A chlorpheniramine soft capsule and its preparation method

Abstract

This invention belongs to the field of biomedical technology and provides a clofazimine soft capsule and its preparation method. The clofazimine soft capsule of this invention uses soybean oil as a solvent, which reduces costs compared to rapeseed oil and hydrogenated soybean oil; it also uses soybean lecithin as a suspending agent, which is less expensive than lecithin. The cost of Novartis' clofazimine soft capsules per kilogram is approximately 2896 yuan, while the cost of the clofazimine soft capsules obtained by this invention per kilogram is approximately 1895 yuan, a cost reduction of 35%. Furthermore, the dissolution curve of the clofazimine soft capsules obtained by this invention is very close to that of Novartis' original drug, with a similarity factor f2 of 75.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a chlorfazimine soft capsule, its preparation method, and its application. Background Technology

[0002] Clofazimine not only has a slow-acting bactericidal effect against Mycobacterium leprae, but is also effective against Mycobacterium tuberculosis and Mycobacterium ulcerativecognition when used in combination with other antimycobacterial drugs. Currently, clofazimine soft capsules are used in many countries as an anti-leprosy and anti-tuberculosis drug.

[0003] Clofazimine soft capsules are a common liquid oral capsule formulation. The active ingredient is clofazimine, and the strength is 50mg. Clofazimine is highly lipophilic and extremely hydrophobic, resulting in very slow absorption when administered via injection. Currently, it is mostly administered orally. Clofazimine can cross the blood-brain barrier in small amounts and can also cross the placenta. Due to its high lipophilicity, it mainly deposits in adipose tissue and the cells of the reticuloendothelial system. It is taken up by macrophages throughout the body and distributed to mesenteric lymph nodes, adrenal glands, subcutaneous fat, liver, gallbladder, bile, spleen, small intestine, muscles, bones, breast milk, and skin. Tissue concentrations are higher than blood concentrations, while concentrations in cerebrospinal fluid are low.

[0004] The contents of Novartis chlorofazimine soft capsules are: butylated hydroxytoluene, citric acid, propylene glycol, rapeseed oil and lecithin, beeswax, and hydrogenated soybean oil.

[0005] The formula for Novartis chlorofazimine soft capsules is: sodium ethylparaben, sodium propylparaben, vanillin, gelatin, 85% glycerin, black iron oxide, red iron oxide, and p-methoxyacetophenone.

[0006] The aforementioned Novartis clofazimine soft capsules are expensive, and the specific formulation is kept confidential. Summary of the Invention

[0007] In view of this, the purpose of this invention is to provide a clofazimine soft capsule and its preparation method. The clofazimine soft capsule provided by this invention has low cost, and its dissolution curve is very close to that of the original drug Novartis' clofazimine soft capsule.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0009] The present invention provides a chlorfazimine soft capsule, comprising contents and a capsule encapsulating the contents;

[0010] The contents comprise the following components in parts by weight:

[0011] 49.9–50.1 parts of chlorfazimine, 199–201 parts of soybean oil, 2.9–3.1 parts of propylene glycol, 2–4 parts of soybean lecithin, 0.19–0.21 parts of anhydrous citric acid, 0.09–0.11 parts of butylated hydroxytoluene, and 0.24–0.26 parts of beeswax.

[0012] Preferably, the rubber sheet comprises the following components in parts by weight:

[0013] 1490-1510 parts glycerin, 0.9-1.1 parts sodium ethylparaben, 0.9-1.1 parts sodium propylparaben, 49-51 parts red iron oxide, 14-16 parts black iron oxide, 5490-5510 parts water, and 5490-5510 parts gelatin.

[0014] This invention also provides a method for preparing the chlorpheniramine soft capsules described in the above technical solution, comprising the following steps:

[0015] The contents are sprayed between two rubber sheets through a nozzle and then molded to obtain the chlorfenapyr soft capsules.

[0016] Preferably, the rubber sheet is made on a gelatin box at a temperature of 50–60°C; and the thickness of the rubber sheet is 0.70–0.90 mm.

[0017] Preferably, during the spraying process, the temperature of the spray is 37-39°C and the rotation speed is 1-3 rpm.

