Self-nanoemulsion drug release system

Abstract

The present invention relates to a self-nanoemulsion drug release system comprising an oil phase and / or an emulsifier and / or a co-emulsifier. The oil phase is prepared from MCT 70, Labrafac Lipophile WL 1349, GTCC, IPM, Labrafil M 1944 CS, Labrafil M 2125 CS, Ethyl oil or any combination of the MCT 70, the Labrafac Lipophile WL 1349, the GTCC, the IPM, the Labrafil M 1944 CS, the Labrafil M 2125 CS and the Ethyl oil; the emulsifying agent is prepared from Tween 80, HS 15, Cremophor EL, Kolliphor ELP, Cremophor RH40 or any combination of the Tween 80, the HS 15, the Cremophor EL, the Kolliphor ELP and the Cremophor RH40; the co-emulsifier is prepared from PEG (Polyethylene Glycol) 200, Transcutol HP, Transcutol P, PEG 400 or any combination of the PEG 200, the Transcutol HP, the Transcutol P and the PEG 400. By utilizing the system, the solubility and permeability of the medicine can be improved, and the absorption of the medicine is enhanced.

Description

Technical Field

[0001] The invention relates to a self-nanoemulsion drug release system, and more particularly to a self-nanoemulsion drug release system of ginkgolide drugs. Background Art

[0002] In recent years, component Chinese medicine has increasingly become a research hotspot for scholars of traditional Chinese medicine. Component Chinese medicine emphasizes the integrity of Chinese medicine, attaches importance to the contribution of each component to the overall efficacy, and emphasizes the synergistic or antagonistic effects between components to achieve therapeutic effects. The active ingredients of Chinese medicine components are complex and diverse, and most of them are limited in their development and application due to low solubility. For example, many flavonoids, terpenes, and alkaloids have good pharmacological activity, but their poor solubility affects their release and absorption in the body, which seriously affects their efficacy. From the perspective of pharmaceutical research, the effective synchronous release of each component of Chinese medicine components is the key to achieving therapeutic effects. Therefore, how to use appropriate formulation methods in a targeted manner to effectively improve the solubility of Chinese medicine components and achieve synchronous release of each component is of great significance to the development and application of component Chinese medicine.

[0003] Ginkgolide components (GKC) are one of the main effective components for the treatment of cardiovascular and cerebrovascular diseases. However, the solubility of GKC components is poor, which limits its absorption in the body after oral administration; GKC is easily opened and inactivated in an alkaline environment; in addition, the half-life of GKC is short, which makes the administration too frequent. Summary of the invention

[0004] In order to improve the solubility of drugs after oral administration, prolong the retention time of drugs in the stomach, and improve their bioavailability, the present invention provides a self-nanoemulsion drug release system, characterized in that: it comprises a preparation composed of active ingredients and excipients,

[0005] The system comprises an oil phase and / or an emulsifier and / or an emulsifier assistant; the active ingredient ginkgolide drugs include ginkgolide K, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and / or bilobalide.

[0006] Optionally, the ginkgolide drug GKC mainly includes ginkgolide A and ginkgolide B, and the weight ratio of the two is GA content: 30%-35%, GB content: 55%-60%. Preferably, GA content: 33.0%, GB content: 57.1%.

[0007] Specifically, the oil phase includes MCT 70, Labrafac Lipophile WL 1349, GTCC, IPM, Labrafil M 1944CS, Labrafil M 2125CS, Ethyl oleate or any combination thereof; the emulsifier includes Tween 80, HS15, Cremophor EL, Kolliphor ELP, Cremophor RH40 or any combination thereof; the co-emulsifier includes PEG 200, Transcutol HP, Transcutol P, PEG 400 or any combination thereof;

[0008] Preferably, the oil phase is MCT 70, Labrafac Lipophile WL 1349, GTCC, the emulsifier is Tween 80, HS15, Cremophor EL and Kolliphor ELP, and the co-emulsifier is PEG 200, Transcutol HP, Transcutol P.

[0009] Specifically, the usage ratio of the oil phase: emulsifier: co-emulsifier is 10-40%: 20-60%: 15-50%; preferably, it is 15-30%: 30-60%: 20-50%; more preferably, it is 15-20%: 30-40%: 40-50%; most preferably, it is 15-16.5%: 34-35.5%: 48-50%.

[0010] The total drug loading of the ginkgolide component is 20-200 mg·mL -1 , the particle size of the nanoemulsion after emulsification is 20-500nm;

[0011] Preferably, the total drug loading of the ginkgolide component is 50-100 mg·mL -1 , the particle size of the nanoemulsion after emulsification is 20-200nm;

[0012] More preferably, the total drug loading of the ginkgolide component is 50-80 mg·mL -1 , the particle size of the nanoemulsion after emulsification is 20-50nm.

[0013] Most preferably, the total drug loading of the ginkgolide component is 65-80 mg·mL -1 , the particle size of the nanoemulsion after emulsification is 30-40nm.

[0014] Furthermore, it also includes a precipitation inhibitor; the precipitation inhibitor includes: HPMC K4M, HPMC E15LV, PVPK30, PS-630 or any combination thereof; the dosage is 0.01-2%, preferably 0.1-1%, more preferably 0.5%-1%.

