Ethyl eicosapentaenoate soft capsule and preparation process thereof

Abstract

The invention relates to the technical field of soft capsule preparations, and discloses an ethyl eicosapentaenoate soft capsule and a preparation process thereof, and the ethyl eicosapentaenoate soft capsule is composed of a content and a capsule shell; the prescription of the content comprises ethyl eicosapentaenoate and vitamin E; the capsule shell is composed of anti-crosslinking gelatin, glycerol, sorbitol, glycine and water in a mass ratio of 1: (0.15-0.2): 0.2: (< = 0.01): (0.9-1.056); and the anti-crosslinking gelatin is one of succinate plasticized anti-crosslinking gelatin, citrate succinate plasticized anti-crosslinking gelatin, BB 180 / 08 RXL type Jiaxita gelatin and 180AB 8 ST type Rosirogelatin. According to the invention, the problems of fogging, whitening and precipitation of the capsule shell appearance of the soft capsule sample after stability acceleration for 3 months and long-term 3 months are fundamentally solved, and the problem of slow disintegration time limit of the soft capsule sample during the soft capsule stabilization period is further solved.

Description

Technical Field

[0001] The present invention relates to the technical field of soft capsule preparations, in particular to an eicosapentaenoic acid ethyl ester soft capsule and a preparation process thereof. Background Art

[0002] Icosapent ethyl soft capsules: Originally developed by Amarin Pharmaceuticals Ireland Ltd., they are clinically indicated as an adjunct to statin therapy. They are the only FDA-approved adjunct to statins at the maximum tolerated dose and the first drug in the world to simultaneously lower blood lipids and reduce cardiovascular risk. The original developer of these capsules received import approval on May 29, 2023 (National Medicine Approval No. HJ20230058).

[0003] Anhui Wellman Pharmaceutical Co., Ltd. is currently conducting research on generic eicosapentaenoic acid ethyl soft capsules. During the project's accelerated stability testing of samples for three months and long-term testing for three months, it was found that the sample capsule shells had fogging and white precipitation. To address this issue, the project team analyzed and studied the potential causes of the soft capsule shell appearance problems from the aspects of capsule shell components and process, and proposed a technical solution to solve the capsule shell precipitation phenomenon. Summary of the Invention

[0004] Aiming at the problem of hazy, white and precipitated capsule shells of ethyl eicosapentaenoic acid soft capsule samples with accelerated stability for three months and long-term stability for three months, the present invention provides ethyl eicosapentaenoic acid soft capsules and a preparation process.

[0005] An eicosapentaenoic acid ethyl ester soft capsule, which consists of contents and a capsule shell; The prescription composition of the contents is icosapentaenoic acid ethyl ester and vitamin E; The capsule shell formulation consists of anti-cross-linking gelatin, glycerol, sorbitol, glycine and water, and the corresponding mass ratio of the formulation is 1:(0.15-0.2):0.2:(≤0.01):(0.9-1.056).

[0006] Preferably, the anti-cross-linking gelatin is one of succinate plasticized anti-cross-linking gelatin, succinate citrate plasticized anti-cross-linking gelatin, BB 180 / 08 RXL type Gelita gelatin, and 180 AB 8 ST type Rousselot gelatin.

[0007] Preferably, the succinate plasticized cross-linking resistant gelatin is prepared by acylation reaction between the succinic anhydride functional groups of the acylating agent monosuccinic anhydride succinate-based reagent and the amino functional groups of 150 LB Rousselot Type 8 gelatin.

[0008] Preferably, the succinic acid citrate plasticized cross-linking resistant gelatin is prepared by acylation reaction between the succinic anhydride functional groups of the acylating agent monosuccinic anhydride succinic acid citrate reagent and the amino functional groups of 150 LB Rousselot gelatin type 8.

[0009] Preferably, the eicosapentaenoic acid ethyl ester soft capsule consists of 70-90 wt% of the contents and 10-30 wt% of the capsule shell.

