Irecoxib phospholipid complex self-microemulsifying drug delivery system as well as preparation method and application of imrecoxib phospholipid complex self-microemulsifying drug delivery system

Abstract

The invention discloses an imrecoxib phospholipid complex self-microemulsifying drug delivery system as well as a preparation method and application thereof. The drug delivery system comprises the following components in parts by weight: 8-20 parts of imrecoxib, 8-40 parts of phospholipid, 10-60 parts of an oil phase, 20-75 parts of an emulsifier and 15-60 parts of a co-emulsifier. The imrecoxib phospholipid complex self-microemulsion drug delivery system prepared by the invention has high stability of a phospholipid complex, high emulsifying energy of liquid self-microemulsion and a good drug solubilizing effect, and the permeability of a biological membrane is improved, so that the oral bioavailability of imrecoxib is improved, and the drug effect is further improved; in addition, the self-microemulsion drug delivery system is good in stability and low in toxicity. In addition, the preparation method disclosed by the invention is simple to operate and good in repeatability, and has good social and economic benefits. The imrecoxib phospholipid complex self-micro-emulsification system is used as a pharmaceutical preparation, so that the probability that the medicine is absorbed by gastrointestinal tracts in a dissolved state can be increased, the efficacy of imrecoxib is improved, and more choices are provided for micro-emulsion oral administration dosage forms.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an irelcoxib phospholipid complex self-microemulsifying drug delivery system and a preparation method and application thereof. Background Art

[0002] Imrecoxib (ARXB) has a molecular formula of C 21 H 23 NO3S, with a molecular weight of 369.477 and a CAS number of 395683-14-4, has a structural formula as shown below. It has a good COX-2 selective inhibitory effect, blocks the synthesis of prostaglandins from arachidonic acid by inhibiting cyclooxygenase (COX); inhibits the release of bradykinin, changes lymphocyte response, reduces the migration and phagocytosis of granulocytes and monocytes, produces anti-inflammatory, analgesic, antipyretic and other effects, and is the most commonly used drug for controlling osteoarthritis symptoms.

[0003]

[0004] As a COX-2 selective inhibitor, ericoxib is the first choice of non-steroidal anti-inflammatory drugs due to its strong inhibitory effect and small gastrointestinal side effects. At a certain dose, it can specifically inhibit COX-2 without affecting COX-1. It has analgesic and anti-inflammatory effects while reducing the incidence of adverse reactions, greatly improving the safety of the drug in the digestive system. ericoxib has significant characteristics such as good efficacy, high safety, and low side effects. At present, ericoxib is widely used in clinical practice, mainly for arthritis, perioperative analgesia, postoperative heterotopic ossification, hand-foot syndrome, etc., among which osteoarthritis is the most effective. At the same time, ericoxib may also have certain efficacy in other disease areas such as tumors and acute pancreatitis, which requires more future research to prove.

[0005] Phospholipid complexes (phytosome or phospholipid) refer to complexes formed by the combination of drugs and phospholipids in a certain ratio in a non-proton transfer system solvent. Phospholipids are not only important components of cell membranes, but also very effective emulsifiers due to the amphiphilicity of phospholipid molecules.

[0006] Self-microemulsion drug delivery system (SMEDDS) is a homogeneous clear liquid formed by drugs, oil phase, emulsifiers and co-emulsifiers. It spontaneously emulsifies under gastrointestinal motility or ambient temperature (usually body temperature) and gentle stirring to form isotropic transparent or translucent oil-in-water (O / W) microemulsions with a particle size of 10 to 100 nm. SMEDDS is a drug delivery system that increases the solubility of poorly soluble drugs. The system can form nanoemulsions with a large gastrointestinal surface area, avoid intestinal protein excretion, reduce first-pass metabolism, increase lymphatic transport pathways, etc., to improve the bioavailability of poorly soluble drugs.

[0007] Irecoxib belongs to BCS Class II drugs. Its low solubility in water leads to its low bioavailability, which limits the development of its dosage form. Currently, the only product on the market is Irecoxib tablets. However, Irecoxib tablets have some disadvantages. First, its low solubility causes the drug dissolution rate and dissolution rate to become the rate-limiting steps of absorption, which greatly affects the bioavailability; secondly, gastrointestinal metabolism and the first-pass effect of the liver further affect the absorption of the drug in the body. Therefore, increasing the solubility of Irecoxib to improve its bioavailability has become the key to its formulation research and development.

[0008] Therefore, the research focus in this field is to develop a self-microemulsifying drug delivery system of levofloxacin phospholipid complex with good stability, simple preparation method, high levofloxacin content and high solubility by screening out suitable drug / phospholipid ratio, oil phase with high solubility for levofloxacin and good safety, emulsifier and co-emulsifier. Summary of the invention

[0009] Purpose of the invention: In order to solve the problems existing in the prior art, the present invention proposes an erlotoxib phospholipid complex self-microemulsifying drug delivery system and its preparation method and application, which effectively improves the solubility and dissolution rate of erlotoxib and has good stability, mobile phase and drug loading capacity.