[0015] Furthermore, the dissolution rate of the ginkgolide component or any component thereof is greater than 90% within 5 minutes, and / or the cumulative release rate within 60 minutes is greater than 90%.

[0016] Furthermore, the self-nanoemulsion drug release system is a solid supersaturated self-nanoemulsified preparation.

[0017] The solid supersaturated self-nanoemulsified preparation is solidified by direct adsorption method. The solidification step comprises adding GKC-S-SNEDDS (saturated self-nanoemulsified preparation) drop by drop into the solidified material, grinding while adding drop by drop, and drying to obtain the solid supersaturated self-nanoemulsified preparation.

[0018] Furthermore, the solidifying material in the solid supersaturated self-nanoemulsifying preparation includes a poorly soluble carrier and a water-soluble carrier; further, it includes lactose, PEG 4000, microcrystalline cellulose, Aerosil 200, Aerosil 300, SyloidAL-1FP, Syloid244FP, Syloid XDP3050, Syloid XDP3150 or any combination thereof.

[0019] Specifically, the particle size of the solid supersaturated self-nanoemulsifying preparation after self-emulsification is 20-200 nm, more preferably 20-50 nm.

[0020] Furthermore, the cumulative dissolution rate of the ginkgolide component or any component thereof within 10 minutes is greater than 90%.

[0021] Specifically, the ginkgolides in the system are substantially in a non-crystalline form.

[0022] Further, the PXRD pattern of the solid supersaturated self-nanoemulsified preparation (solid GKC-S-SNEDDS) is as follows: Figure 8 shown.

[0023] The present invention also proposes a dosage form comprising any of the above self-nanoemulsion drug release systems, such as an oral dosage form, an injection dosage form or an external administration preparation. Further, it is selected from decoctions, granules, capsules, tablets, pills, oral liquids, tinctures, syrups, suppositories, gels, sprays, injections, etc. Preferably, it is a gastric floating controlled release preparation.

[0024] The present invention also provides a self-nanoemulsion drug release system, which comprises an oil phase and / or an emulsifier and / or an auxiliary emulsifier; the oil phase comprises MCT 70, Labrafac Lipophile WL 1349, GTCC, IPM, Labrafil M1944CS, Labrafil M 2125CS, Ethyl oleate or any combination thereof; the emulsifier comprises Tween 80, HS15, Cremophor EL, Kolliphor ELP, Cremophor RH40 or any combination thereof; the auxiliary emulsifier comprises PEG 200, Transcutol HP, Transcutol P, PEG 400 or any combination thereof.

[0025] Specifically, the usage ratio of the oil phase: emulsifier: co-emulsifier is 10-40%: 20-60%: 15-50%; preferably, it is 15-30%: 30-60%: 20-50%; more preferably, it is 15-20%: 30-40%: 40-50%; most preferably, it is 15-16.5%: 34-35.5%: 48-50%.

[0026] Furthermore, it also includes a precipitation inhibitor; the precipitation inhibitor includes: HPMC K4M, HPMC E15LV, PVPK30, PS-630 or any combination thereof; the dosage is 0.01-2%, preferably 0.1-1%, more preferably 0.5%-1%.

[0027] The weight ratio of each formula of GKC-S-SNEDDS is preferably 15.43% GTCC, 34.57% Kolliphor HS15, 50% Transcutol HP, and 0.5% PS-630.

[0028] Furthermore, the self-nanoemulsion drug release system is a solid supersaturated self-nanoemulsified preparation.

[0029] The solid supersaturated self-nanoemulsified preparation is solidified by direct adsorption method. The solidification step comprises adding GKC-S-SNEDDS drop by drop into the solidified material, grinding while adding drop by drop, and drying to obtain the solid supersaturated self-nanoemulsion.

[0030] Furthermore, the solidifying material in the solid supersaturated self-nanoemulsifying preparation includes a poorly soluble carrier and a water-soluble carrier; further, it includes lactose, PEG 4000, microcrystalline cellulose, Aerosil 200, Aerosil 300, SyloidAL-1FP, Syloid244FP, Syloid XDP3050, Syloid XDP3150 or any combination thereof.

[0031] Specifically, the particle size of the solid supersaturated self-nanoemulsifying preparation after self-emulsification is 20-200 nm, more preferably 20-50 nm.