[0018] Preferably, the method for preparing the contents includes the following steps:

[0019] A portion of soybean oil, propylene glycol, soybean lecithin, anhydrous citric acid, butylated hydroxytoluene, and beeswax were mixed to obtain a first mixed system.

[0020] The first mixture system and chlorpyrifos are mixed to obtain the second mixture system;

[0021] The second mixture and the remaining soybean oil are mixed in a third mixture to obtain the contents.

[0022] Preferably, the temperature of the first mixing and the second mixing are independently 65–75°C; and the time is independently 20–40 min.

[0023] The third mixing temperature is 65–75°C, and the time is 5–15 min.

[0024] Preferably, the method for preparing the rubber sheet includes the following steps:

[0025] Red iron oxide, black iron oxide, and a portion of glycerol were mixed to obtain a colorant suspension;

[0026] After heating and dissolving the remaining glycerin, water, sodium ethylparaben, and sodium propylparaben are added, followed by gelatin to obtain a sol.

[0027] The colorant suspension and sol are mixed and degassed to obtain a gel solution;

[0028] The adhesive liquid is made into a rubber sheet.

[0029] Preferably, the temperature at which the remaining glycerin is heated and dissolved is 65–75°C; and the temperature at which the gelatin is added is greater than or equal to 70°C.

[0030] Preferably, the degassing includes sequentially performing stirring degassing and standing degassing;

[0031] The vacuum degree for stirring and degassing is -0.06 to -0.08 MPa;

[0032] The vacuum degree of the static degassing is -0.7 to -1.0 bar, and the time is greater than or equal to 60 minutes.

[0033] This invention provides a chlorfenapyridine soft capsule. The chlorfenapyridine soft capsule of this invention uses soybean oil as a solvent, which reduces costs compared to rapeseed oil and hydrogenated soybean oil; it also uses soybean lecithin as a suspending agent, which is cheaper than lecithin. Specifically, the cost of each kilogram of Novartis' chlorfenapyridine soft capsule is approximately RMB 2896, while the cost of each kilogram of the chlorfenapyridine soft capsule obtained by this invention is approximately RMB 1895, a cost reduction of 35%. Furthermore, the dissolution curve of the chlorfenapyridine soft capsule obtained by this invention is very close to that of Novartis' original drug, with a similarity factor f2 of 75. Attached Figure Description

[0034] Figure 1 Dissolution profiles for LY-240701 and Novartis chlorfazimine soft capsules;

[0035] Figure 2 Dissolution profiles for LY-240702 and Novartis chlorfazimine soft capsules;

[0036] Figure 3 Dissolution curves for LY-240801 and Novartis chlorfazimine soft capsules. Detailed Implementation

[0037] The present invention provides a chlorfazimine soft capsule, comprising contents and a capsule encapsulating the contents;

[0038] The contents comprise the following components in parts by weight:

[0039] 49.9–50.1 parts of chlorfazimine, 199–201 parts of soybean oil, 2.9–3.1 parts of propylene glycol, 2–4 parts of soybean lecithin, 0.19–0.21 parts of anhydrous citric acid, 0.09–0.11 parts of butylated hydroxytoluene, and 0.24–0.26 parts of beeswax.

[0040] Unless otherwise specified, all raw materials used in this invention are preferably commercially available products.

[0041] The chlorfazimine soft capsule provided by the present invention includes contents and a capsule encapsulating the contents.

[0042] In this invention, the contents comprise 49.9 to 50.1 parts by weight of clofazimine, preferably 50 parts. In this invention, the clofazimine is the active pharmaceutical ingredient for clofazimine soft capsules.

[0043] In this invention, the contents comprise 199-201 parts by weight of soybean oil, preferably 200 parts. In this invention, the soybean oil is used as the solvent for the chloroform soft capsules, and compared to existing hydrogenated soybean oil and rapeseed oil, it has advantages such as high fluidity, low allergenicity, and low cost.

[0044] In this invention, the contents comprise 2.9 to 3.1 parts by weight, preferably 3 parts, of propylene glycol. In this invention, the propylene glycol serves as a suspending agent for clofazimine soft capsules, thereby improving the stability of the contents.

