A highly stable yanhuning injection and a preparation method thereof

Abstract

The invention discloses a highly stable indomethacin injection and a preparation method thereof, belonging to the field of pharmaceutical preparation technology, wherein indomethacin exists in the form of indomethacin microcapsules in the injection; the indomethacin microcapsules are water-in-oil-in-water type; the first capsule material of the indomethacin microcapsules is a complex of polylactic-co-glycolic acid copolymer and lactic acid, and the content of lactic acid accounts for 3-5% of the polylactic-co-glycolic acid copolymer; the second capsule material of the indomethacin microcapsules is hydroxypropyl-β-cyclodextrin. The present invention prepares the indomethacin active ingredient into water-in-oil-in-water type microcapsules, and the second capsule material selects hydroxypropyl-β-cyclodextrin with excellent water solubility, which overcomes the defect that the first capsule material polylactic-co-glycolic acid copolymer has poor water solubility. The quality stability of the indomethacin injection prepared by the present invention reaches a better level, which is of great significance for improving the safety performance of the clinical application of indomethacin injection.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparation, and particularly relates to a highly stable indomethacin injection and a preparation method thereof. Background Art

[0002] Yanhuning, molecular formula C 28 H 34 KNaO 10 ·H2O, chemical name 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinic acid half ester potassium sodium salt monohydrate. Yanhuning is a dehydrated andrographolide succinic acid half ester potassium sodium salt made by esterification, dehydration and salt formation of andrographolide, an extract of the plant Andrographis paniculata. It is the same substance as the active metabolite of Yanhuning in the body (Yanhuning is the monopotassium salt of andrographolide half ester). Yanhuning has the effects of clearing away heat and detoxification, and antiviral effects: 1. Clearing away heat and detoxification: Yanhuning has the effect of inhibiting fever caused by bacterial endotoxins, can make fever subside, and can fight against irritability caused by fever. 2. Anti-inflammatory effect: Yanhuning can fight against the increase in capillary permeability caused by chemical irritants xylene and human inflammatory mediator histamine, and can inhibit early increase in capillary permeability and inflammatory exudation and edema. 3. Antiviral effect: Mainly used for the treatment of viral pneumonia and viral upper respiratory tract infection.

[0003] In clinical practice, yanhuning is mostly used as an injection drug for the treatment of pneumonia and viral upper respiratory tract infections. However, yanhuning has poor stability in water and is easily hydrolyzed and oxidized, resulting in a certain degree of quality defects, which makes it very easy for yanhuning injection to deteriorate in quality during storage, affecting its clinical application.

[0004] In order to improve the stability of yanhuning injection in the prior art, antioxidants are usually added or yanhuning is microencapsulated. For example, a Chinese invention patent entitled "Yanhuning injection and its preparation method" (publication number CN105796484A) discloses that the present invention discloses a yanhuning injection, which is prepared from the following raw materials and auxiliary materials in weight volume percentage: yanhuning 0.05-0.1%, L-cysteine ​​0-0.02%, citric acid 0.001-0.02%, ethylenediaminetetraacetic acid 0-0.001%, tartaric acid 0.001-0.05%, sodium chloride 0.9%, and the balance is water. After the injection was stored at room temperature for 28 days, the main content reduction rate was 0.74%. The Chinese invention patent entitled "A drug microcapsule and a method for producing an injection thereof" (CN101278923A) uses microencapsulation technology to embed the active ingredient of indomethacin and provides a microcapsule injection with stable quality. However, the capsule material used is chitosan, which has low solubility in water. As a result, after being prepared into microcapsules, the water solubility of indomethacin in the injection solution will be reduced to a certain extent. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides an injectable yanhuning injection and a preparation method thereof, and yanhuning is embedded by microencapsulation technology to improve its stability.

[0006] The technical solution adopted by the present invention to solve the above technical problems is as follows:

[0007] The first aspect of the present invention discloses a highly stable indomethacin injection, in which indomethacin exists in the form of indomethacin microcapsules; the indomethacin microcapsules are of water-in-oil-in-water type; the first capsule material of the indomethacin microcapsules is a complex of polylactic acid-glycolic acid copolymer and lactic acid, and the content of lactic acid accounts for 3-5% of the polylactic acid-glycolic acid copolymer; the second capsule material of the indomethacin microcapsules is hydroxypropyl-β-cyclodextrin.

