Solid dispersion of curcumin derivative as well as preparation and application of solid dispersion

Abstract

The invention discloses a curcumin derivative C66 solid dispersion as well as a preparation method and application thereof, and belongs to the field of pharmaceutical chemicals. In the solid dispersion, C66 is dispersed in a carrier material in a microcrystal or amorphous form. Compared with a C66 raw material medicine, the C66 solid dispersion has the advantage that the dissolution rate of C66 in a dissolution medium is remarkably increased. In a Beagle dog oral bioavailability test, the absolute bioavailability of the C66 solid dispersion is 6.66 times that of a C66 raw material medicine. Meanwhile, the stability of the C66 solid dispersion is good, the dissolution speed after 6 months of acceleration test, and related substances, isomers and the like meet quality control requirements. The powder has good flowability and good preparation processing performance, and can be conveniently prepared into capsules by adopting a powder direct filling process and prepared into tablets by adopting a powder direct compression process. Therefore, a foundation is laid for further development of C66 preparation products.

Description

A solid dispersion of curcumin derivatives and its preparation and application Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a solid dispersion of a curcumin derivative (C66) and a preparation method and application thereof. Background Art

[0002] With the advent of an aging population, the incidence of cardiovascular and cerebrovascular diseases caused by chronic inflammation is increasing, and complications caused by diabetes, obesity, hypertension, etc. have seriously affected human health and quality of life. In the case of high blood sugar or high blood pressure, multiple tissues and organs of the body will undergo a series of pathological changes and damage, resulting in a variety of complications, especially kidney damage, which initially manifests as microalbuminuria. As the course of the disease prolongs and urine protein increases, the kidneys' ability to eliminate toxins from the blood gradually decreases, eventually developing into end-stage renal disease, and life can only be maintained by hemodialysis or kidney transplantation. With the accelerated development of my country's economy and the arrival of an aging population, the morbidity and mortality of metabolic diseases such as diabetes, hypertension, and their complications will continue to rise in the future, becoming one of the most prominent problems in my country's health sector.

[0003] At present, the treatment of kidney diseases caused by diabetes, hypertension, etc. is still unsatisfactory. In the early stage of diabetic nephropathy, the treatment is still mainly based on lowering blood sugar, blood pressure and blood lipids for the treatment of diabetes. In the late stage of diabetic nephropathy, the treatment of kidney disease is mainly based on dialysis therapy and kidney transplantation. Among them, the treatment of renal failure in the late stage is already a helpless measure. In the early treatment of diabetic nephropathy, although the current treatment methods can delay the kidney damage caused by diabetes, it cannot reverse the kidney damage that has occurred, and it still cannot prevent the progression of kidney disease to end-stage renal failure. After a lot of research in the early stage, this project team used curcumin, an active ingredient of traditional Chinese medicine, as the lead compound, and independently designed and synthesized hundreds of curcumin structural analogues. From them, they screened and found that the new curcumin analogue C66 can effectively relieve kidney disease caused by diabetes, hypertension, hyperlipidemia and obesity. We have completed a lot of pharmacological mechanism research and drugability evaluation on C66 in the early stage, and found that C66 has a high drugability. Its chemical structure is shown below:

[0004] The project team has previously obtained patent authorization for C66 as a treatment for kidney disease and heart disease caused by diabetes (ZL 201110146331.2). It has also applied for a patent for C66 as a treatment for kidney disease caused by obesity, hypertension, and hyperlipidemia (201910619696.9), a compound crystal form patent (201910831988.9), etc.

[0005] Summary of the Invention

[0006] Technical problems to be solved by the invention:

[0007] In previous studies, we found that C66 has good permeability, but poor water solubility. The experimental data are shown in Table 1 below:

[0008] Table 1. C66 solubility

[0009] We also investigated the solubility of C66 in sodium dodecyl sulfate (SDS) and Tween 80 (T80). Based on the recommended surfactant dosages in the excipient manual, the China Food and Drug Administration (CFDA), and the US Food and Drug Administration (FDA), the surfactant content in the solution was 1% to 3%. The saturation concentrations of C66 in the surfactant solutions are shown in Table 2:

[0010] Table 2. Solubilization effect of SDS and Tween 80 on C66

[0011] The above results indicate that the solubility of the C66 API in water is poor, and surfactants can improve it. Both sodium lauryl sulfate and Tween 80 can increase the solubility of C66 in water, with sodium lauryl sulfate having a greater solubilizing effect than Tween 80 at the same concentration. However, overall, the 3% SDS solution with the highest solubility only yields 22.484 μg / mL, meaning that only 22.484 mg can be dissolved in 1000 mL of dissolution medium. Even for 10 mg capsules, the 3- to 10-fold sink capacity is insufficient.

[0012] We also prepared a series of buffer solutions (pH 1.0, pH 1.2, pH 2.0, pH 4.0, pH 5.0, pH 6.0, pH 6.8, and pH 7.4) based on pharmacopoeial recommendations to investigate the solubility of C66 at varying pH levels. Excess C66 powder was added to each solution and shaken at 37°C for 24 hours. The C66 concentration was then determined using high-performance liquid chromatography. The results showed that C66 did not dissolve in any of the solutions.

