Compound SYN045 soft capsules and process for their preparation

Abstract

The present application belongs to the technical field of pharmaceutical preparations, and specifically provides a compound SYN045 soft capsule and a preparation method thereof. The present application adopts a fixed proportion of plant oil and polyoxyethylene glyceryl oleate combination to prepare the content, which helps to reduce the degradation of SYN045 in the content drug solution, ensures the stability of the active ingredient, and obtains a compound SYN045 soft capsule with good drug dissolution, high drug content, low impurity generation, and high bioavailability. Further, through prescription optimization of the soft capsule shell, a fixed proportion of plasticizer is selected, the mass ratio of glycerol and sorbitol is 1:2-3, the transfer of the compound SYN045 to the soft capsule shell is reduced, and thus the quality stability problem of the soft capsule preparation product during drug storage is solved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound SYN045 soft capsule and a preparation method thereof. BACKGROUND

[0002] Pulmonary arterial hypertension is a malignant disease characterized by elevated pulmonary vascular resistance and pulmonary arterial pressure caused by pulmonary arterial lesions. Severe cases can lead to right heart failure and even death. The latest data shows that the incidence and prevalence of pulmonary arterial hypertension in adults are 0-6 cases per million and 48-55 cases per million, respectively. Due to rapid disease progression, high mortality and disability, pulmonary arterial hypertension is regarded as a “malignant tumor” in the cardiovascular field. For the treatment of pulmonary arterial hypertension, the European Society of Cardiology and other organizations mainly recommend that patients use targeted drugs. Targeted therapy aims to restore the imbalance of vasoactive mediators through the prostacyclin pathway, endothelin pathway and NO pathway. The currently used targeted drugs mainly include prostacyclin analogs, prostacyclin receptor agonists, ERAs, PDE5is and sGC stimulators.

[0003] The compound SYN045, with the chemical name 6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide, is a small molecule compound with a completely new structure. Through the optimization of the structure of the lead compound, the prostacyclin receptor (PGI2) agonist SYN045 with high targeting and low side effects is obtained. Preclinical studies show that it has outstanding antihypertensive effect, can significantly improve the symptoms related to high pulmonary pressure in pulmonary arterial hypertension model rats, and at the same time, it improves the tolerance dose and survival rate of rats, has high safety, and the target indication is pulmonary arterial hypertension.

[0004] The compound SYN045 has poor solubility and strong hydrophobicity, and has low solubility in aqueous solution and different pH buffers. If it is prepared into ordinary oral solid preparations such as tablets or capsules, there are problems such as slow and incomplete drug dissolution, low bioavailability, etc., thereby limiting the exertion of its curative effect. Moreover, since the compound SYN045 has high drug activity, the product specification after development into a preparation will be very low.

[0005] Soft capsule preparations are suitable for poorly soluble drugs, especially for the dispensing of low-dose and hydrophobic drugs, and have high content uniformity and high bioavailability. Therefore, it is necessary to develop a soft capsule preparation product of the compound SYN045 to meet the clinical needs. SUMMARY

[0006] In view of this, the application provides a compound SYN045 soft capsule and a preparation method thereof.

[0007] An object of the present application is to provide a compound SYN045 soft capsule, which is composed of a content and a soft capsule shell, wherein the content comprises the following components in mass percentage: compound SYN045 0.02%-0.28%, vegetable oil 85.0%-91.5%, polyoxyethylene glycerol oleate 8.0%-14.5%, preservative 0.05%-0.15%, and antioxidant A 0.10%-0.30%; wherein the sum of the percentages of the above components is 100%.

[0008] Optionally, the vegetable oil in the content is one or more of soybean oil, corn oil, peanut oil, olive oil, or rapeseed oil.

[0009] In some embodiments, the preservative in the content is one or more of propyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, p-hydroxybenzoic acid butyl ester, or benzoic acid.

[0010] In some embodiments, the antioxidant A in the content is one or more of butylated hydroxyanisole, dibutylhydroxytoluene, vitamin E, or propyl gallate.

[0011] The present application uses a fixed ratio of vegetable oil and polyoxyethylene glycerol oleate to form the content, which obtains a compound SYN045 soft capsule with good drug dissolution, high drug content, less impurity generation, and high bioavailability.

