Carboxyamidotriazole soft capsule

Abstract

The invention discloses a carboxamide triazole soft capsule which comprises a content and a capsule shell, and the content comprises the following components in parts by weight: 50-100 parts of carboxamide triazole, 300-400 parts of polyethylene glycol 400 and 18-30 parts of a crystal inhibitor; the capsule skin is prepared from gelatin, purified water, glycerol, lemon yellow and titanium dioxide according to the ratio of 1 to (0.8 to 1.0) to (0.30 to 0.60) to (0.0001 to 0.0002) to (0.001 to 0.004). The water absorption capacity of the content of the carboxamide triazole soft capsule is improved, and the risk that raw material medicines are separated out due to the fact that the capsule shell of the soft capsule absorbs water in the environment to enter the content is reduced. The crystallization behavior of active ingredients in the content of the carboxamidotriazole soft capsule in the gastrointestinal tract environment is controlled or adjusted, the re-dissolution rate of crude drugs in the content after crystallization is improved, dissolution is complete, the absorption effect is improved, and the difference between batches or individuals of products is reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to a carboxyamidotriazole soft capsule. BACKGROUND

[0002] Carboxyamidotriazole is one of the most representative drugs in the anti-angiogenic class of anticancer drugs. At present, carboxyamidotriazole has completed phase III clinical research, and the soft capsule dosage form is adopted. In view of the poor stability of carboxyamidotriazole soft capsules in the long-term storage process in the early clinical stage, sometimes there are unqualified conditions such as precipitation of raw materials and excessive content of related substances, and the patent CN 112353778B provides an improved soft capsule prescription and preparation process, so that the drug content of the soft capsule does not decrease and the related substances do not increase significantly during long-term storage. The soft capsule of the product is sealed and packaged with HDPE plastic bottles, the bottle cap is sealed during long-term storage, isolated from the external environment, and the stability in the bottle is good. However, when the patient uses it, the original sealed packaging is destroyed, and the product is packaged in multiple doses, so that the soft capsules will absorb moisture from the environment after frequent opening, increasing the risk of precipitation of raw materials in the soft capsules.

[0003] The content prescription provided by the patent CN 112353778B is composed of carboxyamidotriazole raw materials, polyethylene glycol 400, vitamin E and glycerol. Because polyethylene glycol 400 has a large oral dose, it can cause gastrointestinal discomfort and other adverse reactions, including nausea, vomiting, etc. At present, the impurities increase rapidly at high temperature, in order to ensure the appropriate shelf life, it needs to be stored in a cool place, which greatly increases the cost of transportation and storage. Therefore, reducing the amount of polyethylene glycol 400 and improving the stability of the soft capsule have become difficult problems to be solved. SUMMARY

[0004] The present application aims to overcome at least one of the above-mentioned defects of the prior art, and provides a carboxyamidotriazole soft capsule to achieve better drug absorption, higher drug dosage and lower toxicity.

[0005] In view of this, the purpose of the present application is to add one or more crystallization inhibitors in the prescription to inhibit or regulate the crystallization behavior of the active ingredients in the carboxyamidotriazole soft capsule in water, on the one hand to reduce the risk of precipitation of raw materials in the content of the soft capsule during use after opening the packaging bottle, and on the other hand to reduce the amount of polyethylene glycol 400 and improve the dissolution effect of the drug after oral administration of the soft capsule.

[0006] The application provides a carboxyamine triazole soft capsule, which comprises content and a capsule shell, wherein the content comprises the following components and their weight fractions: carboxyamine triazole 50-100 parts, polyethylene glycol 400 300-400 parts, and crystal inhibitor 18-30 parts; and the capsule shell comprises gelatin, purified water, glycerol, tartrazine and titanium dioxide, and the ratio of the gelatin, the purified water, the glycerol, the tartrazine and the titanium dioxide is 1:0.8-1.0:0.30-0.60:0.0001-0.0002:0.001-0.004.

[0007] The crystal inhibitor is one or more of povidone, PVPVA64, Soluplus and poloxamer.

[0008] Preferably, the crystal inhibitor is one or more of PVP-K12, PVP-K30 and PVP-K60.

[0009] More preferably, the crystal inhibitor is povidone K12.