[0013] To further investigate the impact of the low solubility of C66 on oral absorption, we conducted an oral bioavailability study. Six male Beagle dogs, weighing 8.00-8.62 kg, were randomly assigned to two groups of three (oral administration group 1) and an intravenous administration group (male dogs), receiving a single gavage. All dogs were fasted for 12 hours before dosing, but not water. Four hours after dosing, food was given to all dogs, with free access to water. In the oral group, 1% CMC-Na was mixed with the C66 API to prepare a 0.6 mg / mL suspension, which was then administered orally. In the intravenous group, the required amount of C66 API was dissolved in 5% DMSO, 10% polyethylene glycol-15-hydroxystearate, and 85% (20%) 2-hydroxypropyl-β-cyclodextrin to prepare a clear solution of 1 mg / mL. Blood samples were collected at various time points after dosing, and C66 concentrations in the blood samples were determined by liquid chromatography-mass spectrometry (LC-MS / MS), and concentration-time curves were constructed. The analysis of the area under the curve (AUC) showed that the absolute bioavailability of oral C66 was only 7.16%, calculated based on the AUC of the intravenous injection group as 100%.

[0014] Given C66's poor water solubility and low oral bioavailability, it is necessary to appropriately solubilize C66 to improve its oral bioavailability. This invention achieves this goal by utilizing solid dispersion technology. However, since C66 is a Class 1.1 new drug under development by the project team, no literature or patent reports regarding C66 solid dispersions have been found.

[0015] Therefore, the technical problems to be solved by the present invention are as follows:

[0016] The present invention provides a solid dispersion of a curcumin derivative C66, and its preparation and application. By preparing the solid dispersion, the water solubility and oral bioavailability of C66 are effectively improved, making it more suitable for pharmaceutical preparation. In addition, the solid dispersion overcomes the shortcomings of conventional solid dispersions, such as poor physical stability and easy aging.

[0017] The technical solutions of the present invention are as follows:

[0018] A solid dispersion of a curcumin derivative, comprising a curcumin derivative and a carrier material;

[0019] The curcumin derivative is C66, and its structure is shown in formula (I):

[0020] The carrier material is not limited to one, two or three of polyethylene glycol 6000, povidone K30, copovidone S630, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose (HPMC);

[0021] The curcumin derivative is dispersed in the carrier material in the form of microcrystals or amorphous forms.

[0022] In the present invention, a curcumin derivative is uniformly dispersed in a specific carrier material in a microcrystalline or amorphous form. The resulting solid dispersion can effectively improve the water solubility and bioavailability of the curcumin derivative, and its water solubility is maintained for a long time, overcoming the common disadvantage of other conventional solid dispersions that they are easily aged.

[0023] Preferably, the mass ratio of the curcumin derivative to the carrier material is 1:0.5 to 1:25.

[0024] Preferably, the carrier material of the solid dispersion is polyethylene glycol 6000 and copovidone S630. The ratio of C66 to the carrier can be 1:0.5 to 1:20.

[0025] Preferably, the ratio of C66 to polyethylene glycol 6000 is 1:9 to 1:15, and the ratio of C66 to copovidone S630 is 1:5 to 1:20.

[0026] The C66 solid dispersion prepared using polyethylene glycol 6000 as a carrier is a microcrystalline solid dispersion, in which C66 is dispersed in polyethylene glycol 6000 in the form of micro / fine crystals; the C66 solid dispersion prepared using copovidone S630 or povidone K30 as a carrier is an amorphous solid dispersion, in which C66 is dispersed in the carrier material in an amorphous form.

[0027] Preferably, the dispersion method is spray drying, hot melt extrusion or melt dispersion.

[0028] The spray drying method comprises the following steps: firstly completely dissolving or dispersing the curcumin derivative and the carrier material with a solvent, then removing the solvent with a spray dryer to obtain a dry solid, which is then sieved to obtain a solid dispersion.

[0029] The process of the hot melt extrusion method is as follows: the carrier material and the curcumin derivative are physically mixed, then extruded using a hot melt extruder to prepare a sample, and then crushed and sieved to obtain a solid dispersion.

[0030] The process of the melt dispersion method is as follows: the carrier material is heated and melted, and then the curcumin derivative is added for melt dispersion, followed by cooling, crushing and sieving to obtain a solid dispersion.

[0031] The present invention also provides a method for preparing the C66 solid dispersion, comprising the following steps: weighing appropriate amounts of C66 API, povidone K30, or hydropropyl methylcellulose acetate succinate into a stoppered conical flask, then measuring 50 mL of each organic solvent, sealing the flask, ultrasonically shaking, and dissolving until clear to obtain a mixed solution for later use. Spray drying is performed using a spray dryer. The inlet air temperature is set to 60-65°C, and the solution is atomized and dried by a peristaltic pump. The peristaltic pump infusion rate is set to 20 mL / min, and the outlet air temperature is controlled at 35-40°C. The sample is collected by a cyclone collector to obtain a C66-PVP K30 solid dispersion or a C66-HPMCAS solid dispersion. The C66 content in the C66-PVP K30 solid dispersion is 30-40%, and the C66 content in the C66-HPMCAS solid dispersion is 15-20%. The organic solvent includes but is not limited to one or more of methanol, ethanol, acetone, isopropanol, ethyl acetate, toluene, 1,4-dioxane, acetonitrile, methyl tert-butyl ether, isopropyl acetate, heptane, and methyl isobutyl ketone.