[0008] As a further preferred embodiment of the present invention, the content of inflammatory amine in the inflammatory amine microcapsules is 45.00-55.00 mg / mL; and the pH value is 6.5-7.0.

[0009] As a further preferred embodiment of the present invention, the pH regulator of the yanhuning injection is sodium hydroxide or citric acid.

[0010] As a further preferred embodiment of the present invention, every 100 g of water for injection contains 5 g of indomethacin, 1.2 g of citric acid and 0.027 g of sodium hydroxide.

[0011] The preparation method of the yanhuning microcapsules comprises the following steps:

[0012] S01, dissolving the prescribed amount of lindane in ultrapure water to prepare a lindane aqueous solution as an inner aqueous phase for standby use;

[0013] S02, dissolving polylactic acid-glycolic acid copolymer in dichloromethane and mixing evenly, adding lactic acid dropwise and stirring again to mix evenly, and the resulting mixed solution is used as an oil phase for standby use;

[0014] S03, dissolving hydroxypropyl-β-cyclodextrin in ultrapure water and stirring evenly to form an external water phase;

[0015] S04, slowly drop the inner water phase into the oil phase for shear emulsification, with a rotation speed of 5000-8000rpm and a shear time of 10-15s to form a W1 / O primary emulsion;

[0016] S05, adding the W1 / O primary emulsion dropwise into the external aqueous phase for secondary shear emulsification at a speed of 3000-4000 rpm and a shear time of 20-30 s to form a W1 / O / W2 emulsion;

[0017] S06, adding the W1 / O / W2 emulsion into a sodium chloride aqueous solution and stirring at room temperature, allowing the dichloromethane to evaporate, and then centrifuging to collect the microcapsules.

[0018] As a further preference of the present invention, the mass concentration of the polylactic acid-glycolic acid copolymer in the oil phase is 55-60%; the volume ratio of the inner aqueous phase to the oil phase is 1:5; the mass concentration of hydroxypropyl-β-cyclodextrin in the outer aqueous phase is 45%; and the volume ratio of the W1 / O primary emulsion to the outer aqueous phase is 2:(5-6).

[0019] The second aspect of the present invention discloses a method for preparing a highly stable yanhuning injection, comprising the following steps:

[0020] (1) Sodium hydroxide and citric acid are dissolved in ultrapure water to prepare sodium hydroxide solution and citric acid solution with a concentration of 10 wt.% respectively;

[0021] (2) adjusting the pH value of the solution to 6.40-6.80 using the sodium hydroxide solution and the citric acid solution;

[0022] (3) dissolving the prescribed amount of yanhuning microcapsules in the drug solution under stirring, and then adjusting the pH value to 6.60-7.00 again with sodium hydroxide aqueous solution and citric acid aqueous solution;

[0023] (4) Filtration, filling, and freeze-drying.

[0024] As a further preferred embodiment of the present invention, the freeze-drying process is as follows: pre-freeze at -40°C for 2-4 hours; evacuate, slowly heat to 20°C, maintain for 6-12 hours until the water line disappears; continue to heat to 35°C, maintain for 3-6 hours, and the freeze-drying is completed.

[0025] As a further preference of the present invention, the filtration process is as follows: adding the prescribed amount of activated carbon and adsorbing for 30 minutes; transferring the drug solution to a concentrated preparation tank, and then coarsely filtering it to a dilute preparation tank through a titanium rod and a 1.0 μm microporous filter element, sampling to inspect the intermediate properties, pH value, visible foreign matter, bacterial endotoxin and content, and sampling to check the bacterial content of the drug solution before filtration.

[0026] The specific testing standards for intermediate products are as follows:

[0027] Properties: Light yellow clear liquid;

[0028] pH value: 6.5-7.0;

[0029] Visible foreign matter: Take 20mL of the solution for inspection, there should be no visible foreign matter;

[0030] Content: Contains inflammatory amine (C 28 H 34 KNaO 10H2O) should be 45.00~55.00mg / mL;

[0031] Bacterial endotoxin: <0.25EU / mg.

[0032] Light inspection: Check whether the product name, specification and batch number of the inspected product are consistent with the batch production instruction, detect unqualified products (empty bottles, incorrect filling quantity, broken bottles, dirty bottles, foreign objects, skirts, burrs, etc.) and classify and count the number.