[0032] Compared with common preparations, the beneficial effects of the present invention are: 1. The product of the present invention can improve the solubility and permeability of the drug and enhance the absorption of the drug. 2. The product of the present invention has a smaller drug loading amount but can achieve a higher bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Comparison of self-emulsification areas for screening surfactants;

[0034] Figure 2 Comparison of self-emulsification areas for screening surfactants;

[0035] Figure 3 The effects of precipitation inhibition of different supersaturated additives on GA (A) and GB (B);

[0036] Figure 4 The effects of different amounts of PS-630 precipitation inhibition on GA (A) and GB (B);

[0037] Figure 5 The transmission electron microscopy morphology of GKC-S-SNEDDs after dilution with water;

[0038] Figure 6 Release curves of GA (A) and GB (B) at pH 1.2HCl (n=3);

[0039] Figure 7 The drug release capacity of different adsorbent materials for GA (A) and GB (B) in hydrochloric acid at pH 1.2;

[0040] Figure 8 is the powder X-ray diffraction pattern of the solid state;

[0041] Fig. 9 The transmission electron microscopy morphology of solid GKC-S-SNEDDs after dilution with water;

[0042] Fig.10 Release curves of GA (A) and GB (B) in solid GKC-S-SNEDDS and GKC-S-SNEDDS (n=3). DETAILED DESCRIPTION

[0043] The following is a more detailed description of the specific embodiments of the present invention in conjunction with the accompanying drawings and examples, so that the scheme of the present invention and its advantages in various aspects can be better understood. However, the specific embodiments and examples described below are only for the purpose of illustration, rather than for limiting the present invention.

[0044] Example 1 Preparation of Ginkgolide Supersaturated Self-nanoemulsion

[0045] Table 1. Instruments used in the experiment

[0046]

[0047]

[0048] Table 2. Raw materials used in the experiment

[0049]

[0050]

[0051] 1.1 Determination of equilibrium solubility of different excipients for ginkgolide components

[0052] According to the properties of each excipient, several candidate excipients were selected for the oil phase (MCT 70, Labrafac Lipophile WL 1349, GTCC, IPM, Labrafil M 1944CS, Labrafil M 2125CS, Ethyl oleate), emulsifier (Tween 80, HS15, Cremophor EL, Kolliphor ELP, Cremophor RH40), and co-emulsifier (PEG 200, Transcutol HP, Transcutol P, PEG 400) for GKC-SNEDDS formulation screening. Excessive amounts of ginkgolide API were added to a certain amount of excipients, sealed and vortexed to mix, ultrasonicated until no longer dissolved, and then spun at 100 r·min. -1 , 37 ± 0.5 ° C constant temperature shaker for 72 hours to reach dissolution equilibrium. Then place it at a speed of 10000 r / min -1 The mixture was centrifuged in a centrifuge for 10 min, an appropriate amount of supernatant was accurately taken and diluted with methanol to an appropriate concentration, and after filtering with a 0.22 μm microporous filter membrane, the saturated solubility of each auxiliary material in GA and GB was determined by HPLC.

[0053] Conclusion: The oil-phase excipients screened for formulations all had low solubility for the ginkgolide component. Among them, the solubility for GKC was from high to low: MCT 70, Labrafac Lipophile WL 1349, GTCC, IPM. Among the different emulsifiers, the total solubility for the ginkgolide component was in the following order: Tween 80>HS 15>Cremophor EL>KolliphorELP>Cremophor RH40. The co-emulsifiers used in the experiment all had a large equilibrium solubility for the ginkgolide component, among which PEG 200 had the largest solubility, followed by Transcutol HP and Transcutol P, and the smallest was PEG 400. See Table 3 for details.

[0054] Table 3. Equilibrium solubility of different excipients for ginkgolide components (n=3)

[0055]

[0056]

[0057] In order to maximize the drug loading and emulsification ability of GKC-SNEDDS, several excipients with greater solubility for ginkgolide components were selected for further screening. MCT 70, Labrafac Lipophile WL1349, and GTCC were selected as the oil phase, Tween 80, HS15, Cremophor EL, and Kolliphor ELP were selected as the emulsifiers, and PEG200, Transcutol HP, and Transcutol P were selected as the co-emulsifiers.

[0058] 1.2 Phase separation experiment

[0059] Good mutual solubility between excipients is an important indicator for screening excipients suitable for self-nanoemulsion preparations. Weigh the oil phase, emulsifier and co-emulsifier in a mass ratio of 1:2:2, use a vortex mixer to fully mix the excipients, let it stand for a period of time, and visually inspect whether the mixed solution is turbid or stratified. If the visual observation phenomenon is not obvious, centrifuge the mixed solution at 3000r·min-1 for 15min and observe it. The experimental results can be seen in Table 4.

[0060] From the results of the phase separation experiment, it can be seen that PEG200, the oil phase and the emulsifier used in the experiment all showed stratification after being mixed and allowed to stand. Therefore, in the next step of prescription screening, only Transcutol HP and Transcutol P were used as emulsifiers.

[0061] Table 4. Phase separation experimental results

[0062]

[0063]

[0064] 1.3 Screening of oil phase, emulsifier and co-emulsifier

[0065] The emulsifier and the co-emulsifier were mixed in a certain ratio (Km = 3:1, 2:1, 1:1, 1:2, 1:3) to obtain a mixed surfactant (S), and then the oil phase (O) and the mixed surfactant (S) were weighed in a ratio of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 9:1, respectively. The total oil mass was 1g. After mixing evenly, they were slowly added dropwise to 100mL of purified water in a 37°C water bath at 100r·min-1. The state of the emulsion was observed, and the grade of the emulsion was evaluated according to Table 5. The oil phase, surfactant and co-surfactant were the three sides of an equilateral triangle, and the ternary phase diagram was drawn using Origin 2018 software. The corresponding points of the experimental groups that could form grades A and B in the ternary phase diagram were connected to determine the optimal self-nanoemulsification area, and the emulsification area of ​​the enclosed area was calculated using Image J software. The size of the emulsified area that can be formed was compared.