[0032] Preferably, the organic solvent is acetone or ethanol.

[0033] As another preferred embodiment, the organic solvent is a mixed solvent of acetone and ethanol;

[0034] Volume ratio of acetone and ethanol: 1:0.5~1:1.5.

[0035] The present invention provides another method for preparing the C66 solid dispersion, comprising the following steps: weighing a prescribed amount of PEG 6000 into a beaker, heating in a water bath, stirring until completely dissolved, then adding the prescribed amount of C66, continuing to stir until completely melted, and holding the mixture for a period of time. The hot sample is then spread evenly on a stainless steel plate, naturally cooled until solidified, and then pulverized and sieved to obtain the C66 solid dispersion.

[0036] Preferably, the ratio of C66 to polyethylene glycol 6000 is 1:1 to 1:15; further preferably, the ratio of C66 to polyethylene glycol 6000 is 1:12 to 1:15, and most preferably is 1:12.

[0037] Preferably, the water bath temperature is 70-90°C.

[0038] Preferably, the holding time is 0.5 to 2.0 hours.

[0039] The present invention also provides a method for scalably preparing the C66 solid dispersion, comprising the following steps: weighing an appropriate amount of C66 raw material and copovidone S630 and placing them in a sampling bag, premixing and passing through a 40-mesh sieve, and continuing to mix to obtain a premixed powder. A hot melt extruder is used to prepare the solid dispersion. Hot melt extrusion is performed after setting parameters such as the nozzle temperature and screw speed. The sample flows out of the nozzle in the form of a light yellow transparent colloid, rapidly cools and solidifies to form a light yellow transparent solid, is caught with a stainless steel plate, broken into small pieces, and an appropriate amount of sample is taken and crushed with a universal grinder, passed through a 100-mesh sieve, to obtain a C66 solid dispersion.

[0040] Preferably, the nozzle temperature is selected to be 130-150°C.

[0041] Preferably, the screw rotation speed is selected to be 100-400 rpm.

[0042] The present invention also compared the solubility of the C66 API and the C66 solid dispersion, and compared the oral bioavailability using Beagle dogs as a model animal. Furthermore, the stability of the C66 solid dispersion was also investigated. The results showed that the water solubility, oral bioavailability, and stability of the C66 solid dispersion all met the expected requirements.

[0043] The present invention also provides a use of the C66 solid dispersion in the treatment or prevention of various primary and secondary chronic kidney diseases such as diabetic nephropathy, hypertensive nephropathy, nephrotic syndrome, chronic glomerulonephritis, IgA nephropathy, lupus nephritis, hepatitis B-related nephritis, Henoch-Schonlein purpura nephritis, membranous nephropathy, and post-renal transplantation.

[0044] The present invention also provides two pharmaceutical preparations (capsules and tablets), which contain C66 solid dispersion and one or more pharmaceutically acceptable inert non-toxic carriers or excipients.

[0045] Compared with the prior art, the beneficial effects of the present invention are embodied in:

[0046] The present invention has discovered that solid dispersion technology can be used for the solubilization of the curcumin derivative C66, and provides excipients, preparation methods, and suitable formulations that can be used for the C66 solid dispersion. Compared with the C66 bulk drug, the solid dispersion can significantly improve the water solubility of C66, thereby improving oral bioavailability. Compared with other conventional solid dispersions, the solid dispersion of the present invention has good physical stability, overcomes the disadvantage that conventional solid dispersions are easily aged, and after a 6-month accelerated stability test, indicators such as solubility, related substances, and impurities meet the quality standard requirements (based on the relevant technical guidelines of the National Center for New Drug Evaluation). At the same time, the solid dispersion has relatively good fluidity and good drugability. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG1 is an X-ray powder diffraction pattern of the curcumin derivative C66-povidone K30 amorphous solid dispersion of the present invention.

[0048] FIG2 is an X-ray powder diffraction pattern of the curcumin derivative C66-polyethylene glycol 6000 microcrystalline solid dispersion of the present invention.

[0049] FIG3 is an X-ray powder diffraction pattern of the curcumin derivative C66-copovidone S630 amorphous solid dispersion of the present invention. DETAILED DESCRIPTION

[0050] Specific embodiments of the present invention are described with reference to the following examples, which are intended to illustrate the invention and not to limit it in any way.

[0051] Example 1 Preparation of Curcumin Derivative C66 Solid Dispersion

[0052] (1) Weigh 6.01 g of C66 API and 12.00 g of povidone K30 into a stoppered conical flask. Then, add 50 mL of acetone and 50 mL of ethanol, respectively. Seal the flask tightly and shake ultrasonically to dissolve until clear. The resulting mixed solution is set aside.

[0053] (2) Drying was performed using a Buchi B290 spray dryer with a 1.5 mm nozzle, an inlet air temperature of 60-65°C, a peristaltic pump infusion rate of 20 mL / min, and an outlet air temperature controlled at 35-40°C. The outlet air temperature was used as the primary control parameter and was maintained within the stated range by adjusting the inlet air temperature.

[0054] (3) Scrape the sample powder in the cyclone collector. The powder is a C66-povidone K30 solid dispersion, wherein the C66 content is 33.33%. Weigh it, calculate the yield, and seal it for storage.