[0045] In this invention, the contents comprise 2 to 4 parts by weight of soybean lecithin, preferably 3 parts. In this invention, the soybean lecithin serves as a suspending agent for chlorofazimine soft capsules, improving the stability of the contents; compared to existing lecithin, it exhibits more balanced emulsification stability, is less prone to decomposition and oxidation, and has lower cost.

[0046] In this invention, the contents comprise 0.19 to 0.21 parts by weight of anhydrous citric acid, preferably 0.2 parts. In this invention, the anhydrous citric acid serves as a pH adjuster for the contents.

[0047] In this invention, the contents comprise 0.09 to 0.11 parts by weight, preferably 0.1 parts, of butylated hydroxytoluene. In this invention, the butylated hydroxytoluene acts as an antioxidant in the contents, thereby improving the stability of the clofazimine soft capsules.

[0048] In this invention, the contents comprise 0.24 to 0.26 parts by weight, preferably 0.25 parts, of beeswax. In this invention, the beeswax acts as a suspending agent, improving the stability of the contents.

[0049] In this invention, the rubber sheet comprises 1490-1510 parts by weight of glycerin, preferably 1500 parts. In this invention, the glycerin serves as a humectant.

[0050] In this invention, the rubber sheet comprises 0.9 to 1.1 parts by weight, preferably 1 part, of sodium ethylparaben. In this invention, the sodium ethylparaben serves as a preservative.

[0051] In this invention, the rubber sheet comprises 0.9 to 1.1 parts by weight, preferably 1 part, of sodium propylparaben. In this invention, the sodium propylparaben serves as a preservative.

[0052] In this invention, the rubber sheet comprises 49 to 51 parts by weight, preferably 50 parts, of red iron oxide. In this invention, the red iron oxide serves as a light-blocking agent.

[0053] In this invention, the rubber sheet comprises 14 to 16 parts by weight, preferably 15 parts, of black iron oxide. In this invention, the black iron oxide serves as a light-blocking agent.

[0054] In this invention, the rubber sheet comprises 5490-5510 parts by weight of water, preferably 5500 parts. In this invention, the water is preferably purified water. In this invention, the water is used as a solvent.

[0055] In this invention, the rubber sheet comprises 5490 to 5510 parts by weight of gelatin, preferably 5500 parts. In this invention, the gelatin is the main material of the rubber sheet.

[0056] This invention also provides a method for preparing the chlorpheniramine soft capsules described in the above technical solution, comprising the following steps:

[0057] The contents are sprayed between two rubber sheets through a nozzle and then molded to obtain the chlorfenapyr soft capsules.

[0058] In this invention, the method for preparing the contents preferably includes the following steps:

[0059] A portion of soybean oil, propylene glycol, soybean lecithin, anhydrous citric acid, butylated hydroxytoluene, and beeswax were mixed to obtain a first mixed system.

[0060] The first mixture system and chlorpyrifos are mixed to obtain the second mixture system;

[0061] The second mixture and the remaining soybean oil are mixed in a third mixture to obtain the contents.

[0062] This invention involves mixing a portion of soybean oil, propylene glycol, soybean lecithin, anhydrous citric acid, butylated hydroxytoluene, and beeswax to obtain a first mixed system. In this invention, the preferred temperature for the first mixing is 65–75°C, more preferably 70°C; the preferred time is 20–40 min, more preferably 30 min. In this invention, the first mixing is preferably carried out under water bath conditions. In this invention, the first mixing is preferably carried out in a sol-gel tank.

[0063] After obtaining the first mixed system, the present invention further mixes the first mixed system with chlorfenapyridine to obtain a second mixed system. In the present invention, the temperature of the second mixing is preferably 65–75°C, more preferably 70°C; the time is preferably 20–40 min, more preferably 30 min. In the present invention, the second mixing is preferably carried out in a sol-gel tank.

[0064] After obtaining the second mixing system, the present invention further mixes the second mixing system with the remaining soybean oil to obtain the contents. In the present invention, the temperature of the third mixing is preferably 65–75°C, more preferably 70°C; the time is preferably 5–15 min, more preferably 10 min. In the present invention, the third mixing is preferably carried out in a storage tank.

