Phytate gallium-tranilast-plga nanosuspension and method of making the same

Abstract

The application discloses a kind of gallium phytate-tranilast-PLGA nano suspension and preparation method thereof.It includes the following steps: under stirring condition, organic phase is added dropwise into aqueous phase, ultrasonic mixing, solvent removal;Organic phase is the mixed solution containing tranilast and PLGA;The concentration of tranilast in organic phase is 0.5g / L-2.5g / L, and the concentration of PLGA is 5g / L-25g / L;Aqueous phase is the mixed solution containing gallium phytate and polyvinyl alcohol;The volume ratio of organic phase and aqueous phase is 1:2-1:6.The gallium phytate-tranilast-PLGA nano suspension of the application, nanoparticle morphology is uniform, and has high encapsulation efficiency, high drug loading, good stability;In vitro sustained-release effect is good, and the gallium phytate loaded can effectively play antibacterial role, and tranilast can inhibit scar tissue proliferation, and lay important key foundation for subsequent development of stent surface functional coating.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical nano-preparation, in particular to a gallium phytate-triprolide-PLGA nano-suspension and a preparation method thereof. BACKGROUND

[0002] PLGA is a kind of degradable polymer compound, which is polymerized from lactic acid and glycolic acid, and its degradation product is non-toxic. The release rate can be controlled by adjusting the ratio of the two. PLGA has been proved to have good biocompatibility, good film and capsule forming properties, and sustained drug release properties, and is widely used in the field of drug preparation as a sustained-release material.

[0003] TRL is an antiallergic drug and H1 receptor blocker, which is mainly used for preventing and treating bronchial asthma and allergic rhinitis in clinic. It also has therapeutic effect on atopic dermatitis and hypertrophic scar, and can effectively inhibit the formation of collagen, cell proliferation and fibrosis, and can inhibit TGF-β1. TRL is a poorly soluble drug, which has very low solubility in water, and is easily soluble in organic solvents such as N,N-dimethylformamide and pyridine. Its bioavailability in vivo is low, so its clinical application is limited. At present, there is no related report on preparing TRL into nano-preparation, and there is no precedent of loading TRL into PLGA.

[0004] Ga 3+ ) can inhibit bacterial growth and adhesion by blocking the iron metabolism system, and has excellent antibacterial performance. Gallium ion has been approved by the US Food and Drug Administration (FDA) for clinical use, and has no toxicity to the human body. PA is a kind of natural organic phosphate polymer compound. There is no related report on chelating gallium ion and phytic acid in the prior art. SUMMARY

[0005] The present application provides a gallium phytate-triprolide-PLGA nano-suspension and a preparation method thereof.

[0006] Tranilast is a kind of oral medicine in clinic, and is an antiallergic drug, which is usually used for asthma without sustained release. At present, there is no related report on preparation of tranilast nano-preparation at home and abroad, and there is no precedent of loading tranilast by polylactic acid-glycolic acid copolymer (PLGA). Through continuous exploration and experiment of the inventors, the phytic acid gallium-tranilast-PLGA nano-suspension has good biocompatibility and no cytotoxicity; phytic acid can effectively chelate gallium ions and has antibacterial effect; tranilast can produce sustained release effect in vitro and can continuously inhibit the proliferation of scar tissue, and is expected to be applied to the functional coating of stents (with sustainable antibacterial and anti-proliferation effects). The inventors overcame many technical obstacles in the preparation of the phytic acid gallium-tranilast-PLGA nano-suspension, mainly as follows:

[0007] Firstly, the dosage relationship between tranilast and PLGA has a great influence on the encapsulation, dispersion and sustained release performance of the product. For example, in the organic phase, when the drug concentration is too low, the drug content in the system is small, and the encapsulation effect of the drug is poor; when the drug concentration is too large, the viscosity of the organic phase will increase, which will affect the formation and dispersion ability of the nanoparticles. In the organic phase, when the PLGA concentration is too low, the encapsulation efficiency is affected; when the PLGA concentration is too high, the viscosity of the system will increase and a film will be formed, which is not conducive to the dispersion and encapsulation rate of the nanoparticles.