[0010] Preferably, the mass ratio of eicosapentaenoic acid ethyl ester to vitamin E is 1:(0.001-0.003).

[0011] The preparation process of the above-mentioned eicosapentaenoic acid ethyl ester soft capsule comprises the following steps: Step 1, preparation of the contents: according to the prescribed amount of the contents, under nitrogen protection, add vitamin E to ethyl eicosapentaenoate, and stir evenly at room temperature to obtain the contents; Step 2, sol preparation: weigh purified water and heat it in a sol tank. When the temperature of the purified water reaches 55-65°C, add glycerin and stir evenly, then add sorbitol and glycine. Continue to heat it to 80-90°C and add gelatin. Stir until the gelatin is completely melted into a gelatin solution. After vacuum degassing, let it stand at a constant temperature of 50-60°C for later use. Step 3: The contents and the sol are passed through a soft capsule press to prepare soft capsules to obtain eicosapentaenoic acid ethyl ester soft capsules.

[0012] The above-mentioned eicosapentaenoic acid ethyl ester soft capsule is used as an auxiliary medicine for clinical statin treatment.

[0013] The beneficial effects of the present invention are as follows: First: By using the technical means of reducing the proportion of glycine in the capsule shell of the eicosapentaenoic acid ethyl soft capsule sample, the problem of fogging and white precipitation in the capsule shell of the eicosapentaenoic acid ethyl soft capsule sample with accelerated stability for 3 months and long-term stability for 3 months was solved from the root.

[0014] Second: Rousselot gelatin (model 150 LB 8), which has a lower raw material cost, was modified to resist cross-linking using anhydride polyester-based reagents (monosuccinic anhydride succinate-based reagents or monosuccinic anhydride succinate-based reagents) to obtain plasticized anti-cross-linked gelatin. The plasticized anti-cross-linked gelatin was used as an optimized component of the capsule shell formulation of the eicosapentaenoic acid ethyl soft capsule sample, solving the problem of delayed disintegration time of the eicosapentaenoic acid ethyl soft capsule sample during the stability period. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the appearance of the 0-day soft capsule.

[0016] Figure 2 To accelerate the appearance of room temperature soft capsules after 3 months.

[0017] Figure 3 For the appearance of long-term 3-month soft capsules.

[0018] Figure 4 This is the infrared spectrum of the precipitate on the surface of the capsule shell.

[0019] Figure 5 The infrared spectrum of the shell is normal.

[0020] Figure 6 This is the infrared spectrum of gelatin.

[0021] Figure 7 This is the infrared spectrum of glycerol.

[0022] Figure 8 This is the infrared spectrum of sorbitol.

[0023] Figure 9 This is the infrared spectrum of glycine.

[0024] Figure 10 This is a comparison of the infrared spectra of glycine and the precipitate. DETAILED DESCRIPTION

[0025] The following problems were found during the research process of generic eicosapentaenoic acid ethyl soft capsules: On day 0, the appearance of the soft capsule is Figure 1 Stability accelerated 3 months sample capsule appearance see Figure 2 , long-term stability 3 months sample capsule appearance see Figure 3 ; Depend on Figure 2 and Figure 3 The results showed that the capsule shells of the samples with accelerated stability for 3 months and long-term stability for 3 months had fogging and white precipitation.

[0026] In response to the issue of hazy and white precipitation on the shell of the above-mentioned sample capsule, an investigation and research was conducted. The specific process and results are as follows: The soft capsules with obvious white precipitation were selected and the precipitation on the surface of the capsule shell was analyzed by infrared spectroscopy. The analysis results are shown in Figure 4 , and infrared analysis was performed on the normal capsule shell, and the analysis results are shown in Figure 5 ; Depend on Figure 4 and Figure 5 The analytical results lead to the following conclusions: (1) Judging from the NH and amide C=O peaks, the precipitate was completely separated from the gelatin matrix; (2) The precipitate contains 1750cm -1 saturated ester groups; (3) The precipitate does not contain NH and -OH; (4) The precipitate has a wavelength of 680 cm -1, 890cm -1 and 930cm -1 Three characteristic absorptions; Furthermore, infrared detection was performed on the components of the capsule shell formulation, and the analytical results are shown in Figure 6 、 Figure 7 、 Figure 8 and Figure 9 , and compared them one by one with the precipitate detection results, and the infrared spectrum comparison results of glycine and precipitate were obtained. Figure 10 ; By comparing the absorption characteristic peaks of key functional groups in the infrared spectrum, it was confirmed that the soft capsule shell precipitate was glycine, and no -OH characteristic absorption peak was found in the spectrum of the precipitate, indicating that sorbitol and glycine in the capsule shell did not undergo esterification reaction.