[0010] Technical solution: To achieve the above purpose, the present invention adopts the following technical solution: an erlotoxib phospholipid complex self-microemulsifying drug delivery system, comprising the following ingredients by weight: 8-20 parts of erlotoxib, 8-40 parts of phospholipids, 10-60 parts of oil phase, 20-75 parts of emulsifier, and 15-60 parts of co-emulsifier.

[0011] Wherein, further, the amount of Erelcoxib may be 12 parts, 14 parts, 16 parts or 18 parts;

[0012] The phospholipids may be 10, 15, 20, 25, 30, 35 or 40 parts; the oil phase may be 12, 15, 20, 25, 30 or 35 parts; the emulsifier may be 25, 30, 35, 40, 45, 50, 55, 60, 65 or 70 parts; the co-emulsifier may be 15, 20, 25, 30, 35, 40, 45, 50 or 55 parts.

[0013] Furthermore, the irelcoxib phospholipid complex self-microemulsifying drug delivery system comprises the following components by weight: 8-14 parts of irelcoxib, 8-30 parts of phospholipids, 12-30 parts of oil phase, 20-55 parts of emulsifier, and 15-30 parts of co-emulsifier.

[0014] Furthermore, the irelcoxib phospholipid complex self-microemulsifying drug delivery system comprises the following components by weight: 8-14 parts of irelcoxib, 10-18 parts of phospholipids, 15-25 parts of oil phase, 45-55 parts of emulsifier, and 20-25 parts of co-emulsifier.

[0015] Furthermore, the phospholipids include any one of phospholipids and soybean lecithin, preferably soybean lecithin. The selected phospholipids must be able to improve the biocompatibility and affinity of the drug with the gastrointestinal mucosa in the body, increase permeability and retention effect.

[0016] Furthermore, the oil phase includes any one of ethyl oleate, triacetin, castor oil, and medium chain triglycerides, or a combination of at least two thereof, preferably ethyl oleate. The selected oil phase must exhibit a large drug solubility. An oil phase with a high solubilizing ability can ensure the optimal drug loading of the self-microemulsification preparation and the absorption of the drug in the body, and the preparation has good stability during storage, and the drug is not easy to precipitate.

[0017] Furthermore, the emulsifier includes polyoxyethylene 35 castor oil and / or polyoxyethylene hydrogenated castor oil, preferably polyoxyethylene 35 castor oil. The selected emulsifier is a non-ionic surfactant with an HLB value of >12, which has high safety to human body and high self-emulsification efficiency.

[0018] Furthermore, the co-emulsifier includes any one of 1,2-propylene glycol, polyethylene glycol 400, and diethylene glycol monoethyl ether, or a combination of at least two of them, preferably diethylene glycol monoethyl ether.

[0019] The present invention adopts the above-mentioned phospholipids, oil phase, emulsifier and co-emulsifier to have a greater drug loading advantage. The irelcoxib phospholipid complex self-microemulsification is prepared by adding specific excipients in a certain ratio, so that the irelcoxib phospholipid complex self-microemulsification drug delivery system has better fluidity and higher drug loading capacity.

[0020] The invention also discloses a method for preparing the above-mentioned irelcoxib phospholipid complex self-microemulsifying drug delivery system, comprising the following steps:

[0021] (1) dissolving an appropriate amount of erlotinib and phospholipid in an organic solvent, stirring under constant temperature and magnetic stirring, removing the organic solvent by rotary evaporation, adding 50-80 mL of dichloromethane for redissolution, filtering, and drying under reduced pressure to obtain an erlotinib phospholipid complex;

[0022] (2) heating and stirring the emulsifier and the co-emulsifier in a water bath magnetic ion stirrer to mix uniformly to obtain a premixed solution;

[0023] (3) The irelcoxib phospholipid complex is completely dissolved in the premixed solution, and then the oil phase is added, and the mixture is heated and stirred on a water bath magnetic ion stirrer to be uniformly mixed to obtain a self-microemulsion.

[0024] Furthermore, the constant temperature magnetic stirring conditions of step (1) are 30-45°C water bath heating, 300-500 rpm stirring for 3-5h, and the rotary evaporation conditions are 40-55°C rotary evaporation.

[0025] Furthermore, in step (1), the water bath heating in the constant temperature magnetic stirring conditions can be 30°C, 35°C, 40°C or 45°C; the stirring speed can be 300rpm, 350rpm, 400rpm, 450rpm or 500rpm; and the stirring time can be 3h, 3.5h, 4h, 4.5h or 5h.