[0055] Example 2 Preparation of Curcumin Derivative C66 Solid Dispersion

[0056] Prescription composition:

[0057] Process description:

[0058] (1) Weigh the prescribed amount of PEG 6000 into a beaker, heat in an 85°C water bath, and stir manually with a glass rod until completely melted;

[0059] (2) After PEG 6000 is completely melted, add the prescribed amount of API, heat in an 85°C water bath, and stir manually with a glass rod until completely dissolved;

[0060] (3) After the sample is completely dissolved, continue to keep it in an 85°C water bath for 30-40 minutes;

[0061] (4) After the heat preservation is completed, the sample is spread evenly on a stainless steel plate while still hot and allowed to cool naturally until the sample solidifies;

[0062] (5) Grind the solidified sample and pass it through an 80-mesh standard sieve to obtain C66 solid dispersion.

[0063] Example 3 Preparation of Curcumin Derivative C66 Solid Dispersion

[0064] 120.0 g of API and 600.0 g of copolyvidone S630 were weighed and placed in a sampling bag. The mixture was manually mixed for about 1 min, passed through a 40-mesh standard sieve, and then manually mixed for about 2 min to obtain a premixed powder. The sample was prepared using a hot melt extruder (Process 11, Thermo). The process parameters were set as follows:

[0065] The two batches of samples flowed out of the nozzle in the form of light yellow transparent colloid, quickly cooled and solidified into light yellow transparent solid, and were collected using a stainless steel plate and broken into small pieces. Appropriate amounts of samples were taken from each sample and crushed using a universal grinder, and passed through a 100-mesh standard sieve.

[0066] Example 4 X-ray powder diffraction spectrum of curcumin derivative C66 solid dispersion:

[0067] Measuring instrument: Smart Lab-3kw powder X-ray diffractometer, Rigaku Corporation, Japan.

[0068] Measurement conditions:

[0069] The sample was transferred to a zero-background XRPD sample tray and gently pressed to make the test sample surface flat and uniform.

[0070] Figure 1 is an X-ray diffraction pattern of the C66 solid dispersion prepared in Example 1. The pattern shows that the C66-povidone K30 solid dispersion has no sharp diffraction peaks in the range of 5° to 30°, and the diffraction signal is relatively flat, indicating that the solid dispersion is an amorphous solid dispersion. Figure 2 is an X-ray diffraction pattern of the C66 solid dispersion prepared in Example 2. Unlike Figure 1, the diffraction pattern of the C66-polyethylene glycol 6000 solid dispersion has more sharp diffraction peaks. By comparison, the diffraction peaks come from C66 and polyethylene glycol 6000. Figure 2 shows that the C66-polyethylene glycol 6000 solid dispersion is a microcrystalline solid dispersion, which is different from Example 1. Figure 3 is an X-ray diffraction pattern of the C66-copolypyrrolidone S630 solid dispersion prepared in Example 3 by hot melt extrusion technology. Similar to Figure 1, no sharp diffraction peaks are found in Figure 3. This solid dispersion is also an amorphous solid dispersion.

[0071] Example 5 Actual solubilization effect of curcumin derivative C66 solid dispersion:

[0072] Dissolution rate of the C66-copolyvidone S630 solid dispersion prepared in Example 3 in a 1% SDS pH 1.0 solution:

[0073] Experimental method: ChP (2020) Part IV General Rules 0931 Dissolution and Release Determination Method II (Paddle Method), rotation speed 75 rpm, medium volume 900 mL, sampling and rehydration volume 10 mL.

[0074] Dissolution medium: 1% SDS pH 1.0 solution (take 1g SDS, add appropriate amount of degassed purified water, stir to dissolve, add 9mL hydrochloric acid, add degassed purified water to 1000mL, mix well, and the solution is obtained)

[0075] Sampling time points: 15, 30, 45, 60 min.

[0076] Detection method: ChP (2020) Part IV General Rules 0401 Ultraviolet-visible spectrophotometry, detection wavelength 305nm.

[0077] Reference substance stock solution: Accurately weigh 20 mg of C66 self-made reference substance, place it in a 50 mL volumetric flask, add appropriate amount of acetonitrile to dissolve it, add acetonitrile to make up to volume, shake well, and obtain the solution.

[0078] Reference substance solution: Accurately pipette 1 mL of reference substance stock solution into a 50 mL volumetric flask, add dissolution medium to the volume, and shake well.

[0079] Test solution: Manually sample 10 mL, filter through a 0.45 μm filter membrane, discard 3 mL, and collect the filtrate.

[0080] Measurement results:

[0081] In contrast, the cumulative dissolution rate of the crushed and sieved C66 API (particle size D0.9 <15 μm) in a 3% sodium dodecyl sulfate (SDS, anionic surfactant) aqueous solution over 60 minutes was 25.3%. The maximum cumulative dissolution rate in aqueous solutions of Triton X-100 (a nonionic surfactant) with varying concentrations was 26.3%. The maximum cumulative dissolution rate in aqueous solutions of cetyltrimethylammonium bromide (CTAB, a cationic surfactant) with varying concentrations was 18.9%. None of these met the quality control requirement of a dissolution rate of 85% or more between 30 and 60 minutes. Therefore, preparing C66 into a solid dispersion can significantly increase its dissolution rate.