[0066] Emulsification effect classification

[0067]

[0068] (1) Screening of oil phase

[0069] Carry out cross-compatibility experiments according to Table 5 and draw the corresponding ternary phase diagram.

[0070] From the results of the self-emulsification area of ​​the ternary phase diagram, it can be seen that when the types of emulsifiers and co-emulsifiers used are fixed, the self-emulsification area of ​​GTCC with the oil phase is larger than that of MCT 70 and Labrafac Lipophile WL 1349, indicating that GTCC has the strongest emulsification ability, followed by MCT 70, and Labrafac Lipophile WL 1349 has the weakest emulsification ability.

[0071] Table 5. Prescription design for screening oil phase type

[0072]

[0073]

[0074] Table 6. Results of self-emulsification area of ​​ternary phase diagram

[0075]

[0076] (2) Screening of emulsifiers

[0077] The types of fixed oil phase and co-emulsifier remain unchanged, and the emulsification ability of different emulsifiers is compared, that is, the size of the self-emulsification area formed is compared. When GTCC is used in the oil phase, whether the co-emulsifier is Transcutol HP ( Figure 1 ) or Transcutol P( Figure 2 ), the emulsifying ability of the four emulsifiers investigated was in the following order: Kolliphor ELP>Kolliphor HS 15>Cremophor EL>Tween 80. Combining the results of the equilibrium solubility test of different excipients on the ginkgolide components, the equilibrium solubility of Kolliphor ELP on GKC was only 7.56 mg·mL -1 , while the saturated solubility of Kolliphor HS 15 for GKC was 48.48 mg·mL -1 In order to increase the drug loading capacity of GKC-SNEDDS, Kolliphor HS 15 is preferably used as the emulsifier in the formulation.

[0078] (3) Screening of emulsifier

[0079] After screening, it was found that the oil phase and emulsifier were GTCC and KolliphorHS 15 respectively. When the auxiliary emulsifier was Transcutol HP, the area of ​​the self-emulsification region formed was 1059766; when the auxiliary emulsifier was Transcutol P, the area of ​​the self-emulsification region formed in the ternary phase diagram was 1020116. When the oil phase was GTCC and the emulsifier was KolliphorHS 15, the emulsification ability of Transcutol HP was stronger than that of Transcutol P. Therefore, Transcutol HP was selected as the auxiliary emulsifier.

[0080] 1.4 Optimizing prescription

[0081] In order to further determine the specific dosage of each phase, this study used D-optimal mixture design combined with normalization method for comprehensive evaluation to optimize the prescription.

[0082] According to the above experimental results, the independent variables and their ranges are: X1 = oil phase ratio (%), 15-30%; X2 = emulsifier ratio (%), 30-60%; X3 = co-emulsifier ratio (%), 20-50%. Y1 = drug loading (mg·mL -1 ) and Y2 = particle size of the nanoemulsion after dilution (nm) were used as the evaluation indicators. Design Expert 12 software was used for experimental design. GTCC, KolliphorHS 15, and TranscutolHP were weighed according to the experimental design table, and an excess of ginkgolide raw materials were added, vortexed and dissolved by ultrasound, and then heated at 37°C and 100 r·min.-1 The mixture was balanced in a constant temperature shaker for 72 hours, then centrifuged, the supernatant was taken, appropriately diluted with methanol, and the total drug loading was determined according to the chromatographic conditions. At the same time, the particle size of the nanoemulsion after each group of preparations was diluted 100 times was measured with a particle size analyzer.

[0083] Chromatographic conditions:

[0084] In this paper, high performance liquid chromatography was used to determine the contents of GA and GB.

[0085] Chromatographic column: YMC-Pack ODS-A column (150*4.6mm, 5μm);

[0086] Mobile phase: water-methanol-isopropanol (86:7:7, v / v / v);

[0087] Detection wavelength: 220nm;

[0088] Column temperature: 40°C;

[0089] Flow rate: 1.0 mL min-1;

[0090] Injection volume: 20 μL.

[0091] Table 7. Experimental results of D-optimal mixture design (n=3)

[0092]

[0093] The optimal dosage of GKC-SNEDDS was determined to be: 15.43% GTCC, 34.57% KolliphorHS 15, 50% Transcutol HP. And experimentally determined, the total drug loading of the ginkgolide component in this prescription was (66.71±0.26) mg·mL -1 The particle size of the nanoemulsion after emulsification was (35.38±1.80) nm, and this prescription was used as the basis for subsequent screening experiments. At the same time, based on the above calculation results, according to the prescription of 15.01% GTCC, 35.33% KolliphorHS 15, and 49.66% Transcutol HP, the total drug loading of the ginkgolide component was measured to be (75.32±0.22) mg·mL -1 The particle size of the nanoemulsion after emulsification was (39.10±1.30) nm. According to the formula of 16.10% GTCC, 34.01% Kolliphor HS15, and 49.89% Transcutol HP, the total drug loading of the ginkgolide component was (71.98±0.33) mg·mL -1 The particle size of the nanoemulsion after emulsification of the preparation was (30.10±1.10) nm.