[0026] Furthermore, the conditions for uniform mixing in steps (2) and (3) are both heating in a water bath at 25-50° C. and stirring at 200-400 rpm for 10-30 min.

[0027] Preferably, in step (2) and step (3), the water bath heating under the mixing uniform condition can be 30°C, 35°C, 40°C or 45°C; the stirring speed can be 220rpm, 240rpm, 260rpm, 280rpm, 300rpm, 320rpm, 340rpm, 360rpm or 380rpm; and the stirring time can be 12min, 14min, 16min, 18min, 20min, 22min, 24min, 26min or 28min.

[0028] Furthermore, the microemulsion particle size of the self-microemulsion is 20.12-35.23nm, which can be 20.5nm, 21.0nm, 21.5nm, 22.0nm, 22.5nm, 23.0nm, 23.5nm, 24.0nm, 24.5nm, 25.0nm, 25.5nm, 26.0nm, 26.5nm, 27.0nm, 27.5nm, 28.0nm, 28.5nm, 29.0nm, 29.5nm, 30.0nm, 30.5nm, 31.0nm, 31.5nm, 32.0nm, 32.5nm, 33.0nm, 33.5nm, 34.0nm, 34.5nm, 35.0nm, etc.

[0029] When the stirring time is too short or the stirring speed is too slow, the problem of larger particle size of the self-microemulsion will arise. The reason is that both the oil phase and the emulsifier are viscous liquids. When not stirred, they are in a state of slight stratification. When the stirring speed is too slow or the stirring time is too short, the microemulsion pre-concentrate cannot be stirred evenly, resulting in a relatively large particle size of the microemulsion formed when self-microemulsification occurs in water.

[0030] The invention also discloses the application of the irelcoxib self-microemulsifying drug delivery system in the preparation of non-steroidal anti-inflammatory drugs.

[0031] Beneficial effects: Compared with the prior art, the present invention has the following advantages: (1) The self-microemulsifying drug delivery system of the phospholipid complex prepared by the present invention has the high stability of the phospholipid complex and the high emulsifying ability of the liquid self-microemulsion, has a good drug solubilizing effect, increases the permeability of the biological membrane, thereby improving the oral bioavailability of ericoxib, and further improves the efficacy; and the phospholipid complex self-microemulsifying drug delivery system has good stability and low toxicity. (2) The preparation method provided by the present invention is simple to operate and has good repeatability, and has good social and economic benefits. (3) The present invention uses the self-microemulsifying drug delivery system of the phospholipid complex as a pharmaceutical preparation, and the obtained pharmaceutical preparation can increase the probability of the drug being absorbed by the gastrointestinal tract in a dissolved state, improve the efficacy of ericoxib, and provide more choices for microemulsion oral administration dosage forms. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the appearance morphology of the irevoxib phospholipid complex self-microemulsion prepared in Example 1;

[0033] Figure 2 The transmission electron microscopic image of the irevoxib phospholipid complex self-microemulsion prepared in Example 1;

[0034] Figure 3 The dissolution curve of the irelcoxib phospholipid complex self-microemulsion drug delivery system and irelcoxib tablets prepared in Example 1;

[0035] Figure 4 The dissolution curves of the irelcoxib phospholipid complex self-microemulsifying drug delivery system and irelcoxib original drug prepared in Example 1;

[0036] Figure 5 The plasma drug-dose curves of the irelcoxib phospholipid complex self-microemulsifying drug delivery system and irelcoxib original drug prepared in Example 1 are shown. DETAILED DESCRIPTION

[0037] The present invention is further described below in conjunction with specific embodiments.

[0038] In the present invention, unless otherwise specified, percentages and percentage contents are all by mass. Unless otherwise specified, the experimental methods used are all conventional methods, and the materials and reagents used can be purchased from commercial sources.

[0039] Analytical balance: BS210S, Sartorius, Germany;

[0040] Magnetic stirrer: HJ-6B, Jintan Chengxi Zhengrong Experimental Instrument Factory;

[0041] Vortex mixer: XH-C, Jintan Baita Xinbao Instrument Factory;

[0042] Vacuum rotary evaporator: RE-52AA, Shanghai Zhenjie Experimental Equipment Co., Ltd.;

[0043] Particle size analyzer: Zeta sizer Nano ZS90, Malvern, UK;

[0044] Transmission electron microscope: JEM-2100, JEOL, Tokyo, Japan;

[0045] Water purifier: EPED-Z1-5T, Nanjing EPED;

[0046] High performance liquid chromatograph: LC-20AT, Shimadzu, Japan;

[0047] Dissolution apparatus: RC 806D, Tianda Tianfa;

[0048] Stability test chamber: LAZI-250-YG, Taihong Medical Equipment Instrument;

[0049] Desktop centrifuge: TGL-20M, Shanghai Luxiangyi Centrifuge Instrument;

[0050] Drug testing:

[0051] Irecoxib (purity ≧99%) (CAS No.: 395683-14-4) Jiangsu Hengrui Pharmaceuticals;

[0052] Irecoxib tablets (100 mg) Jiangsu Hengrui Medicine Co., Ltd.