[0065] In this invention, the method for preparing the rubber sheet preferably includes the following steps:

[0066] Red iron oxide, black iron oxide, and a portion of glycerol were mixed to obtain a colorant suspension;

[0067] After heating and dissolving the remaining glycerin, water, sodium ethylparaben, and sodium propylparaben are added, followed by gelatin to obtain a sol.

[0068] The colorant suspension and sol are mixed and degassed to obtain a gel solution;

[0069] The adhesive liquid is made into a rubber sheet.

[0070] This invention involves mixing red iron oxide, black iron oxide, and a portion of glycerol to obtain a colorant suspension. In this invention, the mixing of red iron oxide, black iron oxide, and a portion of glycerol is preferably carried out under stirring conditions.

[0071] In this invention, the remaining glycerin is dissolved by heating, and then water, sodium ethylparaben, and sodium propylparaben are added, followed by the addition of gelatin to obtain a sol. In this invention, the temperature at which the remaining glycerin is dissolved by heating is preferably 65–75°C, more preferably 70°C; the temperature at which the gelatin is added is preferably greater than or equal to 70°C.

[0072] After obtaining the colorant suspension and sol, the present invention mixes the colorant suspension and sol and degass ...

[0073] After obtaining the adhesive, the present invention processes the adhesive into a rubber sheet. In the present invention, the rubber sheet is preferably formed on a gelatin box, the temperature of the gelatin box is preferably 50–60°C, and the thickness of the rubber sheet is preferably 0.70–0.90 mm. In the present invention, a cooling fan is preferably turned on when forming the rubber sheet from the adhesive. In the present invention, the rubber sheet exhibits excellent toughness.

[0074] In this invention, during the spraying process, the temperature of the spray is preferably 37-39°C, the rotation speed is preferably 1-3 rpm, and more preferably 2 rpm.

[0075] After molding, the present invention preferably further includes: pre-drying and shaping the molded sample sequentially, and then air-drying it. In this invention, the pre-drying is preferably performed in a pre-drying drum, and the molded sample is preferably conveyed to the pre-drying drum via a conveyor belt. In this invention, the air-drying is preferably performed on a tray, and the air-drying is preferably performed at room temperature.

[0076] The following detailed description of the chlorpheniramine soft capsules and their preparation method provided by the present invention, with reference to the embodiments, should not be construed as limiting the scope of protection of the present invention.

[0077] Example 1

[0078] The contents of clofazimine soft capsules are shown in Table 1.

[0079] Table 1 Contents Formulation

[0080] name Dosage per tablet (mg) mass percentage / % Chlorpheniramine 50.00 19.49 soybean oil 200.00 77.96 Propylene glycol 3.00 1.17 Soybean phospholipids 3.00 1.17 Anhydrous citric acid 0.20 0.08 Butylated hydroxytoluene 0.10 0.04 beeswax 0.25 0.10 total 256.55 100

[0081] The formula for the capsule shell of chlorfazimine soft capsules is shown in Table 2.

[0082] Table 2 Rubber Formulation Table

[0083] name Prescription dosage (g) mass percentage / % glycerin 1500.00 11.94 Sodium ethylparaben 1.00 0.01 Sodium hydroxypropyl ester 1.00 0.01 Red iron oxide 50 0.40 Black iron oxide 15 0.12 water 5500.00 43.77 Capsule gelatin 5500.00 43.77 total 12567 100

[0084] The preparation method of the above-mentioned chlorfenapyridine soft capsules is as follows:

[0085] 1) Weighing: Weigh out each material according to the prescription composition.

[0086] 2) Dispersion of colorant: Mix the prescribed amounts of red iron oxide, black iron oxide and some glycerol in a beaker until there is no color difference, and obtain a colorant suspension for later use.

[0087] 3) Preparation of the sol solution: First, set the temperature of the sol tank to 70±5℃, add the remaining glycerin, and heat until dissolved; add the prescribed amount of purified water, sodium ethylparaben, and sodium propylparaben and dissolve them. After heating to a suitable temperature (above 70℃), add the prescribed amount of gelatin and stir, monitoring the gelatin's melting state. Once the gelatin has completely dissolved, a sol is obtained. Add the colorant suspension obtained in 2) to the sol obtained in 3), stir, and disperse evenly. Open the vacuum valve and start vacuuming (vacuum degree: -0.06~-0.08MPa), stirring and degassing until no large bubbles are visible, then stop stirring; continue vacuuming until the vacuum degree is -0.7~-1.0 bar, and let stand for at least 60 minutes to obtain the sol solution; keep the sol solution at 60~65℃ for later use.