[0027] Glycine in the capsule shell acts as an antioxidant and, on the other hand, affects the disintegration time of the soft capsule during stability by blocking the amino groups that are the main binding sites in the gelatin cross-linking reaction. The reason for the precipitation of glycine is that glycine is supersaturated in the capsule shell. Calculations show that the saturated solubility ratio of glycine to gelatin at 0°C is 0.0105 (based on a 5% capsule shell moisture content), and at 25°C, it is 0.0187 (based on a 5% capsule shell moisture content). In order to take into account the disintegration time limit of soft capsules during stability and the possible precipitation risk of glycine, the following two schemes are proposed to optimize the shell formulation of eicosapentaenoic acid ethyl soft capsules: First, the ratio of glycine to gelatin is adjusted to 0.01 (i.e., glycine does not reach saturation even under extreme conditions, and is approximately 50% of saturation concentration under room temperature storage conditions). The preferred capsule shell formulation composition is gelatin: glycerol: sorbitol: glycine: water = 1:0.2:0.2:0.01:0.9. Second: the proportion of glycine is reduced to 0.005, which is less than 30% of the saturated concentration ratio. The amount of glycine in the capsule shell is less than 30% of the saturated solubility. The risk of glycine precipitation during the stable period is low, but at the same time, the amount of glycine is reduced by 6 times compared with the current prescription, which may affect the stability and disintegration of the soft capsule. The risk of disintegration time during the stability of the soft capsule is relatively high. At this time, succinic anhydride reagents are used to modify the gelatin. The anhydride reacts with the amino group in the gelatin to increase the amino blocking rate and reduce the free amino group content in the gelatin. That is, the gelatin is subjected to anti-cross-linking treatment, which can play a dual technical role of simultaneously reducing the risk of disintegration time and glycine precipitation during the stable period of the soft capsule.

[0028] Based on this, it is proposed to solve the problem of capsule shell precipitation by reducing the proportion of glycine in the capsule shell. Based on this, a monosuccinic anhydride succinate-based reagent is developed and synthesized, and gelatin is modified using the monosuccinic anhydride succinate-based reagent to obtain succinate-plasticized anti-cross-linking gelatin. Furthermore, a monosuccinic anhydride succinic acid citrate reagent is further developed and synthesized, and gelatin is modified using the monosuccinic anhydride succinic acid citrate reagent to obtain succinic acid citrate plasticized anti-cross-linking gelatin, so as to reduce the risk of disintegration time limit of soft capsules during stability period. Example 1:

[0029] An eicosapentaenoic acid ethyl ester soft capsule, consisting of 75wt% of contents and 25wt% of capsule shell; Among them, the mass ratio of the ingredients in the content prescription is eicosapentaenoic acid ethyl ester: vitamin E = 1:0.002; An optimization experiment was conducted on the shell formulation of icosapentaenoic acid ethyl soft capsules, and the specific experimental scheme is shown in Table 1 below; Table 1 Optimization scheme of the capsule shell formulation of icosapentaenoic acid ethyl ester soft capsule

[0030] Among them, the price of Rousselot gelatin (model 150 LB 8) is 83 yuan / kg; The price of Gelita gelatin (model BB 180 / 08 RXL) is 270 yuan / kg; The price of Rousselot gelatin (model 180 AB 8 ST) is 90 yuan / kg; Gelita gelatin (Type BB 180 / 08 RXL) and Rousselot gelatin (Type 180 AB 8 ST) are both cross-linked gelatin and share the same anti-cross-linking mechanism. Example 2:

