Clofazimine soft capsule and preparation method thereof

Abstract

The invention belongs to the technical field of biological medicines, and provides a clofazimine soft capsule and a preparation method thereof. According to the clofazimine soft capsule, the soybean oil is used as a solvent, and compared with rapeseed oil and hydrogenated soybean oil, the cost is reduced; soybean lecithin is used as a suspending aid, and compared with lecithin, the cost is low. The cost of each kilogram of the nohua pharmaceutical clofazimine soft capsule is about 2896 yuan, the cost of each kilogram of the clofazimine soft capsule is about 1895 yuan, and the cost is reduced by 35%. Meanwhile, the dissolution curve of the clofazimine soft capsule obtained by the invention is very close to the dissolution curve of the original research medicine of the nohua preparation, and the similar factor f2 reaches 75.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, and in particular to a clofazimine soft capsule and a preparation method and application thereof. BACKGROUND

[0002] Clofazimine not only has a slow bactericidal effect on Mycobacterium leprae, but also is effective on Mycobacterium tuberculosis and Mycobacterium ulcerans when combined with other anti-mycobacterial drugs. At present, clofazimine soft capsules are used as anti-leprosy and anti-tuberculosis drugs in many countries.

[0003] The clofazimine soft capsule is a common liquid oral capsule, and the active ingredient is clofazimine with a specification of 50 mg. Clofazimine has strong liposolubility and strong hydrophobicity, so the absorption is very slow through the injection route. At present, it is mainly administered through the oral route. Clofazimine can pass through the blood-brain barrier in a small amount and can also pass through the placenta. Due to the high lipophilicity of the drug, it is mainly deposited in the cells of adipose tissue and the reticuloendothelial system, is taken up by macrophages throughout the body, and is distributed to the mesenteric lymph nodes, adrenal glands, subcutaneous fat, liver, gallbladder, bile, spleen, small intestine, muscle, bone, milk and skin, and the tissue concentration is higher than the blood concentration, and the concentration in the cerebrospinal fluid is low.

[0004] The content formula of the Novartis clofazimine soft capsule is: butylated hydroxytoluene, citric acid, propylene glycol, rapeseed oil and lecithin, yellow beeswax, hydrogenated soybean oil.

[0005] The skin formula of the Novartis clofazimine soft capsule is: sodium nipagin, sodium nipasol, vanillin, gelatin, 85% glycerol, black iron oxide, red iron oxide, and p-methoxyacetophenone.

[0006] The above-mentioned Novartis clofazimine soft capsule has high cost, and the specific ratio is secret. SUMMARY

[0007] Therefore, the purpose of the present application is to provide a clofazimine soft capsule and a preparation method thereof. The clofazimine soft capsule provided by the present application has low cost, and the dissolution curve is very close to that of the original research drug Novartis clofazimine soft capsule.

[0008] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions:

[0009] The present application provides a clofazimine soft capsule, which comprises a content and a rubber skin for sealing the content.

[0010] The content comprises the following components in parts by weight:

[0011] Clarithromycin 49.9-50.1 parts, soybean oil 199-201 parts, propylene glycol 2.9-3.1 parts, soybean phospholipid 2-4 parts, anhydrous citric acid 0.19-0.21 parts, dibutyl hydroxytoluene 0.09-0.11 parts, and yellow beeswax 0.24-0.26 parts.

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

[0013] Glycerin 1490-1510 parts, sodium hydroxyethyl benzoate 0.9-1.1 parts, sodium hydroxypropyl benzoate 0.9-1.1 parts, red iron oxide 49-51 parts, black iron oxide 14-16 parts, water 5490-5510 parts, and gelatin 5490-5510 parts.

[0014] The present application also provides a preparation method of the above-mentioned technical solution, comprising the following steps:

[0015] The content is sprayed between the two rubber skins by a spraying body, and the spraying body is molded to obtain the above-mentioned soft capsule.

[0016] Preferably, the rubber skin is prepared on a gelatin box, and the temperature of the gelatin box is 50-60℃; the thickness of the rubber skin is 0.70-0.90mm.