[0053] Phospholipids (CAS No.: 123465-35-0) Shanghai Aladdin;

[0054] Soybean lecithin (CAS No.: 8002-43-5) Shanghai Aladdin;

[0055] Triacetin (CAS No.: 102-76-1) Sinopharm Group;

[0056] Medium chain triglycerides (CAS No.: 538-24-9) BASF New Materials;

[0057] Isopropyl myristate (CAS No.: 110-27-0) Sinopharm Group;

[0058] Ethyl oleate (CAS No.: 111-62-6) Sinopharm Group;

[0059] Castor oil (CAS No.: 8001-79-4) Sinopharm Group;

[0060] Oleic acid (CAS No.: 112-80-1) Sinopharm Group;

[0061] Corn oil (CAS No.: 8001-30-7) Jiangxi Lanpusheng Pharmaceutical Co., Ltd.

[0062] Span 80 (CAS No.: 1338-43-8) Sinopharm Group;

[0063] Tween 80 (CAS No.: 9005-65-6) Sinopharm Group;

[0064] Polyoxyethylene 35 castor oil (molecular weight: 172) BASF new materials;

[0065] Polyoxyethylene hydrogenated castor oil (molecular weight: 375) BASF New Materials;

[0066] Polyethylene glycol 400 (CAS No.: 25322-68-3) BASF New Materials;

[0067] Diethylene glycol monoethyl ether (CAS No.: 112-15-2) Shanghai Aladdin;

[0068] 1,2-Propanediol (CAS No.: 57-55-6) Shanghai Aladdin;

[0069] Glycerol (CAS No.: 56-81-5) Shanghai Aladdin;

[0070] Ethanol (CAS No.: 64-17-5) Sinopharm Group;

[0071] Methanol (CAS No.: 67-56-1) Sinopharm Group;

[0072] Irbesartan (≧99%) (CAS No.: 138402-11-6) China Food and Drug Inspection Institutes.

[0073] Embodiment 1:

[0074] This embodiment provides a self-microemulsifying drug delivery system of lecithin phospholipid complex, wherein the raw materials are as follows in parts by weight: 10 parts of phospholipid (soy lecithin), 50 parts of emulsifier (polyoxyethylene 35 castor oil), 18 parts of co-emulsifier (diethylene glycol monoethyl ether), 14 parts of lecithin, and 18 parts of oil phase (ethyl oleate);

[0075] The preparation method comprises the following steps:

[0076] (1) Dissolve irelcoxib and soybean lecithin in an organic solvent, stir under constant temperature magnetic stirring, remove the organic solvent by rotary evaporation, add 50-80 mL of dichloromethane for re-dissolution, filter, and dry under reduced pressure to obtain irelcoxib phospholipid complex. The stirring conditions are heating in a 40° C. water bath, stirring at 400 rpm for 1 hour, and the rotary evaporation conditions are rotary evaporation at 45° C.

[0077] (2) At room temperature, the emulsifier and the co-emulsifier were placed in a beaker, placed in a 37°C water bath, and stirred at 400 rpm for 30 min to obtain a premixed solution;

[0078] (3) Add the levofloxacin phospholipid complex to the obtained premixed solution and mix well. Place the mixture in a 37°C water bath and stir at 400 rpm for 30 min. After the drug is completely dissolved, add the oil phase and stir well to obtain a levofloxacin phospholipid complex self-microemulsion.

[0079] Embodiment 2:

[0080] This embodiment provides a self-microemulsifying drug delivery system of lecithin phospholipid complex, wherein the raw materials are as follows in parts by weight: 14 parts of phospholipid (soybean lecithin), 46 parts of emulsifier (polyoxyethylene 35 castor oil), 22 parts of auxiliary emulsifier (diethylene glycol monoethyl ether), 12 parts of lecithin, and 20 parts of oil phase (ethyl oleate);

[0081] The preparation method comprises the following steps:

[0082] (1) Dissolve irelcoxib and soybean lecithin in an organic solvent, stir under constant temperature magnetic stirring, remove the organic solvent by rotary evaporation, add 50-80 mL of dichloromethane for re-dissolution, filter, and dry under reduced pressure to obtain irelcoxib phospholipid complex. The stirring conditions are heating in a 40° C. water bath, stirring at 400 rpm for 1 hour, and the rotary evaporation conditions are rotary evaporation at 45° C.