[0033] The present invention has the following technical effects:

[0034] (1) Indole is easily soluble in water, but its stability in water is poor, and it is easily hydrolyzed and oxidized. In the present invention, the active ingredient of indole is prepared into water-in-oil-in-water microcapsules, and the second capsule material is hydroxypropyl-β-cyclodextrin with excellent water solubility, which overcomes the defect of the first capsule material polylactic acid-glycolic acid copolymer having poor water solubility.

[0035] (2) The first capsule material is made of polylactic acid-glycolic acid copolymer, which is polymerized from lactic acid and glycolic acid and has good biocompatibility and degradability. Its final degradation products in the human body are carbon dioxide and water. It is safe and non-toxic and will not have a negative impact on the human body. In addition, polylactic acid-glycolic acid copolymer has good film-forming properties and can achieve effective encapsulation of indomethacin.

[0036] (3) The present invention dopes a small amount of lactic acid into the first capsule material. Lactic acid has certain reducing properties and can prevent the oxidation of indomethacin. At the same time, the degradation intermediate product of polylactic acid-glycolic acid copolymer itself is lactic acid, so it is well compatible with lactic acid and will not destroy its film-forming property.

[0037] (4) The injection of the present invention uses acetic acid and sodium hydroxide as pH regulators. Citric acid has a certain antioxidant effect, which can resist the oxidation of the unencapsulated part of inflammatory oxaline or the released inflammatory oxaline, further extending its stability period. DETAILED DESCRIPTION

[0038] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0039] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0040] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0041] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present application description and examples are exemplary only.

[0042] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0043] The embodiment of the present invention discloses a highly stable indomethacin injection, in which indomethacin exists in the form of indomethacin microcapsules; the indomethacin microcapsules are of water-in-oil-in-water type; the first capsule material of the indomethacin microcapsules is a complex of polylactic acid-glycolic acid copolymer and lactic acid, and the content of lactic acid accounts for 3-5% of the polylactic acid-glycolic acid copolymer; the second capsule material of the indomethacin microcapsules is hydroxypropyl-β-cyclodextrin.

[0044] In some embodiments, the content of indomethacin in the indomethacin microcapsules is 45.00-55.00 mg / mL; and the pH value is 6.5-7.0.

[0045] In some embodiments, the pH adjuster of the yanhuning injection is sodium hydroxide or citric acid.

[0046] In some embodiments, every 100 g of water for injection contains 5 g of indomethacin, 1.2 g of citric acid, and 0.027 g of sodium hydroxide.

[0047] In some embodiments, the method for preparing the yanhuning microcapsules comprises the following steps:

[0048] S01, dissolving the prescribed amount of lindane in ultrapure water to prepare a lindane aqueous solution as an inner aqueous phase for standby use;

[0049] S02, dissolving polylactic acid-glycolic acid copolymer in dichloromethane and mixing evenly, adding lactic acid dropwise and stirring again to mix evenly, and the resulting mixed solution is used as an oil phase for standby use;

[0050] S03, dissolving hydroxypropyl-β-cyclodextrin in ultrapure water and stirring evenly to form an external water phase;

[0051] S04, slowly drop the inner water phase into the oil phase for shear emulsification, with a rotation speed of 5000-8000rpm and a shear time of 10-15s to form a W1 / O primary emulsion;

[0052] S05, adding the W1 / O primary emulsion dropwise into the external aqueous phase for secondary shear emulsification at a speed of 3000-4000 rpm and a shear time of 20-30 s to form a W1 / O / W2 emulsion;

[0053] S06, adding the W1 / O / W2 emulsion into a sodium chloride aqueous solution and stirring at room temperature, allowing the dichloromethane to evaporate, and then centrifuging to collect the microcapsules.

[0054] In some embodiments, the mass concentration of polylactic acid-glycolic acid copolymer in the oil phase is 55-60%; the volume ratio of the inner aqueous phase to the oil phase is 1:5; the mass concentration of hydroxypropyl-β-cyclodextrin in the external aqueous phase is 45%; and the volume ratio of the W1 / O primary emulsion to the external aqueous phase is 2:(5-6).