[0012] Further, during the stability study of the soft capsule containing the above content, it is found that the drug component compound SYN045 in the soft capsule is easy to migrate from the content to the capsule shell, causing drug leakage and accelerating drug degradation, resulting in an increase in impurities and a decrease in the content of effective ingredients. The prescription of the capsule shell needs to be optimized.

[0013] In some embodiments, the soft capsule shell of the compound SYN045 soft capsule described above comprises the following components in mass percentage: gelatin 44%-49%, plasticizer 16.0%-18.0%, light shielding agent 0.60%-0.70%, antioxidant B 0.07%-0.09%, and purified water 34%-38%; wherein the plasticizer is a mixture of glycerol and sorbitol; the mass ratio of the glycerol and sorbitol is 1:2-3.

[0014] Optionally, the light shielding agent in the soft capsule shell is titanium dioxide.

[0015] Further, the antioxidant B in the soft capsule shell is one or both of glycine and sodium metabisulfite.

[0016] The present application solves the quality stability problems of soft capsule preparation in the process of drug storage, such as low drug content, many impurities, poor dissolution, etc., by optimizing the prescription of the soft capsule shell, selecting a fixed ratio of plasticizer, and reducing the transfer of compound SYN045 to the soft capsule shell.

[0017] More preferably, the content of the soft capsule of the compound SYN045 described above comprises the following components in mass percentage: compound SYN045 0.22%, soybean oil 88.5%, polyoxyethylene glycol 11%, propyl p-hydroxybenzoate 0.09%, and butylated hydroxyanisole A 0.13%.

[0018] More preferably, the soft capsule shell raw material of the soft capsule of the compound SYN045 described above comprises the following components in mass percentage: gelatin 48%, glycerol 4.8%, sorbitol 11.7%, titanium dioxide 0.62%, glycine 0.07%, and purified water 34.5%.

[0019] The second object of the present application is to provide a preparation method of the soft capsule of the compound SYN045 described above, comprising the following steps:

[0020] S1, stirring the gelatin, glycerol, sorbitol, light shielding agent, antioxidant B, and purified water in a prescription amount at 65-75°C, mixing uniformly, vacuuming to remove bubbles, and preparing for use, to obtain a soft capsule shell solution;

[0021] S2, adding polyoxyethylene glycol oleate and vegetable oil in a prescription amount to a material tank, heating to 55-65°C and stirring, adding SYN045 raw material, preservative, and antioxidant A in a prescription amount, controlling the temperature at 55-65°C, and stirring until completely dissolved, vacuuming to remove bubbles, and preparing for use, to obtain a soft capsule content liquid;

[0022] S3, adding the soft capsule shell solution and the soft capsule content liquid to a pill making machine, adjusting the loading amount and the thickness of the gelatin, pressing the pills, drying, and packaging, to obtain SYN045 soft capsules.

[0023] Further, the light shielding agent is titanium dioxide.

[0024] Further, the antioxidant B is one or both of glycine or sodium pyrosulfite.

[0025] Further, the vegetable oil is one or more of soybean oil, corn oil, peanut oil, olive oil, or rapeseed oil.

[0026] Further, the preservative is one or more of propyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, p-hydroxybenzoic acid butyl ester, or benzoic acid.

[0027] Further, the antioxidant A is one or more of butylated hydroxyanisole, butylated hydroxytoluene, vitamin E, or propyl gallate.

[0028] The present application helps to accelerate the dissolution rate of the raw drug by pre-mixing the prescription amount of polyoxyethylene glycerol oleate with vegetable oil before adding the compound SYN045, the optimized preparation process is simple to operate and also ensures product quality, which is beneficial to industrialized production and application. DETAILED DESCRIPTION

[0029] The present application will be further described in detail through specific embodiments, which are only used to help understand the present application and enable those skilled in the art to implement or use the present application, and do not constitute any limitation on the present application.