[0008] Secondly, the volume ratio of the organic phase to the aqueous phase is called the oil-water ratio, which determines the emulsification difficulty and the stability of the nanoparticles. Too high or too low oil-water ratio will have a significant influence on the morphology, particle size and stability of the nanoparticles.

[0009] The present application solves the above technical problems through the following technical solutions.

[0010] The present application provides a preparation method of phytic acid gallium-tranilast-PLGA nano-suspension, which comprises the following steps: under stirring conditions, the organic phase is added dropwise into the aqueous phase, ultrasonic mixing, and removing the solvent to obtain the phytic acid gallium-tranilast-PLGA nano-suspension;

[0011] The organic phase is a mixed solution containing tranilast and polylactic acid-glycolic acid copolymer (PLGA); in the organic phase, the concentration of tranilast is 0.5g / L-2.5g / L; the concentration of polylactic acid-glycolic acid copolymer (PLGA) is 5g / L-25g / L;

[0012] The aqueous phase is a mixed solution containing phytic acid gallium and polyvinyl alcohol (PVA);

[0013] The volume ratio of the organic phase to the aqueous phase is 1:2-1:6.

[0014] In the present application, the emulsion (O / W) can be obtained by adding the organic phase dropwise into the aqueous phase under stirring conditions.

[0015] In the present application, the preparation method of the nanosuspension, the organic phase must be added dropwise into the aqueous phase under stirring. This specific operation can effectively disperse the organic phase in the continuous phase (aqueous phase), and under the condition of continuous stirring, the change of the oil-water surface tension of the carrier material can quickly form nanoparticles. If the aqueous phase is added into the organic phase, it is not conducive to the formation of nanoparticles.

[0016] In the present application, the stirring can be conventional in the art, and the stirring speed is generally 600-800 rpm / min.

[0017] In the present application, the speed of dropwise addition of the organic phase has no special requirements, and generally can be dispersed. The speed of dropwise addition can be uniform or non-uniform.

[0018] In the present application, the preparation method of the organic phase can be conventional in the art, and preferably includes the following steps: dissolving the triprolidine and the PLGA in an organic solvent, and stirring to dissolve sufficiently.

[0019] In the present application, the type of organic solvent in the organic phase can be a solvent that can sufficiently dissolve PLGA and the drug triprolidine in the art. The organic solvent in the organic phase is preferably a mixed solvent of halogenated alkane and alcohol.

[0020] The halogenated alkane can be dichloromethane.

[0021] The alcohol solvent can be an alcohol with a carbon atom number of 1-5, such as methanol or ethanol, and is preferably ethanol.

[0022] In the mixed solvent of halogenated alkane and alcohol, the volume ratio of halogenated alkane to alcohol can be (3-5):1, for example 4:1.

[0023] In the present application, the concentration of triprolidine in the organic phase is preferably 0.6 g / L-2.2 g / L, for example 0.8 g / L, 1 g / L, 1.2 g / L, 1.5 g / L, 1.8 g / L or 2.0 g / L.

[0024] In the present application, the concentration of polylactic acid-glycolic acid copolymer (PLGA) in the organic phase is preferably 6 g / L-22 g / L, for example 8 g / L, 10 g / L, 13 g / L, 15 g / L, 18 g / L or 20 g / L.

[0025] In the present application, the volume ratio of the organic phase to the aqueous phase is preferably 1:25-1:55, for example 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.

[0026] In the present application, the polylactic acid-glycolic acid copolymer (PLGA) is generally formed by polymerization of lactic acid and glycolic acid. In the polylactic acid-glycolic acid copolymer (PLGA), the molar ratio of polylactic acid and glycolic acid can be (40-60): 50, for example 50:50.

[0027] In the present application, the average molecular weight of the polylactic acid-glycolic acid copolymer (PLGA) can be 38000-54000 Da.