[0055] The embodiment of the present invention also discloses a method for preparing a highly stable yanhuning injection, comprising the following steps:

[0056] (1) Sodium hydroxide and citric acid are dissolved in ultrapure water to prepare sodium hydroxide solution and citric acid solution with a concentration of 10 wt.% respectively;

[0057] (2) adjusting the pH value of the solution to 6.40-6.80 using the sodium hydroxide solution and the citric acid solution;

[0058] (3) dissolving the prescribed amount of yanhuning microcapsules in the drug solution under stirring, and then adjusting the pH value to 6.60-7.00 again with sodium hydroxide aqueous solution and citric acid aqueous solution;

[0059] (5) Filtration, filling, and freeze-drying.

[0060] In some embodiments, the freeze-drying process is as follows: pre-freeze at -40°C for 2-4 hours; evacuate, slowly heat to 20°C, maintain for 6-12 hours until the water line disappears; continue to heat to about 35°C, maintain for 3-6 hours, and the freeze-drying is completed.

[0061] In some embodiments, the filtration process is as follows: add the prescribed amount of activated carbon and adsorb for 30 minutes; transfer the drug solution to a concentrated preparation tank, and then coarsely filter it through a titanium rod and a 1.0 μm microporous filter element to a dilute preparation tank, take samples to test the intermediate properties, pH value, visible foreign matter, bacterial endotoxins and content, and take samples to check the bacterial count of the drug solution before filtration.

[0062] The specific testing standards for intermediate products are as follows:

[0063] Properties: Light yellow clear liquid;

[0064] pH value: 6.5-7.0;

[0065] Visible foreign matter: Take 20mL of the solution for inspection, there should be no visible foreign matter;

[0066] Content: Contains inflammatory amine (C 28 H 34 KNaO 10 H2O) should be 45.00~55.00mg / mL;

[0067] Bacterial endotoxin: <0.25EU / mg.

[0068] Light inspection: Check whether the product name, specification and batch number of the inspected product are consistent with the batch production instruction, detect unqualified products (empty bottles, incorrect filling quantity, broken bottles, dirty bottles, foreign objects, skirts, burrs, etc.) and classify and count the number.

[0069] The raw materials used in the following examples of the present invention were all obtained through commercial routes.

[0070] It should be noted that the technical details not explicitly stated in the embodiments of the present invention, such as “checking the water pressure, temperature and visible foreign matter, circulating water pressure, compressed air pressure when the machine is turned on”, etc., can be implemented by conventional technical means known to those skilled in the art, and are not the main points of the present invention, so they are not elaborated in detail.

[0071] Example 1

[0072] A type of indomethacin injection, with a product specification of 80 mg per vial.

[0073] The main components are shown in Table 1.

[0074] Table 1

[0075]

[0076]

[0077] Step A: Yanhuning needs to be microencapsulated before use. The specific steps are as follows:

[0078] S01, dissolving the prescribed amount of yanhuning in ultrapure water (water for injection) to prepare an yanhuning aqueous solution as an internal aqueous phase for standby use;

[0079] S02, dissolving polylactic acid-glycolic acid copolymer in dichloromethane and mixing evenly, adding lactic acid dropwise and stirring again to mix evenly, and the resulting mixed solution is used as an oil phase for standby use; the concentration of polylactic acid-glycolic acid copolymer in the oil phase is 55wt.%, and the amount of lactic acid added is 3.5% of the polylactic acid-glycolic acid copolymer;

[0080] S03, dissolving hydroxypropyl-β-cyclodextrin in ultrapure water and stirring evenly to form an external aqueous phase with a concentration of 45wt.%;

[0081] S04, slowly dropping the inner water phase into the oil phase for shear emulsification, with a rotation speed of 5000-8000rpm and a shear time of 10-15s to form a W1 / O primary emulsion; wherein the volume ratio of the inner water phase to the oil phase is 1:5;

[0082] S05, adding the W1 / O primary emulsion dropwise into the external aqueous phase for secondary shear emulsification at a speed of 3000-4000 rpm and a shear time of 20-30 s to form a W1 / O / W2 emulsion; wherein the volume ratio of the W1 / O primary emulsion to the external aqueous phase is 2:5;

[0083] S06. Add the W1 / O / W2 emulsion into a sodium chloride aqueous solution (0.9 wt.%) and stir at room temperature for 10 min to evaporate the dichloromethane, then centrifuge (1500 rpm) to collect the microcapsules, wash them three times with ultrapure water, and lyophilize to obtain the indomethacin microcapsules for later use.