[0030] During the development of the new drug preparation of the compound SYN045, it is found that the raw material SYN045 has poor solubility in water and strong hydrophobicity, and due to its high activity, the dose is low and the preparation specification is small, which leads to great difficulty in preparation development. However, it is accidentally found in the solubility study that the raw material has high solubility affinity in vegetable oil matrix such as soybean oil and peanut oil, can be dissolved and wrapped with the drug, can realize precise control of the dose, can effectively ensure the content uniformity of the preparation under very low preparation specification, and is suitable for soft capsule preparation product development.

[0031] However, it is found that SYN045 is not stable in vegetable oil during prescription screening, and by adding polyoxyethylene glycerol oleate in the content drug solution, it helps to reduce the degradation of SYN045 in the content drug solution, and ensures the stability of the active ingredient.

[0032] The present application will be further described in detail through specific embodiments, which are only used to help understand the present application and enable those skilled in the art to implement or use the present application, and do not constitute any limitation on the present application.

[0033] Example 1

[0034] Preparation of SYN045 soft capsules (1000 capsules)

[0035] A SYN045 soft capsule comprises the following components in mass percentage:

[0036]

[0037] Preparation method:

[0038] 1. Take the above prescription amount of gelatin, glycerol, sorbitol, titanium dioxide, glycine and purified water in a gelatinizing pot, stir and gelatinize at 69-71℃, mix evenly, vacuum exhaust air bubbles for standby, and obtain a soft capsule shell solution;

[0039] 2. Add the prescribed amount of polyoxyethylene glycol oleate and soybean oil into the material mixing tank, heat to 60-61 °C and stir, add the prescribed amount of SYN045 drug substance, propyl p-hydroxybenzoate and butylated hydroxyanisole, control the temperature at 59-60 °C and stir until completely dissolved, vacuumize to remove bubbles, and obtain the soft capsule content liquid;

[0040] 3. Add the soft capsule shell solution and the soft capsule content liquid into the pill making machine, adjust the loading amount and the thickness of the gelatin, press the pills, dry and package, and obtain the SYN045 soft capsules.

[0041] Example 2

[0042] Preparation of SYN045 soft capsules (1000 capsules)

[0043] A SYN045 soft capsule comprises the following components in the following mass percentages:

[0044]

[0045] Preparation method:

[0046] 1. Take the above-mentioned prescribed amount of gelatin, glycerol, sorbitol, titanium dioxide, glycine and purified water in the gelatin mixing tank, stir at 65-68 °C, mix well, vacuumize to remove bubbles, and obtain the soft capsule shell solution;

[0047] 2. Add the prescribed amount of polyoxyethylene glycol oleate and soybean oil into the material mixing tank, heat to 55-57 °C and stir, add the prescribed amount of SYN045 drug substance, propyl p-hydroxybenzoate and butylated hydroxyanisole, control the temperature at 55-58 °C and stir until completely dissolved, vacuumize to remove bubbles, and obtain the soft capsule content liquid;

[0048] 3. Add the soft capsule shell solution and the soft capsule content liquid into the pill making machine, adjust the loading amount and the thickness of the gelatin, press the pills, dry and package, and obtain the SYN045 soft capsules.

[0049] Example 3

[0050] Preparation of SYN045 soft capsules (1000 capsules)

[0051] A SYN045 soft capsule comprises the following components in the following mass percentages:

[0052]

[0053] Preparation method:

[0054] 1. Take the above-mentioned prescribed amount of gelatin, glycerol, sorbitol, titanium dioxide, glycine and purified water in the gelatin mixing tank, stir at 73-75 °C, mix well, vacuumize to remove bubbles, and obtain the soft capsule shell solution;

[0055] 2. Add the prescribed amount of polyoxyethylene glycol oleate and soybean oil into the material mixing tank, heat to 62-65°C and stir, add the prescribed amount of SYN045 drug substance, propyl p-hydroxybenzoate and butyl hydroxyanisole, control the temperature at 64-65°C and stir until completely dissolved, vacuumize to remove air bubbles for standby, obtain the soft capsule content liquid;

[0056] 3. Add the soft capsule shell solution and the soft capsule content liquid into the pill making machine, adjust the loading amount and the thickness of the gelatin, press the pills, dry and package, obtain the SYN045 soft capsules.

