Menadione soft capsule and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and discloses a menadione soft capsule and a preparation method thereof, the capsule comprises a capsule shell and a content filled in the capsule shell, the content comprises the following substances by weight: 12%-20% of menadione, 25%-38% of a surfactant, and the balance of an oily solvent; the capsule shell comprises the following substances in percentage by weight: 30%-35% of a film-forming agent, 12.75%-17% of a plasticizer, 15%-18% of an enteric-coated material, 2%-4% of a metal ion chelating agent, 0.1%-1.0% of a pH regulator, 0.2%-0.8% of an opacifying agent, 0.05%-0.1% of a coloring agent and the balance of purified water; the metal ion chelating agent is aspartic acid; the film-forming agent is a composition of sodium alginate and gelatin. According to the scheme, the menadione enteric soft capsule has enteric solubility and excellent preparation property, can be dissolved in acid under the condition that the menadione enteric soft capsule is not dissolved in weak base, and is beneficial to improving absorption of menadione in small intestines, so that the bioavailability is improved; and the crosslinking phenomenon in the long-term storage process can be reduced, so that the long-term storage of the product is facilitated.

Description

TECHNICAL FIELD

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

[0002] Tetraenyl menadione is a compound with naphthoquinone structure, which is yellow to light yellow oily liquid or low melting point solid, insoluble in water, soluble in organic solvents and vegetable oil, heat-resistant but easy to be destroyed by light; due to its quinone structure, it may undergo acid-base catalytic reaction under acidic or basic conditions, resulting in its decomposition or conversion into other compounds. Clinical studies have shown that tetraenyl menadione has osteogenesis effect, promotes calcium metabolism, and can also inhibit bone resorption caused by osteoclasts, thereby increasing bone density and preventing and treating osteoporosis. According to its drug properties (tetraenyl menadione has the characteristics of light decomposition) and the marketed dosage form, a soft capsule is developed. The capsule shell is a unique component of soft capsule preparation, which can effectively isolate the drug from external air or water vapor, protect the drug in the soft capsule, and make it more stable. Since the absorption site of tetraenyl menadione in the body is the end of the small intestine, the development of enteric soft capsules has a certain targeting effect, which can avoid the premature disintegration and release of tetraenyl menadione soft capsules in the stomach, leading to the degradation of tetraenyl menadione under the action of gastric acid. However, there is a serious problem with soft capsule preparations, that is, as the storage time is prolonged, the gelatin in the capsule shell will age and cause cross-linking, resulting in prolonged disintegration time or slow or even no release of the drug in the capsule.

[0003] Chinese patent CN101467983A discloses a tetraenyl menadione soft capsule and a preparation method thereof, and the composition of the drug solution is: tetraenyl menadione: vegetable oil: cosolvent: preservative = 1:10-30:0.1-0.5:0.01-1; wherein the cosolvent is Tween 80 and / or Tween 60; the vegetable oil is selected from one or more of corn oil, soybean oil, peanut oil and tea oil; the preservative is selected from one or more of hydroxybenzoic acid ester, hydroxybenzoic acid ethyl ester and hydroxybenzoic acid propyl ester. The composition of the capsule shell material is gelatin: glycerol: sorbitol: water: titanium dioxide: lemon yellow = 0.8-1.2:0.2-0.4:0.15-0.35:0.8-1.2:0.01-0.05:0.001-0.003, and the composition of the capsule shell is all conventional soft capsule shell materials. This scheme uses Tween 80 and / or Tween 60 as a cosolvent, which has the risk of hemolysis; uses hydroxybenzoic acid ester, hydroxybenzoic acid ethyl ester and hydroxybenzoic acid propyl ester as a preservative, which can cause allergic reactions, such as dermatitis, and has certain harmfulness to the human body.

[0004] Chinese patent CN103655510A discloses a tetraenyl menadione soft capsule and a preparation method thereof. The composition of the medicine liquid comprises tetraenyl menadione, vegetable oil and a solubilizing agent, wherein the vegetable oil is selected from one of sesame oil, corn oil, peanut oil, soybean oil, almond oil, peach kernel oil, cottonseed oil, sunflower seed oil and olive oil; the solubilizing agent is one or more of Span 20, Span 60, Span 80, glyceryl monobehenate, glyceryl monolinoleate, propylene glycol monooctanoate, propylene glycol monolaurate, glyceryl monooleate, high-purity diethylene glycol monoethyl ether, linoleic acid polyethylene glycol-6 glyceride, lauric acid polyethylene glycol-6 glyceride, medium-chain triglyceride, caprylic capric glyceride, caprylic capric propylene glycol ester, propylene glycol fatty acid ester, polyglyceryl oleate and oleic acid polyethylene glycol glyceride. The composition of the capsule shell comprises gum, plasticizer, water and light shielding agent, and the prescription of the capsule shell is the conventional soft capsule shell material. The capsule shell material of the scheme adopts the conventional soft capsule shell material, so that cross-linking of the capsule shell occurs during long-term storage, which has certain influence on the quality of the product.

[0005] In summary, the gelatin in the capsule shell will age and cause cross-linking during long-term storage, and the preservatives and solubilizing agents used will cause adverse reactions of the capsule medicine. SUMMARY

[0006] The present application aims to provide a tetraenyl menadione soft capsule with excellent anti-crosslinking performance and precise enteric properties, and a preparation method thereof, so as to solve the technical problems that the capsule shell is prone to cross-linking during long-term storage, which causes the disintegration time to be prolonged or the medicine in the capsule to be released slowly or even unable to be released.

[0007] To achieve the above-mentioned purpose, the present application adopts the following technical scheme: a tetraenyl menadione soft capsule, comprising a capsule shell and contents filled in the capsule shell, wherein the contents comprise the following substances by weight percentage: 12%-20% of tetraenyl menadione, 25%-38% of a surfactant, and the balance of an oily solvent; the capsule shell comprises the following substances by weight percentage: 30%-35% of a film-forming agent, 12.75%-17% of a plasticizer, 15%-18% of an enteric material, 2%-4% of a metal ion chelating agent, 0.1-1.0% of a pH regulator, 0.2%-0.8% of a light shielding agent, 0.05%-0.1% of a coloring agent, and the balance of purified water; the metal ion chelating agent is aspartic acid; and the film-forming agent is a combination of sodium alginate and gelatin.