[0031] The preparation process of eicosapentaenoic acid ethyl ester soft capsules comprises the following steps: Step 1, preparation of the contents: according to the prescribed amount of the contents, under nitrogen protection, add vitamin E to ethyl eicosapentaenoate, and stir evenly at room temperature to obtain the contents; Step 2, sol preparation: weigh purified water and heat it in a sol tank. When the temperature of the purified water reaches 60°C, add glycerol and stir, then add sorbitol and glycine. Continue to heat it to 85°C and add gelatin. Stir for 2 hours to completely melt the gelatin into a sol. After vacuum degassing, let it stand at a constant temperature of 60°C for later use. Step 3: The contents and the sol are passed through a soft capsule pelletizing machine to prepare soft capsules to obtain 1g of eicosapentaenoic acid ethyl soft capsules. Example 3:

[0032] The peroxide value of the icosapentaenoic acid ethyl ester soft capsule samples was tested at 0 days and after the 1.5-month or 1-month accelerated stability test according to the peroxide value determination method specified in the General Chapter 0731 Fats and Fatty Oils Determination Method of the 2020 Edition of the Chinese Pharmacopoeia. The disintegration time limit of the samples was also tested according to the General Chapter 0921 Disintegration Time Test Method of the 2020 Edition of the Chinese Pharmacopoeia. After the 3-month accelerated stability test and the 3-month long-term stability test, the samples of icosapentaenoic acid ethyl ester soft capsules were tested for fogging, whitening, and precipitation. The above experimental results are shown in Table 2 below; Table 2 Experimental results of eicosapentaenoic acid ethyl ester soft capsules

[0033] Among them, the accelerated test conditions are: temperature 40℃±2℃, relative humidity 75%±5%; the long-term test conditions are: temperature 25℃±2℃, relative humidity 60%±10%; From the above experimental results, the following conclusion can be drawn: Combining the regulatory means of reducing the glycine ratio with the technical improvement means of implementing anti-cross-linking treatment on gelatin can achieve the beneficial technical effect of simultaneously reducing the risk of disintegration time and glycine precipitation during the stability period. Experimental Example 1:

[0034] Monosuccinic anhydride succinate-based reagent: The acyl chloride functional group of monoethyl succinate chloride undergoes a nucleophilic substitution reaction with the highly nucleophilic hydroxyl functional group in L-malic acid, and the activation of monoethyl succinate chloride promotes the dehydration reaction of the two carboxylic acid functional groups of L-malic acid to generate a monosuccinic anhydride succinate-based reagent; The experimental steps for synthesizing the monosuccinic anhydride succinate-based reagent are as follows: 13.4 g of L-malic acid and 30 mL of succinic acid monoethyl chloride are heated to 80° C. and stirred for 5 h. Unreacted products are removed by rotary evaporation. 100 mL of petroleum ether / chloroform (V / V=3 / 1) is added. The mixture is allowed to stand for precipitation and filtered. The filter cake is washed with petroleum ether and dried to obtain the monosuccinic anhydride succinate-based reagent. Its chemical structure is: ; The hydrogen spectrum characterization results of the monosuccinic anhydride succinate-based reagent are: 1 H NMR (400MHz, CDCl3, δ, ppm): 6.19-6.22 (t, 1H), 4.09-4.13 (m, 2H), 2.95-3.25 (m, 2H), 2.60-2.75 (m, 4H), 1.20-1.23 (t, 3H). Experimental Example 2:

[0035] Monosuccinic anhydride succinic acid citrate reagent: Equal molar amounts of triethyl citrate and succinyl chloride undergo a nucleophilic substitution reaction between the hydroxyl functional group and the acyl chloride functional group to obtain a tetraester chloride monomer; The acyl chloride functional group of the tetraester chloride monomer undergoes a nucleophilic substitution reaction with the hydroxyl functional group in L-malic acid, and the activation of the tetraester chloride monomer promotes the dehydration reaction of the two carboxylic acid functional groups of L-malic acid to generate a monosuccinic anhydride succinic acid citrate reagent; The experimental steps for synthesizing monosuccinic anhydride succinic acid citrate reagent are: 22 mL of triethyl citrate, 10 mL of succinyl chloride and 12.5 mL of triethylamine were heated to 45°C and stirred for reaction for 5 h. Unreacted succinyl chloride was removed by distillation under reduced pressure, and the mixture was washed with deionized water and dried to obtain a tetraester chloride monomer. 4 g of L-malic acid, 23.65 g of tetraester chloride monomer and 60 mL of N,N-dimethylformamide were heated to 90°C and stirred for reaction for 5 h. The mixture was distilled under reduced pressure. 100 mL of petroleum ether / chloroform (V / V=3 / 1) was added to the crude product, and the mixture was allowed to stand for precipitation. The mixture was filtered, and the filter cake was washed with petroleum ether and dried to obtain a monosuccinic anhydride succinic acid citrate reagent having the chemical formula: ; The hydrogen spectrum characterization results of the monosuccinic anhydride succinic acid citrate reagent are as follows: 1 H NMR (400MHz, CDCl3, δ, ppm): 6.15-6.17 (t, 1H), 4.19-4.23 (m, 2H), 4.04-4.08 (m, 4H), 2.95-3.29(m, 6H), 2.65-2.76(m, 4H), 1.25-1.27(t, 3H), 1.15-1.17(t, 6H). Experimental Example 3:

[0036] Succinate plasticized anti-crosslinking gelatin: Using a monosuccinic anhydride succinate-based reagent as an acylating agent, the succinic anhydride functional group of the acylating agent reacts with the amino functional group in gelatin to produce succinate plasticized anti-crosslinking gelatin; The experimental steps for preparing succinate-plasticized anti-cross-linking gelatin are as follows: Rousselot gelatin (model 150 LB 8) is mixed with distilled water to prepare a gelatin solution (the mass ratio of gelatin to distilled water is 1:5), placed in a constant temperature heated magnetic stirrer, stirred at 45°C to dissolve it, and after complete dissolution, taken out and cooled to room temperature, the pH value is adjusted to 9.5 with 1 mol / L sodium hydroxide solution, and a monosuccinic anhydride succinate-based reagent is added (the mass ratio of monosuccinic anhydride succinate-based reagent to gelatin is 1:8). 1 mol / L sodium hydroxide solution is added dropwise to stabilize the pH value at 9.5, and the temperature is raised to 45°C and stirred for 2 hours. The solution is transferred into a dialysis bag and dialyzed in distilled water for 48 hours. After dialysis is completed, the solution is taken out and air-dried at 40°C to constant weight to obtain succinate-plasticized anti-cross-linking gelatin. Experimental Example 4:

[0037] Succinic acid citrate plasticized anti-crosslinking gelatin: Succinic acid citrate plasticized anti-crosslinking gelatin is prepared by acylation reaction of the succinic anhydride functional group of the monosuccinic anhydride succinic acid citrate reagent with the amino functional group in gelatin; The experimental steps for preparing succinic acid citrate plasticized anti-crosslinking gelatin differ from those for preparing succinate plasticized anti-crosslinking gelatin only in that a monosuccinic anhydride succinic acid citrate reagent is used instead of a monosuccinic anhydride succinate-based reagent.

Claims

1. An eicosapentaenoic acid ethyl ester soft capsule, characterized in that: Eicosapentaenoic acid ethyl ester soft capsules are composed of contents and capsule shell; The prescription composition of the contents is icosapentaenoic acid ethyl ester and vitamin E; The capsule shell formulation consists of anti-cross-linking gelatin, glycerol, sorbitol, glycine and water, and the corresponding mass ratio of the formulation is 1:(0.15-0.2):0.2:(≤0.01):(0.9-1.056).