[0094] 1.5 Screening of supersaturation-promoting substances

[0095] For poorly soluble drugs, low solubility means that the blood drug concentration cannot reach the therapeutic level. Supersaturated solutions can increase passive absorption by increasing drug concentration. Therefore, whether there is a suitable precipitation inhibitor with high stability is the key to successfully preparing poorly water-soluble oral drugs and improving their absorption. After preliminary screening in the early experiments, Soluplus, HPMC K4M, HPMC E15LV, PVP K30, and PS-630 were selected for further research.

[0096] 0.5% of various precipitation inhibitors (Polymer precipitation inhibitor, PPI) were added to 1g of GKC-SNEDDS as supersaturation-promoting substances, and ultrasonically dispersed them evenly in the oily liquid. They were added to conical flasks containing 100mL of pH1.2 HCl solution, and then placed in a constant temperature oscillating box at 100r·min-1 and 37±0.5℃, and 1mL was sampled at 5, 15, 30, 45, 60, 90, 120, 180, and 240min, without rehydration, diluted and filtered, and the concentrations of GA and GB were measured by HPLC. The ability of the preparation to maintain the supersaturated state of the drug after adding different supersaturation-promoting substances was compared, and the appropriate supersaturation-promoting substances were screened out.

[0097] The concentrations of GA and GB at each sampling time point are shown in Figure 3 As can be seen from the figure, GKC-SNEDDS without precipitation inhibitors is unstable in pH 1.2 HCl solution. As time goes by, the concentration of GKC decreases continuously. Within 120 minutes, the concentrations of GA and GB drop to 195.67μg·mL-1 and 186.307μg·mL-1, respectively. After adding various supersaturation-promoting substances, the precipitation inhibition effect on GKC-SNEDDS in pH 1.2 HCl solution is obvious. However, Soluplus interferes with the chromatographic peak of the drug during content detection, making the measured values ​​of GA and GB concentrations greater than the theoretical values, so Soluplus is not considered for the supersaturation-promoting substances. Figure 3 It can be seen that the ability of HPMC K4M, HPMC E15LV, PVP K30, and PS-630 to inhibit GKC precipitation is not much different, but in the experimental process, it was found that the experimental group using HPMC K4M as PPI had obvious precipitation after about 8 hours. Therefore, further stability tests were conducted on HPMC E15LV, PVP K30, and PS-630, and the results are as follows:

[0098]

[0099] Note: “-” indicates no crystallization; “*” indicates very little crystallization; “**” indicates a small amount of crystallization; “***” indicates a large amount of crystallization.

[0100] Since HPMC E15LV and PVP K30 also produced precipitation at 24h and 48h, respectively, PS-630, which has the best and lasting precipitation inhibition effect, was selected as the supersaturation-promoting substance to prepare the supersaturated ginkgolide self-nanoemulsion (GKC-S-SNEDDS).

[0101] (2) Screening of dosage

[0102] In order to determine the specific dosage of the supersaturation promoting substance PS-630, 0.3%, 0.5%, 0.7%, and 1.0% PS-630 were added to GKC-SNEDDS, and ultrasonic mixing was performed to obtain GKC-S-SNEDDS. They were added to conical flasks containing 100mL of pH 1.2 HCl solution, and then placed in a constant temperature oscillating box at 100r·min-1 and 37±0.5℃. 1mL of samples were taken at 5, 15, 30, 45, 60, 90, 120, 180, and 240min, respectively. No liquid was added, and the drug concentration was measured by HPLC after dilution and filtration. The stability of drug release after adding different amounts of supersaturation promoting substances (PS-630) was compared, so as to screen its dosage.

[0103] like Figure 4 As shown in the figure, within the dosage range of the supersaturation-promoting substance (PS-630), as the dosage of the supersaturation-promoting substance increases, the precipitation inhibition effect increases, but it can be seen that within the dosage range of 0.5% to 1.0%, there is no significant difference in the amount of PPI on the supersaturation-promoting effect. Considering that the increase in the dosage of PPI will take a longer time to dissolve in the preparation, and will also increase the viscosity of the preparation, the dosage of the supersaturation-promoting substance (PS-630) is selected to be 0.5%.

[0104] 1.5 Quality evaluation of supersaturated self-nanoemulsion preparations of ginkgolides

[0105] (1) Microscopic morphology

[0106] GKC-S-SNEDDS was prepared according to the above preferred recipe and heated at 37°C and 100 r·min. -1 Under the conditions, 1:100 (v / v) was dispersed in distilled water to form a clear and transparent self-nanoemulsion. An appropriate amount of self-nanoemulsion was added to the copper mesh, left to dry, and then 20 μL of 1% phosphotungstic acid solution was added for staining, left to stand for 5 minutes, and dried at room temperature. The appearance, morphology, and surface morphology of the emulsion formed after GKC-S-SNEDDS dispersion were observed under a transmission electron microscope.