[0057] Example 4

[0058] Preparation of SYN045 soft capsules (1000 capsules)

[0059] A SYN045 soft capsule comprises the following components in the following mass percentages:

[0060]

[0061]

[0062] Preparation method:

[0063] 1. Take the prescribed amount of gelatin, glycerin, sorbitol, titanium dioxide, glycine and purified water in the gelatin mixing tank, mix at 68-70°C, mix well, vacuumize to remove air bubbles for standby, obtain the soft capsule shell solution;

[0064] 2. Add the prescribed amount of polyoxyethylene glycol oleate and soybean oil into the material mixing tank, heat to 56-58°C and stir, add the prescribed amount of SYN045 drug substance, propyl p-hydroxybenzoate and butyl hydroxyanisole, control the temperature at 59-63°C and stir until completely dissolved, vacuumize to remove air bubbles for standby, obtain the soft capsule content liquid;

[0065] 3. Add the soft capsule shell solution and the soft capsule content liquid into the pill making machine, adjust the loading amount and the thickness of the gelatin, press the pills, dry and package, obtain the SYN045 soft capsules.

[0066] Example 5

[0067] Preparation of SYN045 soft capsules (1000 capsules)

[0068] A SYN045 soft capsule comprises the following components in the following mass percentages:

[0069]

[0070]

[0071] Preparation method:

[0072] 1. Take the above prescription amount of gelatin, glycerin, sorbitol, titanium dioxide, glycine and purified water in the glue tank 73~75℃ stirring glue, mix evenly, vacuum exhaust bubble ready for use, get soft capsule shell solution;

[0073] 2, the prescription amount of polyoxyethylene glycol oleic acid and corn oil into the material tank, heated to 55~56℃ stirring, adding the prescription amount of SYN045 raw material, propyl paraben and butylated hydroxyanisole, control the temperature at 59~60℃ stirring to completely dissolved, vacuum exhaust bubble ready for use, get soft capsule content drug solution;

[0074] 3, the soft capsule shell solution, soft capsule content drug solution into the pill making machine, adjust the amount of loading and the thickness of the glue, dry, packaging, get SYN045 soft capsules.

[0075] Example 6

[0076] SYN045 soft capsule preparation (1000)

[0077] A SYN045 soft capsule, comprising the following mass percent of components:

[0078]

[0079]

[0080] Preparation method:

[0081] 1. Take the above prescription amount of gelatin, glycerin, sorbitol, titanium dioxide, glycine and purified water in the glue tank 69~71℃ stirring glue, mix evenly, vacuum exhaust bubble ready for use, get soft capsule shell solution;

[0082] 2, the prescription amount of polyoxyethylene glycol oleic acid and peanut oil into the material tank, heated to 63~65℃ stirring, adding the prescription amount of SYN045 raw material, ethyl paraben and dibutyl hydroxytoluene, control the temperature at 58~60℃ stirring to completely dissolved, vacuum exhaust bubble ready for use, get soft capsule content drug solution;

[0083] 3, the soft capsule shell solution, soft capsule content drug solution into the pill making machine, adjust the amount of loading and the thickness of the glue, dry, packaging, get SYN045 soft capsules.

[0084] Example 7

[0085] SYN045 soft capsule preparation (1000)

[0086] A SYN045 soft capsule, comprising the following mass percent of components:

[0087]

[0088]

[0089] Preparation method:

[0090] 1. Take the above prescription amount of gelatin, glycerin, sorbitol, titanium dioxide, sodium pyrosulfite and purified water in the gelatinizing pot, stir and gelatinize at 73-75°C, mix evenly, vacuum exhaust air bubbles for standby, get soft capsule shell solution;

[0091] 2. Add the prescription amount of polyoxyethylene glyceryl oleate and olive oil to the material pot, heat to 56-58°C and stir, add the prescription amount of SYN045 raw material, p-hydroxybenzoic acid ester and vitamin E, control the temperature at 62-63°C and stir until completely dissolved, vacuum exhaust air bubbles for standby, get soft capsule content liquid;

[0092] 3. Add the soft capsule shell solution and soft capsule content liquid to the pill making machine, adjust the loading amount and the thickness of the gelatin, press the pills, dry and package, get SYN045 soft capsules.