[0017] Preferably, the temperature of the spraying body is 37-39℃, and the rotating speed is 1-3rpm during the spraying process.

[0018] Preferably, the preparation method of the content comprises the following steps:

[0019] Part of the soybean oil, propylene glycol, soybean phospholipid, anhydrous citric acid, dibutyl hydroxytoluene and yellow beeswax are first mixed to obtain a first mixed system;

[0020] The first mixed system and the above-mentioned clarithromycin are second mixed to obtain a second mixed system;

[0021] The second mixed system and the rest of the soybean oil are third mixed to obtain the content.

[0022] Preferably, the temperature of the first and second mixing is independently 65-75℃, and the time is independently 20-40min;

[0023] The temperature of the third mixing is 65-75℃, and the time is 5-15min.

[0024] Preferably, the preparation method of the rubber skin comprises the following steps:

[0025] The red iron oxide, black iron oxide and part of the glycerin are mixed to obtain a colorant suspension;

[0026] After the rest of the glycerin is heated and dissolved, water, sodium hydroxyethyl benzoate and sodium hydroxypropyl benzoate are added, and then gelatin is added to obtain a sol;

[0027] The colorant suspension and the sol are mixed and defoamed to obtain a glue solution;

[0028] The glue solution is made into a glue skin.

[0029] Preferably, the temperature for heating and dissolving the rest of the glycerin is 65-75 DEG C, and the temperature for adding the gelatin is greater than or equal to 70 DEG C.

[0030] Preferably, the defoaming includes stirring defoaming and standing defoaming in sequence;

[0031] The vacuum degree for the stirring defoaming is -0.06 to -0.08 MPa;

[0032] The vacuum degree for the standing defoaming is -0.7 to -1.0 bar, and the time is greater than or equal to 60 min.

[0033] The present application provides a clofazimine soft capsule. The clofazimine soft capsule of the present application uses soybean oil as a solvent, which reduces the cost compared with rapeseed oil and hydrogenated soybean oil; and uses soybean phospholipid as a suspending agent, which is lower in cost compared with lecithin. Specifically, the cost of Novartis clofazimine soft capsule is about 2896 yuan per kilogram, and the cost of the clofazimine soft capsule obtained by the present application is about 1895 yuan per kilogram, which is 35% lower in cost. At the same time, the dissolution curve of the clofazimine soft capsule obtained by the present application is very close to the dissolution curve of the original research drug of Novartis, and the similarity factor f2 reaches 75. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The dissolution curves of LY-240701 and Novartis clofazimine soft capsule;

[0035] Figure 2 The dissolution curves of LY-240702 and Novartis clofazimine soft capsule;

[0036] Figure 3 The dissolution curves of LY-240801 and Novartis clofazimine soft capsule. DETAILED DESCRIPTION

[0037] The present application provides a clofazimine soft capsule, which comprises a content and a glue skin encapsulating the content;

[0038] The content comprises the following components in parts by weight:

[0039] Clarithromycin 49.9-50.1 parts, soybean oil 199-201 parts, propylene glycol 2.9-3.1 parts, soybean phospholipid 2-4 parts, anhydrous citric acid 0.19-0.21 parts, dibutyl hydroxytoluene 0.09-0.11 parts, and yellow bee wax 0.24-0.26 parts.

[0040] In the present application, the raw materials used in the present application are preferably commercially available products.

[0041] The soft capsule of the present application comprises content and a capsule skin encapsulating the content.

[0042] In the present application, the content comprises 49.9-50.1 parts of clarithromycin, preferably 50 parts, in terms of parts by weight. In the present application, the clarithromycin is the raw material of the soft capsule of clarithromycin.

[0043] In the present application, the content comprises 199-201 parts of soybean oil, preferably 200 parts, in terms of parts by weight. In the present application, the soybean oil is a solvent for the soft capsule of clarithromycin, which has the advantages of high flowability, low allergenicity, and low cost compared with the existing hydrogenated soybean oil and rapeseed oil.