[0008] The key process for preparing the same is as follows: firstly, a proper amount of purified water is used to fully dissolve aspartic acid so as to uniformly disperse the same in the solution system, thereby maximizing the chelation of metal ions. Subsequently, enteric material, plasticizer, pH regulator, light shielding agent, colorant and the remaining purified water are added by means of stepwise addition, so as to promote the rapid and uniform diffusion and distribution of the above-mentioned auxiliary materials, especially the metal ion chelator, in the whole gel solution system. The scheme lies in using aspartic acid as a chelator to effectively complex metal ions in the solvent system, preventing the cross-linking reaction of gelatin catalyzed by the metal ions, thereby avoiding the influence of the excessively long disintegration time of the capsule shell on the normal release and curative effect of the drug. In addition, the inventor optimizes the dissolution performance of the soft capsule by precisely regulating the addition ratio of the enteric material in the prescription, so that the soft capsule can meet the strict enteric dissolution standard: not disintegrated in artificial gastric juice (pH 1.2) for 2 hours, but disintegrated in artificial intestinal juice (pH 6.8) within 1 hour. In summary, the tetramethylphenazinium soft capsule prepared by the scheme not only effectively solves the problem of slow disintegration caused by the cross-linking of gelatin, but also has reliable enteric protection function, thereby ensuring the timely release of the drug at the target site.

[0009] Preferably, the surfactant is one or more of propylene glycol laurate and propylene glycol dicaprylate. Propylene glycol laurate is a monoester formed by esterification of propylene glycol (hydrophilic part) and lauric acid (hydrophobic part). Its molecular structure has a clear hydrophilic head (hydroxyl group) and a hydrophobic tail (lauric acid chain). The hydrophilic end (propylene glycol group) and the hydrophobic end (lauric acid chain) can be adsorbed at the oil-water interface, reducing the interfacial tension, increasing the solubility of oil-soluble ingredients, and improving the uniformity of the formula. Propylene glycol dicaprylate is a diester formed by esterification of propylene glycol and two caprylic acids (8-carbon fatty acids). It has strong hydrophobicity, and the hydrophilic end is covered by an ester bond, making it more oil-loving. Due to its weak amphiphilicity due to the diester structure, it is mainly used as an oil phase regulator to optimize the formula in terms of solubility and compatibility, improving texture and stability. The use of both can also achieve amphiphilicity through the ester bond and carbon chain structure in the molecule, increasing the solubility of oil-soluble ingredients and improving their stability.

[0010] Preferably, the oily solvent is glyceryl monooleate, which is highly safe, dissolves fat-soluble substances, promotes solution emulsification, prevents oil-water separation, and maintains the stability of the solution system; it can promote drug solvents and improve bioavailability.

[0011] Preferably, the ratio of sodium alginate and gelatin is 2:5. Sodium alginate is a natural anionic polysaccharide, which forms a film through intermolecular hydrogen bonding and ionic cross-linking. The film has the advantages of compactness, good oxygen barrier property, transparency and good biocompatibility, but also has the disadvantages of brittleness, poor flexibility, easy to absorb moisture and swell in high humidity environment, and strength decline. Gelatin is a water-soluble protein obtained by partial hydrolysis of collagen. It forms a film through heat-reversible gelation and conformational transformation, intermolecular hydrogen bonding or van der Waals force. The film has the advantages of good flexibility, high gloss, good oxygen barrier property, excellent biocompatibility and biodegradability, but also has the disadvantages of low mechanical strength, strong hydrophilicity, poor moisture resistance, and easy to absorb water and become soft. The combination of sodium alginate and gelatin does not simply add up the properties, but produces a synergistic effect through molecular-level interaction. The two form a film through electrostatic attraction or intermolecular interaction such as hydrogen bonding and functional complementation, overcoming the limitations of single material, especially in mechanical properties, barrier property, biocompatibility and functional adjustability.

[0012] Preferably, the plasticizer is a combination of glycerol, sorbitol and triethyl citrate, and the ratio of glycerol, sorbitol and triethyl citrate is 3:1:0.25. Glycerol and sorbitol are commonly used plasticizers in soft capsules. Glycerol has strong hydrophilicity but is prone to migration; sorbitol has good moisturizing property but limited solubility; triethyl citrate is hydrophobic but has poor compatibility. Each of them has obvious defects when used alone, such as using only glycerol will cause the soft capsule shell to become brittle over time, and using only triethyl citrate will result in poor flexibility. The combination of the three has a synergistic effect. Glycerol provides immediate flexibility, sorbitol provides stronger combination with gelatin, providing medium and long-term support, and achieving more balanced strength and elasticity; sorbitol and triethyl citrate have lower migration, which can jointly lock glycerol, improving the stability of soft capsules during shelf life; effectively solving the common problems of soft capsules in storage such as "hardening, cracking and leakage" of the shell.

[0013] Preferably, the pH regulator is citric acid, and the pH value is 4.5-6.8. As a polybasic organic acid, citric acid mainly plays a role in pH adjustment and metal chelation in soft capsule formulations. It can adjust the pH value of the glue solution to optimize the process; in an acidic environment, the amino groups in the gelatin molecules are protonated and cannot undergo condensation with aldehyde groups, thereby preventing gelatin crosslinking reactions and improving the stability of soft capsules during shelf life. As a chelating agent, it can also chelate metal ions, especially Fe 3+ , Cu 2+ , etc. from water or raw materials, preventing oxidation reactions between these ions and the contents, thereby improving the stability of the formulation.

[0014] Preferably, the enteric material is one or more of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate and cellulose acetate phthalate.

[0015] Preferably, the light shielding agent is calcium carbonate, and the colorant is sunset yellow. Calcium carbonate is safe and low in cost.