[0088] 4) Preparation of contents: First, set the water bath temperature to 70±5℃. Add about 1 / 4 of the prescription amount of soybean oil, propylene glycol, soybean lecithin, beeswax, anhydrous citric acid and butylated hydroxytoluene to the water bath. After heating and stirring in the water bath for 30 minutes, add the active pharmaceutical ingredient clofazimine. Continue stirring for another 30 minutes. Transfer the solution to a storage tank (the remaining soybean oil can be used for rinsing). After adding the remaining soybean oil, stir and mix in the storage tank to obtain the contents for later use.

[0089] 5) Shot Compression: The gelatin solution is formed into a uniformly thick sheet using a gelatin box (sheet thickness: 0.80±0.1mm; with the air cooler on, gelatin box temperature: 50~60℃). The sheet is tough. The prepared contents are poured into the drug supply system of the compression equipment, sprayed between two pre-adjusted sheets, and then pressed into shot using a mold. The temperature of the spray is adjusted to 38±1℃, and the rotation speed is adjusted to 2 rpm.

[0090] 6) Drying: The molded samples are conveyed into a pre-drying rotary drum for pre-drying and shaping. The capsules after exiting the drum are placed in a tray and air-dried at room temperature to obtain chlorfazimine soft capsules.

[0091] Repeat steps 1) to 6) to obtain different batches of chlorfazimine soft capsules, denoted as LY-240601, LY-240701, LY-240702 and LY-240703.

[0092] Reference preparation: Clofazimine soft capsules; Manufacturer: Novartis, Switzerland; Batch number: MK0207.

[0093] The obtained chlorfenapyridine soft capsules were subjected to a dissolution test under the following conditions:

[0094] Dissolution medium one: Take 16.4 mL of 12 mol / L dilute hydrochloric acid, add 800 mL of water and 10 g of pepsin, shake well, add 50 g of sodium dodecyl sulfate to dissolve, and dilute with water to 1000 mL to obtain dissolution medium one.

[0095] Dissolution medium two: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution, add 118 mL of 0.2 mol / L sodium hydroxide solution and 50 g of sodium dodecyl sulfate, dilute with water to 1000 mL, dissolve and shake well to obtain dissolution medium two.

[0096] Take 900 mL of dissolution medium, paddle 50 rpm, and determine the dissolution rate according to the method for determination of dissolution and release (General Rule 0931, Method II). The dissolution curve data of Example 1 and the reference preparation are shown in Tables 3 and 4.

[0097] Table 3 Dissolution data for different types of chlorpheniramine maleate soft capsules

[0098]

[0099]

[0100] Figure 1 The dissolution profiles of LY-240701 and Novartis chlorfazimine soft capsules are shown in Table 3. Figure 1 It can be seen that the similarity factor f2 is 68.4, which is greater than 50, indicating that the two dissolution curves are highly similar.

[0101] Table 4 Dissolution data of different chlorpheniramine maleate soft capsules

[0102]

[0103] Figure 2 The dissolution profiles of LY-240702 and Novartis chlorfazimine soft capsules are shown in Table 4. Figure 2 It can be seen that the similarity factor f2 is 75, which is greater than 50, indicating that the two dissolution curves are highly similar.

[0104] Comparative Example 1

[0105] The difference from Example 1 is that no soybean lecithin is added to the contents; otherwise, it is similar to Example 1 and is designated as LY-240602.

[0106] Comparative Example 2

[0107] The difference from Example 1 is that the soybean lecithin in the contents is replaced with lecithin, and the mass of lecithin is 3.00 mg. Otherwise, it is similar to Example 1 and is referred to as LY-240603.

[0108] The dissolution data of Example 1, Comparative Examples 1-2, and the reference formulation are shown in Table 5.