[0044] In the present application, the content comprises 2.9-3.1 parts of propylene glycol, preferably 3 parts, in terms of parts by weight. In the present application, the propylene glycol serves as a suspending agent for the soft capsule of clarithromycin, which can improve the stability of the content.

[0045] In the present application, the content comprises 2-4 parts of soybean phospholipid, preferably 3 parts, in terms of parts by weight. In the present application, the soybean phospholipid serves as a suspending agent for the soft capsule of clarithromycin, which can improve the stability of the content, has more balanced emulsification stability compared with the existing lecithin, is not prone to decomposition and oxidation, and has low cost.

[0046] In the present application, the content comprises 0.19-0.21 parts of anhydrous citric acid, preferably 0.2 parts, in terms of parts by weight. In the present application, the anhydrous citric acid serves as a pH regulator for the content.

[0047] In the present application, the content comprises 0.09-0.11 parts of dibutyl hydroxytoluene, preferably 0.1 parts, in terms of parts by weight. In the present application, the dibutyl hydroxytoluene serves as an antioxidant for the content, which can improve the stability of the soft capsule of clarithromycin.

[0048] In the present application, the content comprises 0.24-0.26 parts of yellow bee wax, preferably 0.25 parts, in terms of parts by weight. In the present application, the yellow bee wax serves as a suspending agent, which can improve the stability of the content.

[0049] In the present application, the rubber skin includes glycerin 1490-1510 parts by weight, preferably 1500 parts. In the present application, the glycerin serves as a humectant.

[0050] In the present application, the rubber skin includes sodium hydroxyphenyl propyl ester 0.9-1.1 parts by weight, preferably 1 part. In the present application, the sodium hydroxyphenyl propyl ester serves as a preservative.

[0051] In the present application, the rubber skin includes sodium hydroxyphenyl propyl ester 0.9-1.1 parts by weight, preferably 1 part. In the present application, the sodium hydroxyphenyl propyl ester serves as a preservative.

[0052] In the present application, the rubber skin includes red iron oxide 49-51 parts by weight, preferably 50 parts. In the present application, the red iron oxide serves as an opacifying agent.

[0053] In the present application, the rubber skin includes black iron oxide 14-16 parts by weight, preferably 15 parts. In the present application, the black iron oxide serves as an opacifying agent.

[0054] In the present application, the rubber skin includes water 5490-5510 parts by weight, preferably 5500 parts. In the present application, the water is preferably purified water. In the present application, the water serves as a solvent.

[0055] In the present application, the rubber skin includes gelatin 5490-5510 parts by weight, preferably 5500 parts. In the present application, the gelatin serves as the main material of the rubber skin.

[0056] The present application also provides a preparation method of the soft clomazone capsule as described in the technical solutions above, including the following steps:

[0057] The content is sprayed between two rubber skins by a spray body, and the soft clomazone capsule is obtained through molding.

[0058] In the present application, the preparation method of the content preferably includes the following steps:

[0059] Part of the soybean oil, propylene glycol, soybean phospholipid, anhydrous citric acid, dibutyl hydroxytoluene and yellow beeswax are first mixed to obtain a first mixed system;

[0060] The first mixed system and clomazone are second mixed to obtain a second mixed system;

[0061] The second mixed system and the rest of the soybean oil are third mixed to obtain the content.

[0062] The present application first mixes part of soybean oil, propylene glycol, soybean phospholipid, anhydrous citric acid, dibutyl hydroxytoluene and yellow beeswax to obtain a first mixed system. In the present application, the temperature of the first mixing is preferably 65-75℃, and further preferably 70℃; the time is preferably 20-40min, and further preferably 30min. In the present application, the first mixing is preferably carried out under the condition of water bath. In the present application, the first mixing is preferably carried out in a sol tank.

[0063] After obtaining the first mixed system, the present application second mixes the first mixed system and clofazimine to obtain a second mixed system. In the present application, the temperature of the second mixing is preferably 65-75℃, and further preferably 70℃; the time is preferably 20-40min, and further preferably 30min. In the present application, the second mixing is preferably carried out in a sol tank.