[0016] To achieve the above object, the present application also provides a preparation method of tetraenemenaquinone enteric soft capsules, comprising: (1) dissolving the sol: add the prescription amount of 85% purified water into the gelatinizing tank and heat to 80-100°C, add the prescription amount of aspartic acid, and after the above materials are completely dissolved, add the prescription amount of sodium alginate, enteric material, plasticizer, pH adjuster, light shielding agent, colorant and the remaining amount of purified water, and cool to 70-77°C, and after the temperature is stable, add the capsule gelatin; after the gelatin is completely dissolved, start vacuumizing, the vacuum degree is -0.06 to -0.09 MPa, keep the gel liquid boiling without overflowing, until the gel liquid has no obvious bubbles, stop stirring, turn off the vacuum, and keep at 55-60°C for standby; (2) liquid preparation: uniformly disperse the prescription amount of tetraenemenaquinone, oil solvent and surfactant, and keep standby; (3) pill pressing: control the light in the preparation room to be yellow light, the temperature to be 18-22°C, and the humidity to be less than 50%; the temperature of the gelatin box is 55-60°C, and the temperature of the spraying body is 39-43°C; adjust and control the thickness of the gelatin to be kept at 0.70-0.85 mm, and the content is automatically filled to press the gelatin pills; (4) shaping and drying: dry and shape the soft capsules after being pressed into pills, the shaping time is 2-3 h; continue to dry the shaped soft capsules, control the temperature to be kept at 22-28°C, and control the humidity to be kept below 40%, and dry for 10-12 h to obtain tetraenemenaquinone enteric soft capsules.

[0017] Preferably, the dispersion speed in step (2) is 400-500 rpm, the water bath temperature is 22-35°C, and the time is 15-25 minutes.

[0018] The tetraenemenaquinone enteric soft capsules prepared by the preparation method have a multi-level stabilization and functionalization system constructed through precise cooperation of prescription design, material selection and process control, and have the following advantages: 1) aspartic acid is used as a metal ion chelating agent to selectively chelate metal ions to avoid the reaction of metal ions with oil esters to produce aldehydes, thereby cutting off the gelatin crosslinking reaction from the source; at the same time, citric acid is used as a pH adjuster and metal chelating agent to make the gelatin protonated under acidic conditions and lose the ability to react with aldehydes; in the aspect of chelation, aspartic acid forms a synergistic complement to establish a double defense line and actively inhibit gelatin crosslinking.

[0019] 2) By compounding different properties of film-forming agents and plasticizers, the ability of the capsule shell to resist cross-linking is structurally enhanced. The film-forming agent is compounded to form a rigid-flexible interpenetrating network, sodium alginate provides rigidity and high oxygen / water resistance, and the triple helix structure of gelatin provides elasticity and bioadhesion; this composite structure is more compact, stronger and more thermally stable than a single gelatin structure, providing a more robust physical barrier for the contents. The plasticizer compounding is a gradient plasticizing and stabilizing combination, glycerol provides immediate flexibility, sorbitol provides medium-term support and locks in moisture through strong hydrogen bonding of multiple hydroxyl groups, and hydrophobic triethyl citrate not only migrates slowly itself, but also reduces the overall hydrophilicity of the gel skin, reducing stress caused by moisture fluctuations, and improving compatibility with oily contents. The three work together to ensure that the mechanical properties of the gel skin are stable over the entire shelf life, avoiding embrittlement caused by plasticizer migration and volatilization.

[0020] 3) Directly adding enteric material to the gel solution to make the enteric material embedded in the gel skin to achieve soft capsule enteric positioning, rather than enteric coating of the soft capsule, to avoid appearance defects such as "roughness, pitting, spots, delamination, even peeling, and dented shell" after coating the soft capsule, which in turn affects dissolution consistency and therapeutic reproducibility, and even affects commodity value.

[0021] In summary, the tetraenemenaquinone enteric soft capsules prepared by the preparation method of the present application have superior enteric and formulation properties, and are insoluble in acid and weakly soluble under alkaline conditions, which is beneficial to improve the absorption of tetraenemenaquinone in the small intestine and thus improve the bioavailability; and cross-linking phenomenon during long-term storage is avoided as much as possible, which is beneficial to long-term storage of the product. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The following are dissolution curve results of Examples 1-3 of the present application.

[0023] Figure 2 The following are chromatograms of the content determination of the test sample of the present application. DETAILED DESCRIPTION

[0024] The following will be further described in detail through specific embodiments: The materials used in the following examples can be selected but are not limited to: Aspartic acid (batch number 082508271) was purchased from Yuanda Bafeng (Hubei) Pharmaceutical Co., Ltd.; gelatin (batch number 3596177) was purchased from Rousselot (Da'an) Gelatin Co., Ltd.; sodium alginate (batch number 04172503) was purchased from Qingdao Mingyue Algae Group Co., Ltd.; glycerol (batch number 20250611) was purchased from Nanchang Baiyun Pharmaceutical Co., Ltd.; sorbitol (batch number F303C240501) and citric acid (batch number F3010250401) were both purchased from Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.; triethyl citrate (batch number Y57241215-1) was from Bengbu Fengyuan Tushan Pharmaceutical Co., Ltd.; sunset yellow (batch number 12224030) was purchased from Nantong Branch of Shanghai Dyestuff Research Institute Co., Ltd.; tetraene Menaquinone (batch number 910250501) was purchased from Shandong New Era Pharmaceutical Co., Ltd.; propylene glycol laurate (batch number 205237) and glyceryl monooleate (batch number 205434) were both purchased from Guangzhou Tianrun Pharmaceutical Co., Ltd.; propylene glycol dioctanoate (batch number 5989) was purchased from Haibo (Shanghai) Pharmaceutical Technology Co., Ltd.; calcium carbonate (022504003), hydroxypropyl methylcellulose phthalate (batch number B0222055022), hydroxypropyl methylcellulose acetate succinate (batch number 0124LG001), and cellulose acetate ester (batch number 022401005) were all from Luofu Pharmaceutical Technology (Shanghai) Co., Ltd.; hydroxypropyl methylcellulose (batch number TF20250515) was from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.

[0025] The equipment used in the experiment was: Agilent 1260 high performance liquid chromatograph (Agilent Technologies, Inc.); YWJ100-Ⅱ fully automatic soft capsule machine (Xinhangcheng Shangjie (Langfang) Technology Development Co., Ltd.); ZB-1D intelligent disintegration analyzer (Tianjin University Precision Instrument Factory); MS16001LE electronic balance (METTLER TOLEDO); EU50 electric stirrer (Shanghai Fluke Technology Development Co., Ltd.); FADT-1202 automatic dissolution analyzer (Shanghai Fucos Analytical Instruments Co., Ltd.); DV2TRVTJ0 rotational viscometer (AMETEK BROOKFIELD).