[0109] Table 5 Dissolution data of different chlorpheniramine maleate soft capsules

[0110]

[0111]

[0112] As can be seen from Table 5, the similarity factor f2 of soft capsules prepared with added soybean lecithin is 75.3, which is slightly higher than that of soft capsules prepared with added lecithin (74.6). Moreover, the cost of soybean lecithin is more than 20% lower than that of lecithin. The similarity factor f2 of soft capsules prepared without added soybean lecithin is 49.3, which is lower than 50, and the dissolution curves are not similar.

[0113] Comparative Example 3

[0114] The difference from Example 1 is that the soybean oil in the contents is replaced with sunflower seed oil. Otherwise, it is similar to Example 1 and is referred to as LY-240604.

[0115] The dissolution data of Example 1, Comparative Example 3, and the reference formulation are shown in Table 6.

[0116] Table 6 Dissolution data of different chlorhexidine soft capsules (dissolution medium 1)

[0117]

[0118] As can be seen from Table 6, when soybean oil is used as a solvent, the similarity factor f2 is 69.5, which is slightly higher than that of rapeseed oil (67.9). Moreover, the cost of soybean oil is 15% to 25% lower than that of rapeseed oil, so it is advisable to switch to the lower-cost soybean oil.

[0119] Comparative Example 4

[0120] The difference from Example 1 is that 150mg of soybean oil was added to the contents, otherwise it is similar to Example 1, and it is denoted as LY-240501.

[0121] Comparative Example 5

[0122] The difference from Example 1 is that 180mg of soybean oil was added to the contents, otherwise it is similar to Example 1, and it is denoted as LY-240502.

[0123] Comparative Example 6

[0124] The difference from Example 1 is that 220 mg of soybean oil was added to the contents, otherwise it is similar to Example 1, and it is denoted as LY-240503.

[0125] The dissolution data of Example 1, Comparative Examples 4-6, and the reference formulation are shown in Table 7.

[0126] Table 7. Dissolution rate of different soybean oils (dissolution medium 1)

[0127]

[0128]

[0129] Adjusting the amount of soybean oil in the formulation has a significant impact on the dissolution of the preparation. Therefore, the soybean oil dosage is tentatively set at 200 mg / capsule.

[0130] Comparative Example 7

[0131] The contents and rubber formulation of Comparative Example 7 are shown in Tables 8 and 9, respectively.

[0132] Table 8 Contents Formulation

[0133] name Dosage per tablet (mg) mass percentage / % Chlorpheniramine 50.00 20 soybean oil 200.00 80 total 250 100

[0134] Table 9 Rubber Formulation

[0135] name Prescription dosage (g) mass percentage / % glycerin 1500.00 11.97 Ethylparaben 1.00 0.01 95% ethanol 10 0.08 Red iron oxide 5 0.04 Black iron oxide 15 0.12 water 5500.00 43.87 Capsule gelatin 5500.00 43.87 Light liquid paraffin 5 0.04 total 12536 100

[0136] The preparation method is the same as in Example 1, and the resulting chlorfacitinib soft capsules are designated as LY-240801.

[0137] Dissolution data for Comparative Example 7 and the reference formulation are shown in Table 10 and Figure 3 As shown.

[0138] Table 10 Dissolution data of different chlorpheniramine maleate soft capsules

[0139]

[0140] Figure 3 The dissolution profiles of LY-240801 and Novartis' chlorfazimine soft capsules are shown below. Figure 3 As can be seen from Table 10, the dissolution rate of the old formulation of chlorofazimine soft capsules is lower than that of the new formulation, and the similarity factor f2 is 47.2, which is lower than 50.

[0141] Comparative Example 8

[0142] The difference from Example 1 is that the mass of gelatin used in the capsules in the gelatin shell is 5000g.

[0143] Comparative Example 9

[0144] The difference from Example 1 is that the mass of gelatin used in the capsules in the gelatin shell is 5300g.

[0145] With a rubber thickness of 0.8 mm, the conditions of rubbers with different moisture contents were compared, and the results are shown in Table 11.

[0146] Table 11. Water Content in Rubber Sheets

[0147] Water content in rubber / g state 5000 minor cracks 5300 Slight cracks 5500 No cracks

[0148] Comparative analysis revealed that adding less than 5500g of water to the rubber formula would cause cracks during the drying process, affecting product quality. Therefore, the recommended water content for the rubber is 5500g.