[0064] After obtaining the second mixed system, the present application third mixes the second mixed system and the rest of soybean oil to obtain the content. In the present application, the temperature of the third mixing is preferably 65-75℃, and further preferably 70℃; the time is preferably 5-15min, and further preferably 10min. In the present application, the third mixing is preferably carried out in a slurry storage tank.

[0065] In the present application, the preparation method of the rubber skin preferably comprises the following steps:

[0066] Mixing red iron oxide, black iron oxide and part of glycerol to obtain a colorant suspension;

[0067] After heating and dissolving the rest of glycerol, adding water, sodium hydroxyphenyl ethyl ester and sodium hydroxyphenyl propyl ester, and then adding gelatin to obtain a sol.

[0068] Mixing the colorant suspension and the sol and defoaming to obtain a glue solution;

[0069] Preparation of the glue solution into a rubber skin.

[0070] The present application mixes red iron oxide, black iron oxide and part of glycerol to obtain a colorant suspension. In the present application, the mixing of red iron oxide, black iron oxide and part of glycerol is preferably carried out under stirring.

[0071] The present application heats and dissolves the rest of glycerol, adds water, sodium hydroxyphenyl ethyl ester and sodium hydroxyphenyl propyl ester, and then adds gelatin to obtain a sol. In the present application, the temperature of heating and dissolving the rest of glycerol is preferably 65-75℃, and further preferably 70℃; the temperature of adding gelatin is preferably greater than or equal to 70℃.

[0072] After obtaining the colorant suspension and sol, the colorant suspension and sol are mixed and defoamed to obtain a glue liquid. In the present application, the defoaming preferably comprises stirring defoaming and standing defoaming in sequence. In the present application, the vacuum degree of the stirring defoaming is preferably -0.06 to -0.08 MPa; the time of the stirring defoaming is not particularly limited in the present application, until no obvious air bubbles are present. In the present application, the vacuum degree of the standing defoaming is preferably -0.7 to -1.0 bar, and the time is preferably greater than or equal to 60 min.

[0073] After obtaining the glue liquid, the glue liquid is made into a glue skin. In the present application, the glue skin is preferably made on a gelatin box, the temperature of the gelatin box is preferably 50 to 60℃, and the thickness of the glue skin is preferably 0.70 to 0.90 mm. In the present application, when the glue liquid is made into a glue skin, a cooling fan is preferably turned on. In the present application, the glue skin has excellent toughness.

[0074] In the present application, during the spraying of the spray body, the temperature of the spray body is preferably 37 to 39℃, and the rotation speed is preferably 1 to 3 rpm, and further preferably 2 rpm.

[0075] After the molding, the present application preferably further comprises: sequentially performing pre-drying setting and airing of the sample obtained by molding. In the present application, the pre-drying setting is preferably performed in a pre-drying rotating cage, and the sample obtained by molding is preferably conveyed into the pre-drying rotating cage by a conveying belt. In the present application, the airing is preferably performed in a tray, and the airing is preferably performed at room temperature.

[0076] The clofazimine soft capsules and the preparation method thereof provided by the present application will be described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0077] Example 1

[0078] The content formula of the clofazimine soft capsules is shown in Table 1.

[0079] Table 1 Content Formula

[0080] Name Single grain amount (mg) Mass percentage / % Clofazimine 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 Bee wax 0.25 0.10 Total 256.55 100

[0081] The glue skin formula of the clofazimine soft capsules is shown in Table 2.

[0082] Table 2 Glue Skin Formula

[0083] Name Prescription amount (g) Mass percentage / % Glycerol 1500.00 11.94 Sodium benzoate 1.00 0.01 Sodium propylparaben 1.00 0.01 Red iron oxide 50 0.40 Black iron oxide 15 0.12 Water 5500.00 43.77 Gelatin for capsules 5500.00 43.77 Total 12567 100

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

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

[0086] 2) Dispersion of colorants: Mix the prescribed amount of red iron oxide, black iron oxide and part of glycerin in a beaker, and stir until uniform without color difference. The colorant suspension is ready for use.