2. The eicosapentaenoic acid ethyl ester soft capsule according to claim 1, wherein The anti-cross-linked gelatin is one of succinate plasticized anti-cross-linked gelatin, succinate citrate plasticized anti-cross-linked gelatin, BB 180 / 08 RXL type Gelita gelatin, and 180 AB 8 ST type Rousselot gelatin.

3. The eicosapentaenoic acid ethyl ester soft capsule according to claim 2, wherein Succinate-plasticized cross-link-resistant gelatin is prepared by acylation of the succinic anhydride functional groups of a monosuccinic anhydride acylating reagent with the amino functional groups of 150 LB Rousselot gelatin type 8. The chemical formula of the monosuccinic anhydride succinate-based reagent is: 。 4. The eicosapentaenoic acid ethyl ester soft capsule according to claim 3, characterized in that: The preparation method of the monosuccinic anhydride succinate-based reagent comprises the following steps: a nucleophilic substitution reaction occurs between the acyl chloride functional group of monoethyl succinate chloride and the strongly nucleophilic hydroxyl functional group in L-malic acid, and the activation of the monoethyl succinate chloride promotes a dehydration reaction of two carboxylic acid functional groups of the L-malic acid to generate the monosuccinic anhydride succinate-based reagent.

5. The eicosapentaenoic acid ethyl ester soft capsule according to claim 2, characterized in that: Succinic acid citrate plasticized anti-crosslinking gelatin is prepared by acylation reaction of the succinic anhydride functional groups of the acylating reagent monosuccinic anhydride succinic acid citrate reagent with the amino functional groups of 150LB Rousselot gelatin type 8; The chemical formula of monosuccinic anhydride succinic acid citrate reagent is: 。 6. The eicosapentaenoic acid ethyl ester soft capsule according to claim 5, characterized in that: The preparation method of monosuccinic anhydride succinic acid citrate reagent is: The same molar amount of triethyl citrate and succinyl chloride undergoes a nucleophilic substitution reaction between the hydroxyl functional group and the acyl chloride functional group to obtain an acyl chloride tetraester monomer; The acyl chloride functional group of the tetraester chloride monomer undergoes a nucleophilic substitution reaction with the strongly nucleophilic hydroxyl functional group in L-malic acid, and the activation of the tetraester chloride monomer promotes the dehydration reaction of the two carboxylic acid functional groups of L-malic acid to generate a monosuccinic anhydride succinic acid citrate reagent.

7. The eicosapentaenoic acid ethyl ester soft capsule according to claim 1, characterized in that: The eicosapentaenoic acid ethyl ester soft capsule consists of 70-90wt% of content and 10-30wt% of capsule shell.

8. The eicosapentaenoic acid ethyl ester soft capsule according to claim 1, characterized in that: The mass ratio of eicosapentaenoic acid ethyl ester to vitamin E in the content prescription is 1:(0.001-0.003).

9. The preparation process of an eicosapentaenoic acid ethyl ester soft capsule according to any one of claims 1 to 8, characterized in that: The following steps are involved: Step 1, preparation of the contents: according to the prescribed amount of the contents, under nitrogen protection, add vitamin E to ethyl eicosapentaenoate, and stir evenly at room temperature to obtain the contents; Step 2, sol preparation: weigh purified water and heat it in a sol tank. When the temperature of the purified water reaches 55-65°C, add glycerin and stir evenly, then add sorbitol and glycine. Continue to heat it to 80-90°C and add gelatin. Stir until the gelatin is completely melted into a gelatin solution. After vacuum degassing, let it stand at a constant temperature of 50-60°C for later use. Step 3: The contents and the sol are passed through a soft capsule press to prepare soft capsules to obtain eicosapentaenoic acid ethyl ester soft capsules.

10. The eicosapentaenoic acid ethyl ester soft capsule according to any one of claims 1 to 8, characterized in that: Eicosapentaenoic acid ethyl ester soft capsules are used as an auxiliary drug for clinical statin treatment.

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