[0107] The experimental results are as follows Figure 5 As shown, it was observed that the emulsion droplets of GKC-S-SNEDDS after emulsification were spherical, the morphology distribution was basically uniform, and the particle size was about 30 nm.

[0108] (2) Particle size and Zeta potential

[0109] 1 g of GKC-S-SNEDDS was prepared and dispersed in distilled water at a ratio of 1:100 (v / v) at 37 °C and 100 r·min-1. The obtained supersaturated ginkgolide nanoemulsion was filtered through a 0.45 μm microporous filter membrane, and the particle size and Zeta potential of the nanoemulsion were determined using a Malvern laser particle size analyzer.

[0110] The particle size of GKC-S-SNEDDS after emulsification was measured to be (34.53±0.34) nm, the PDI was (0.13±0.03), and the Zeta potential was -(3.36±0.05) mV. It can be seen that the particle size of the emulsion obtained after GKC-S-SNEDDS emulsification is small and uniform. Since the emulsifier used in the formula is a non-ionic surfactant and the other components are not charged, the system is nearly electrically neutral.

[0111] (3) Investigation of self-emulsification efficiency

[0112] The self-made supersaturated ginkgolide nanoemulsion was dripped into beakers containing 100 mL of distilled water and pH 1.2 hydrochloric acid solution. The beakers were placed at 37 °C and 100 r·min. -1 The results show that GKC-S-SNEDDS can form clear and transparent emulsions after emulsification in distilled water and hydrochloric acid solution with pH 1.2, and there is no significant difference in the emulsification time, particle size, and PDI of the nanoemulsions. The emulsions are still clear and transparent after being placed at room temperature for 24 hours.

[0113] A certain amount of GKC-S-SNEDDS was loaded into the No. 0 capsule shell, and the same amount of ginkgolide API as that contained in the self-nanoemulsion preparation was poured into the capsule shell as a control. The dissolution experiment was carried out according to the basket method in the "Dissolution and Release Determination Method" of Part IV of the 2020 edition of the "Chinese Pharmacopoeia". 250mL of pH 1.2HCl solution was used as the dissolution medium, the temperature was 37±0.5℃, the speed was 50r·min-1, and 5mL was sampled at 5, 10, 15, 20, 30, 45, and 60min, respectively. At the same time, an equal volume of blank dissolution medium at the same temperature was added, and the sample solution was filtered with a 0.45μm microporous membrane, the initial filtrate was discarded, and the subsequent filtrate was detected according to the chromatographic conditions. The cumulative dissolution of the GKC-S-SNEDDS preparation and the GKC API at each time point was calculated using the external standard method.

[0114] Chromatographic conditions:

[0115] In this paper, high performance liquid chromatography was used to determine the contents of GA and GB.

[0116] Chromatographic column: YMC-Pack ODS-A column (150*4.6mm, 5μm);

[0117] Mobile phase: water-methanol-isopropanol (86:7:7, v / v / v);

[0118] Detection wavelength: 220nm;

[0119] Column temperature: 40°C;

[0120] Flow rate: 1.0 mL min-1;

[0121] Injection volume: 20 μL.

[0122] The dissolution of GKC-S-SNEDDS and GKC API in pH 1.2 HCl solution is shown in Figure 6 Compared with the release of ginkgolide API, GKC-S-SNEDDS releases drugs rapidly, and the cumulative dissolution rate is significantly higher than that of API. The cumulative dissolution rates of ginkgolide API within 60 minutes are 48.59% (GA) and 46.03% (GB), while GKC-S-SNEDDS rapidly dissolves 92.72% (GA) and 93.81% (GB) within 5 minutes, and the cumulative release rates of GA and GB within 60 minutes are 99.56% and 99.76%, respectively. This indicates that GKC-S-SNEDDS significantly improves the in vitro dissolution behavior of the drug.

[0123] The present invention first prepares the ginkgolide component into a self-nanoemulsion preparation to improve its solubility in the body. At the same time, since SNEDDS contains an emulsifier that can be used as an absorption promoter, the permeability of GKC can also be enhanced.

[0124] Example 2 Preparation of Ginkgolide Solid Supersaturated Self-nanoemulsified Preparation

[0125] In order to overcome the defects of traditional liquid SNEDDS preparations, GKC-S-SNEDDS was solidified by direct adsorption method. The adsorption capacity and drug release capacity of the solidifying material were examined to screen out the suitable type and amount of the solidifying material. The prepared solid GKC-S-SNEDDS was characterized and its quality evaluated.

[0126] Table 8. Instruments used in the experiment

[0127]

[0128]

[0129] Table 9. Raw materials used in the experiment

[0130]

[0131] 2.1 Preparation process

[0132] Solidification of GKC-S-SNEDDS: Weigh the solidification material in a mortar according to the prescription ratio, add GKC-S-SNEDDS drop by drop, and grind while adding, so that the solidification material fully absorbs the GKC-S-SNEDDS droplets. After absorbing the prescribed amount of GKC-S-SNEDDS, place the solidified GKC-S-SNEDDS in an oven at 50°C for 2 hours to obtain a white Ginkgolide solid supersaturated self-nanoemulsion.