[0084] Step B: Preparation of Yanhuning Injection

[0085] 1. Process:

[0086] 1) Cleaning and sterilization of vials: Remove the inner packaging of the required vials, pick out unqualified bottles, and transport them to the bottle washing station. Use water for injection for cleaning. When the machine is turned on, check the water pressure, temperature, visible foreign matter, circulating water pressure, and compressed air pressure. After a 30-second test wash, extract 20 bottles to check the cleanliness of the vials. After passing the test, start washing the bottles. The cleanliness of the vials, injection water pressure, circulating water pressure, visible foreign matter, and compressed air pressure should all meet the requirements every 2 hours.

[0087] For dry heat sterilization of vials, check and record the thermometer of the sterilization section on time. Check once at the beginning of each batch of filling, and the bacteria and bacterial endotoxins of the vials should meet the regulations; check the cleanliness of the vials after sterilization before the beginning and end of each batch of filling.

[0088] 2) Rubber stopper cleaning and sterilization: Put the required rubber stoppers into the rubber stopper cleaning machine and clean them as required, and take samples to check the visible foreign matter in the cleaning water, which should meet the regulations. Then sterilize the rubber stoppers at 121℃ for 30 minutes, vacuum dry, hot air dry, cool, and set aside. Check visible foreign matter, sterility, and bacterial endotoxins once for each cabinet, which should meet the regulations.

[0089] 2. Preparation and filtration of liquid medicine

[0090] 1) Operation requirements: Conduct integrity test on sterilizing filter before sterilization;

[0091] 2) Check whether the raw material and auxiliary material name, batch number, quantity, supplier, etc. are consistent with the batch production instructions.

[0092] 3) Add 28-32°C water for injection into the dissolving tank, start stirring the dissolving tank, set the stirring frequency, add the prescribed amount of citric acid and sodium hydroxide into the dissolving tank while stirring, and stir for 10 minutes until all dissolved.

[0093] 4) Weigh an appropriate amount of sodium hydroxide (or citric acid) and dissolve it in 500 mL of water for injection to prepare a 10% sodium hydroxide solution (or citric acid solution) for later use.

[0094] 5) Use 10% sodium hydroxide solution or 10% citric acid solution to adjust the pH value of the drug solution to 6.40-6.80. Add the prescribed amount of Yanhuning microcapsules (pure or dry) into the dissolving tank while stirring, and stir until all dissolved.

[0095] 6) Use 10% sodium hydroxide solution or 10% citric acid solution to adjust the pH value of the solution to 6.60-7.00.

[0096] 7) After the pH value is determined to be qualified, adjust the volume and stir for 10 minutes to make the solution uniform.

[0097] 8) Add the prescribed amount of activated carbon (for injection) and adsorb for 30 minutes; transfer the drug solution to a concentrated preparation tank, and then filter it through a titanium rod and a 1.0μm microporous filter element to a dilute preparation tank. Take samples to test the properties, pH value, visible foreign matter, bacterial endotoxins and content of the intermediates, and take samples to check the bacterial content of the drug solution before filtration.

[0098] Intermediate product standards:

[0099] Properties: Light yellow clear liquid;

[0100] pH value: 6.5-7.0;

[0101] Visible foreign matter: Take 20mL of the solution for inspection, there should be no visible foreign matter;

[0102] Content: Contains inflammatory amine (C 28 H 34 KNaO 10 H2O) should be 45.00~55.00mg / mL;

[0103] Bacterial endotoxin: <0.25EU / mg.

[0104] 9) Notify the personnel at the filling station to receive the liquid, and filter the liquid through 0.45μm and 0.22μm filter elements before sending it to the filling station.

[0105] 3. Filling

[0106] After filtering, the prepared liquid medicine is filled and semi-stoppered using a filling machine.

[0107] 4. Freeze drying and capping

[0108] After filling and semi-stoppering, the samples are put into the freeze dryer in the workshop for freeze drying.

[0109] Freeze drying control parameters:

[0110] Pre-freeze: Keep at -40℃ for 24 hours.

[0111] Primary drying: Vacuum, slowly raise the temperature to 20°C, and maintain for 10 hours until the water line disappears.

[0112] Secondary drying: Continue to raise the temperature to about 35°C and maintain for 4 hours, and freeze drying is completed.

[0113] After discharging, the material is capped and sampled for inspection.