[0082] Example 6 Effect of Curcumin Derivative C66 Solid Dispersion on Oral Bioavailability of C66

[0083] (1) Plasma detection method

[0084] An AB Sciex 5500 (LC-MS / MS) was used with an electrospray ionization source (ESI) and multiple reaction monitoring (MRM) scanning in positive ion mode. Gradient elution was performed using a 0.1% formic acid aqueous solution-acetonitrile mobile phase. Unknown samples were protein precipitated with methanol and then injected for analysis at a flow rate of 0.3 mL / min. Column: 1.7 μm, XB-C18 2.1*100 mm. Guard column: Phenomenex UHPLC C18 2.1 mm. C66 linear range: 1.000–288.0 ng / mL, limit of quantification: 1.000 ng / mL.

[0085] (2) Test method

[0086] Nine male Beagle dogs, weighing 8.00-8.62 kg, were selected and randomly divided into three groups (3 dogs each) based on body weight: oral administration group 1, oral administration group 2 (solid dispersion sample obtained in Example 3), and an intravenous administration group (male dogs). The dogs were administered a single oral gavage. They fasted for 12 hours prior to administration, but were allowed to drink water. Four hours after administration, they were fed and given free access to water.

[0087] The dosage design of each group is as follows:

[0088] Note: The dosage of C66 solid dispersion is calculated based on the raw material.

[0089] Blood collection time:

[0090] Blood sampling time points for the oral administration group were set as follows: before administration and 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after administration, 0.5 to 1.0 mL of blood was collected from the small saphenous vein on the outside of the hind limb or the cephalic vein on the inside of the forelimb and placed in a sodium heparin anticoagulant tube. Blood sampling time points for the intravenous administration group were set as follows: before administration and 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 10 hours and 24 hours after administration, 0.5 to 1.0 mL of blood was collected from the small saphenous vein on the outside of the hind limb or the cephalic vein on the inside of the forelimb and placed in a sodium heparin anticoagulant tube. AUC was calculated using Phoenix Winnonlin 8.0 software. 0-t , AUC 0-∞ , t 1 / 2 And other main pharmacokinetic parameters.

[0091] Test sample preparation method:

[0092] Oral administration group 1: Weigh the required amount of C66 API and add appropriate amount of 1% CMC-Na to prepare a 0.6 mg / mL suspension.

[0093] Oral administration group 2: Weigh the required amount of C66 solid dispersion and add appropriate amount of 1% CMC-Na to prepare a 0.6 mg / mL suspension.

[0094] Intravenous administration group: Weigh the required amount of C66 API and dissolve it in 5% DMSO + 10% polyethylene glycol-15-hydroxystearate + 85% (20% 2-hydroxypropyl-β-cyclodextrin) to prepare a 1 mg / mL clear solution. Prepare the solution on the day of administration. The specific volume is calculated based on the dog's body weight at the time of grouping.

[0095] 3 Test results

[0096] After oral administration of C66 API and solid dispersion (3 mg / kg) to Beagle dogs, C66 was rapidly absorbed in the body, with the peak time being basically the same, reaching the peak in about 1.0 h. At the same time, it was eliminated quickly from the body, with the half-life of the oral and intravenous groups being t 1 / 2 About 1.0h and 0.5h respectively; AUC of oral administration group 1, oral administration group 2, and intravenous administration group 0-t and AUC 0-∞ The ratios of the two groups were all greater than 80% (88%, 99%, 99%), indicating that the blood sampling time point was set reasonably, and the absorption phase, equilibrium phase and elimination phase were well taken into account.

[0097] After Beagle dogs were intravenously administered with C66 raw material (1 mg / kg), animal 3M01 was observed to vomit yellow gastric juice 11 minutes after administration, lie down in the cage 19 minutes after administration, and return to normal 53 minutes after administration; animal 3M03 lie down in the cage and breathe rapidly 13 minutes after administration, and return to normal 43 minutes after administration.

[0098] AUC 0-t Calculation showed that the oral bioavailability of C66 API was 7.16%, and that of C66 solid dispersion was 47.66%. The oral bioavailability of C66 solid dispersion was 6.66 times that of C66 API.

[0099] Specific parameter results are shown in Tables 3 and 4.

[0100] Table 4 Main pharmacokinetic parameters of C66 API and solid dispersion after oral administration and intravenous injection in Beagle dogs

[0101] Note: The calculation formula for absolute bioavailability is: F(AUC 0-t )=AUC 0-tOral*Dose IV / AUC 0-t Intravenous * oral dose × 100%; the formula for calculating relative bioavailability is: F (AUC 0-t )=AUC 0-t Oral administration group 1*Dose oral administration group 2 / AUC 0-t Oral administration group 2*Dose oral administration group 1×100%; “*” indicates that the results of animal 1M03 were significantly different from those of the other two animals and were not included in the calculation of the Mean and SD of this group.

[0102] Example 7 Anti-aging and stability of curcumin derivative C66 solid dispersion

[0103] Room temperature storage conditions: packed in plastic sampling bags, sealed, stored at room temperature, away from light;

[0104] Accelerated test conditions: aluminum foil bag packaging, sealed, 40±2℃, 75%±5%RH, sample placement;

[0105] Sample: solid dispersion obtained in Examples 1, 2, and 3.

