A curcumin nanocrystal pharmaceutical composition, preparation method thereof, and application thereof

Abstract

The present application relates to a curcumin nanocrystal composition, the composition contains 1-18% (m / v) of curcumin nanocrystal, 0.1-10% (m / v) of stabilizer, 0.1-10% (m / v) of surfactant and 0-10% (m / v) of suspending agent in mass volume percentage, wherein the particle size of the curcumin nanocrystal is less than or equal to 100 nm, the stabilizer is selected from any one or combination of hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone PVPK12PF, polyvinylpyrrolidone PVPK15, polyvinylpyrrolidone PVPK17PF, lecithin, polyethylene glycol, poloxamer Pluronics F68, poloxamer Pluronics F108, the surfactant is selected from any one or combination of sodium cholate, sodium deoxycholate, sodium docusate, sodium dodecyl sulfate (SDS), sodium dodecyl sulfonate (SLS), sodium alginate, and the suspending agent is selected from any one or combination of sucrose, dextran, glycerol, povidone, hydroxypropyl cellulose, methyl cellulose, hypromellose, sodium carboxymethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gum arabic, dextrin. The composition of the present application has the advantages of fast onset, good stability, high bioavailability, safety and effectiveness.

Description

[0001] This application is a divisional application of the invention patent application No. 202211583584.0, filed on December 9, 2022. TECHNICAL FIELD

[0002] The present application belongs to the technical field of medicine, and specifically relates to a curcumin nanocrystal pharmaceutical composition, a preparation method thereof and application thereof. BACKGROUND

[0003] Human body is prone to exertional heat stroke in high humidity and high temperature environment. Exertional heat stroke presents acute onset and dangerous clinical manifestations, and can involve multiple organs and systems, resulting in high mortality and morbidity. Effective prevention and rapid-acting first-aid drugs should be immediately administered, but there is still a lack of specific drugs for preventing and treating exertional heat stroke at home and abroad.

[0004] Curcumin (CUR) is a lipophilic polyphenolic component in turmeric, which has the effects of anti-cancer, anti-virus, anti-bacteria, anti-diabetes, anti-oxidation, anti-inflammation, treatment of rheumatoid arthritis, osteoarthritis, inflammation-related cardiovascular diseases, inflammatory bowel disease, allergic asthma, etc. It is used for maintaining blood indicators, correcting electrolyte disorders, maintaining the functions of multiple organs and systems damaged by heat stroke, and is used as an anti-inflammatory agent, a postoperative analgesic, an antipyretic agent, etc. It is used for preventing and treating lung injury, myocardial injury, liver and kidney injury, brain injury, intestinal mucosal pathological injury and other lesions caused by heat stroke. However, curcumin is a poorly soluble BCS IV drug, and effective measures need to be taken to improve the solubility and bioavailability of the drug.

[0005] SUMMARY

[0006] The present application aims to provide a curcumin nanocrystal composition, which contains 1-18% (m / v) of curcumin nanocrystals, 0.1-10% (m / v) of a stabilizer, 0.1-10% (m / v) of a surfactant and 0-10% (m / v) of a suspending agent in terms of mass volume percentage, wherein the particle size of the curcumin nanocrystals is ≤100 nm, the stabilizer is selected from any one or combination of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone PVPK12 PF, polyvinylpyrrolidone PVPK15, polyvinylpyrrolidone PVPK17 PF, lecithin, polyethylene glycol, poloxamer pluronic F68, poloxamer pluronic F108, the surfactant is selected from any one or combination of sodium cholate, sodium deoxycholate, sodium docusate, sodium dodecyl sulfate (SDS), sodium dodecyl sulfonate (SLS), sodium alginate, and the suspending agent is selected from any one or combination of sucrose, dextran, glycerol, povidone, hydroxypropyl cellulose, methyl cellulose, hypromellose, sodium carboxymethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gum arabic, dextrin.