[0010] Further, the weight percentage of the carboxyamine triazole and the polyethylene glycol is 1:6-8.

[0011] Further, the content further comprises an antioxidant, and the antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, citric acid and disodium edetate.

[0012] Preferably, the weight fraction of the antioxidant is 0.003-0.005 parts.

[0013] Further, the content further comprises a pH regulator, and the pH regulator is one or more of phosphate, triethanolamine and tromethamine.

[0014] Preferably, the weight fraction of the pH regulator is 0.05-0.2 parts.

[0015] Further, the content further comprises purified water, and the weight fraction of the purified water is 3-6 parts.

[0016] Further, the ratio of the gelatin, the purified water, the glycerol, the tartrazine and the titanium dioxide in the capsule shell is 1:0.9-1.0:0.40-0.50:0.00010-0.00014:0.002-0.003.

[0017] Compared with the prior art, the application has the following beneficial effects:

[0018] The application improves the water absorption capacity of the content of the carboxyamine triazole soft capsule, and reduces the risk of the raw material drug being precipitated due to the absorption of the water in the environment by the capsule shell of the soft capsule into the content.

[0019] And the weight percentage of the carboxylic amine triazole and polyethylene glycol is 1:3~8, and the unexpected discovery in the research process can reduce the use of polyethylene glycol 400 in single-specification preparation while suppressing the effect of crystal, and does not affect drug absorption, reduces the occurrence of adverse reactions.

[0020] The soft capsule product is stored at 30 DEG C, and the quality meets the set requirements, and the transportation and storage costs are reduced. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 It is a microscopic observation diagram of the crystal inhibition effect of different amounts of PVP-K12 in example 7 of the present application.

[0022] Figure 2 It is a microscopic observation diagram of the water test of the prescription with 5% povidone K12 crystal inhibitor.

[0023] Figure 3 It is a microscopic observation diagram of the water test of the prescription without crystal inhibitor.

[0024] Figure 4 It is a microscopic structure of high humidity test for 10 days (left: with crystal inhibitor; right: without crystal inhibitor).

[0025] Figure 5 It is a microscopic observation diagram of the dispersion of different prescriptions in water (left: prescription with crystal inhibitor; right: prescription without crystal inhibitor).

[0026] Figure 6 It is a dissolution curve diagram of the new prescription with crystal inhibitor and the original prescription without crystal inhibitor. DETAILED DESCRIPTION

[0027] The drawings in the examples, the technical solutions in the examples of the present application are described in more detail. In the drawings, the same or similar reference numerals represent the same or similar elements or elements with the same or similar functions throughout. The described examples are part of the examples of the present application, not all examples. The examples described below by reference to the drawings are exemplary and are intended to explain the present application, and cannot be understood as a limitation of the present application. Based on the examples in the present application, all other examples obtained by those skilled in the art without creative labor are within the scope of protection of the present application. The examples of the present application are described in detail below in conjunction with the drawings.

[0028] It should be noted that if the present application examples involve directional indications (such as up, down, left, right, front, back, etc.), the directional indications are only used to explain the relative position relationship, movement condition, etc. between the components in a certain posture (as shown in the drawings), if the certain posture changes, the directional indications also change accordingly.

[0029] Furthermore, if the embodiments of this application involve descriptions such as "first" or "second," these descriptions are for descriptive purposes only and should not be construed as indicating or implying their relative importance or implicitly specifying the number of technical features indicated. Therefore, features defined with "first" or "second" may explicitly or implicitly include at least one of those features. Additionally, the technical solutions of various embodiments can be combined with each other, but this must be based on the ability of those skilled in the art to implement them. If the combination of technical solutions is contradictory or impossible to implement, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection claimed in this application. Examples 1-6

[0030] Examples 1-6 and Comparative Examples 1-2 are screening experiments for types of anti-crystallization agents.