[0087] 3) Preparation of the gelatin solution: First, set the temperature of the sol tank to 70±5°C, and add the remaining glycerin and heat until dissolved. Add the prescribed amount of purified water, and dissolve the sodium hydroxyethyl benzoate and sodium hydroxypropyl benzoate. When the temperature is appropriate (greater than 70°C), add the prescribed amount of gelatin and stir. Pay attention to the melting state of the gelatin. When the gelatin is completely dissolved, the sol is ready. Add the colorant suspension obtained in 2) to the sol obtained in 3), and stir until uniform. Open the vacuum valve and start vacuuming (vacuum degree: -0.06 to -0.08 MPa). Stir and degas until no obvious bubbles are present, and then stop stirring. Continue vacuuming until the vacuum degree is -0.7 to -1.0 bar, and let stand for at least 60 minutes. The gelatin solution is ready and should be kept at 60 to 65°C.

[0088] 4) Preparation of the content: First, set the temperature of the water bath to 70±5°C. Add about 1 / 4 of the prescribed amount of soybean oil, propylene glycol, soybean phospholipid, anhydrous citric acid and dibutyl hydroxytoluene to the water bath. After stirring for 30 minutes, add the raw drug clofazimine. Continue stirring for another 30 minutes, and then transfer the drug 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 content, which is ready for use.

[0089] 5) Pelletizing: Prepare the gelatin solution into a thick and uniform gelatin skin (gelatin skin thickness: 0.80±0.1 mm) using the gelatin box. Turn on the air conditioner, and set the temperature of the gelatin box to 50 to 60°C. The gelatin skin should be flexible. Pour the prepared content into the drug supply system of the pelletizing equipment, and spray it between two adjusted gelatin skins using the spray body. The gelatin pellets are obtained by pressing through the mold. Adjust the temperature of the spray body to 38±1°C, and adjust the rotation speed to 2 rpm.

[0090] 6) Drying: The samples after mold pressing are sent to the pre-drying rotating cage for pre-drying and setting. The capsules after being taken out of the cage are placed in a tray and dried at room temperature to obtain the clofazimine soft capsules.

[0091] Repeat 1) to 6) to obtain different batches of clofazimine soft capsules, which are designated 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 clofazimine soft capsules are subjected to dissolution test under the following conditions:

[0094] Dissolution medium 1: Take 16.4 mL of 12 mol / L dilute hydrochloric acid, add 800 mL of water and 10 g of pepsin, shake well, then add 50 g of sodium dodecyl sulfate to dissolve, dilute with water to 1000 mL to obtain dissolution medium 1.

[0095] Dissolution medium 2: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution, add 118 mL of 0.2 mol / L sodium hydroxide solution, 50 g of sodium dodecyl sulfate, and dilute with water to 1000 mL, shake well to obtain dissolution medium 2.

[0096] Take 900 mL of dissolution medium, paddle method 50 revolutions, dissolution is determined according to dissolution and release determination method (general rule 0931 second method), the dissolution curve data of example 1 and reference preparation are shown in table 3~table 4.

[0097] Table 3 dissolution data of different clofazimine soft capsules

[0098]

[0099]

[0100] Figure 1 The dissolution curves of LY-240701 and Novartis clofazimine soft capsules are shown in table 3 and table 4. Figure 1 It can be seen that the similarity factor f2 is 68.4, which is greater than 50, and the two dissolution curves are highly similar.

[0101] Table 4 dissolution data of different clofazimine soft capsules

[0102]

[0103] Figure 2 The dissolution curves of LY-240702 and Novartis clofazimine soft capsules are shown in table 4 and table 5. Figure 2 It can be seen that the similarity factor f2 is 75, which is greater than 50, and the two dissolution curves are highly similar.

[0104] Comparative example 1

[0105] The difference from example 1 is that no soybean phospholipid is added in the content, and the others are similar to example 1, which is recorded as LY-240602.

[0106] Comparative example 2

[0107] The difference from example 1 is that the soybean phospholipid in the content is replaced by lecithin, and the mass of lecithin is 3.00 mg, and the others are similar to example 1, which is recorded as LY-240603.