[0007] In a preferred technical scheme of the present application, the content of curcumin nanocrystals in the composition is 2-15% (m / v), the content of the stabilizer is 0.5-5% (m / v), the content of the surfactant is 0.2-8% (m / v), the content of the suspending agent is 1-8% (m / v), and the particle size of the curcumin nanocrystals is ≤80 nm in terms of mass volume percentage.

[0008] In a preferred technical scheme of the present application, the content of curcumin nanocrystals in the composition is 3-12% (m / v), the content of the stabilizer is 0.9-3.6% (m / v), the content of the surfactant is 0.3-5% (m / v), the content of the suspending agent is 1-6% (m / v), and the particle size of the curcumin nanocrystals is ≤75 nm in terms of mass volume percentage.

[0009] In a preferred technical scheme of the present application, the composition contains 1-15% (m / v) of curcumin nanocrystals, 0.1-5% (m / v) of polyvinylpyrrolidone PVPK17 PF, 0.1-15% (m / v) of sodium deoxycholate and 0-10% (m / v) of sucrose in terms of mass volume percentage, and the balance is water, wherein the particle size of the curcumin nanocrystals is ≤80 nm.

[0010] In a preferred technical scheme of the present application, the composition contains 3-12% (m / v) of curcumin nanocrystals, 0.9-3.6% (m / v) of polyvinylpyrrolidone PVPK17 PF, 0.3-5% (m / v) of sodium deoxycholate and 1-6% (m / v) of sucrose in terms of mass volume percentage, and the balance is water, wherein the particle size of the curcumin nanocrystals is ≤75 nm.

[0011] In the preferred technical solution of the present application, the composition contains 3% (m / v) of curcumin nanocrystals, 0.9% (m / v) of povidone PVPK17 PF, 0.3% (m / v) of sodium deoxycholate and 6% (m / v) of sucrose, with the balance being water, in terms of mass / volume percentage, wherein the particle size of the curcumin nanocrystals is ≤75 nm.

[0012] In the preferred technical solution of the present application, the composition contains 12% (m / v) of curcumin nanocrystals, 3.6% (m / v) of povidone PVPK17 PF and 1.2% (m / v) of sodium deoxycholate, with the balance being water, in terms of mass / volume percentage, wherein the particle size of the curcumin nanocrystals is ≤75 nm.

[0013] Another object of the present application is to provide a preparation method of a curcumin nanocrystal pharmaceutical composition, which contains 1-18% (m / v) of curcumin nanocrystals, 0.1-10% (m / v) of a stabilizer, 0.1-10% (m / v) of a surfactant and 0-10% (m / v) of a suspending agent, in terms of mass / volume percentage, wherein the particle size of the curcumin nanocrystals is ≤100 nm, the stabilizer is selected from any one or a combination of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone PVPK12 PF, polyvinylpyrrolidone PVPK15, polyvinylpyrrolidone PVPK17 PF, lecithin, polyethylene glycol, poloxamer pluronic F68 and poloxamer pluronic F108, the surfactant is selected from any one or a combination of sodium cholate, sodium deoxycholate, sodium docusate, sodium dodecyl sulfate (SDS), sodium dodecyl sulfonate (SLS) and sodium alginate, and the suspending agent is selected from any one or a combination of sucrose, dextran, glycerol, povidone, hydroxypropyl cellulose, methyl cellulose, hypromellose, sodium carboxymethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gum arabic and dextrin, the method comprising the following steps:

[0014] (1) A required amount of the stabilizer is weighed and dissolved in water, and a required amount of curcumin is added, followed by stirring at 500-1500 rpm for 30-60 min, and then high-speed shearing at 1000-3500 rpm for 1-10 min to obtain a sheared mixed solution;

[0015] (2) The prepared sheared mixed suspension is ground at 800-2000 rpm for 1-30 min, and then a required amount of a surfactant solution and / or a suspending agent solution is added, followed by grinding at 800-2000 rpm for 30-90 min to obtain the curcumin nanocrystal pharmaceutical composition.

[0016] In a preferred technical solution of the present invention, the curcumin nanocrystal content in the composition is 2-15% (m / v), the stabilizer content is 0.5-5% (m / v), the surfactant content is 0.2-8% (m / v), the suspending agent content is 1-8% (m / v), and the curcumin nanocrystal particle size is ≤80nm.