[0028] In the present application, the concentration of gallium phytate in the aqueous phase is preferably 1.0-2.0 g / L, for example 1.2 g / L, 1.5 g / L or 1.8 g / L.

[0029] In the present application, the concentration of polyvinyl alcohol in the aqueous phase is preferably 5 g / L-30 g / L, for example 7.5 g / L, 10 g / L, 15 g / L or 20 g / L.

[0030] In the present application, the preparation method of the aqueous phase can be conventional in the art, and preferably comprises the following steps: mixing the gallium phytate solution and the polyvinyl alcohol solution (PVA).

[0031] In the gallium phytate solution, the concentration of gallium phytate is preferably 2.0 g / L-6.0 g / L, for example 4.0 g / L, 5.0 g / L or 6.0 g / L.

[0032] In the polyvinyl alcohol solution (PVA), the concentration of polyvinyl alcohol PVA is preferably 5 g / L-25 g / L, for example 10 g / L, 15 g / L or 20 g / L.

[0033] In the present application, the purpose of ultrasonic is to make the primary nanodispersion system in the system more homogeneous and stable, and to make the particle size more uniform.

[0034] In the present application, the power of ultrasonic can be 80 W-150 W, for example 130 W.

[0035] In the present application, the time of ultrasonic can be conventional in the art, and is preferably 6 min-14 min, for example 8 min, 10 min, 12 min or 13 min. When the ultrasonic time is too low, the homogenization effect of the suspension is not good, resulting in different particle sizes in the suspension; when the ultrasonic time is too high, the temperature in the system rises, which can have a destructive effect on the formation of nanoparticles.

[0036] In the present application, during the ultrasonic process, it is generally required to follow ON / OFF: 2s / 1s. Here, on is set for 2s, off is set for 1s, and the time of on is the ultrasonic time.

[0037] In this invention, the solvent removal operation and conditions can be conventional in the art. For example, organic solvents can be evaporated by magnetic stirring or rotary evaporation to further improve the stability and encapsulation efficiency of the nanoparticles. The endpoint of solvent removal is generally the complete evaporation of organic solvents in the system.

[0038] In this invention, during the solvent removal process, the stirring speed can be 600-1000 r / min, for example 800 r / min.

[0039] In this invention, the stirring time during the solvent removal process can be 3-6 hours, for example, 4 hours or 5 hours.

[0040] In this invention, after the solvent removal operation, preferably, filtration is performed using a 0.22μm filter membrane.

[0041] The present invention also provides a gallium phytate-tranilast-PLGA nanosuspension prepared by the preparation method described above.

[0042] In this invention, the particle size range of the phytic acid gallium-tranister-PLGA nanosuspension can be 175nm-228nm.

[0043] In this invention, the average particle size of the nanoparticles in the gallium phytate-tranister-PLGA nanosuspension can be 183.6 nm.

[0044] This invention also provides a gallium phytate-tranilast-PLGA nanosuspension: wherein,

[0045] The nano-suspension comprises nanoparticles and a suspension; the nanoparticles comprise gallium phytate, tranilast, and polylactic-co-glycolic acid copolymer (PLGA), wherein the polylactic-co-glycolic acid copolymer (PLGA) encapsulates gallium phytate and tranilast.

[0046] The mass ratio of the tranilast to the polylactic-co-glycolic acid copolymer (PLGA) is 1:(5-15);

[0047] The mass ratio of the tranister to the gallium phytate is (2-6):1.

[0048] In this invention, the mass ratio of tranilast to polylactic-co-glycolic acid copolymer (PLGA) is preferably 1:(5.5-14), for example 1:6.67, 1:7, 1:8, 1:9, 1:10 or 1:12.

[0049] In this invention, the mass ratio of tranilast to gallium phytate is preferably (2.2-5.5):1, for example 3:1, 3.5:1, 4:1, 4.5:1 or 5:1.

[0050] In this invention, the gallium phytate-tranilast-PLGA nanosuspension can be semi-transparent.