[0108] The dissolution data of example 1 and comparative examples 1~2 and reference preparation are shown in table 5.

[0109] Table 5 Dissolution data of different soft capsules of clofazimine

[0110]

[0111]

[0112] From Table 5, it can be seen that the similarity factor f2 of the soft capsule prepared by adding soybean phospholipid is 75.3, slightly higher than 74.6 of the soft capsule prepared by adding lecithin, and the cost of soybean phospholipid is more than 20% lower than that of lecithin; the soft capsule prepared without adding soybean phospholipid is 49.3, lower than 50, and the dissolution curve is not similar.

[0113] Comparative Example 3

[0114] The difference from Example 1 is that the soybean oil in the content is replaced by sunflower oil, and the others are similar to Example 1, which is recorded as LY-240604.

[0115] The dissolution data of Example 1 and Comparative Examples 3 and 4 and the reference preparation are shown in Table 6.

[0116] Table 6 Dissolution data of different soft capsules of clofazimine (dissolution medium one)

[0117]

[0118] From Table 6, it can be seen that the similarity factor f2 of the soft capsule prepared by adding soybean oil is 69.5, slightly higher than 67.9 of the soft capsule prepared by adding rapeseed oil, and the cost of soybean oil is 15%-25% lower than that of rapeseed oil, and it is replaced by soybean oil with lower cost.

[0119] Comparative Example 4

[0120] The difference from Example 1 is that 150 mg of soybean oil is added to the content, and the others are similar to Example 1, which is recorded as LY-240501.

[0121] Comparative Example 5

[0122] The difference from Example 1 is that 180 mg of soybean oil is added to the content, and the others are similar to Example 1, which is recorded as LY-240502.

[0123] Comparative Example 6

[0124] The difference from Example 1 is that 220 mg of soybean oil is added to the content, and the others are similar to Example 1, which is recorded as LY-240503.

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

[0126] Table 7 Dissolution data of different soybean oil (dissolution medium one)

[0127]

[0128]

[0129] The amount of soybean oil in the prescription has a significant effect on the dissolution of the preparation. Therefore, the amount of soybean oil is temporarily set to 200 mg per tablet.

[0130] Comparative Example 7

[0131] The content and the rubber skin formula of Comparative Example 7 are shown in Table 8 and Table 9, respectively.

[0132] Table 8 Content Formula

[0133] Name Single grain amount (mg) Mass percentage / % Clofazimine 50.00 20 Soybean oil 200.00 80 Total 250 100

[0134] Table 9 Rubber Skin Formula

[0135] Name Prescription amount (g) Mass percentage / % Glycerol 1500.00 11.97 Hydroxybenzoic acid ethyl ester 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 Gelatin for capsules 5500.00 43.87 Light liquid paraffin 5 0.04 Total 12536 100

[0136] The preparation method is the same as that of Example 1, and the obtained clofazimine soft capsules are recorded as LY-240801.

[0137] The dissolution data of Comparative Example 7 and the reference preparation are shown in Table 10 and Figure 3 .

[0138] Table 10 Dissolution Data of Different Clofazimine Soft Capsules

[0139]

[0140] Figure 3 The dissolution curves of LY-240801 and Novartis clofazimine soft capsules are shown in Figure 3 and Table 10. It can be seen that the dissolution of the old prescription clofazimine soft capsules is lower than that of the new prescription, 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 for capsules in the rubber skin is 5000 g.

[0143] Comparative Example 9

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

[0145] In the case of a rubber skin thickness of 0.8 mm, the state of the rubber skin with different water contents is compared, and the results are shown in Table 11.

[0146] Table 11 Water Content in Rubber Skin

[0147] Water content in the rubber / g State 5000 Slight cracking 5300 Slight cracking 5500 No cracking

[0148] By comparison, it is found that if the water added in the rubber formula is less than 5500g, cracks will be generated in the drying process, affecting the product quality, and the water added in the rubber formula is temporarily set to 5500g.