[0114] Main control parameters:

[0115] The amount of drug solution prepared should not exceed ±1kg of the theoretical preparation amount.

[0116] Solution preparation time: The solution preparation process should be completed within 5 hours.

[0117] Storage time limit of drug solution: The prepared drug solution should be filled within 24 hours.

[0118] 5. Light inspection:

[0119] Check whether the product name, specification and batch number of the inspected products are consistent with the batch production instructions, and classify and count the number of unqualified products (empty bottles, inappropriate filling volume, broken bottles, dirty bottles, foreign objects, skirts, burrs, etc.).

[0120] Example 2

[0121] The only difference from Example 1 is that in step A, the volume ratio of the W1 / O primary emulsion to the external aqueous phase is 2:6.

[0122] Example 3

[0123] The only difference from Example 1 is that the content of lactic acid accounts for 5% of the polylactic acid-glycolic acid copolymer.

[0124] Example 4

[0125] The only difference from Example 1 is that the content of lactic acid accounts for 3% of the polylactic acid-glycolic acid copolymer.

[0126] Comparative Example 1

[0127] The only difference from Example 1 is that the content of lactic acid is 0.

[0128] Comparative Example 2

[0129] The only difference from Example 1 is that the embedding of the second capsule material is omitted.

[0130] Comparative Example 3

[0131] The only difference from Example 1 is that the embedding step is omitted and the injection is directly prepared using the active ingredient of yanhuning.

[0132] Test Example 1 - Storage Stability Test

[0133] The indomethacin injection prepared in Examples 1-4 and Comparative Examples 1-3 was stored at 40±2°C and relative humidity ±5% and subjected to an accelerated stability test. After three and six months, the injection was dissolved in 0.9wt.% saline (to make the indomethacin concentration 50.00mg / mL) and the changes in various indicators were observed. The results are shown in Table 2.

[0134] Table 2

[0135]

[0136]

[0137]

[0138] Note: The decline rate of the active ingredient of indomethacin refers to the decline rate compared to the initial value.

[0139] As can be seen from Table 2, all indicators of the injections prepared in Examples 1-4 are kept good, indicating that their storage stability is good. In Comparative Example 1, compared with Example 1, lactic acid doping is omitted in the first capsule material. Although the transparency and properties change slightly, the component decline is significantly increased. The possible reason is that the microcapsule material gradually begins to degrade, and some of the released indigoferin undergoes oxidation or hydrolysis; Comparative Example 2 is not coated with the second capsule material. Due to the poor water solubility of the first capsule material, precipitation occurs after storage for a period of time, and the transparency is seriously reduced; Comparative Example 3 is not microencapsulated, and the properties and transparency are seriously deteriorated, the pH decreases significantly, and the decline rate of the active ingredient of indigoferin is also reduced, indicating that a serious quality decline problem has occurred.

[0140] Test Example 2-Safety Test

[0141] (1) According to the abnormal toxicity test method in the 2020 edition of the Chinese Pharmacopoeia, the Yanhuning injection prepared in Examples 1-4 of the present invention was diluted with sodium chloride solution to a certain concentration of test solution and injected into mice that met the test requirements. The test results showed that there was no death in the mice within 7 days, indicating that the abnormal toxicity of this product met the requirements.

[0142] (2) According to the pyrogen test method in the Chinese Pharmacopoeia 2020 edition, the test results of the yanhuning injection prepared in Examples 1-4 also met the requirements.