[0051] In this invention, the phytate gallium-tranilast-PLGA nanosuspension contains nanoparticles that are regularly spherical in shape, with a particle size ranging from 175 nm to 228 nm, and are negatively charged.

[0052] In this invention, in the gallium phytate-tranilast-PLGA nanosuspension, gallium phytate, tranilast, and polylactic acid-glycolic acid copolymer (PLGA) exist primarily in an amorphous form within the nanounits.

[0053] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0054] The reagents and raw materials used in this invention are all commercially available.

[0055] The positive and progressive effects of this invention are as follows:

[0056] This invention employs an emulsification solvent evaporation method to prepare gallium phytate-tranilast-PLGA nanosuspension. The nanoparticles exhibit uniform morphology and size, with a particle size range of 175 nm to 228 nm, high encapsulation efficiency (97%-98.8%), and high drug loading (7.6%-9.8%). Furthermore, preliminary findings indicate that the nanoparticle size and zeta potential change minimally within 21 days, demonstrating good stability. The drug exhibits a sustained-release effect within 14 days, laying a crucial foundation for the subsequent development of functional coatings on the scaffold surface.

[0057] The phytate gallium-tranilast-PLGA nanosuspension of the present invention has good biocompatibility and is non-toxic to cells; phytate can effectively chelate gallium ions and has antibacterial effect, while improving the bioavailability of tranilast. Tranilast can produce a sustained-release effect in vitro and can continuously inhibit the proliferation of scar tissue. Attached Figure Description

[0058] Figure 1 This is a transmission electron microscope (TEM) image of the gallium phytate-tranister-PLGA nanosuspension prepared in Example 2.

[0059] Figure 2 The particle size and zeta potential of the gallium phytate-tranister-PLGA nanosuspension prepared in Example 2 are shown.

[0060] Figure 3 The particle size and zeta potential of the gallium phytate-tranister-PLGA nanosuspension prepared in Example 2 after being left for different times are shown.

[0061] Figure 4This refers to the in vitro drug release of the gallium phytate-tranilast-PLGA nanosuspension and the pure drug prepared in Example 2. Detailed Implementation

[0062] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0063] In the following examples, the main raw materials are sourced from the following sources:

[0064] PLGA was purchased from Shanghai Maclean Biotechnology Co., Ltd. (GA:LA was 50:50; molecular weight was 38,000-54,000); tranilast was purchased from Shanghai Aladdin Biotechnology Co., Ltd.; 70% phytic acid solution was purchased from Shanghai Maclean Biotechnology Co., Ltd.; gallium(III) nitrate hydrate was purchased from Shanghai Maclean Biotechnology Co., Ltd.; PVA powder was purchased from Sigma-Aldrich.

[0065] Example 1

[0066] 225 mg PLGA and 15 mg tranilast were dissolved in 15 mL of a dichloromethane-ethanol (4:1) mixture as the organic phase, and a mixture of 10 mL of 6 g / L gallium phytate solution and 30 mL of 20 g / L PVA aqueous solution as the aqueous phase. Under stirring (600 rpm / min), the organic phase was added dropwise to the aqueous phase. The mixture was sonicated at 130 W for 10 min (ON / OFF: 2 s / 1 s; here it means 2 s on and 1 s off, with a total on time of 10 min). The mixture was stirred at 800 r / min for 4 h to evaporate the organic solvent. The solution was then filtered through a 0.22 μm filter membrane to obtain a gallium phytate-tranilast-PLGA nanosuspension.

[0067] Example 2

[0068] 150 mg PLGA and 15 mg tranilast were dissolved in 15 mL of a dichloromethane-ethanol (4:1) mixture as the organic phase, and a mixture of 10 mL of 6 g / L gallium phytate solution and 30 mL of 20 g / L PVA aqueous solution as the aqueous phase. Under stirring (600 rpm / min), the organic phase was added dropwise to the aqueous phase. The mixture was sonicated at 130 W for 10 min (ON / OFF: 2 s / 1 s), and stirred at 800 r / min for 4 h to evaporate the organic solvent. The mixture was then filtered through a 0.22 μm filter membrane to obtain a gallium phytate-tranilast-PLGA nanosuspension.