[0149] Comparative Example 10

[0150] The difference from Example 1 is that the temperature of the spraying body is 36℃.

[0151] Comparative Example 11

[0152] The difference from Example 1 is that the temperature of the spraying body is 40℃.

[0153] In the case of the rubber thickness of 0.8mm, the influence of different spraying body temperatures is compared, and the results are shown in Table 12.

[0154] Table 12 Influence of spraying body temperature

[0155] Spray body temperature °C Sealing state 36 Cannot seal 38±1 Normal 40 Melting signs

[0156] By comparison, it is found that in the case of the rubber thickness of 0.8mm, 38±1℃ can normally seal. Due to the influence of different rubber parameters, rubber thickness, environmental temperature and other parameters, the heat sealing effect of the spraying body will be affected, and the temperature of the spraying body is temporarily set to 38±1℃.

[0157] The cost of each kilogram of Novartis pharmaceutical clofazimine soft capsules is about 2896 yuan, and the cost of each kilogram of the clofazimine soft capsules obtained by the present application is 1895 yuan, which is 35% lower.

[0158] The above only describes the preferred embodiments of the present application, and it should be pointed out that for ordinary skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A soft capsule of clofazimine, characterized in that, The content, and a rubber skin encapsulating the content; The content comprises the following components in parts by weight: 49.9-50.1 parts of clofazimine, 199-201 parts of soybean oil, 2.9-3.1 parts of propylene glycol, 2-4 parts of soybean phospholipid, 0.19-0.21 parts of anhydrous citric acid, 0.09-0.11 parts of dibutyl hydroxytoluene, and 0.24-0.26 parts of bee wax.

2. The clofazimine softgel capsules according to claim 1, wherein, The rubber skin comprises the following components in parts by weight: 1490-1510 parts of glycerol, 0.9-1.1 parts of sodium hydroxyethyl benzoate, 0.9-1.1 parts of sodium hydroxypropyl benzoate, 49-51 parts of red iron oxide, 14-16 parts of black iron oxide, 5490-5510 parts of water, and 5490-5510 parts of gelatin.

3. Process for the preparation of soft capsules of clofazimine according to any one of claims 1 to 2, characterized in that, The method comprises the following steps: The content is sprayed between two rubber skins by a spraying body, and the clofazimine soft capsules are obtained by molding.

4. The production method according to claim 3, characterized by, The rubber skin is prepared on a gelatin box with a temperature of 50-60℃, and the thickness of the rubber skin is 0.70-0.90 mm.

5. The preparation method according to claim 3, characterized in that, During the spraying process, the temperature of the spraying body is 37-39℃, and the rotating speed is 1-3 rpm.

6. The preparation method according to claim 3, characterized in that, The method for preparing the content comprises the following steps: Part of the soybean oil, propylene glycol, soybean phospholipid, anhydrous citric acid, dibutyl hydroxytoluene, and bee wax are first mixed to obtain a first mixed system; The first mixed system and clofazimine are second mixed to obtain a second mixed system; The second mixed system and the remaining soybean oil are third mixed to obtain the content.

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

8. The preparation method according to claim 3, characterized in that, The method for preparing the rubber skin comprises the following steps: Red iron oxide, black iron oxide, and part of glycerol are mixed to obtain a colorant suspension; After the remaining glycerol is heated and dissolved, water, sodium hydroxyethyl benzoate, and sodium hydroxypropyl benzoate are added, and then gelatin is added to obtain a sol; The colorant suspension and the sol are mixed and defoamed to obtain a glue solution; The glue solution is prepared into a rubber skin.

9. The production method according to claim 8, characterized by, The temperature for heating and dissolving the remaining glycerol is 65-75℃, and the temperature for adding the gelatin is greater than or equal to 70℃.

10. The method of claim 8, wherein, The defoaming comprises stirring defoaming and standing defoaming in sequence; The vacuum degree of the stirring defoaming is -0.06 to -0.08 MPa; The vacuum degree of the standing defoaming is -0.7 to -1.0 bar, and the time is greater than or equal to 60 min.

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