[0133] 2.2 Investigation of adsorption capacity of solidified materials

[0134] The selection of appropriate solidifying materials is the key to the preparation of solid self-nanoemulsions. The surface properties of the solidifying materials not only affect the amount of adsorbed self-nanoemulsions, but also affect the release of drugs. This study screened some commonly used poorly soluble carriers and water-soluble carriers, including lactose, PEG 4000, microcrystalline cellulose, Syloid244FP, Aerosil 200, Aerosil 300, Syloid AL-1FP, Syloid XDP3050, and Syloid XDP3150.

[0135] Weigh 500 mg of each solid adsorbent material in a mortar, add blank S-SMEDDS drop by drop, and grind in the same direction until SNEDDS is completely adsorbed. When the powder is slightly moist and does not stick to the wall, it is considered that each solid adsorbent material has reached a saturated state. The amount adsorbed from the nanoemulsion is recorded by weight loss method, which is the maximum absorption amount of the solid adsorbent material.

[0136] The results showed that the water-soluble carriers lactose and PEG4000 had weaker adsorption capacity on the self-nanoemulsion prepared in this study than the insoluble carriers. Three solidifying materials were temporarily selected for screening, namely Syloid 244FP, Syloid XDP3150, and Syloid XDP3050.

[0137] Table 10. Maximum adsorption capacity of SNEDDS by adsorbent materials (n=3)

[0138]

[0139] 2.3 Investigation of drug release ability of solidified materials

[0140] The drug release capacity of Syloid 244FP, Syloid XDP3150 and Syloid XDP3050 was investigated. GKC-S-SNEDDS was adsorbed according to the maximum adsorption amount of each solidified material, and an appropriate amount of solidified GKC-S-SNEDDS was weighed and added to the release medium of 250mL pH1.2 HCl solution to investigate the in vitro drug release capacity.

[0141] The release of solid self-nanoemulsions prepared with different solidifying materials is shown in Figure 7 From the release curves of GA and GB, it can be seen that the release extent and release rate are as follows: Syloid XDP3050, Syloid 244FP, SyloidXDP3150; among them, the release extent of Syloid XDP3050 is much greater than that of other materials.

[0142] 2.4 Quality Evaluation

[0143] (1) Solid-state characterization (powder X-ray diffraction (PXRD))

[0144] PXRD analysis was performed on GKC API, Syloid XDP3050, physical mixture, solid GKC-S-SNEDDS and blank solid S-SNEDDS. The scanning angle range was 10° to 60° and the scanning speed was 5° min. -1 .

[0145] The PXRD analysis results are as follows Figure 8 As shown, GKC API has many sharp diffraction peaks in the range of 10° to 60°, indicating that GKC API exists mainly in a crystalline state. In the physical mixture, due to the very low content of GKC API and the influence of the grinding preparation method, the intensity of the diffraction peak is greatly reduced, but there is still a small diffraction peak near 12.5°. The X-ray diffraction spectrum of solid GKC-S-SNEDDS is similar to that of blank solid S-SNEDDS and Syloid XDP3050. The characteristic diffraction peaks of GKC API have basically disappeared, indicating that GKC API exists in a non-crystalline form in solid GKC-S-SNEDDS.

[0146] (2) Microscopic morphology

[0147] Accurately weigh an appropriate amount of the solidified GKC-S-SNEDDS preparation and stir it at 37°C with a magnetic stirring speed of 100 r·min. -1Under the conditions, disperse in distilled water. Use a 0.45μm microporous filter to filter the diluted suspension, take a small amount of the filtrate and drop it on the copper mesh, let it stand and dry, then add 20μL of 1% phosphotungstic acid solution to dye, let it stand for 5 minutes, and dry it at room temperature. Observe the appearance and morphology of the emulsion formed after the solidified GKC-S-SNEDDS is dispersed under a transmission electron microscope.

[0148] The experimental results are as follows Fig. 9 As shown, it was observed that the emulsion droplets of solid GKC-S-SNEDDS after self-emulsification were spherical and regular in shape, with a particle size of about 30 nm.

[0149] (3) Particle size and Zeta potential

[0150] A solid self-nanoemulsion containing 1 g of GKC-S-SNEDDS was weighed and diluted 100 times in distilled water at 37° C. under slight stirring. The diluted suspension was filtered through a 0.45 μm microporous filter membrane, and the particle size and Zeta potential of the nanoemulsion were measured using a Malvern laser particle size analyzer.

[0151] The particle size of solid GKC-S-SNEDDS after emulsification was measured to be (32.67±0.81) nm, PDI was (0.35±0.10), and Zeta potential was -(3.42±0.73) mV. It can be seen that there is no significant change in the particle size and Zeta potential of solidified GKC-S-SNEDDS and liquid GKC-S-SNEDDS.

[0152] (4) Redispersibility study

[0153] The solidified GKC-S-SNEDDS was diluted in different multiples of pH 1.2 HCl solution and filtered through a 0.45 μm microporous filter membrane to remove the insoluble carrier material. The filtrate was still a clear, transparent, slightly blue, uniform emulsion, and the particle size did not change significantly, indicating that the self-emulsification efficiency of the solidified GKC-S-SNEDDS did not change.