[0093] Example 8

[0094] Preparation of SYN045 soft capsules (1000 pieces)

[0095] A SYN045 soft capsule, comprising the following components in mass percentage:

[0096]

[0097]

[0098] Preparation method:

[0099] 1. Take the above prescription amount of gelatin, glycerin, sorbitol, titanium dioxide, sodium pyrosulfite and purified water in the gelatinizing pot, stir and gelatinize at 72-73°C, mix evenly, vacuum exhaust air bubbles for standby, get soft capsule shell solution;

[0100] 2. Add the prescription amount of polyoxyethylene glyceryl oleate and rapeseed oil to the material pot, heat to 61-63°C and stir, add the prescription amount of SYN045 raw material, benzoic acid and propyl gallate, control the temperature at 63-65°C and stir until completely dissolved, vacuum exhaust air bubbles for standby, get soft capsule content liquid;

[0101] 3. Add the soft capsule shell solution and soft capsule content liquid to the pill making machine, adjust the loading amount and the thickness of the gelatin, press the pills, dry and package, get SYN045 soft capsules.

[0102] Example 9

[0103] Preparation of SYN045 soft capsules (1000 capsules)

[0104] A SYN045 soft capsule comprising the following components in mass percentage:

[0105]

[0106] Preparation method:

[0107] 1. Take the above prescription amount of gelatin, glycerin, sorbitol, titanium dioxide, glycine and purified water in the gelatinizing pot and stir at 70-72°C, mix well, vacuum exhaust air bubbles for standby, get soft capsule shell solution;

[0108] 2. Add the prescription amount of polyoxyethylene glyceryl oleate and soybean oil to the material pot, heat to 55-56°C and stir, add the prescription amount of SYN045 raw material, propyl paraben and butylated hydroxyanisole, control the temperature at 58-60°C and stir until completely dissolved, vacuum exhaust air bubbles for standby, get soft capsule content liquid;

[0109] 3. Add the soft capsule shell solution and soft capsule content liquid to the pill making machine, adjust the loading amount and the thickness of the gelatin, press the pills, dry and package, get SYN045 soft capsules.

[0110] Example 10

[0111] Preparation of SYN045 soft capsules (1000 capsules)

[0112] A SYN045 soft capsule comprising the following components in mass percentage:

[0113]

[0114] Preparation method:

[0115] 1. Take the above prescription amount of gelatin, glycerin, sorbitol, titanium dioxide, glycine and purified water in the gelatinizing pot and stir at 65-67°C, mix well, vacuum exhaust air bubbles for standby, get soft capsule shell solution;

[0116] 2. Add the prescription amount of polyoxyethylene glyceryl oleate and soybean oil to the material pot, heat to 61-62°C and stir, add the prescription amount of SYN045 raw material, propyl paraben and butylated hydroxyanisole, control the temperature at 61-63°C and stir until completely dissolved, vacuum exhaust air bubbles for standby, get soft capsule content liquid;

[0117] 3. Add the soft capsule shell solution and soft capsule content liquid to the pill making machine, adjust the loading amount and the thickness of the gelatin, press the pills, dry and package, get SYN045 soft capsules.

[0118] Comparative Example 1

[0119] Preparation of SYN045 soft capsules (1000 capsules)

[0120] A SYN045 soft capsule comprises the following components in mass percentage:

[0121]

[0122] The preparation method is the same as that of Example 1, except that the amount of polyoxyethylene glycerol oleate in Example 1 is reduced, and the types and amounts of other raw and auxiliary materials are the same.

[0123] Comparative Example 2

[0124] Preparation of SYN045 soft capsules (1000 capsules)

[0125] A SYN045 soft capsule comprises the following components in mass percentage:

[0126]

[0127] The preparation method is the same as that of Example 1, except that polyoxyethylene glycerol oleate in Example 1 is replaced by polyethylene glycol laurylate, and the types and amounts of other raw and auxiliary materials are the same.

[0128] Comparative Example 3

[0129] Preparation of SYN045 soft capsules (1000 capsules)

[0130] A SYN045 soft capsule comprises the following components in mass percentage:

[0131]

[0132]

[0133] The preparation method is the same as that of Example 1, except that the amount of sorbitol in Example 1 is reduced, and the types and amounts of other raw and auxiliary materials are the same.