[0026] 1) Screening of aspartic acid dosage in rubber formulation While keeping the film-forming agent, plasticizer, opacifier, colorant, and purified water constant, the amount of aspartic acid was screened based on indicators such as rubber elasticity, adhesive viscosity, and disintegration time, as shown in Table 1; the results are shown in Tables 2 and 3.

[0027] Disintegration time limit inspection method: according to the 2020 edition of the Chinese Pharmacopoeia, the basket is suspended on the support through the upper end of the stainless steel shaft, immersed in a 1000 ml beaker, the basket position is adjusted so that the sieve is 25 mm away from the bottom of the beaker when it is lowered to the low point, the beaker contains water with a temperature of 37°C ± 2°C, the water level is adjusted so that the sieve is at a place 15 mm below the water surface when the basket is raised to the high point, the top of the basket cannot be immersed in the solution. Take 6 test samples, operate according to the above instrument device and inspection method, start the disintegration instrument for inspection, each particle should completely disintegrate within 1 hour.

[0028] Table 1 aspartic acid dosage screening Material Name Formulation 1 Formulation 2 Formulation 3 Formulation 4 Aspartic Acid 7.5 6 4.5 3 Gelatin 214.3 214.3 214.3 214.3 Sodium Alginate 85.7 85.7 85.7 85.7 Glycerin 72 72 72 72 Sorbitol 24 24 24 24 Triethyl Citrate 6 6 6 6 Calcium Carbonate 2.25 2.25 2.25 2.25 Sunset Yellow 0.3 0.3 0.3 0.3 Purified Water 300 300 300 300 According to the prescription in Table 1, about 85% of the purified water is added to the gelatinizing tank, heated to 95°C, and the prescribed amount of aspartic acid is added. After the aspartic acid is completely dissolved, the prescribed amount of sodium alginate, glycerol, sorbitol, triethyl citrate, calcium carbonate, sunset yellow and the remaining purified water are added, and the temperature is lowered to 75°C. After the temperature is stable, the gelatin for capsules is added. After the gelatin is completely dissolved, vacuum is started. The vacuum degree is -0.08 MPa. The gel liquid is kept boiling without overflowing until there are no obvious bubbles in the gel liquid. Then stop stirring and turn off the vacuum. Keep the temperature at 58°C. Then the above gel liquid is prepared into soft capsules by a soft capsule machine and dried for 10 hours. The obtained soft capsules are obtained.

[0029] Table 2 aspartic acid dosage screening results (1) Number Elasticity of the Rubber Viscosity of the Rubber / mPa-s Formulation 1 Good elasticity, moderate hardness 7320 Formulation 2 Good elasticity, moderate hardness 7500 Formulation 3 General elasticity, moderate hardness 7160 Formulation 4 General elasticity, moderate hardness 7080 The above prepared soft capsules are soaked in a 5% (W / V) formaldehyde aqueous solution for 45 seconds, then taken out, washed with purified water and dried in a well ventilated place. The disintegration time limit of each soft capsule is measured.

[0030] Table 3 aspartic acid dosage screening results (2) According to the experimental results in Tables 2 and 3, the disintegration time limit of the soft capsules treated by formaldehyde simulation cross-linking has obvious differences. When the amount of aspartic acid is 2.5% and 2% of the amount of film forming agent, i.e. prescription 1 and prescription 2, the soft capsules have obvious anti-crosslinking effect. When the amount of aspartic acid is 1.5% and 1% of the amount of film forming agent, i.e. prescription 3 and prescription 4, the anti-crosslinking effect of the soft capsules is obviously weakened. The results show that the soft capsules prepared by adding 2%-2.5% of the amount of film forming agent to the gelatin have good anti-crosslinking property.

[0031] 2) Screening of enteric material in gelatin formula Under the condition that the film forming agent, plasticizer, metal ion chelating agent, light shielding agent, coloring agent and purified water remain unchanged, the enteric material is screened according to the indicators of gelatin elasticity, gel viscosity and disintegration time limit, as shown in Table 4. The results are shown in Tables 5, 6 and 7.

[0032] Disintegration Time Test Method: According to the 2020 edition of the Chinese Pharmacopoeia, the basket is suspended on the support through the upper end of the stainless steel shaft, immersed in a 1000 ml beaker, the position of the basket is adjusted so that the mesh is 25 mm away from the bottom of the beaker when it is lowered to the low point, the beaker contains water with a temperature of 37°C ± 2°C, the water level is adjusted so that the mesh is at 15 mm below the water surface when the basket is raised to the high point, and the top of the basket cannot be immersed in the solution. Take 6 test samples, first check in hydrochloric acid solution (9→1000) without baffle for 2 hours according to the above test method, and each capsule shell should not have cracks or disintegration phenomenon; remove the basket, wash it with a small amount of water, then add a baffle to each tube, and then check in artificial intestinal fluid according to the above method. It should meet the requirements within 1 hour (the disintegration time of enteric-coated soft capsules is measured by this method below).

[0033] Table 4: Enteric-coated material screening Material Name Formulation 5 Formulation 6 Formulation 7 Formulation 8 Gelatin 25.7 25.7 25.7 25.7 Sodium Alginate 10.3 10.3 10.3 10.3 Glycerin 9 9 9 9 Sorbitol 3 3 3 3 Triethyl Citrate 0.75 0.75 0.75 0.75 Hydroxypropyl Methylcellulose Phthalate 13.9 — — — Hydroxypropyl Methylcellulose Acetate Succinate — 13.9 — — Cellulose Acetate Phthalate — — 13.9 — Hydroxypropyl Methylcellulose — — — 13.9 Aspartic Acid 1.5 1.5 1.5 1.5 Citric Acid 0.6 0.6 0.6 0.6 Purified Water 36 36 36 36 Prepare soft capsules according to the above prescription, and the preparation method is the same as that of the soft capsules in the "Aspartic Acid Dosage Screening" section and perform disintegration time test.