[0083] (2) At room temperature, the emulsifier and the co-emulsifier were placed in a beaker, placed in a 45°C water bath, and stirred at 300 rpm for 30 min to obtain a premixed solution;

[0084] (3) Add the levofloxacin phospholipid complex to the obtained premixed solution and mix well. Place the mixture in a 45° C. water bath and stir at 300 rpm for 30 min. After the drug is completely dissolved, add the oil phase and stir well to obtain the levofloxacin self-microemulsion.

[0085] Embodiment 3:

[0086] This embodiment provides a self-microemulsifying drug delivery system of lecithin phospholipid complex, wherein the raw materials are as follows in parts by weight: 12 parts of phospholipid (soybean lecithin), 48 parts of emulsifier (polyoxyethylene 35 castor oil), 20 parts of co-emulsifier (diethylene glycol monoethyl ether), 16 parts of lecithin, and 16 parts of oil phase (ethyl oleate);

[0087] The preparation method comprises the following steps:

[0088] (1) Dissolve irelcoxib and soybean lecithin in an organic solvent, stir under constant temperature magnetic stirring, remove the organic solvent by rotary evaporation, add 50-80 mL of dichloromethane for re-dissolution, filter, and dry under reduced pressure to obtain irelcoxib phospholipid complex. The stirring conditions are heating in a 40° C. water bath, stirring at 400 rpm for 1 hour, and the rotary evaporation conditions are rotary evaporation at 45° C.

[0089] (2) At room temperature, the emulsifier and the co-emulsifier were placed in a beaker, placed in a 45°C water bath, and stirred at 300 rpm for 30 min to obtain a premixed solution;

[0090] (3) Add the levofloxacin phospholipid complex to the obtained premixed solution and mix well. Place the mixture in a 45° C. water bath and stir at 300 rpm for 30 min. After the drug is completely dissolved, add the oil phase and stir well to obtain the levofloxacin self-microemulsion.

[0091] Embodiment 4:

[0092] This embodiment provides an irelcoxib phospholipid complex self-microemulsifying drug delivery system, which differs from Example 1 in that the irelcoxib is adjusted to 10 parts, and the insufficient part is supplemented by phospholipids, oil phase, emulsifier and co-emulsifier in a ratio of 10:18:50:18 while keeping the total number of raw materials unchanged. Other raw materials and preparation methods refer to Example 1.

[0093] Embodiment 5:

[0094] This embodiment provides an erlotinib phospholipid complex self-microemulsifying drug delivery system, which differs from Example 1 in that the erlotinib is adjusted to 18 parts, and the excess part is reduced by phospholipids, oil phase, emulsifier and co-emulsifier in a ratio of 10:18:50:18 while keeping the total number of raw materials unchanged. Other raw materials and preparation methods refer to Example 1.

[0095] Embodiment 6-8:

[0096] This embodiment provides an irectocolitide phospholipid complex self-microemulsifying drug delivery system, which differs from Embodiment 1 in that the oil phase is replaced by equal amounts of triacetin, castor oil, and medium-chain triglycerides, respectively; other raw materials, amounts, and preparation methods refer to Embodiment 1.

[0097] Embodiment 9-10:

[0098] This embodiment provides an irelcoxib phospholipid complex self-microemulsifying drug delivery system, which differs from Embodiment 1 in that the emulsifiers are replaced by equal amounts of polyoxyethylene hydrogenated castor oil and Tween 80, respectively; other raw materials, dosages and preparation methods refer to Embodiment 1.

[0099] Comparative experiment:

[0100] Pour 900 mL of dissolution medium into the dissolution cup, balance the dissolution temperature to 37±0.5°C, take commercially available erlotinib tablets (100 mg) and the erlotinib phospholipid complex microemulsification system of Example 1 (containing 100 mg erlotinib) and add them into the dissolution cup, start timing immediately, take out 5 mL of sample solution and add 5 mL of dissolution medium at the time intervals set at 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, filter the sample solution through a 0.45 μm filter membrane, calculate the concentration of erlotinib based on the reference substance, and draw a dissolution curve with the sampling time point as the horizontal coordinate and the cumulative dissolution of the drug as the vertical coordinate, as shown in FIG. Figure 3 It can be seen that the dissolution rate of the prepared erlotoxib phospholipid complex within 2 hours reaches more than 95%, which is much higher than the drug dissolution rate of the commercially available erlotoxib tablets within 2 hours.

[0101] Test Example 1:

[0102] I. Stability test

[0103] The stability test of the irelcoxib phospholipid complex self-microemulsifying drug delivery system prepared in Examples 1-5 was carried out to examine the transmittance and appearance at 0h and 24h when the drug loading was 18%, 16%, 14%, 12%, and 10%, respectively. The results are shown in Table 1:

[0104] Table 1 Stability test of the self-microemulsifying drug delivery system of levofloxacin phospholipid complex prepared in Examples 1-5

[0105] It can be seen from the data in the above table that when the drug loading is 10-14%, the microemulsion formed by the self-emulsification of the ericoxib phospholipid complex self-microemulsion is clear and transparent with a slight blue opalescence at 0h, and after being placed for 24h, it is still clear and transparent with a slight blue opalescence, and the transmittance has not changed; when the drug loading is 16-18%, the microemulsion formed by the self-emulsification of the ericoxib liquid self-microemulsion is clear and transparent with a slight blue opalescence at 0h, and after being placed for 24h, it has a slight milky white color, the transmittance is reduced, and a small amount of drug crystals are precipitated. In summary, the drug loading of ericoxib in the ericoxib phospholipid complex self-microemulsion drug delivery system is preferably 12-14%.