[0134] Comparative Example 4

[0135] Preparation of SYN045 soft capsules (1000 capsules)

[0136] A SYN045 soft capsule comprises the following components in mass percentage:

[0137]

[0138] The preparation method is the same as that of Example 1, except that the amount of sorbitol in Example 1 is increased, and the types and amounts of other raw and auxiliary materials are the same.

[0139] Comparative Example 5

[0140] Preparation of SYN045 soft capsules (1000 capsules)

[0141] A SYN045 soft capsule comprises the following components in mass percentage:

[0142]

[0143] The preparation method is the same as that in Example 1, except that sorbitol in Example 1 is replaced by propylene glycol, and the types and amounts of other raw and auxiliary materials are the same.

[0144] Stability study of Test Example 1

[0145] In order to investigate the stability of the product, the samples prepared in Examples 1-10 and Comparative Examples 1-5 were subjected to accelerated testing. The above products were placed under the same packaging under accelerated conditions (40℃±2℃, relative humidity 75%±5%), and samples were taken at 0 months and 6 months, respectively, to compare the changes in content, dissolution and related substances. The results are shown in Table 1.

[0146] Content detection method:

[0147] Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four chapters 0512).

[0148] Solvent methanol-water (80:20)

[0149] Take 10 capsules of the product, pour the contents into a 100ml volumetric flask, and rinse the inside of the soft capsule shell with solvent to ensure that the contents are completely poured into the volumetric flask, add an appropriate amount of solvent, ultrasonic to dissolve, and then dilute to the mark with solvent, shake well, and filter.

[0150] Take an appropriate amount of SYN045 reference substance, accurately weigh, ultrasonic dissolve and quantitatively dilute to prepare a solution containing about 60μg per 1ml, and shake well. The preparation of the compound SYN045 reference substance refers to the patent CN202410701022.4.

[0151] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler; 0.2% (v / v) formic acid aqueous solution-methanol (20:80) as the mobile phase; flow rate of 1ml per minute; column temperature of 30℃; detection wavelength of 280nm; injection volume of 20μl.

[0152] Determination method: accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate by external standard method with peak area. The content requirement is 90%-110%.

[0153] Related substance detection method:

[0154] Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General 0512).

[0155] The test solution was prepared by accurately weighing an appropriate amount of the contents of the product, dissolving and quantitatively diluting with the mobile phase to prepare a solution containing about 0.5 mg of compound SYN045 per 1 mL, filtering, and taking the filtrate.

[0156] Chromatographic conditions Chromatographic column: Welchrom-C 18 Chromatographic column (4.6 mm x 200 mm, 5 μm); mobile phase: 0.1 mol / L sodium dihydrogen phosphate solution (phosphoric acid to adjust pH to 4.0) - acetonitrile (55:45); flow rate 1.0 mL / min; detection wavelength 280 nm; injection volume 20 μL.

[0157] Determination method: accurately measure the test solution, inject it into the liquid chromatograph, and record the chromatogram.

[0158] Limit: if there are impurity peaks in the test solution chromatogram, calculate the total amount of impurities by the area normalization method, the total amount of impurities should not be more than 1.5%, the single largest impurity should not be more than 0.5%, and the single other impurity should not be more than 0.2%.

[0159] Dissolution detection method:

[0160] Determine according to dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General 0931 second method) and high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General 0512).

[0161] Use 900 ml of 0.3% SDS in pH 1.0 hydrochloric acid solution as the dissolution medium, and the rotation speed is 50 revolutions per minute. Take samples at 10 min, 15 min, 20 min, and 30 min, respectively. Take the test solution and the control solution, and determine the content at a wavelength of 280 nm. Calculate the dissolution of each tablet at different times, and the dissolution requirement is 20 min ≥ 85%.