[0031] The effects of commonly used crystallization inhibitors such as povidone PVP-K12, PVP-K30, PVP-K60, hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose (HPC) on crystallization inhibition were investigated. Different amounts of water were added to the original formulation and formulations containing different crystallization inhibitors, and the mixtures were stirred thoroughly. Crystal precipitation was observed, and the results are shown in Table 2. The original formulation, without any crystallization inhibitors, became cloudy after adding 15% water, with a large amount of crystals precipitating. The formulations containing HPMC and HPC showed slight turbidity and fewer crystals after adding 15% water, but a large amount of crystals precipitated upon adding 20% ​​water. The PVP-containing formulation showed no crystal precipitation at 15% water, but became cloudy and precipitated upon adding 20% ​​water. Therefore, PVP, PVPVA64, Soluplus, and poloxamer showed better crystallization inhibition effects, while HPMC and HPC also had some crystallization inhibition effects on this product, but the effects were less pronounced. In addition, other types of povidone, such as PVP-K30 and PVP-K60, can achieve the same effect. Therefore, PVP was chosen as the crystallization inhibitor for this study. Table 1 Prescriptions for different crystallization inhibitors Table 2 Comparison of the crystal-inhibiting effects of different crystallization inhibitors Example 7

[0032] Example 7 and Comparative Examples 3-4 are screening experiments for the dosage of the anti-crystallizer.

[0033] The effect of different dosages of povidone-K12 (PVP-K12) on crystal inhibition was investigated. Different amounts of water were added to the original formulation and formulations with different dosages of PVP-K12, and the mixtures were stirred thoroughly. Crystal precipitation was observed, and the results are shown in Table 3. The original formulation, which contains no crystallization inhibitor, became cloudy after adding 15% water, with a large amount of crystals precipitating. The formulations with 2.5% and 1.0% PVP-K12 became cloudy after adding 20% ​​water, with a significant amount of crystals precipitating; under a microscope, the crystals appeared distinctly granular. The formulation with 5.0% PVP-K12 became slightly cloudy after adding 20% ​​water, with a small amount of crystals precipitating; under a microscope, the crystals were small and inconspicuous. Therefore, the 5% dosage of PVP-K12 showed the best crystal inhibition effect. Microscopic observation images are shown below. Figure 1 As shown. Table 3 Comparison of crystal-inhibiting effects of different dosages of PVP-K12 Examples 8-12

[0034] Examples 8-12 are for screening the types of antioxidants.

[0035] Screening of antioxidants and pH adjusters

[0036] The original formulation was relatively simple, containing only the solvent PEG400 and glycerin, with a small amount of dl-α-tocopherol added as an antioxidant. Because the main solvent PEG400 contains small amounts of peroxides and acidic residues, variations may occur between different batches and manufacturers, resulting in poor stability of the soft capsules or batch-to-batch variability, especially under high-temperature conditions. Furthermore, the addition of crystallization inhibitors may alter the solution microenvironment, leading to impurity growth. Therefore, this study investigated the effects of adding other antioxidants and pH adjusters on stability.

[0037] This embodiment examines the stability of the contents solution by using other antioxidants based on the original formulation. Table 4 Antioxidant Screening Table 5. Results of antioxidant screening (30℃)

[0038] The above experiments show that the formulation using butylated hydroxyanisole, butylated hydroxytoluene, citric acid, and disodium edetate as antioxidants has better stability than the original formulation. Even after adding a crystallization inhibitor, the stability decreased slightly, but it was still better than the original formulation. Examples 13-14

[0039] Examples 13-14 investigated the dosage of butylated hydroxyanisole as an antioxidant. Table 6 Screening of Antioxidant Dosage Table 7 Results of Antioxidant Dosage Screening (30℃)

[0040] There was no difference in stability when the dosage of butylated hydroxyanisole was in the range of 0.001 to 0.2%. Examples 15-19

[0041] Examples 15-19 and Comparative Example 9 are screenings for different pH ranges:

[0042] The study investigated the effect of adding pH adjusters (phosphate buffer solutions of different pH values) on stability. Table 8 Screening of phosphate buffer solutions at different pH values Ingredients Example 15 Example 16 Example 17 Example 18 Example 19 Comparative Example 7 API 10.88 10.88 10.88 10.88 10.88 10.88 PEG 400 76.92 76.82 76.72 76.63 76.52 76.02 Butylated hydroxyanisole 0.01 0.01 0.01 0.01 0.01 0.01 Glycerin 7.00 7.00 7.00 7.00 7.00 7.00 Povidone K12 5.00 5 5 5 5 5 pH 4.0 Phosphate Buffer 1.00 / / / / / pH 6.0 Phosphate Buffer / 1.00 / / / / pH 7.0 Phosphate Buffer / / 1.00 / / / pH 8.0 Phosphate Buffer / / / 1.00 / / pH 10.0 Phosphate Buffer / / / / 1.00 / pH 11.0 Phosphate Buffer / / / / / 1.00 Table 9 Results of screening phosphate buffer solutions at different pH values ​​(30℃)