[0017] In a preferred technical solution of the present invention, the curcumin nanocrystal content in the composition is 3-12% (m / v), the stabilizer content is 0.9-3.6% (m / v), the surfactant content is 0.3-5% (m / v), the suspending agent content is 3-6% (m / v), and the curcumin nanocrystal particle size is ≤75nm.

[0018] In a preferred technical solution of the present invention, the composition contains, by mass volume percentage, 1-15% (m / v) of curcumin nanocrystals, 0.1-5% (m / v) of povidone PVPK17 PF, 0.1-15% (m / v) of sodium deoxycholate, and 0-10% (m / v) of sucrose, with the remainder being water, wherein the particle size of the curcumin nanocrystals is ≤80 nm.

[0019] In a preferred technical solution of the present invention, the composition contains, by mass volume percentage, 3-12% (m / v) of curcumin nanocrystals, 0.9-3.6% (m / v) of povidone PVPK17 PF, 0.3-5% (m / v) of sodium deoxycholate, and 1-6% (m / v) of sucrose, with the remainder being water, wherein the particle size of the curcumin nanocrystals is ≤75 nm.

[0020] In the preferred technical solution of the present invention, the composition contains, by mass volume percentage, 3% (m / v) of curcumin nanocrystals, 0.9% (m / v) of povidone PVPK17 PF, 0.3% (m / v) of sodium deoxycholate and 6% (m / v) of sucrose, with the balance being water, wherein the particle size of the curcumin nanocrystals is ≤75 nm.

[0021] In the preferred technical solution of the present invention, the composition contains 12% (m / v) curcumin nanocrystals, 3.6% (m / v) povidone PVPK17 PF, 1.2% (m / v) sodium deoxycholate, and the balance is water, measured by mass volume percentage, wherein the curcumin nanocrystal particle size is ≤75nm.

[0022] In the preferred technical solution of the present invention, the stirring speed of step (1) is 600-1200 rpm, the high-speed shearing speed is 2000-3200 rpm, and the high-speed shearing time is 3-10 min; the grinding speed of step (2) is 1000-1500 rpm.

[0023] In the preferred technical scheme of the present application, the stirring speed of step (1) is 800-1000 rpm, and the grinding speed of step (2) is 1200-1500 rpm.

[0024] Another object of the present application is to provide the use of the curcumin nanocrystal composition for preparing a medicament for preventing and treating heat stroke or its complications, wherein the composition contains 1-18% (m / v) of curcumin nanocrystals, 0.1-10% (m / v) of a stabilizer, 0.1-10% (m / v) of a surfactant, and 0-10% (m / v) of a suspending agent, wherein the particle size of the curcumin nanocrystals is ≤100 nm, the stabilizer is selected from any one or combination of hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone PVP K12 PF, polyvinylpyrrolidone PVP K15, polyvinylpyrrolidone PVP K17 PF, lecithin, polyethylene glycol, poloxamer pluronic F68, poloxamer pluronic F108, the surfactant is selected from any one or combination of sodium cholate, sodium deoxycholate, sodium docusate, sodium dodecyl sulfate (SDS), sodium dodecyl sulfonate (SLS), sodium alginate, and the suspending agent is selected from any one or combination of sucrose, dextran, glycerol, povidone, hydroxypropyl cellulose, methyl cellulose, hypromellose, sodium carboxymethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gum arabic, and dextrin.