[0106] Dissolution curve test results (test conditions are the same as above):

[0107] Determination results of related substances:

[0108] Content determination results:

[0109] Result analysis:

[0110] The C66 solid dispersions obtained in Examples 1, 2, and 3 showed no significant changes in content or related substances after storage for six months at both room temperature and accelerated conditions. While the dissolution rate slowed slightly, the cumulative dissolution rate at 45 minutes was >80%, and the cumulative dissolution rate at 60 minutes was >85%, indicating substantial stability. The significant degradation commonly observed in other solid dispersions was absent. More specifically, after six months of storage at room temperature and accelerated conditions, Example 2 exhibited the smallest decrease in dissolution rate, followed by Example 1, and Example 3 exhibited the largest decrease. This indicates that while Examples 1, 2, and 3 still met quality requirements for dissolution after six months of accelerated testing, they exhibited subtle differences in their anti-aging performance.

[0111] In summary, after the normal and mild accelerated stability tests, the key quality attributes of the C66 solid dispersions obtained in Examples 1, 2, and 3 all met the quality control requirements.

[0112] Example 8 Determination of angle of repose

[0113] Method: Funnel method

[0114] Procedure: Take a glass Petri dish and measure its radius R. Secure a separate glass funnel to a wooden stand and place the glass Petri dish upside down beneath the funnel, aligning the funnel outlet with the center of the Petri dish base. The distance between the funnel outlet and the center of the Petri dish base is 4.0-5.0 cm. Slowly add an appropriate amount of the C66 solid dispersion prepared in Example 3 from the top of the funnel. The dispersion gradually accumulates on the Petri dish base, forming a cone. Measure the cone height H until the highest cone is reached.

[0115] Calculation formula: Angle of repose α = arctan(H / R). Repeat the measurement three times and take the average value. The results are shown in Table 6.

[0116] Table 6 Determination of angle of repose

[0117] The average value of the angle of repose is 41.98°. The C66 solid dispersion has good fluidity and can be conveniently used in various formulation processes.

[0118] Example 9 Scale-up preparation of curcumin derivative C66 solid dispersion

[0119] Referring to the pilot test recipe process obtained in the previous experiment, according to the C66 API: polyethylene glycol 6000 = 1:12 (g / g) feed ratio, the prescription amount of C66 API and polyethylene glycol 6000 were weighed, premixed evenly, and a hot melt extruder was used to prepare a solid dispersion, which was crushed and sieved to obtain the C66 solid dispersion. This time, 2.3 kg of C66 API and 27.6 kg of polyethylene glycol 6000 were added. The main equipment used included a hot melt extruder (Pharma 24, Thermo), a hammer mill (D6A, ​​Fitzpatrick), a universal grinder (40B, Jiangsu Guibao Group Co., Ltd.), etc. This example was carried out in a GMP production workshop.

[0120] After installing and debugging the hot melt extruder accessories, turn on the heat to the preset value, start the screw and add the material to prepare the solid dispersion; use a stainless steel plate to catch the material, about 0.2kg per plate, and use a stainless steel shovel to scoop out the material after it cools and solidifies, and set aside. The temperature parameters of the hot melt extruder are set as follows:

[0121] Crushing:

[0122] Crushing 1: The solidified flakes were crushed in a hammer mill using the back of a knife, a 0.079-inch aperture screen, and a rotor speed of 5000.

[0123] Crushing 2: Turn on the 40B universal crusher (80 mesh sieve), crushing speed 50Hz, and pass through 80 mesh after crushing.

[0124] After crushing and sieving, the material was a light yellow powder, identical to the pilot sample. The sample assayed for content was 101.6 ± 1.1% of the theoretical value. Related substance testing revealed a slight increase in the isomer content of the scaled-up C66 solid dispersion compared to the API, but both were <0.2%. There were no significant differences in process impurities, indicating that the scaled-up sample met the requirements for related substances. Furthermore, the scaled-up sample exhibited a dissolution rate exceeding 90% in 60 minutes, similar to the pilot sample, meeting the target dissolution rate of greater than 85% in 60 minutes.

[0125] This example shows that the scale-up production of C66 solid dispersion is relatively smooth, and the main detection indicators have good reproducibility with the small-scale sample, which confirms the feasibility of scale-up production.

[0126] Example 10 The dissolution rate of the solid dispersion of curcumin derivative C66 using PEG 4000 and poloxamer 188 as carriers decreased significantly after storage

[0127] (1) Weigh 2.05 g of C66 API and 10.08 g of HPMCAS into a stoppered conical flask. Then, add 50 mL of acetone and 50 mL of ethanol. Seal the flask tightly and shake ultrasonically to dissolve until clear. Mixture 1 is obtained and set aside.

[0128] (2) Weigh 2.01 g of C66 API and 10.10 g of PEG 4000 into a stoppered conical flask. Then, add 50 mL of acetone and 50 mL of ethanol. Seal the flask tightly and shake ultrasonically to dissolve until clear. Mixture 2 is obtained and set aside.

[0129] (3) Weigh 2.03 g of C66 API and 10.13 g of Poloxamer 188 into a stoppered conical flask, then add 50 mL of acetone and 50 mL of ethanol, seal the flask tightly, and shake ultrasonically to dissolve until clear, to obtain mixed solution 3, which is set aside.