[0162] Table 1 Stability study test data

[0163]

[0164] Test conclusion:

[0165] It is found by experimental study that the samples prepared in Examples 1-10 have high content, less impurities and good stability. After 6 months of accelerated experiment, the content of active ingredient in the content does not decrease obviously, the problem of migration of active ingredient in the content to the soft capsule shell is solved, and the impurities do not increase obviously, the total impurities are still less than 1.0%, the maximum single impurity is less than 0.5%, other single impurities are less than 0.2%, all of which meet the impurity limit requirements in the quality standard. At the same time, the dissolution of the sample is high and stable, and there is no problem of significant reduction of dissolution during storage. After 6 months of acceleration, the dissolution at 15 min is more than 90%, which meets the requirement of dissolution at 20 min being more than 85%.

[0166] The amount of polyoxyethylene glyceryl oleate used in Comparative Example 1 is too low, resulting in a very low content of the preparation product, only 87.3% at 0 month, more impurities, total impurities 1.58%, maximum single impurity 0.61%, and other single impurities 0.27%, which cannot meet the quality standard requirements, and the stability of the preparation is very poor. After 6 months of accelerated experiment, the content is significantly reduced to 81.0%, the impurities increase significantly, the total impurities are 2.02%, the maximum single impurity is 0.83%, and the other single impurities are 0.35%, and the dissolution is very low, the dissolution at 20 min is only 75.9%, which is far beyond the requirements of the quality standard, and the product quality cannot be guaranteed.

[0167] In Comparative Example 2, polyoxyethylene glyceryl oleate is replaced by polyethylene glycol glyceryl laurate, resulting in a significantly low content of the preparation product, only 80.6% at 0 month, and significantly more impurities, total impurities 2.11%, maximum single impurity 0.86%, and other single impurities 0.37%, which cannot meet the quality standard requirements, and the stability of the preparation is very poor. After 6 months of accelerated experiment, the content is significantly reduced to 73.1%, the impurities increase significantly, the total impurities are 2.63%, the maximum single impurity is 1.13%, and the other single impurities are 0.49%, and the dissolution is very low, the dissolution at 20 min is only 66.4%, which is far beyond the requirements of the quality standard, and the product quality cannot be guaranteed.

[0168] In Comparative Example 3, the amount of sorbitol used in the soft capsule shell is too low, resulting in a significant decrease in the content of active ingredient in the content after 6 months of accelerated experiment, from 101.8% at 0 month to 76.6%, and migration of active ingredient in the content to the soft capsule shell; at the same time, the impurities increase, the total impurities are 1.57% after 6 months of accelerated experiment, the maximum single impurity is 0.63%, and the other single impurities are 0.26%, which cannot meet the quality standard requirements; and the dissolution decreases significantly, the dissolution at 20 min is only 71.9% after 6 months of accelerated experiment, which does not meet the requirements of the quality standard, and the product quality cannot be guaranteed.

[0169] The sorbitol used in the soft capsule shell in Comparative Example 4 is in an excessive amount, and the soft capsule shell is prone to cross-linking reaction, which may form a water-insoluble film on the inside or the outside surface of the soft capsule shell during the dissolution process, resulting in prolonged disintegration time, decreased content dissolution release rate and degree, and only 79.2% of the sample at 0 month is dissolved in 20 min, and after 6 months of accelerated experiment, only 69.3% of the sample is dissolved in 20 min, which do not meet the requirements of the quality standard, and the product quality cannot be guaranteed.

[0170] In Comparative Example 5, the sorbitol used in the soft capsule shell is replaced by propylene glycol, which results in more obvious decrease of the content of the active ingredient in the content from 102.5% at 0 month to 65.5% after 6 months of accelerated experiment, migration of the active ingredient in the content to the soft capsule shell, increase of impurities, total impurities of 2.51% after 6 months of accelerated experiment, maximum single impurity of 1.08%, and other single impurities of 0.46%, which cannot meet the requirements of the quality standard, and the dissolution rate is obviously decreased, and only 62.0% of the sample is dissolved in 20 min after 6 months of accelerated experiment, which does not meet the requirements of the quality standard, and the product quality cannot be guaranteed.

[0171] In summary, the compound SYN045 soft capsule has high content, less impurities and high dissolution rate, and after 6 months of accelerated experiment, the total impurities are still less than 1.0%, the maximum single impurity is less than 0.5%, the other single impurities are less than 0.2%, the dissolution rate is high, and the dissolution rate in 15 min is more than 90%, which meets the requirement of the quality standard that the dissolution rate in 20 min is more than 85%, improves the bioavailability, guarantees the safety and effectiveness of clinical medication, and greatly improves the product quality.