[0034] Table 5: Enteric-coated material screening results (1) Number Elasticity of the Rubber Viscosity of the Rubber / mPa-s Formulation 5 Good elasticity, moderate hardness 7320 Formulation 6 Good elasticity, moderate hardness 7500 Formulation 7 Good elasticity, moderate hardness 7760 Formulation 8 Good elasticity, moderate hardness 7880 Table 6: Enteric-coated material screening results (2) From the above experimental results of Table 5 and Table 6, it can be seen that the soft capsules added with hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate and cellulose acetate phthalate did not disintegrate within 2 hours in artificial gastric juice (pH 1.2), while 4 of the gelatin capsules added with hydroxypropyl methylcellulose completely disintegrated within 50 minutes, but 2 did not disintegrate. Therefore, adding hydroxypropyl methylcellulose alone to prepare gelatin capsules cannot meet the standard of enteric-coated soft capsules, and hydroxypropyl methylcellulose is not considered as an enteric-coated material. The soft capsules that did not disintegrate in artificial gastric juice (pH 1.2) for 2 hours in Formulations 5, 6 and 7 are first washed with purified water, and then the disintegration time is measured in artificial intestinal fluid (pH 6.8).

[0035] Table 7: Enteric-coated material screening results (3) Sample Formulation 5 Formulation 6 Formulation 7 1 24’42’’ 23’31’’ 25’31’’ 2 27’19’’ 26’23’’ 28’23’’ 3 29’45’’ 29’18’’ 32’18’’ 4 31’29’’ 32’51’’ 34’51’’ 5 33’05’’ 36’44’’ 36’21’’ 6 38’33’’ 39’38’’ 39’33’’ Average 30’49’’ 31’24’’ 32’49’’ From the above experimental results, it can be seen that the soft capsules added with hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate and cellulose acetate phthalate can completely disintegrate within 1 hour in artificial intestinal fluid (pH 6.8), indicating that these three materials can be added to the gelatin capsules as enteric-coated materials to prepare enteric-coated soft capsules.

[0036] 3) Screening of the amount of enteric material hydroxypropyl methylcellulose phthalate in the capsule shell formula The amount of hydroxypropyl methylcellulose phthalate was screened with the disintegration time as the index, while the film-forming agent, plasticizer, metal ion chelating agent, pH regulator, sunscreen, colorant, and purified water remained unchanged, as shown in Table 8; the results are shown in Tables 9 and 10.

[0037] Table 8 Screening of the amount of enteric material hydroxypropyl methylcellulose phthalate Material Name Formulation 9 Formulation 10 Formulation 11 Formulation 12 Gelatin 27.9 27.1 22.9 20 Sodium Alginate 11.1 10.9 9.1 8 Glycerin 9 9 6.6 9 Sorbitol 3 3 2.2 3 Triethyl Citrate 0.75 0.75 0.75 0.75 Hydroxypropyl Methylcellulose Phthalate 8 10 25 30 Aspartic Acid 1.5 1.5 1.5 1.5 Citric Acid 0.6 0.6 0.6 0.6 Purified Water 39 38 32 28 The soft capsules were prepared according to the above experimental formula, and the preparation method was the same as that in the “screening of the amount of aspartic acid” and the disintegration time was determined.

[0038] Table 9 Results of screening of the amount of enteric material hydroxypropyl methylcellulose phthalate (1) From the above experimental results, it can be seen that the soft capsules of formula 9 disintegrated in 1 hour in artificial gastric juice (pH 1.2), and the capsule shells of formulas 10, 11, and 12 did not disintegrate in 2 hours in artificial gastric juice (pH 1.2). Then, the soft capsules of formulas 10, 11, and 12 that did not disintegrate in artificial gastric juice (pH 1.2) were washed clean with purified water, and then their disintegration times were determined in artificial intestinal juice (pH 6.8).

[0039] Table 10 Results of screening of the amount of enteric material hydroxypropyl methylcellulose phthalate (2) From the above experimental results, it can be seen that when the amount of enteric material added is less than 10% of the capsule shell formula, the soft capsules disintegrate in artificial gastric juice (pH 1.2); when the amount of enteric material added is more than 25% of the capsule shell formula, the capsule shell does not disintegrate in artificial intestinal juice (pH 6.8); when the amount of enteric material added is between 10% and 25% of the capsule shell formula, it meets the requirements of not disintegrating in artificial gastric juice (pH 1.2) for 2 hours and disintegrating in artificial intestinal juice (pH 6.8) for 1 hour, so the capsule shell prepared when the amount of enteric material added is between 10% and 25% of the capsule shell formula meets the requirements for the preparation of enteric capsules. In this scheme, the amount of enteric material is adjusted to solve the problem of too fast disintegration after aspartic acid is added to improve the cross-linking resistance of the capsules, so that the prepared soft capsules have good cross-linking resistance and their disintegration time also meets the requirements for the use of drugs.

[0040] 4) Screening of the amounts of sodium alginate and gelatin in the capsule shell formula The ratio of sodium alginate and gelatin (1:5, 2:5, 3:5, 4:5) was screened with the appearance elasticity, viscosity, water permeability and disintegration time as indexes while keeping the plasticizer and purified water unchanged, as shown in Table 11; the results are shown in Table 12.

[0041] The water permeability test method adopts the cup method (weight gain method). First, the weight of distilled water and the beaker is precisely measured, then the gelatin film is sealed on the mouth of the high-humidity beaker containing distilled water, and the outside is a dry environment. Water vapor penetrates the film driven by the humidity difference, and the weight change of distilled water within 24 hours is recorded. The water vapor transmission amount is calculated according to the weight change of distilled water.

[0042] Table 11 Screening of sodium alginate and gelatin dosage According to the prescription in Table 11, the prescription amount of purified water, sodium alginate, glycerol, sorbitol, and triethyl citrate is added to the gelatinizing tank and the temperature is set to 75°C. Stirring is performed, and when the temperature reaches 75°C, gelatin is added. After the gelatin is completely dissolved, vacuum is started, with a vacuum degree of -0.08 MPa. The gel solution is kept boiling without overflowing until there are no obvious bubbles in the gel solution. Then, the stirring is stopped, the vacuum is turned off, and the temperature is kept at 60°C. After that, the above gel solution is prepared into soft capsules by a soft capsule machine and dried for 10 hours to obtain the soft capsules.