[0043] Compared to untreated phosphate buffer, phosphate buffer with pH 6.0–10.0 significantly reduced maximum degradation impurities (MRIs). Phosphate buffer with pH 4.0 had some effect on reducing MPIs, but not significantly. Phosphate buffer with pH 11.0 had no effect on reducing MPIs. Therefore, the optimal pH range for the contents of the soft capsules of this invention is 4.0–10.0, and more preferably pH 6.0–10.0. Examples 20-21

[0044] Examples 20-21 investigate the effects of other pH adjusters on stability. Table 10 Screening of pH Adjusters Ingredients Example 20 Example 21 API 10.88 10.88 PEG 400 76.62 76.02 Butylated hydroxyanisole 0.10 0.10 Glycerin 7.00 7.00 Povidone K12 5.00 5.00 Triethanolamine 0.40 / 9% Tromethamine solution / 1.00 Table 11 Results of pH Adjuster Screening (30℃)

[0045] In this embodiment of the invention, triethanolamine and tromethamine solution is used as pH adjuster, which has good stability and is similar to that of phosphate buffer solution with pH 6.0 to 10.0. Example 22

[0046] This embodiment provides the following scale-up preparation method for the optimal embodiment of carboxyamine triazole soft capsules:

[0047] 1. Glue

[0048] Add lemon yellow and titanium dioxide to purified water (14% of total volume), mix well, and set aside. In a gelling tank, add purified water (86% of total volume), heat to 70℃, and then add gelatin, glycerin, and the aforementioned color paste sequentially, stirring and mixing for 5–15 minutes while simultaneously applying a vacuum of -0.08 to -0.09 MPa to defoam. After gelling is complete, filter the solution through a 100-mesh sieve and place it in a gelatin container (preheated to 55–65℃), keeping it warm until needed.

[0049] 2. Solution preparation

[0050] First, add butylated hydroxyanisole, polyethylene glycol 400, povidone K12, and glycerin to the mixing tank, control the heating temperature at 40-50℃, and stir until completely dissolved. Slowly add carboxytriazole, continue to control the heating temperature at 50-60℃, and stir in the dark for 2-4 hours until completely dissolved. Dissolve sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate in the prescribed amount of purified water, add to the mixing tank, stir for 3-5 minutes, vacuum, and filter the solution through a 100-mesh sieve for later use.

[0051] 3. Making pellets

[0052] The temperature of the insulated glue tank is set to 55-65℃, the spray temperature to 35-45℃, and the gelatin box temperature to 55-65℃. The spray and gelatin box are then heated. After the temperature stabilizes, the equipment is operated to adjust the gelatin thickness to 0.60-0.90mm to ensure consistency on both sides. Capsules are then formed. The amount of each capsule is determined based on the content of the intermediate product, with a tolerance of ±7.5%. The prepared soft capsules are then transported to a drying facility, with the temperature controlled at ≤30℃ and the humidity at ≤30%. The capsules are dried until the moisture content of the contents is <9%.

[0053] The prescription is as follows: Table 12 Optimized soft capsule formulation

[0054] The following is a related investigation into prescription optimization:

[0055] I. Crystallization Experiment

[0056] Different amounts of water (5%, 10%, 15%, 20%) were added to the contents solution, and the precipitation of the active pharmaceutical ingredient in the contents was observed visually and under a microscope, as follows. Figure 2 , 3 The results showed that when the formulation with added crystal inhibitor was diluted to 20% water, slight crystal precipitation occurred, the solution appeared slightly turbid, and fine particles were observed under a microscope; while the formulation without added crystal inhibitor became turbid when diluted to 10% water, flocculent matter was observed under a microscope, and obvious crystal precipitation occurred when diluted to 15%.