[0154] (5) Investigation of in vitro dissolution

[0155] Appropriate amounts of solid GKC-S-SNEDDS of the aforementioned screening prescription and liquid GKC-S-SNEDDS with the same drug content were canned in capsule shells, and in vitro dissolution studies were performed under the same conditions as the in vitro release test method. The cumulative dissolution rates of solid GKC-S-SNEDDS and liquid GKC-S-SNEDDS preparations at each time point were calculated.

[0156] like Fig.10From the dissolution curve, it can be seen that both solid GKC-S-SNEDDS and liquid GKC-S-SNEDDS preparations can be rapidly dissolved in pH 1.2 HCl solution, and the cumulative dissolution rate can reach more than 90% within 10 minutes. The drug in solid GKC-S-SNEDDS needs to be released from the solidifying material Syloid XDP3050 first, but there is no significant difference in the release rate between solid GKC-S-SNEDDS and liquid GKC-S-SNEDDS, indicating that solidified GKC-S-SNEDDS can still improve the dissolution rate and degree of the drug, retaining the advantages of liquid self-nanoemulsifying preparations.

[0157] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A self-nanoemulsion drug release system, characterized in that: The system comprises an oil phase and / or an emulsifier and / or a co-emulsifier; the oil phase comprises MCT 70, Labrafac Lipophile WL 1349, GTCC, IPM, Labrafil M1944CS, Labrafil M 2125CS, Ethyloleate or any combination thereof; the emulsifier comprises Tween 80, HS15, Cremophor EL, Kolliphor ELP, Cremophor RH40 or any combination thereof; the co-emulsifier comprises PEG200, Transcutol HP, Transcutol P, PEG 400 or any combination thereof.

2. The self-nanoemulsion drug release system according to claim 1, characterized in that: The usage ratio of the oil phase: emulsifier: co-emulsifier is 10-40%: 20-60%: 15-50%; preferably, it is 15-30%: 30-60%: 20-50%; more preferably, it is 15-20%: 30-40%: 40-50%; most preferably, it is 15-16.5%: 34-35.5%: 48-50%.

3. A ginkgolide self-nanoemulsion drug release system, characterized in that: Preparations containing active ingredients and excipients, The system comprises an oil phase and / or an emulsifier and / or an emulsifier assistant; the active ingredient ginkgolide drugs include ginkgolide K, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and / or bilobalide.

4. The ginkgolide self-nanoemulsion drug release system according to claim 3, characterized in that: The oil phase comprises MCT 70, Labrafac Lipophile WL 1349, GTCC, IPM, Labrafil M 1944CS, Labrafil M 2125CS, Ethyl oleate or any combination thereof; The emulsifier includes Tween 80, HS15, Cremophor EL, Kolliphor ELP, Cremophor RH40 or any combination thereof; The co-emulsifier includes PEG 200, Transcutol HP, Transcutol P, PEG 400 or any combination thereof.

5. The ginkgolide self-nanoemulsion drug release system according to claim 4, characterized in that: The usage ratio of the oil phase: emulsifier: co-emulsifier is 10-40%: 20-60%: 15-50%; preferably, it is 15-30%: 30-60%: 20-50%; more preferably, it is 15-20%: 30-40%: 40-50%; most preferably, it is 15-16.5%: 34-35.5%: 48-50%.

6. The ginkgolide self-nanoemulsion drug release system according to claim 5, characterized in that: The total drug loading of the ginkgolide component is 20-200 mg·mL -1 , the particle size of the nanoemulsion after emulsification is 20-500nm; Preferably, the total drug loading of the ginkgolide component is 50-100 mg·mL -1 , the particle size of the nanoemulsion after emulsification is 20-200nm; More preferably, the total drug loading of the ginkgolide component is 50-80 mg·mL -1 , the particle size of the nanoemulsion after emulsification is 20-50nm; Most preferably, the total drug loading of the ginkgolide component is 65-80 mg·mL -1 , the particle size of the nanoemulsion after emulsification is 30-40nm.

7. The ginkgolide self-nanoemulsion drug release system according to claim 4, characterized in that: further comprising a precipitation inhibitor; The precipitation inhibitor includes: HPMC K4M, HPMC E15LV, PVP K30, PS-630 or any combination thereof; the dosage is 0.01-2%, preferably 0.1-1%, more preferably 0.5%-1%.

8. The ginkgolide self-nanoemulsion drug release system according to any one of claims 3 to 7, characterized in that: The self-nanoemulsification drug release system is a solid supersaturated self-nanoemulsification preparation.

9. The self-nanoemulsion drug release system according to claim 8, characterized in that: The solidifying material in the solid supersaturated self-nanoemulsifying preparation includes a poorly soluble carrier and a water-soluble carrier; further, it includes lactose, PEG 4000, microcrystalline cellulose, Aerosil 200, Aerosil 300, Syloid AL-1FP, Syloid244FP, Syloid XDP3050, SyloidXDP3150 or any combination thereof.

10. The self-nanoemulsion drug release system according to claim 8, characterized in that: The ginkgolides in this system are substantially in a non-crystalline form.

Images