[0149] Comparative Example 10

[0150] The difference from Example 1 is that the temperature of the spray is 36°C.

[0151] Comparative Example 11

[0152] The difference from Example 1 is that the temperature of the spray is 40°C.

[0153] With a rubber thickness of 0.8 mm, the effects of different spray temperatures were compared, and the results are shown in Table 12.

[0154] Table 12 Investigation of the Influence of Spray Temperature

[0155] Spray body temperature ℃ Sealed state 36 Cannot be sealed 38±1 normal 40 There are signs of melting.

[0156] Comparative analysis revealed that a sealing temperature of 38±1℃ was sufficient for a 0.8mm thick rubber sheet. However, the heat-sealing effect of the spray can be affected by variations in rubber sheet parameters, thickness, and ambient temperature; therefore, the spray temperature is tentatively set at 38±1℃.

[0157] The cost of each kilogram of Novartis clofazimine soft capsules is approximately RMB 2,896, while the cost of each kilogram of clofazimine soft capsules obtained by this invention is RMB 1,895, representing a 35% cost reduction.

[0158] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A soft capsule of clofazimine, characterized in that, Includes the contents and the rubber covering the contents; The contents comprise the following components in parts by weight: Chlorfazimine 49.9~50.1 parts, soybean oil 199~201 parts, propylene glycol 2.9~3.1 parts, soybean lecithin 2~4 parts, anhydrous citric acid 0.19~0.21 parts, butylated hydroxytoluene 0.09~0.11 parts, beeswax 0.24~0.26 parts; The rubber sheet comprises the following components in parts by weight: 1490-1510 parts glycerin, 0.9-1.1 parts sodium ethylparaben, 0.9-1.1 parts sodium propylparaben, 49-51 parts red iron oxide, 14-16 parts black iron oxide, 5490-5510 parts water, and 5490-5510 parts gelatin.

2. The process for the preparation of soft capsules of clofazimine according to claim 1, characterized in that, Includes the following steps: The contents are sprayed between two rubber sheets through a nozzle and then molded to obtain the chlorfenapyr soft capsules.

3. The preparation method according to claim 2, characterized in that, The rubber sheet is made on a gelatin box at a temperature of 50-60°C; the thickness of the rubber sheet is 0.70-0.90 mm.

4. The preparation method according to claim 2, characterized in that, During the spraying process, the temperature of the spray is 37~39℃ and the rotation speed is 1~3rpm.

5. The preparation method according to claim 2, characterized in that, The method for preparing the contents includes the following steps: A portion of soybean oil, propylene glycol, soybean lecithin, anhydrous citric acid, butylated hydroxytoluene, and beeswax were mixed to obtain a first mixed system. The first mixture system and chlorpyrifos are mixed to obtain the second mixture system; The second mixture and the remaining soybean oil are mixed in a third mixture to obtain the contents.

6. The preparation method according to claim 5, characterized in that, The temperature of the first and second mixtures is independently 65~75℃; the time is independently 20~40min; The third mixing temperature is 65~75℃, and the time is 5~15min.

7. The preparation method according to claim 2, characterized in that, The method for preparing the rubber sheet includes the following steps: Red iron oxide, black iron oxide, and a portion of glycerol were mixed to obtain a colorant suspension; After heating and dissolving the remaining glycerin, water, sodium ethylparaben, and sodium propylparaben are added, followed by gelatin to obtain a sol. The colorant suspension and sol are mixed and degassed to obtain a gel solution; The adhesive liquid is made into a rubber sheet.

8. The preparation method according to claim 7, characterized in that, The remaining glycerin is dissolved by heating at a temperature of 65~75℃; the gelatin is added at a temperature greater than or equal to 70℃.

9. The preparation method according to claim 7, characterized in that, The degassing process includes sequentially performing stirring degassing and standing degassing. The vacuum degree for stirring and degassing is -0.06 to -0.08 MPa; The vacuum degree of the static degassing is -0.7 to -1.0 bar, and the time is greater than or equal to 60 minutes.

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