[0025] Another object of the present application is to provide the use of the curcumin nanocrystal composition for the preparation of a medicament for treating any one of rheumatoid arthritis, osteoarthritis, inflammation-related cardiovascular disease, inflammatory bowel disease, allergic asthma, anticancer, antiviral, antibacterial, anti-diabetic, antioxidant, anti-inflammatory, pain or its complications, wherein the composition contains 1-18% (m / v) of curcumin nanocrystals, 0.1-10% (m / v) of a stabilizer, 0.1-10% (m / v) of a surfactant and 0-10% (m / v) of a suspending agent, wherein the particle size of the curcumin nanocrystals is ≤100 nm, the stabilizer is selected from any one of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone PVP K12 PF, polyvinylpyrrolidone PVP K15, polyvinylpyrrolidone PVP K17 PF, lecithin, polyethylene glycol, poloxamer pluronic F68, poloxamer pluronic F108 or a combination thereof, the surfactant is selected from any one of sodium cholate, sodium deoxycholate, sodium docusate, sodium dodecyl sulfate (SDS), sodium dodecyl sulfonate (SLS), sodium alginate or a combination thereof, and the suspending agent is selected from any one of sucrose, dextran, glycerol, povidone, hydroxypropyl cellulose, methyl cellulose, hypromellose, sodium carboxymethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gum arabic, dextrin or a combination thereof.

[0026] In a preferred technical solution of the present application, the pain is selected from any one of abdominoplasty pain, colorectal surgery pain, bunionectomy pain, total knee arthroplasty pain, and post-arthroscopic surgery pain.

[0027] Unless otherwise specified, the present application refers to the percentage between liquids as volume / volume percentage; the present application refers to the percentage between a liquid and a solid as volume / weight percentage; the present application refers to the percentage between a solid and a liquid as weight / volume percentage; and the rest as weight / weight percentage.

[0028] Unless otherwise specified, the present application uses a ball mill (WAB AK71M-2WKF, Switzerland) for grinding and a nanoparticle size analyzer (Nano-ZS90, Malvern, UK) for measuring the particle size.

[0029] Compared with the prior art, the present application has the following beneficial technical effects:

[0030] 1. The curcumin nanocrystal composition of the present application has the advantages of effective prevention and treatment of heat stroke and its complications, prevention and treatment of body and organ damage caused by heat stroke, and treatment of rheumatoid arthritis, osteoarthritis, inflammation-related cardiovascular diseases, inflammatory bowel disease, allergic asthma, anticancer, antiviral, antibacterial, antidiabetic, antioxidant, anti-inflammatory and other diseases or their complications, and has the advantages of fast effect, good stability, high bioavailability, safety and effectiveness.

[0031] 2. The preparation method of the present application has the advantages of simple operation, significantly shortened production cycle, high yield, green environmental protection, significant cost benefit, and is suitable for industrialized mass production. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 Stability investigation of the curcumin nanocrystal pharmaceutical composition of the present application;

[0033] Figure 2 Long-term stability investigation of the curcumin nanocrystal pharmaceutical composition of the present application;

[0034] Figure 3 Stability investigation of the curcumin nanocrystal pharmaceutical composition of the present application;

[0035] Figure 4 Pharmacokinetic study of the curcumin nanocrystal pharmaceutical composition of the present application. DETAILED DESCRIPTION

[0036] The present application is illustrated below with reference to examples, but the present application is not limited to the examples.

[0037] Example 1 Preparation of curcumin nanocrystal composition

[0038] Composition of curcumin nanocrystal composition:

[0039]

[0040] The preparation of curcumin nanocrystal composition includes the following steps:

[0041] (1) 3.6g of povidone K17 PF is weighed, dissolved in 95mL of water, and then 12.0g of curcumin is added, and the mixture is stirred at 800rpm for 30min, and then the prepared curcumin mixture is high-speed sheared at 3000rpm for 3min to prepare a sheared mixture;

[0042] (2) The prepared sheared mixture is introduced into a ball mill, and the grinding beads with a particle size of 0.1mm are used to grind at a speed of 1500r / min for 10min, and then the required amount of sodium deoxycholate solution is added, and the mixture is ground at 1500r / min for 80min to prepare curcumin nanocrystals.

[0043] (3) According to the method of the present application, the prepared curcumin nanocrystal has a particle size of 71 nm, which is suspended in a sucrose solution with a desired concentration, and water is added to make up to 400 ml as needed, and then it is obtained.