[0172] The above only describes the preferred embodiments of the present application, and is not intended to limit the present application, and any modification, equivalent replacement or improvement within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A soft capsule containing compound SYN045, said soft capsule comprising contents and a soft capsule shell, characterized in that, The contents comprise the following components by weight percentage: compound SYN045 0.02%-0.28%, vegetable oil 85.0%-91.5%, polyoxyethylene oleic acid glyceride 8.0%-14.5%, preservative 0.05%-0.15%, and antioxidant A 0.10%-0.30%; The soft capsule shell raw material comprises the following components in weight percentage: gelatin 44%-49%, plasticizer 16.0%-18.0%, light-blocking agent 0.60%-0.70%, antioxidant B 0.07%-0.09%, and purified water 34%-38%; wherein the plasticizer is a mixture of glycerol and sorbitol; the mass ratio of glycerol to sorbitol is 1:2-3.

2. The soft capsule containing compound SYN045 as described in claim 1, characterized in that, The vegetable oil is one or more of soybean oil, corn oil, peanut oil, olive oil, or rapeseed oil.

3. The soft capsule containing compound SYN045 as described in claim 1, characterized in that, The preservative is one or more of propylparaben, ethylparaben, phenylbutyrate, or benzoic acid.

4. The soft capsule containing compound SYN045 as described in claim 1, characterized in that, The antioxidant A is one or more of butylated hydroxyanisole, butylated hydroxytoluene, vitamin E, or propyl gallate.

5. The soft capsule containing compound SYN045 as described in claim 1, characterized in that, The light-blocking agent is titanium dioxide.

6. The soft capsule containing compound SYN045 as described in claim 1, characterized in that, The antioxidant B is one or both of glycine and sodium metabisulfite.

7. The soft capsule containing compound SYN045 as described in claim 1, characterized in that, The contents contain soybean oil as the vegetable oil, propylparaben as the preservative, and butylated hydroxyanisole (BHA) as antioxidant A. The contents comprise the following components by weight percentage: compound SYN045 0.22%, soybean oil 88.5%, polyoxyethylene oleate glyceryl ester 11%, propylparaben 0.09%, and BHA 0.13%. The soft capsule shell contains titanium dioxide as the light-blocking agent and glycine as antioxidant B. The soft capsule shell raw material comprises the following components by weight percentage: gelatin 48%, glycerin 4.8%, sorbitol 11.7%, titanium dioxide 0.62%, glycine 0.07%, and purified water 34.5%.

8. A method for preparing soft capsules of compound SYN045 as described in any one of claims 1-7, characterized in that, Includes the following steps: S1. Take the prescribed amount of gelatin, glycerin, sorbitol, opacifier, antioxidant B and purified water, stir at 65℃~75℃ to dissolve the gel, mix well, vacuum to remove air bubbles and set aside to obtain soft capsule shell solution. S2. Add the prescribed amount of polyoxyethylene oleic acid glyceride and vegetable oil to a chemical tank, heat to 55℃~65℃ and stir, add the prescribed amount of SYN045 raw material, preservative and antioxidant A, control the temperature at 55℃~65℃ and stir until completely dissolved, vacuum to remove air bubbles and set aside to obtain the soft capsule contents liquid. S3. Add the soft capsule shell solution and soft capsule contents solution to the pelleting machine, compress into pellets, dry, and package to obtain SYN045 soft capsules.

9. The method for preparing soft capsules of compound SYN045 as described in claim 8, characterized in that, The light-blocking agent is titanium dioxide; and / or The antioxidant B is one or both of glycine and sodium metabisulfite; and / or The vegetable oil is one or more of soybean oil, corn oil, peanut oil, olive oil, or rapeseed oil; and / or The preservative is one or more of propylparaben, ethylparaben, phenylbutyrate, or benzoic acid; and / or The antioxidant A is one or more of butylated hydroxyanisole, butylated hydroxytoluene, vitamin E, or propyl gallate.

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