[0043] Table 12 Screening of sodium alginate and gelatin dosage Number Elasticity of the Shell Viscosity / mPa-s <![CDATA[Water permeability / g / (m 2 ·24 h)]]> Disintegration Time (n=6) / min 1 Good elasticity of the shell, moderate hardness 7670 66 8’28’’ 2 Good elasticity of the shell, moderate hardness 7550 37 8’15’’ 3 General elasticity of the shell, slightly hard 6500 30 10’30’’ 4 Poor elasticity of the shell, hard 5850 28 11’24’’ From the above experimental results, it can be seen that when the ratio of sodium alginate to gelatin is 1:5, the water permeability is high and the barrier performance is poor; when the ratio of sodium alginate to gelatin is 3:5 or 4:5, the hardness of the gelatin skin is large and the elasticity is general, affecting the appearance. Therefore, the ratio of sodium alginate to gelatin is selected as 2:5.

[0044] 5) Comparison of plasticizer dosage in gelatin skin The plasticizer is screened with the appearance elasticity, hardness, disintegration time and other indexes while keeping the film-forming agent and purified water unchanged, as shown in Table 13; the results are shown in Table 14.

[0045] Hardness test method: YD-20 type soft capsule hardness tester is used to test the hardness of soft capsules.

[0046] Table 13 Comparison of plasticizer dosage According to the prescription of Table 13, the prescription amount of purified water, sodium alginate, glycerol, sorbitol, triethyl citrate is added to the glue tank and the temperature is set to 75°C, stirring, when the temperature is 75°C, add gelatin; after the gelatin is completely dissolved, start vacuum, vacuum degree is -0.08Mpa, keep the glue liquid boiling without overflow, until the glue liquid has no obvious bubbles stop stirring, close the vacuum, 60°C incubation; then the above glue liquid is prepared by soft capsule machine and dried for 10 hours, the obtained soft capsules.

[0047] Table 14 Comparative study results of plasticizer dosage From the above experimental results, the plasticizing effect of the compounded plasticizer (appearance elasticity, hardness, disintegration time) is better than that of single glycerol, sorbitol and triethyl citrate.

[0048] Example 1: Content prescription composition: Ingredient Amount (by weight) Tetraenyl Menadione 12% Propylene Glycol Laurate 38% Glyceryl Monooleate 50% Capsule shell prescription composition: Ingredient Amount (by weight) Gelatin 25% Sodium Alginate 10% Glycerin 9% Sorbitol 3% Triethyl Citrate 0.75% Hydroxypropyl Methylcellulose Phthalate 10% Hydroxypropyl Methylcellulose Acetate Succinate 5% Aspartic Acid 2% Citric Acid 0.6% Calcium Carbonate 0.8% Sunset Yellow 0.05% Purified Water Balance (33.8%) The preparation method is as follows: 1) Content preparation: add the prescription amount of menadione to the prescription amount of lauric acid propylene glycol ester and glyceryl monooleate, use an electric mixer to disperse, speed 400 rpm, disperse in a 35°C water bath for 15 minutes, and obtain.

[0049] 2) Soft capsule preparation: ①Sol: add the prescription amount of about 85% purified water to the glue tank and heat to 85°C, add the prescription amount of aspartic acid, and then add the prescription amount of sodium alginate, glycerol, sorbitol, triethyl citrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, citric acid, calcium carbonate, sunset yellow and purified water, and cool to 75°C. After the temperature is stable, add gelatin; after the gelatin is completely dissolved, start vacuum, vacuum degree is -0.09Mpa, keep the glue liquid boiling without overflow, until the glue liquid has no obvious bubbles stop stirring, close the vacuum, 56°C incubation for standby.

[0050] ②Pill pressing: control the preparation room light to be yellow light, temperature 18~22°C, humidity less than 50%; glue box temperature is 56°C, spray body temperature is 40°C; adjust the control glue skin thickness to keep at 0.75~0.80mm, content automatic filling for glue pill pressing.

[0051] ③Drying: the soft capsules after being pressed into pills are sent into a rolling cage drying machine through a conveyor belt for shaping, the shaping time is 2 h; the shaped soft capsules continue to be dried. The temperature is controlled to be kept at 22-28°C, the humidity is kept below 40%, and the drying is performed for 12 h to obtain the menadiol sodium diphosphate enteric soft capsules.

[0052] Example 2: Content prescription composition: Ingredient Amount (by weight) Tetraenyl Menadione 20% Propylene Glycol Laurate 25% Glyceryl Monooleate 55% Capsule shell prescription composition Ingredient Amount (by weight) Gelatin 22.9% Sodium Alginate 9.1% Glycerin 10.5% Sorbitol 3.5% Triethyl Citrate 0.875% Hydroxypropyl Methylcellulose Phthalate 12% Hydroxypropyl Methylcellulose Acetate Succinate 6% Aspartic Acid 3% Citric Acid 1.0% Calcium Carbonate 0.5% Sunset Yellow 0.075% Purified Water Balance (30.55%) The preparation method is as follows: 1) Content preparation: the prescription amount of menadiol sodium diphosphate is added into the prescription amount of lauric acid propylene glycol ester and glyceryl monooleate, an electric mixer is used, the rotating speed is 450 rpm, and the dispersion is performed in a 28°C water bath for 20 minutes.

[0053] 2) Soft capsule preparation: ①Sol: the prescription amount of about 85% purified water is added into a gelatinizing tank, the temperature is increased to 95°C, the prescription amount of aspartic acid is added, after the aspartic acid is completely dissolved, the prescription amount of sodium alginate, glycerol, sorbitol, triethyl citrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, citric acid, calcium carbonate, sunset yellow and purified water are added, and the temperature is decreased to 73°C, after the temperature is stable, the gelatin is added; after the gelatin is completely dissolved, the vacuum is started, the vacuum degree is -0.08 Mpa, the gel liquid is kept boiling without overflowing, until the gel liquid has no obvious bubbles, the stirring is stopped, the vacuum is closed, and the temperature is kept at 55°C for standby.