[0106] II. Morphology and particle size distribution of lecithin phospholipid complex self-microemulsion

[0107] (I) Appearance inspection

[0108] Test results such as Figure 1 The results show that the prepared irelcoxib phospholipid complex self-emulsion has a clear and transparent liquid appearance. After high-speed centrifugation at 10000rpm for 10 minutes, no phase separation occurs, indicating that the irelcoxib phospholipid complex self-emulsion prepared by the present invention has good kinetic stability. Further, after adding an appropriate amount of water to the irelcoxib phospholipid complex self-emulsion for emulsification, a uniform slightly blue transparent emulsion is formed, which is identified as an O / W type microemulsion after dyeing with methylene blue and Sudan red solution.

[0109] (ii) Transmission electron microscopy observation

[0110] The irelcoxib phospholipid complex self-microemulsion prepared in Example 1 was diluted 100 times with 37°C distilled water, filtered through a 0.45μm filter membrane, and then dripped onto a copper mesh. After 10 minutes, the liquid was removed with filter paper, and then stained with a 10% phosphotungstic acid solution. After 5 minutes, the liquid was removed with filter paper, and the copper mesh was placed on a JEM-2100 transmission electron microscope to observe the state of the microemulsion at different magnifications. After testing, the diameter of the emulsion droplets formed by the irelcoxib phospholipid complex self-microemulsion when it meets water is about 22nm, and the particle size distribution is uniform. The results are as follows: Figure 2 shown.

[0111] (III) Particle size determination

[0112] The irelcoxib phospholipid complex self-microemulsion prepared in Example 1-3 was diluted 100 times with 37° C. distilled water, and the particle size, Zeta potential and polydispersity index PDI of the VST-L-SMEDDS after emulsification were measured using a Zeta sizer Nano ZS90 particle size analyzer. The results are shown in Table 2.

[0113] Table 2 Parameters of the ibracillin phospholipid complex prepared in Examples 1-3 after self-microemulsification

[0114] Group Example 1 Example 2 Example 3 average value SD Particle size (nm) 22.45 22.60 22.99 22.68 0.29 Zeta(mV) -31.90 -31.87 -31.99 -31.92 0.06 PDI 0.140 0.135 0.148 0.141 0.006

[0115] As can be seen from the results in Table 2, the average particle size of the microemulsion formed by the self-emulsion emulsification of the levofloxacin phospholipid complex prepared in Examples 1-3 is about 22 nm, which is normally distributed; the Zeta potential is -31.92 ± 0.06 mv, indicating that the microemulsion has good stability; the polydispersity index (PDI) is 0.141 ± 0.006, indicating that the microemulsion particle size distribution is uniform and has good dispersibility. Therefore, it can be judged that the levofloxacin phospholipid complex can form a uniform microemulsion system after self-emulsion emulsification.

[0116] (IV) Influence of medium and dilution factor

[0117] The irelcoxib phospholipid complex self-microemulsion prepared in Example 1 was added to three different types of dispersion media (hydrochloric acid with a pH value of 1.0, deionized water, and PBS buffer with a pH value of 6.8), and three different volumes of distilled water (50 times, 100 times, and 200 times), respectively, and gently stirred. The timing was started from the time of dropwise addition to deionized water, and the timing was stopped when the self-microemulsion was completely emulsified, and the emulsification efficiency was evaluated by the emulsification time and particle size.

[0118] The emulsification results of the irelcoxib phospholipid complex self-microemulsion in three different types of dispersion media are shown in Table 3, and the emulsification results of the irelcoxib phospholipid complex self-microemulsion at different dilution multiples are shown in Table 4.

[0119] Table 3 Emulsification results of Erelcoxib phospholipid complex self-microemulsion in three different types of dispersion media

[0120] Dispersion medium pH1.0 HCl Double distilled water pH 6.8 PBS Emulsification time(s) 20’84 22’65 22’87 Particle size (nm) 23.1 22.2 20.7 Particle size after 24h (nm) 24.3 22.7 21.8

[0121] Table 4 Emulsification results of different dilution multiples on the self-microemulsion of levofloxacin phospholipid complex

[0122] Dilution multiple 50 100 200 Emulsification time(s) 20’82 19’38 19’48 Particle size (nm) 23.3 22.3 20.3 Particle size after 24h (nm) 23.9 22.5 20.4

[0123] According to the data in Tables 3-4, it can be seen that the irelcoxib phospholipid complex self-microemulsion prepared in the present invention can quickly form a clear, transparent, slightly blue microemulsion in different dispersion media and at different dilution multiples, and the particle size does not change after being placed for 24 hours.

