2, characterized in that: During the preparation process, ≥0.5% of the prescribed amount of medium-chain triglycerides is first used to dissolve butylated hydroxyanisole, butylated hydroxytoluene, and calcitriol, and then the remaining amount of medium-chain triglycerides is added as content, and ethanol is not included / used in the content and the preparation process.

4. The preparation method according to claim 3, characterized in that: The medium chain triglyceride in the process of dissolving the contents is 0.5-2% of the prescribed amount.

5. The preparation method according to claim 3, characterized in that: Rinse the container with 0.5-2% of the prescribed amount of medium chain triglycerides.

6. The preparation method according to claim 5, characterized in that: During the process of preparing the contents, ultrasound is used to assist dissolution.

7. The preparation method according to claim 6, characterized in that: The ultrasonic process has a time of ≤60 min and an ultrasonic temperature of ≤25° C.

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