[0054] ②Pill pressing: the light in the preparation room is controlled to be yellow light, the temperature is 18-22°C, and the humidity is below 50%; the temperature of the gelatin box is 55°C, the temperature of the spraying body is 43°C; the thickness of the gelatin is adjusted and controlled to be kept at 0.75-0.80 mm, the content is automatically filled, and the gelatin pill is pressed.

[0055] ③Drying: the soft capsules after being pressed into pills are sent into a rolling cage drying machine through a conveyor belt for shaping, the shaping time is 2.5 h; the shaped soft capsules continue to be dried. The temperature is controlled to be kept at 22-28°C, the humidity is kept below 40%, and the drying is performed for 11 h to obtain the menadiol sodium diphosphate enteric soft capsules.

[0056] Example 3: Content prescription composition: Ingredient Amount (by weight) Tetraenyl Menadione 18% Propylene Glycol Laurate 26% Propylene Glycol Dioctanoate 10% Glyceryl Monooleate 46% Capsule shell prescription composition: Ingredient Amount (by weight) Gelatin 23.6% Sodium Alginate 9.4% Glycerin 12% Sorbitol 4% Triethyl Citrate 1% Hydroxypropyl Methylcellulose Phthalate 11% Hydroxypropyl Methylcellulose Acetate Succinate 5% Aspartic Acid 4% Citric Acid 0.1% Calcium Carbonate 0.2% Sunset Yellow 0.1% Purified Water Balance (29.6%) The preparation method is as follows: 1) Content preparation: add the prescribed amount of menadione to the prescribed amount of lauric acid propylene glycol ester, propylene glycol dioctanoate, glyceryl monooleate, and disperse using an electric mixer at 500 rpm in a 22°C water bath for 25 minutes, to obtain the content.

[0057] 2) Soft capsule preparation: ① Sol: add the prescribed amount of about 85% purified water to a gelatinization kettle and heat to 100°C, add the prescribed amount of aspartic acid, and after the aspartic acid is completely dissolved, add the prescribed amount of sodium alginate, glycerol, sorbitol, triethyl citrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, citric acid, calcium carbonate, sunset yellow, and purified water, and cool to 77°C, and after the temperature is stable, add gelatin; after the gelatin is completely dissolved, start vacuumizing, the vacuum degree is -0.07 MPa, keep the gel boiling without overflowing until the gel is free of obvious bubbles, stop stirring, turn off the vacuum, and keep at 58°C for standby.

[0058] ② Pill pressing: control the light in the preparation room to be yellow light, the temperature to be 18-22°C, and the humidity to be less than 50%; the temperature of the gel box is 55°C, and the temperature of the spraying body is 42°C; adjust and control the thickness of the gelatin to be kept at 0.72-0.80 mm, and the content is automatically filled to press the gelatin pills.

[0059] ③ Shaping and drying: the soft capsules pressed into pills are conveyed into a rolling cage dryer to be shaped, the shaping time is 2.5 h; the shaped soft capsules are continuously dried. The temperature is controlled to be kept at 22-28°C, the humidity is controlled to be kept below 40%, and the drying time is 12 h to obtain the menadione enteric soft capsules of the present application.

[0060] The menadione enteric soft capsules prepared in Examples 1-3 are subjected to disintegration time limit and dissolution curve research, and the menadione enteric soft capsules prepared in Examples 1-3 are simply referred to as S1, S2, and S3, respectively. The results are shown in Tables 11, 12, and 13.

[0061] The dissolution curve method comprises: according to the 2020 edition of “Chinese Pharmacopoeia” 0931 dissolution and release determination method enteric preparation method 2, determining in-vitro dissolution, using 0.1 mol / L hydrochloric acid solution 900 mL as the dissolution medium, keeping the medium temperature constant at 37℃±0.5℃, taking 6 test samples and placing them in the sinker and then putting them into the dissolution cup, the rotation speed is 50 revolutions per minute, after 120 minutes, discarding the acid solution in the above-mentioned dissolution cup, immediately adding buffer solution 900 ml with a temperature of 37℃±0.5℃, the rotation speed is 50 revolutions per minute, the sampling time points are 0, 60 min, 120 min, 180 min, 240 min, 360 min, 480 min, each time taking 5 mL of sample, after sampling, filtering and determining according to the tetraenyl menadione content determination method, calculating the cumulative dissolution of tetraenyl menadione soft capsules at different time points, and drawing a dissolution curve.

[0062] Preparation of pH 1.2 solution: take 7.65 ml of hydrochloric acid, dilute with water to 1000 mL, shake well, and it is obtained.

[0063] Preparation of buffer solution: take 0.1 mol / L hydrochloric acid solution and 0.2 mol / L sodium phosphate solution, mix uniformly according to the volume ratio of hydrochloric acid solution to phosphoric acid solution 3:1, if necessary, adjust the pH value to 6.8 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution.

[0064] The tetraenyl menadione content determination method comprises: Chromatographic column: chromatographic column with octadecylsilane bonded silica gel as filler Flow: methanol Flow rate: 1.0 ml / min Column temperature: 35℃ Detection wavelength: 270nm Injection volume: 20μl.

[0065] According to the dissolution curve method, the test sample solution is obtained, and the content is determined by high performance liquid chromatography.

[0066] Table 11 Disintegration time limit results of examples 1-3 in simulated gastric acid (pH 1.2) medium After the soft capsules of examples 1-3 are taken out and washed clean with purified water in simulated gastric juice (pH 1.2), the disintegration time limit is determined in artificial intestinal juice (pH 6.8).

[0067] Table 12 Disintegration time limit results of examples 1-3 in artificial intestinal juice (pH 6.8) Sample S1 S2 S3 1 23’32’’ 25’11’’ 27’38’’ 2 28’14’’ 29’53’’ 30’26’’ 3 30’46’’ 33’18’’ 33’16’’ 4 34’21’’ 36’09’’ 36’40’’ 5 37’05’’ 39’42’’ 41’27’’ 6 40’33’’ 42’35’’ 44’39’’ Average 32’25’’ 34’28’’ 35’41’’ From the above results, the enteric soft capsules prepared in Examples 1-3 can not be disintegrated in artificial gastric juice (pH 1.2) for 2 hours, and can be completely disintegrated in artificial intestinal juice (pH 6.8) within 1 hour, which meets the requirements of the pharmacopoeia.