[0130] (4) Drying was performed using a Buchi B290 spray dryer with a 1.5 mm nozzle, an inlet air temperature of 60-65°C, a peristaltic pump infusion rate of 15 mL / min, and an outlet air temperature controlled at 35-40°C. The outlet air temperature was used as the primary control parameter and was maintained within the stated range by adjusting the inlet air temperature.

[0131] (5) Scrape the sample powder in the cyclone collector. This powder is the C66 solid dispersion prepared with different carriers and store it in a sealed container. The C66 solid dispersions obtained from (1), (2), and (3) are respectively designated as solid dispersions 1, 2, and 3.

[0132] (6) The solubility of solid dispersions 1, 2, and 3 was investigated according to the dissolution curve test method described in Example 5.

[0133] (7) Solid dispersions 1, 2, and 3 were placed under the accelerated test conditions described in Example 7 (sealed aluminum foil bag, 40 ± 2°C, 75% ± 5% RH) for 3 months. Their dissolution rates were measured and compared with the dissolution results before placement to determine whether the samples exhibited a decrease in dissolution rate. The experimental results are as follows:

[0134] The results show that the dissolution rate of C66 in solid dispersion 1, using HPMCAS as a carrier, did not decrease significantly after three months of accelerated testing. Solid dispersions 2 and 3, using PEG 4000 and poloxamer 188 as carriers, dissolve rapidly at 1 month and meet quality control requirements. However, after three months, the dissolution rate decreases significantly, with cumulative dissolution rates of only 71.9% and 79.2% over 60 minutes, respectively. This is no longer sufficient to meet the quality control requirement of a cumulative dissolution rate of at least 85% over 30 to 60 minutes. Therefore, while solid dispersion technology can be used to increase the dissolution rate of C66, the appropriate choice of carrier is crucial for the preparation of C66 solid dispersions with anti-aging properties.

[0135] Example 11 Effect of different mass ratios of C66 and PEG 6000 on the anti-aging ability of C66 solid dispersion

[0136] Prescription composition:

[0137] C66-PEG 6000 solid dispersions were prepared according to the process described in Example 2. Samples prepared with a mass ratio of C66 to PEG 6000 of 1:5, 1:12, and 1:20 were recorded as solid dispersions 1, 2, and 3, respectively. The solubility of solid dispersions 1, 2, and 3 was investigated according to the dissolution curve test method described in Example 5. Subsequently, solid dispersions 1, 2, and 3 were placed under the accelerated test conditions described in Example 7 (aluminum foil bag packaging, sealed, 40±2°C, 75%±5% RH) for 3 months, and their dissolution was measured and compared with the dissolution results before placement to analyze the aging of the samples after long-term storage. The experimental results are as follows:

[0138] The results show that the dissolution rates of the three C66 solid dispersions with different mass ratios all met the expected requirements upon initial preparation (0 months), with 60-minute dissolution rates exceeding 90%. However, after 3 months of exposure to accelerated conditions, the dissolution rates changed: the cumulative dissolution rates of solid dispersions 1, 2, and 3 at 60 minutes decreased by 9.9%, 1.1%, and 2.8%, respectively, compared to those at 0 months. Solid dispersion 1 showed a significantly higher rate of decline than solid dispersions 2 and 3, with a 60-minute dissolution rate below 85%, no longer meeting quality requirements. However, the dissolution rates of solid dispersions 2 and 3 remained largely unaffected after 3 months of exposure to accelerated conditions. Therefore, solid dispersions prepared with the same carrier and C66 at different mass ratios exhibit varying aging rates, and the amount and proportion of carrier play a significant role in the anti-aging effects of C66 solid dispersions. Furthermore, although solid dispersion 3 exhibited promising anti-aging effects, its drug loading (4.8%) was significantly lower than that of solid dispersion 2 (7.7%), potentially leading to excessive final drug volume for clinical use. Taking into account the anti-aging effect and drug loading, in this embodiment, solid dispersion 2 has the best drug effect.

[0139] Example 12 Preparation of Curcumin Derivative C66 Solid Dispersion Capsules

[0140] Pass lactose monohydrate through a 200-mesh sieve and the C66 solid dispersion prepared in Example 9 through a 100-mesh sieve for later use. Weigh 416.0 g of 200-mesh lactose monohydrate, 440.0 g of microcrystalline cellulose (SH101), 4.0 g of magnesium stearate, and a solid dispersion containing 40.0 g of C66 in sequence. Place all the raw materials and auxiliary materials in a square cone mixer and mix them evenly for 5 minutes. Take out the materials and add them to the hopper of the fully automatic capsule filling machine. Use 2 # Empty gelatin capsule shells were filled with a theoretical loading of 225 mg per capsule. The filling process was smooth, with capsule weight variation within 3%. The active ingredient C66 content was within ±3% of the intended dosage specification (10 mg), demonstrating filling accuracy that met quality requirements.