[0069] Figure 1This is a transmission electron microscope (TEM) image of the gallium phytate-tranister-PLGA nanosuspension prepared in Example 2.

[0070] Example 3

[0071] 150 mg PLGA and 22.5 mg tranilast were dissolved in 15 mL of a dichloromethane-ethanol (4:1) mixture as the organic phase, and a mixture of 10 mL of 6 g / L gallium phytate solution and 30 mL of 20 g / L PVA aqueous solution as the aqueous phase. Under stirring conditions (600 rpm / min), the organic phase was added dropwise to the aqueous phase. The mixture was sonicated at 130 W for 10 min (ON / OFF: 2 s / 1 s), and stirred at 800 r / min for 4 h to evaporate the organic solvent. The mixture was then filtered through a 0.22 μm filter membrane to obtain a gallium phytate-tranilast-PLGA nanosuspension.

[0072] Example 4

[0073] 150 mg PLGA and 15 mg tranilast were dissolved in 15 mL of a dichloromethane-ethanol (4:1) mixture as the organic phase, and a mixture of 10 mL of 6 g / L gallium phytate solution and 30 mL of 20 g / L PVA aqueous solution as the aqueous phase. Under stirring (600 rpm / min), the organic phase was added dropwise to the aqueous phase. The mixture was sonicated at 130 W for 12 min (ON / OFF: 2 s / 1 s), and stirred at 800 r / min for 4 h to evaporate the organic solvent. The mixture was then filtered through a 0.22 μm filter membrane to obtain a gallium phytate-tranilast-PLGA nanosuspension.

[0074] Example 5

[0075] 150 mg PLGA and 15 mg tranilast were dissolved in 15 mL of a dichloromethane-ethanol (4:1) mixture as the organic phase, and a mixture of 10 mL of 6 g / L gallium phytate solution and 30 mL of 10 g / L PVA aqueous solution as the aqueous phase. Under stirring (600 rpm / min), the organic phase was added dropwise to the aqueous phase. The mixture was sonicated at 130 W for 10 min (ON / OFF: 2 s / 1 s), and stirred at 800 r / min for 4 h to evaporate the organic solvent. The mixture was then filtered through a 0.22 μm filter membrane to obtain a gallium phytate-tranilast-PLGA nanosuspension.

[0076] Example 6

[0077] 75 mg PLGA and 15 mg tranilast were dissolved in 15 mL of a dichloromethane-ethanol (4:1) mixture as the organic phase, and a mixture of 10 mL of 6 g / L gallium phytate solution and 30 mL of 20 g / L PVA aqueous solution as the aqueous phase. Under stirring (600 rpm / min), the organic phase was added dropwise to the aqueous phase. The mixture was sonicated at 130 W for 10 min (ON / OFF: 2 s / 1 s), and stirred at 800 r / min for 4 h to evaporate the organic solvent. The mixture was then filtered through a 0.22 μm filter membrane to obtain a gallium phytate-tranilast-PLGA nanosuspension.

[0078] Example 7

[0079] 150 mg PLGA and 15 mg tranilast were dissolved in 15 mL of a dichloromethane-ethanol (4:1) mixture as the organic phase, and a mixture of 15 mL of 6 g / L gallium phytate solution and 45 mL of 20 g / L PVA aqueous solution as the aqueous phase. Under stirring conditions (600 rpm / min), the organic phase was added dropwise to the aqueous phase. The mixture was sonicated at 130 W for 10 min (ON / OFF: 2 s / 1 s), and stirred at 800 r / min for 4 h to evaporate the organic solvent. The mixture was then filtered through a 0.22 μm filter membrane to obtain a gallium phytate-tranilast-PLGA nanosuspension.