[0044] Example 2 Preparation of curcumin nanocrystal pharmaceutical composition

[0045] Composition of curcumin nanocrystal pharmaceutical composition:

[0046] Curcumin 12 g

[0047] PVP K17 PF 3.6 g (dissolved in 95 ml of water)

[0048] Sodium deoxycholate 1.2 g (dissolved in 5 ml of water)

[0049] The preparation of curcumin nanocrystal composition includes the following steps:

[0050] (1) Weigh 3.6 g of polyvinyl pyrrolidone K17 PF, dissolve it in 95 mL of water, then add 12.0 g of curcumin, stir at 800 rpm for 30 min, then prepare a sheared mixture by high-speed shearing at 3000 rpm for 3 min;

[0051] (2) The sheared mixture prepared in step (1) is introduced into a ball mill, and the grinding beads with a particle size of 0.1 mm are used to grind at 1500 r / min for 10 min, then sodium deoxycholate solution is added, and the grinding is carried out at a speed of 1500 r / min for 80 min, and water is added to make up to 100 ml as needed, to prepare curcumin nanocrystals.

[0052] According to the method of the present application, the prepared curcumin nanocrystal has a particle size of 71.2 nm. Comparative Example 1 Preparation of curcumin nanocrystal pharmaceutical composition

[0053] Composition of curcumin nanocrystal pharmaceutical composition:

[0054] Curcumin 20 g

[0055] Tween 80 6 g

[0056] The preparation of curcumin nanocrystal pharmaceutical composition includes the following steps:

[0057] (1) Weigh curcumin 20 g and Tween 80 6 g, and disperse them in 200 mL of water under stirring conditions to prepare a curcumin suspension;

[0058] (2) The prepared curcumin suspension was poured into a wet grinder for media grinding. The grinding medium was zirconia beads with a diameter of 0.3 mm. The grinding speed was started from 1500 r / min and increased by 500 r / min every 5 minutes to 3000 r / min. The speed was maintained at 3000 r / min for 30 minutes to obtain the curcumin suspension.

[0059] Test Example 1 Study on the long-term stability of curcumin nanocrystal pharmaceutical composition

[0060] 10 ml of each of the curcumin nanocrystal pharmaceutical compositions prepared in Example 1 and Control Example 1 were measured and placed in test tubes, which were then placed naturally at room temperature for 0 month, 1 month, 2 months, 3 months, 4 months, 5 months, and 6 months, and the particle size was measured using a Nano-ZS90 particle size analyzer.

[0061] See the results Figure 1 The curcumin nanocrystal composition prepared by the present invention has good stability.

[0062] Test Example 2 Study on the long-term stability of curcumin nanocrystal pharmaceutical composition

[0063] 50 ml of each of the curcumin nanocrystal pharmaceutical compositions prepared in Example 1 and Comparative Example 1 were measured and placed in test tubes. The tubes were then left to stand naturally at room temperature for 6 months, and their properties and changes were observed.

[0064] See the results Figure 2 The curcumin nanocrystal solution prepared in Example 1 has good stability, while the curcumin nanocrystal composition prepared in Control Example 1 has obvious stratification and poor stability.

[0065] Test Example 3 Stability investigation of curcumin nanocrystal pharmaceutical composition

[0066] 5 mL of each of the curcumin nanocrystal pharmaceutical compositions prepared in Example 1 and Control Example 1 were drawn out using a 5 mL syringe and then injected completely to observe the composition residue in the syringe.

[0067] See the results Figure 3 The curcumin nanocrystal pharmaceutical composition prepared in Control Example 1 had obvious stratification and needed to be shaken before injection. After injection, a large amount of curcumin nanocrystal pharmaceutical solution remained in the syringe, affecting the dosage accuracy, safety and effectiveness of the injected drug.

[0068] Test Example 4 Pharmacokinetic study of curcumin nanocrystal pharmaceutical composition

[0069] Male SD rats (200-220g) were selected (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., animal qualification certificate number: SCXK(Beijing)2016-0011), and were randomly divided into three groups, 10 rats in each group. The test animals were injected with a drug dose of 100mg / kg. Group 1 (physical mixture of curcumin without nanocrystal treatment); group 2 (curcumin nanocrystal composition of Example 1); group 3 (curcumin nanocrystal composition of Example 1).