[0141] Example 13 Preparation of Curcumin Derivative C66 Solid Dispersion Tablets

[0142] Pass lactose monohydrate through a 200-mesh sieve and the C66 solid dispersion obtained in Example 3 through a 100-mesh sieve for later use. Weigh 176.0 g of sieved lactose monohydrate, 870.0 g of microcrystalline cellulose (SH101), 5.0 g of magnesium stearate, 22.6 g of cross-linked sodium carboxymethyl cellulose, and a solid dispersion containing 60.0 g of C66. Place all the raw and auxiliary materials in a square cone mixer and mix them evenly for 5 minutes. Take out the material, add it to the hopper of a fully automatic tablet press, and use a 9 mm diameter arc punch for tableting. The theoretical tablet weight is 189 mg. The tableting process is smooth, the production pressure is relatively stable, and the tablet weight is controlled within ±3%. The hardness of the tablet is 6 to 9 kg, and the C66 content can be controlled within ±3%. The C66 solid dispersion can meet the requirements of the powder direct compression process and prepare tablets of qualified quality.

Claims

1. A solid dispersion of a curcumin derivative, characterized in that including a curcumin derivative and a carrier material; The curcumin derivative is C66, and its structure is shown in formula (I): The carrier material includes but is not limited to one, two or three of polyethylene glycol 6000, povidone K30, copovidone S630, hypromellose acetate succinate, and hydroxypropyl methylcellulose; The curcumin derivative is dispersed in the carrier material in microcrystalline or amorphous form.

2. The solid dispersion of curcumin derivative according to claim 1, characterized in that The mass ratio of the curcumin derivative to the carrier material is 1:0.5 to 1:

25.

3. A method for preparing a solid dispersion of a curcumin derivative as claimed in claim 1 or 2, characterized in that: dispersing the curcumin derivative in the carrier material to obtain the solid dispersion; The dispersion method is spray drying, hot melt extrusion or melt dispersion.

4. The method for preparing a solid dispersion of a curcumin derivative according to claim 3, wherein: The dispersion method is spray drying, and the specific process is as follows: dissolving or dispersing a curcumin derivative and a carrier material in a solvent to obtain a curcumin derivative-carrier material solvent dispersion system, and then drying the curcumin derivative-carrier material solvent dispersion system through a spray dryer to obtain the curcumin derivative solid dispersion; The solvent includes but is not limited to water, ethanol, acetone, or a mixture of two or more solvents.

5. The method for preparing a solid dispersion of a curcumin derivative according to claim 4, wherein: The carrier material is povidone K30, and the weight ratio of the curcumin derivative to the carrier material is 1:0.5 to 1:2.5; The solvent is a mixed solvent of ethanol and acetone, and the volume ratio of ethanol to acetone is 1:0.5～1.5； The inlet air temperature of spray drying is 60-70℃, and the outlet air temperature is 30-40℃.

6. The method for preparing a solid dispersion of a curcumin derivative according to claim 3, wherein: The dispersion method is hot melt extrusion; The curcumin derivative and the carrier material are mixed and placed in a hot melt extruder for hot melt extrusion, and then pulverized and sieved after cooling to obtain the curcumin derivative solid dispersion; The cooling method is room temperature cooling or low temperature cooling; the pulverization method is shearing or rolling.

7. The method for preparing a solid dispersion of a curcumin derivative according to claim 6, wherein: The carrier material is copolyvidone S630; The mass ratio of the curcumin derivative to the carrier material is 1:4-7; The temperature of each zone of the hot melt extruder used is 80-165°C; The nozzle temperature is 130-150°C.

8. A C66 solid dispersion capsule, characterized in that: The capsule is made of the solid dispersion according to any one of claims 1 to 7, a filler and a lubricant; wherein the amount of the filler accounts for 20 to 90% of the total weight of the capsule, and the amount of the lubricant accounts for 0.1% to 5% of the total weight of the capsule; The filler includes but is not limited to one or more of microcrystalline cellulose, lactose, and pregelatinized starch; The lubricant includes but is not limited to one or more of magnesium stearate, talc, and micro-powdered silica gel.

9. A method for preparing the C66 solid dispersion capsule according to claim 8, characterized in that: Take the solid dispersion powder, mix it evenly with the filler and lubricant, and then fill it into capsules to obtain the product.

10. A C66 solid dispersion tablet, characterized in that: The tablet is prepared from the solid dispersion according to any one of claims 1 to 7, a filler, a disintegrant, and a lubricant; wherein the filler accounts for 20 to 90% of the total weight of the tablet, the disintegrant accounts for 0.5 to 15% of the total weight of the tablet, and the lubricant accounts for 0.1% to 5% of the total weight of the tablet; The filler includes but is not limited to one or more of microcrystalline cellulose, lactose, and pregelatinized starch; The disintegrant includes but is not limited to one or more of cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone; The lubricant includes but is not limited to one or more of magnesium stearate, talc, and micro-powdered silica gel.

11. A method for preparing the C66 solid dispersion tablet according to claim 10, characterized in that: The solid dispersion powder is mixed evenly with a filler, a disintegrant and a lubricant and then tabletted to obtain the product.

12. Use of the solid dispersion, solid dispersion capsule or solid dispersion tablet according to any one of claims 1 to 11 in the preparation of a medicament for treating or preventing kidney disease or heart disease.

13. The use according to claim 12, characterized in that The kidney diseases include diabetic nephropathy, hypertensive nephropathy, nephrotic syndrome, chronic glomerulonephritis, IgA nephropathy, lupus nephritis, hepatitis B-related nephritis, Henoch-Schonlein purpura nephritis, membranous nephropathy, and various primary and secondary chronic kidney diseases after kidney transplantation.

Images