[0080] Effect Example

[0081] 1. Determination of particle size and zeta potential

[0082] Three portions of each nano-suspension were diluted 40 times with deionized water for testing. The particle size, zeta potential, and polydispersity index (PDI) of the drug-loaded nanoparticles were determined using a Malvern laser particle size analyzer. The results are shown in Table 1. Figure 2 .

[0083] 2. Preliminary stability of gallium phytate-tranilast-PLGA nanosuspension

[0084] Samples were taken at 1d, 3d, 7d, 14d, and 21d to determine particle size and zeta potential. The results are shown in the figure. Figure 3 The testing method is the same as before.

[0085] Figure 3 The particle size and zeta potential of the gallium phytate-tranister-PLGA nanosuspension prepared in Example 2 are shown. Figure 3 In the study, the particle size and zeta potential of the samples were initially investigated at different time points. The particle size changed slightly within 21 days, but the impact on the overall size was small. The zeta potential remained at around -14mV, indicating good stability.

[0086] 3. Determination of encapsulation efficiency and drug loading

[0087] The encapsulation efficiency and drug loading of gallium phytate-tranilast-PLGA nanosuspension were determined by ultrafiltration centrifugation. 200 μL of gallium phytate-tranilast-PLGA nanosuspension from Examples 1-7 were placed in an ultrafiltration tube (molecular weight cutoff of 3 kDa), centrifuged at 12000 rpm / min for 30 min, and the free drug solution in the outer tube was replenished with deionized water to 200 μL. The sample was injected and measured under the chromatographic conditions described below, and the mass of free tranilast was calculated as m1. 100 μL of gallium phytate-tranilast-PLGA nanosuspension from Examples 1-7 were placed in a 5 mL volumetric flask, 0.5 mL of acetone was added, sonicated for 5 min, and allowed to stand for 30 min. The solution was then diluted to the mark with methanol, filtered through a 0.45 μm filter membrane, and the sample was injected and measured under the chromatographic conditions described below, and the mass of tranilast was calculated as m2. All measurements were performed in triplicate. The encapsulation efficiency and drug loading of the gallium phytate-tranilast-PLGA nanoparticles were calculated according to the following formula, and the results are shown in Table 1.

[0088] Chromatographic conditions:

[0089] Column: Kromasil 100-5-C18 (4.6mm × 250mm, 5μm)

[0090] Mobile phase: Methanol-0.02 mol / L potassium dihydrogen phosphate solution (63:37)

[0091] Flow rate: 1.0 mL / min

[0092] Column temperature: 30℃

[0093] Detection wavelength: 333nm

[0094] Injection volume: 20 μL

[0095] formula:

[0096] Encapsulation efficiency = [(m2-m1) / m2] × 100%

[0097] Drug loading capacity = [(m2-m1) / m PLGA +m 药物 ]×100%

[0098] Table 1. Particle size, PDI, Zeta potential, encapsulation efficiency, and drug loading of nano-suspensions in Examples 1-7

[0099] Example Particle size (nm) Encapsulation efficiency (%) Zeta potential (mV) PDI Drug loading (%) Example 1 186.5±1.05 97.05±0.03 -11.21±0.03 0.081±0.002 9.8±0.01 Example 2 183.6±8.18 98.79±0.01 -14.27±0.77 0.071±0.009 8.5±0.01 Example 3 227.4±0.66 97.19±0.01 -12.22±0.83 0.144±0.005 8.60±0.01 Example 4 217.7±5.83 97.06±0.01 -8.84±0.77 0.058±0.003 8.5±0.01 Example 5 226.6±1.85 97.32±0.03 -14.81±0.29 0.060±0.002 7.6±0.01 Example 6 200.5±2.01 97.04±0.01 -12.82±0.37 0.199±0.001 7.7±0.10 Example 7 213.9±0.70 98.10±0.01 -12.70±0.37 0.074±0.004 9.4±0.01

[0100] Note: The data in Table 1 were measured directly from the suspensions in the examples without any placement. All particle sizes are median particle sizes, taking the value with the largest percentage, and are the average of three measurements. Smaller particle sizes are more stable for absorption and entry into the body. A smaller PDI indicates that the molecular weights are closer and more homogeneous.