[0057] II. High Humidity Test

[0058] Soft capsules with different contents (containing and without crystal inhibitors) were placed under high humidity conditions, and samples were taken at 5 and 10 days. The capsule shells were cut open to observe the properties of the contents. Soft capsules containing crystal inhibitors showed no change in contents after 10 days of high humidity; the contents remained a clear, transparent liquid, and no crystals were observed under a microscope. Soft capsules without crystal inhibitors showed no change in contents after 5 and 10 days of high humidity; the contents remained a clear, transparent liquid, and no crystals were observed under a microscope. Soft capsules without crystal inhibitors showed no change in contents and no crystals after 5 days of high humidity. Figure 4 As shown, the substance became cloudy after 10 days, and crystal precipitation was observed under a microscope.

[0059] III. Soft Capsule Disintegration and Water-Contact Crystallization Behavior

[0060] The contents of the soft capsules were added to 250 ml of purified water at 37°C and gently stirred. The crystallization behavior of the active pharmaceutical ingredient was observed. With the naked eye, the formulation without a crystallization inhibitor precipitated larger crystals in water, which settled to the bottom after standing. The formulation with the added crystallization inhibitor precipitated finer crystals, which were uniformly suspended in the water. The crystal morphology and particle size of the suspension were observed under a microscope, as shown below. Figure 5 The crystal particles precipitated in water without the crystal inhibitor were larger than 10 μm, while the crystal particles precipitated in the formula with the crystal inhibitor were smaller than 5 μm.

[0061] Combination Figure 6 The dissolution curves show that when the dissolution rate of the new formulation with added crystal inhibitor is compared with that of the original formulation without added crystal inhibitor, the dissolution rate is faster with the addition of crystal inhibitor.

[0062] In summary, the carboxyamine triazole soft capsules prepared by this invention have higher stability and faster dissolution rate.

[0063] The above embodiments are merely illustrative of the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to the preferred embodiments above, those skilled in the art should understand that modifications or equivalent substitutions to the technical solutions of the present invention should not depart from the spirit and scope of the present invention. Those skilled in the art can also make other changes within the spirit of the present invention and use them in the design of the present invention, as long as they do not deviate from the technical effects of the present invention. These changes made according to the spirit of the present invention should all be included within the scope of protection claimed by the present invention.

Claims

1. A carboxyamidotriazole soft gelatin capsule comprising a content and a gelatin shell, characterized in that, The content includes the following components and their weight parts: carboxyamine triazole 50-100 parts, polyethylene glycol 400 300-400 parts, crystal inhibitor 18-30 parts; the gelatin includes gelatin: purified water: glycerol: lemon yellow: titanium dioxide, the ratio is 1:0.8-1.0:0.30-0.60:0.0001-0.0002:0.001-0.

004.

2. The carboxylic amine triazole soft capsule according to claim 1, characterized in that, The crystal inhibitor is one or more of povidone, PVPVA64, Soluplus, poloxamer.

3. The carboxylic amine triazole soft capsule according to claim 2, characterized in that, The crystal inhibitor is one or more of PVP-K12, PVP-K30, PVP-K60.

4. The carboxylic amine triazole soft capsule according to claim 1, characterized in that, The weight percentage of carboxyamine triazole and polyethylene glycol is 1:6-8.

5. The carboxylic amine triazole soft capsule according to claim 1, characterized in that, The content further includes an antioxidant, which is one or more of butylated hydroxyanisole, dibutylhydroxytoluene, citric acid, disodium edetate.

6. The carboxylic amine triazole soft capsule according to claim 4, characterized in that, The weight part of the antioxidant is 0.003-0.005 parts.

7. The carboxylic amine triazole softgel capsule of claim 1, wherein, The content further includes a pH adjuster, which is one or more of phosphate, triethanolamine, tromethamine, and the pH range of the pH adjuster is 4-10.

8. The carboxylic amine triazole soft capsule according to claim 6, characterized in that, The weight part of the pH adjuster is 0.05-0.2 parts, and the pH range of the pH adjuster is 6-10.

9. The carboxylic amine triazole soft capsule according to claim 6, characterized in that, The content further includes purified water, and the weight part of the purified water is 3-6 parts.

10. The carboxylic amine triazole softgel capsule of claim 1, wherein, The gelatin in the gelatin includes gelatin: purified water: glycerol: lemon yellow: titanium dioxide, the ratio is 1:0.9-1.0:0.40-0.50:0.00010-0.00014:0.002-0.003.

Images