[0143] The above are only preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A highly stable yanhuning injection, characterized in that: The yanhuning in the injection is in the form of yanhuning microcapsules; the yanhuning microcapsules are water-in-oil-in-water type; the first capsule material of the yanhuning microcapsules is a complex of polylactic acid-glycolic acid copolymer and lactic acid, and the content of lactic acid accounts for 3-5% of the polylactic acid-glycolic acid copolymer; the second capsule material of the yanhuning microcapsules is hydroxypropyl-β-cyclodextrin; The preparation method of the yanhuning microcapsules comprises the following steps: S01, dissolving the prescribed amount of lindane in ultrapure water to prepare a lindane aqueous solution as an inner aqueous phase for standby use; S02, dissolving polylactic acid-glycolic acid copolymer in dichloromethane and mixing evenly, adding lactic acid dropwise and stirring again to mix evenly, and the resulting mixed solution is used as an oil phase for standby use; S03, dissolving hydroxypropyl-β-cyclodextrin in ultrapure water and stirring evenly to form an external water phase; S04, slowly drop the inner water phase into the oil phase for shear emulsification, with a rotation speed of 5000-8000rpm and a shear time of 10-15s to form a W1 / O primary emulsion; S05, adding the W1 / O primary emulsion dropwise into the external aqueous phase for secondary shear emulsification at a speed of 3000-4000 rpm and a shear time of 20-30 s to form a W1 / O / W2 emulsion; S06, adding the W1 / O / W2 emulsion into a sodium chloride aqueous solution and stirring at room temperature, allowing the dichloromethane to evaporate, and then centrifuging to collect microcapsules; The mass concentration of polylactic acid-glycolic acid copolymer in the oil phase is 55-60%; the volume ratio of the inner water phase to the oil phase is 1:5; the mass concentration of hydroxypropyl-β-cyclodextrin in the outer water phase is 45%; and the volume ratio of the W1 / O primary emulsion to the outer water phase is 2:(5-6).

2. The Yanhuning injection according to claim 1, characterized in that The content of indomethacin in the indomethacin microcapsules is 45.00-55.00 mg / mL, and the pH value is 6.5-7.

0.

3. The Yanhuning injection according to claim 1, characterized in that The pH regulator of the yanhuning injection is sodium hydroxide and / or citric acid.

4. The Yanhuning injection according to claim 1, characterized in that Every 100g of water for injection contains 5g of indomethacin, 1.2g of citric acid and 0.027g of sodium hydroxide.

5. A method for preparing the Yanhuning injection according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: (1) dissolving sodium hydroxide and citric acid in ultrapure water respectively to prepare a sodium hydroxide solution and a citric acid solution with a concentration of 10 wt.%; (2) adjusting the pH value of the solution to 6.40-6.80 using the sodium hydroxide solution and the citric acid solution; (3) dissolving the prescribed amount of yanhuning microcapsules in the drug solution under stirring, and then adjusting the pH value to 6.60-7.00 again with an aqueous sodium hydroxide solution and an aqueous citric acid solution; (4) Filtration, filling, and freeze-drying; The preparation method of the yanhuning microcapsules comprises the following steps: S01, dissolving the prescribed amount of lindane in ultrapure water to prepare a lindane aqueous solution as an inner aqueous phase for standby use; S02, dissolving polylactic acid-glycolic acid copolymer in dichloromethane and mixing evenly, adding lactic acid dropwise and stirring again to mix evenly, and the resulting mixed solution is used as an oil phase for standby use; S03, dissolving hydroxypropyl-β-cyclodextrin in ultrapure water and stirring evenly to form an external water phase; S04, slowly drop the inner water phase into the oil phase for shear emulsification, with a rotation speed of 5000-8000rpm and a shear time of 10-15s to form a W1 / O primary emulsion; S05, adding the W1 / O primary emulsion dropwise into the external aqueous phase for secondary shear emulsification at a speed of 3000-4000 rpm and a shear time of 20-30 s to form a W1 / O / W2 emulsion; S06, adding the W1 / O / W2 emulsion into a sodium chloride aqueous solution and stirring at room temperature, allowing the dichloromethane to evaporate, and then centrifuging to collect microcapsules; The mass concentration of polylactic acid-glycolic acid copolymer in the oil phase is 55-60%; the volume ratio of the inner water phase to the oil phase is 1:5; the mass concentration of hydroxypropyl-β-cyclodextrin in the outer water phase is 45%; and the volume ratio of the W1 / O primary emulsion to the outer water phase is 2:(5-6).

6. The preparation method according to claim 5, characterized in that: The freeze-drying process is as follows: keep warm at -40°C for 2-4 hours for pre-freezing; evacuate, slowly heat up to 20°C, maintain for 6-12 hours until the water line disappears; continue to heat up to 35°C, maintain for 3-6 hours, and the freeze-drying is completed.

7. The preparation method according to claim 5, characterized in that: The filtration process is as follows: add the prescribed amount of activated carbon and adsorb for 30 minutes; transfer the drug solution to a concentrated preparation tank, and then coarsely filter it to a dilute preparation tank through a titanium rod and a 1.0µm microporous filter element, take samples to test the intermediate properties, pH value, visible foreign matter, bacterial endotoxin and content, and take samples to check the bacterial content of the drug solution before filtration.

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