[0101] 4. In vitro drug release

[0102] The in vitro drug release characteristics of gallium phytate-tranilast-PLGA nanosuspension were investigated using dialysis.

[0103] Take 4 mL of the gallium phytate-tranilast-PLGA nanosuspension prepared in Example 2, and calculate the drug mass of the suspension by HPLC to determine the drug content as 1.8 mg.

[0104] Four mL of the gallium phytate-tranilast-PLGA nanosuspension prepared in Example 2 and 1.8 mg of the pure drug group (i.e., the control group) were placed in dialysis bags with a molecular weight cutoff of 3500 (purchased from Shanghai Yuanye Biotechnology Co., Ltd., MD3525-5m). The two ends of the dialysis bag were clamped together using a dialysis bag clamp. 400 mL of PBS solution was used as the drug release medium (meeting the leakage conditions). The drug dissolution speed and release temperature were set to 100 rpm / min and 37℃, respectively. Two mL samples were taken at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 2 d, 3 d, 4 d, 5 d, 7 d, 10 d, and 14 d, and 2 mL of PBS solution was added to maintain a constant total volume. After filtering the samples through a 0.22 μm filter membrane, they were injected under the above chromatographic conditions. The cumulative drug release rate and the cumulative percentage of drug release from the nanoparticles were calculated. The results are shown in […]. Figure 4 .

[0105] Depend on Figure 4 It can be seen that the phytate gallium-tranilast-PLGA nanosuspension prepared in Example 2 exhibited a sustained release pattern in vitro, showing a significant sustained-release trend compared to the control group (i.e., the pure drug group). The control group released all of its drug within approximately 6 hours, reaching 96.8%. The phytate gallium-tranilast-PLGA nanosuspension prepared in Example 2 released 66.9% of its drug in the first 24 hours, subsequently showing a sustained-release trend, with a cumulative release rate of 89.7% after 14 days. Specific cumulative release rate data are shown in Table 2 below.

[0106] Table 2

[0107]

Claims

1. A method for preparing a gallium phytate-tunicsfonate-PLGA nanosuspension, characterized in that, It comprises the following steps: under stirring conditions, the organic phase is added dropwise into the aqueous phase, ultrasonic mixing, solvent removal, and the preparation of the gallium phytate-tranilast-PLGA nanosuspension; The organic phase is a mixed solution containing tranilast and polylactic acid-glycolic acid copolymer; in the organic phase, the concentration of tranilast is 0.5g / L-1.2g / L; the concentration of polylactic acid-glycolic acid copolymer is 6g / L-15g / L; The aqueous phase is a mixed solution containing gallium phytate and polyvinyl alcohol; In the aqueous phase, the concentration of gallium phytate is 1.0-2.0g / L; In the aqueous phase, the concentration of polyvinyl alcohol is 10g / L-15g / L; The volume ratio of the organic phase to the aqueous phase is 1:2-1:4.5; In the gallium phytate-tranilast-PLGA nanosuspension, the particle size of the nanoparticles ranges from 175nm to 228nm; The organic solvent in the organic phase is a mixed solvent of halogenated alkane and alcohol solvent; the halogenated alkane is dichloromethane; the alcohol solvent is ethanol; in the mixed solvent of halogenated alkane and alcohol solvent, the volume ratio of halogenated alkane to alcohol solvent is 4:1; The power of the ultrasonic is 80W-150W; the time of the ultrasonic is 6min-14min; during the ultrasonic process, it is carried out according to the requirement of ON / OFF: 2s / 1s.

2. The method of preparing the gallium phytate-cornipyrrol -PLGA nanosuspension as claimed in claim 1, wherein, In the organic phase, the concentration of tranilast is 0.6g / L-1.2g / L.