[0124] III In vitro drug release experiment

[0125] The irectocolitide phospholipid complex self-microemulsifying system prepared in Example 1 was subjected to an in vitro drug release experiment.

[0126] The in vitro dissolution test was performed using the paddle method, and the dissolution medium was pH = 1.0 HCl.

[0127] The specific steps are as follows: 900 mL of dissolution medium is poured into a dissolution cup, the dissolution temperature is balanced to 37 ± 0.5 ° C, 100 mg of the irelcoxib raw material and the irelcoxib phospholipid complex microemulsification system of Example 1 (containing 100 mg of irelcoxib) are added to the dissolution cup, and the timing is started immediately. At the time intervals set at 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, 5 mL of the sample solution is taken out and 5 mL of the dissolution medium is added at the same time. The sample solution is filtered through a 0.45 μm filter membrane, and the concentration of irelcoxib is calculated based on the reference substance, and the dissolution curve is drawn with the sampling time point as the horizontal coordinate and the cumulative dissolution of the drug as the vertical coordinate, as shown in FIG. Figure 4 shown.

[0128] As can be seen from the figure: in the pH = 1.0 HCl dissolution medium, when the time is 120 min, the cumulative release of the erlotoxib raw material is 5.0%, which is almost no release; while the cumulative release of the erlotoxib phospholipid complex self-microemulsion delivery system is 96%, indicating that the self-microemulsion technology can significantly increase the cumulative release of erlotoxib in the dissolution medium.

[0129] IV Stability Test

[0130] (I) Test of influencing factors

[0131] High temperature test: The irelcoxib phospholipid complex self-microemulsifying system prepared in Example 1 was placed in a weighing bottle at 60° C. for 10 days. Samples were taken on the 5th and 10th days to measure relevant indicators.

[0132] Light test: Under the light condition of 4500lx±500lx, a proper amount of the irevoxib phospholipid complex self-microemulsification system prepared in Example 1 was placed in a weighing bottle and placed in a stability test box for 10 days. Samples were taken on the 5th and 10th days, and relevant indicators were measured.

[0133] (II) Accelerated test

[0134] The irelcoxib phospholipid complex self-microemulsifying system prepared in Example 1 was placed in a weighing bottle and placed in a stability test box (40°C ± 2°C; 75% ± 5%), and samples were taken at preset time (in months) to measure relevant indicators for inspection.

[0135] The results of the test on the influencing factors of the self-microemulsification system of the phospholipid complex of irelcoxib are shown in Table 5 (n=3), and the results of the accelerated test on the self-microemulsification system of the phospholipid complex of irelcoxib are shown in Table 6 (n=3).

[0136] Table 5 Experimental results of factors affecting the self-microemulsification system of lecithin phospholipid complex

[0137]

[0138] Table 6 Results of accelerated test of the self-microemulsification system of the levofloxacin phospholipid complex

[0139]

[0140]

[0141] According to the data in Tables 5-6, it can be seen that under the influencing factor test and accelerated test conditions, the appearance of the erlotinib phospholipid complex self-microemulsification system did not change significantly, and no oil leakage was found. The drug content in the erlotinib phospholipid complex self-microemulsification system did not change, and it had good stability. The detection indicators all met the requirements.

[0142] Pharmacokinetics in rats

[0143] The pharmacokinetic experiment in rats was conducted on the irelcoxib phospholipid complex self-microemulsion prepared in Example 1 and the conventional irelcoxib original drug. The experiment specifically includes the following steps:

[0144] (1) Animal dosing and blood sample processing: Twelve SD rats weighing 200±20 g were randomly divided into two groups, each with 6 rats, including the irelcoxib raw material group and the irelcoxib phospholipid complex self-microemulsifying system group. The rats were fasted for 12 h before the experiment and were allowed to drink water freely. After the experiment, the SD rats were weighed and the blood samples were taken at 10 mg / kg. -1 The rats were gavaged at a dose of 100 mg / mL. 0.5 mL of blood was collected from the rat orbit at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h. The blood was placed in an EP tube containing sodium heparin and shaken to mix. The blood sample was then centrifuged at 10,000 rpm for 10 min at 4 °C to separate the plasma. The plasma was collected in a new centrifuge tube and stored at -20 °C for later use. 200 μL of blank plasma from SD rats was accurately transferred to a 1.5 mL EP centrifuge tube and 50 μL of 100 μg mL -1 The irbesartan solution was vortexed for 5 minutes, and then 800 μL of acetonitrile was added to precipitate plasma proteins. After vortexing for 5 minutes, the mixture was centrifuged at 4°C and 10,000 rpm for 10 minutes. The supernatant was gently taken out and filtered with a 0.45 μm filter membrane. The sample was tested and the drug concentration at each time point was calculated. The pharmacokinetic data were statistically analyzed. The results are shown in Table 7.