[0068] Table 13 Dissolution curve results of Examples 1-3 From the above Table 13 and Figure 1 It can be seen that the enteric soft capsules prepared in Examples 1-3 are not dissolved at pH 1.2 for 2 hours, and can be basically completely dissolved at pH 6.8 at 480 min.

[0069] The tetraenemenaquinone enteric soft capsules prepared in the above Examples 1-3 were subjected to stability study. Accelerated experiment was adopted, and the accelerated conditions were temperature 40℃±2℃ and relative humidity 75%±5% according to the “9001 Raw Materials and Preparation Stability Test Guiding Principles” in the fourth part of the Chinese Pharmacopoeia 2020 edition. Samples were taken at 0, 1, 2, 3 and 6 months, and the content of tetraenemenaquinone, disintegration time limit and dissolution were detected. The content determination chromatogram of the test sample is shown in Figure 2 The dissolution method refers to the dissolution curve method, the sampling time is 360 minutes, and the stability test results are shown in the following Table 14.

[0070] Table 14 Stability test results of Examples 1-3 From the above table and Figure 2 It can be seen that the three preparations of Examples 1-3 have good stability under accelerated conditions. Through content determination, related substances, disintegration time limit and 360 min dissolution detection, no degradation phenomenon was found under the accelerated condition of 6 months, and the dissolution and content had no obvious change, and each index met the requirements.

[0071] The tetraenemenaquinone enteric soft capsules of the application have enteric solubility and superior preparation properties. They are not dissolved in acid and are dissolved under weak alkali conditions, which is beneficial to improve the absorption of tetraenemenaquinone in the small intestine and thus improve the bioavailability. Moreover, no cross-linking phenomenon occurs during long-term storage, and the product can be stored for a long time.

[0072] In addition to the above examples, the surfactant in the present scheme can be selected from one or more of lauryl propylene glycol ester and propylene glycol dioctanoate.

[0073] In addition to the above examples, the enteric material in the present scheme can be selected from one or more of hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate and cellulose acetate phthalate.

[0074] In addition to the above examples, the surfactant in the present scheme can be selected from one or more of lauryl propylene glycol ester and propylene glycol dioctanoate. Other similar reagents and selection of similar reaction parameters can be determined by those skilled in the art according to common knowledge. The above-mentioned only are embodiments of the present application, and common knowledge of specific structures, properties and reactant ratios in the scheme are not described in detail herein. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, such as simply adjusting the selection of parameters within or near the specified parameter range. These should also be considered as the protection scope of the present application, and these will not affect the effect of the implementation and the practicability of the patent. The protection scope claimed in the present application should be subject to the content of the claims, and the specific implementation in the description can be used to explain the content of the claims.

Claims

1. A tetraene-menaquinone soft capsule, comprising a capsule shell and contents filled within the capsule shell, characterized in that, The contents comprise the following substances by weight percentage: tetraene-menaquinone 12%–20%, surfactant 25%–38%, and oily solvent balance; the shell comprises the following substances by weight percentage: film-forming agent 30%–35%, plasticizer 12.75%–17%, enteric material 15%–18%, metal ion chelating agent 2%–4%, pH adjuster 0.1%–1.0%, opacifier 0.2%–0.8%, colorant 0.05%–0.1%, and the balance being purified water; the metal ion chelating agent is aspartic acid; the film-forming agent is a composition of sodium alginate and gelatin.

2. The tetraene-menaquinone soft capsule according to claim 1, characterized in that: The surfactant is one or more of propylene glycol lauryl ester and propylene glycol dioctyl ester.

3. The tetraene-menaquinone soft capsule according to claim 1, characterized in that: The oily solvent is glyceryl monooleate.

4. The tetraene-menaquinone soft capsule according to claim 1, characterized in that: The ratio of sodium alginate to gelatin is 2:

5.

5. The tetraene-menaquinone soft capsule according to claim 1, characterized in that: The plasticizer is a composition of glycerol, sorbitol and triethyl citrate, wherein the ratio of glycerol, sorbitol and triethyl citrate is 3:1:0.

25.

6. The tetraene-menaquinone soft capsule according to claim 1, characterized in that: The pH adjuster is citric acid, with a pH value of 4.5-6.

8.

7. The tetraene-menaquinone soft capsule according to claim 1, characterized in that: The enteric material is one or more of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate.

8. The tetraene-menaquinone soft capsule according to claim 1, characterized in that: The opacifier is calcium carbonate, and the colorant is Sunset Yellow.

9. The method for preparing a tetraene-menaquinone soft capsule according to claim 1, characterized in that, include: (1) Sol: Add 85% of the prescribed amount of purified water to the gelling tank and heat it to 80~100°C. Add the prescribed amount of aspartic acid. After the above materials are completely dissolved, add the prescribed amount of sodium alginate, enteric material, plasticizer, pH adjuster, opacifier, colorant and the remaining purified water. Cool down to 70~77°C. After the temperature stabilizes, add the capsule gelatin. After the gelatin is completely dissolved, start vacuuming. The vacuum degree is -0.06~-0.09Mpa. Keep the gelatin boiling without overflowing. Stop stirring and turn off the vacuum when there are no obvious bubbles in the gelatin. Keep it warm at 55~60°C for later use. (2) Solution preparation: Disperse the prescribed amount of tetraene-menaquinone, oily solvent and surfactant evenly and set aside for later use; (3) Shot pressing: Control the lighting in the preparation room to be yellow light, the temperature to be 18~22℃, and the humidity to be less than 50%; the temperature of the glue box to be 55~60℃, and the temperature of the spray to be 39~43℃; adjust and control the thickness of the glue to be maintained at 0.70~0.85mm, and automatically fill the contents to press the glue into capsules; (4) Shaping and drying: The soft capsules after being pressed into pellets are dried and shaped for 2-3 hours. The shaped soft capsules are then dried further, with the temperature controlled at 22-28℃ and the humidity kept below 40%. After drying for 10-12 hours, tetraene-naphthoquinone enteric soft capsules are obtained.

10. The method for preparing a tetraene-menaquinone soft capsule according to claim 9, characterized in that: In step (2), the dispersion speed is 400-500 rpm, the water bath temperature is 22-35°C, and the time is 15-25 minutes.

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