3. The method of preparing the gallium phytate-trientine-PLGA nanosuspension as claimed in claim 2, wherein, The preparation method meets one or more of the following conditions ①-③: ①In the organic phase, the concentration of tranilast is 0.8g / L, 1g / L or 1.2g / L; ②In the organic phase, the concentration of polylactic acid-glycolic acid copolymer is 8g / L, 10g / L, 13g / L or 15g / L; and, ③The volume ratio of the organic phase to the aqueous phase is 1:3, 1:3.5, 1:4 or 1:4.

5.

4. The method of preparing the gallium phytate-cornipyrrol -PLGA nanosuspension as claimed in claim 1, wherein, The preparation method meets one or more of the following conditions ①-④: ①In the aqueous phase, the concentration of gallium phytate is 1.2g / L, 1.5g / L or 1.8g / L; ②In the aqueous phase, the concentration of polyvinyl alcohol is 10g / L or 15g / L; ③The power of the ultrasonic is 130W; and, ④The time of the ultrasonic is 8min, 10min, 12min or 13min.

5. The method of preparing the gallium phytate-tunicoside-PLGA nanosuspension as claimed in claim 1, wherein, The preparation method meets one or more of the following conditions ①-⑤: ①The preparation method of the organic phase comprises the following steps: dissolving the tranilast and the PLGA in the organic solvent, and stirring to fully dissolve; ②In the polylactic acid-glycolic acid copolymer, the molar ratio of polylactic acid to glycolic acid is (40-60):50; ③The average molecular weight of the polylactic acid-glycolic acid copolymer PLGA is 38000-54000Da; ④The preparation method of the aqueous phase comprises the following steps: mixing the gallium phytate solution and the polyvinyl alcohol solution; and, ⑤The stirring speed is 600-800rpm / min. The preparation method meets one or more of the following conditions ①-③:

6. The method of preparing the gallium phytate-cuonamstec-PLGA nanosuspension as claimed in claim 5, wherein, ​ The molar ratio of polylactic acid and glycolic acid in the polylactic acid-glycolic acid copolymer is 50:

50. The concentration of gallium phytate in the gallium phytate solution is 2.0 g / L-6.0 g / L; and The concentration of polyvinyl alcohol in the polyvinyl alcohol solution is 5 g / L-25 g / L.

7. The method of preparing the gallium phytate-cuonamstec-PLGA nanosuspension as claimed in claim 6, wherein The concentration of gallium phytate in the gallium phytate solution is 4.0 g / L, 5.0 g / L or 6.0 g / L; And / or, the concentration of polyvinyl alcohol in the polyvinyl alcohol solution is 10 g / L, 15 g / L or 20 g / L.

8. A gallium phytate-triprolide-PLGA nanosuspension prepared by the preparation method of any one of claims 1-7.

9. The gallium phytate-tunicoside-PLGA nanosuspension of claim 8, wherein, The nanosuspension comprises nanoparticles and a suspension; the nanoparticles comprise gallium phytate, triprolid and polylactic acid-glycolic acid copolymer, and the polylactic acid-glycolic acid copolymer wraps the gallium phytate and triprolid; The mass ratio of the triprolid and the polylactic acid-glycolic acid copolymer is 1:(7-15).

10. The gallium phytate-tunicoside-PLGA nanosuspension of claim 9, wherein, The gallium phytate-triprolide-PLGA nanosuspension meets one or more of the following conditions ①-③: The mass ratio of the triprolid and the polylactic acid-glycolic acid copolymer is 1:(7-14); The particle size of the nanoparticles in the gallium phytate-triprolide-PLGA nanosuspension is in the range of 175 nm-228 nm; and The gallium phytate, the triprolid and the polylactic acid-glycolic acid copolymer in the gallium phytate-triprolide-PLGA nanosuspension substantially exist in the form of amorphous state in the nanounit.

11. The gallium phytate-tunicoside-PLGA nanosuspension of claim 9, wherein, The mass ratio of the triprolid and the polylactic acid-glycolic acid copolymer is 1:7, 1:8, 1:9, 1:10 or 1:12.

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