[0145] Table 7 Pharmacokinetic data

[0146]

[0147]

[0148] (2) Draw the drug-time curve: Draw the plasma drug-time curves of the irelcoxib API group and the irelcoxib phospholipid complex self-microemulsion group. The results are as follows: Figure 5 shown.

[0149] From the data in Table 7 and Figure 4 The pharmacokinetic parameters of the irelcoxib phospholipid complex self-emulsion prepared in Example 1 show that the MRT, C max 、T max The AUC and AUC were higher than those of the irelcoxib bulk drug group, indicating that the irelcoxib phospholipid complex self-microemulsion prepared by the present invention can significantly improve the oral absorption efficiency of irelcoxib, and the oral relative bioavailability of the irelcoxib phospholipid complex self-microemulsion relative to the irelcoxib bulk drug is 650.3%.

[0150] The applicant declares that the present invention illustrates the process method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned process steps, that is, it does not mean that the present invention must rely on the above-mentioned process steps to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0151] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0152] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A self-microemulsifying drug delivery system of levofloxacin phospholipid complex, characterized in that The composition comprises the following components by weight: 8-20 parts of erlotinib, 8-40 parts of phospholipids, 10-60 parts of oil phase, 20-75 parts of emulsifier and 15-60 parts of auxiliary emulsifier.

2. The irectocolitide phospholipid complex self-microemulsifying drug delivery system according to claim 1, characterized in that The composition comprises the following components by weight: 8-14 parts of erlotoxib, 8-30 parts of phospholipids, 12-30 parts of oil phase, 20-55 parts of emulsifier and 15-30 parts of auxiliary emulsifier.

3. The irectocolitide phospholipid complex self-microemulsifying drug delivery system according to claim 1 or 2, characterized in that: The phospholipids include any one of soybean lecithin and phospholipids, preferably soybean lecithin; The oil phase includes any one of ethyl oleate, triacetin, castor oil, and medium chain triglycerides, or a combination of at least two thereof, preferably ethyl oleate.

4. The irectocolitide phospholipid complex self-microemulsifying drug delivery system according to claim 1 or 2, characterized in that: The emulsifier includes polyoxyethylene 35 castor oil and / or polyoxyethylene hydrogenated castor oil, preferably polyoxyethylene 35 castor oil.

5. The irectocolitide phospholipid complex self-microemulsifying drug delivery system according to claim 1 or 2, characterized in that: The auxiliary emulsifier includes any one of 1,2-propylene glycol, polyethylene glycol 400, and diethylene glycol monoethyl ether, or a combination of at least two of them, preferably diethylene glycol monoethyl ether.

6. A method for preparing the irevoxib phospholipid complex self-microemulsifying drug delivery system according to any one of claims 1 to 5, characterized in that The steps include: (1) Dissolve an appropriate amount of erlotinib and phospholipid in an organic solvent, stir under constant temperature and magnetic stirring, remove the organic solvent by rotary evaporation, add 50-80 mL of dichloromethane for re-dissolution, filter, and dry under reduced pressure to obtain erlotinib phospholipid complex; (2) heating and stirring the emulsifier and the co-emulsifier on a water bath magnetic ion stirrer to mix them evenly to obtain a premixed solution; (3) The irelcoxib phospholipid complex is completely dissolved in the premixed solution, and then the oil phase is added, and the mixture is heated and stirred on a water bath magnetic ion stirrer to be uniformly mixed to obtain a self-microemulsion.

7. The method for preparing the irevoxib phospholipid complex self-microemulsifying drug delivery system according to claim 6, characterized in that: The stirring conditions of step (1) are heating in a water bath at 30-45°C and stirring at 300-500 rpm for 3-5 hours, and the rotary evaporation conditions are rotary evaporation at 40-55°C.

8. The method for preparing the irevoxib phospholipid complex self-microemulsifying drug delivery system according to claim 6, characterized in that: The conditions for uniform mixing in step (2) and step (3) are both heating in a water bath at 25-50° C. and stirring at 200-400 rpm for 10-30 min.

9. The method for preparing the irevoxib phospholipid complex self-microemulsifying drug delivery system according to claim 6, characterized in that: The microemulsion particle size of the self-microemulsion is 20.12-35.23 nm.

10. Use of the irevoxib phospholipid complex self-microemulsifying drug delivery system according to any one of claims 1 to 5 in the preparation of non-steroidal anti-inflammatory drugs.

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