[0070] Before the experiment, the test SD rats were fasted for 12h. After the test animals were administered for 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h, 96h, about 0.5mL of blood was taken from the eye socket and placed in an anticoagulant tube. The collected blood sample was centrifuged at 8000r / min for 10min, and 200μL of supernatant was precisely pipetted. The curcumin content in the rat plasma was detected by HPLC-MS / MS method. The results are shown in Table 1 and Figure 4 .

[0071] Table 1

[0072] Parameters Example 1 Comparative Example 1 Physical mixture AUC 0-90 (ng / mL·h)]]> 44863.93 38546.50 5949.27 C max (ng / mL) 2066.54 1532.16 193.54 T max (h)]]> 2.23 3.67 4.31

[0073] The above description of specific embodiments of the present application does not limit the present application, and those skilled in the art can make various changes or modifications to the present application without departing from the spirit of the present application, and all such changes or modifications shall fall within the scope of protection of the claims of the present application.

Claims

1. A curcumin nanocrystal composition, comprising, by mass volume percentage, 2-15% m / v of curcumin, 0.5-5% m / v of povidone PVPK17 PF, 0.2-8% m / v of sodium deoxycholate, and 1-8% m / v of sucrose, with the balance being water, wherein: The particle size of the curcumin nanocrystal is ≤80 nm. The preparation method of the curcumin nanocrystal composition comprises the following steps: (1) Weigh the required amount of povidone PVPK17 PF, dissolve it in water, add the required amount of curcumin, stir at 500-1500 rpm for 30-60 min, and then place it under high-speed shear at 1000-3500 rpm for 1-10 min to prepare a shear mixture; (2) Grind the prepared shear suspension at 800-2000 rpm for 1-30 min, add the required amount of sodium deoxycholate solution, and grind it at 800-2000 rpm for 30-90 min to obtain nanocrystals, which are then suspended in a sucrose solution of the required concentration.

2. The composition according to claim 1, wherein Calculated by mass volume percentage, the composition contains 3-12% m / v of curcumin nanocrystals, 0.9-3.6% m / v of povidone PVPK17 PF, 0.3-5% m / v of sodium deoxycholate and 1-6% m / v of sucrose, and the particle size of the curcumin nanocrystals is ≤75nm.

3. The composition according to any one of claims 1 to 2, wherein the stirring speed in step (1) is 600-1200 rpm, the high-speed shearing speed is 2000-3200 rpm, and the high-speed shearing time is 3-10 min; and the grinding speed in step (2) is 1000-1500 rpm.

4. The composition according to any one of claims 1 to 2, wherein the stirring speed in step (1) is 800-1000 rpm, and the grinding speed in step (2) is 1200-1500 rpm.

5. The method for preparing a curcumin nanocrystal composition according to any one of claims 1 to 4, comprising the steps of: (1) Weigh the required amount of povidone PVPK17 PF, dissolve it in water, add the required amount of curcumin, stir at 500-1500 rpm for 30-60 min, and then place it under high-speed shear at 1000-3500 rpm for 1-10 min to prepare a shear mixture; (2) Grind the prepared shear suspension at 800-2000 rpm for 1-30 min, add the required amount of sodium deoxycholate solution, and grind it at 800-2000 rpm for 30-90 min to obtain nanocrystals, which are then suspended in a sucrose solution of the required concentration.

6. The preparation method according to claim 5, wherein the stirring speed in step (1) is 600-1200 rpm, the high-speed shearing speed is 2000-3200 rpm, and the high-speed shearing time is 3-10 min; and the grinding speed in step (2) is 1000-1500 rpm.

7. The preparation method according to claim 5, wherein the stirring speed in step (1) is 800-1000 rpm, and the grinding speed in step (2) is 1200-1500 rpm.

8. Use of the curcumin nanocrystal composition according to any one of claims 1 to 4 in preparing a medicament for preventing and treating heat stroke.

9. The curcumin nanocrystal composition according to any one of claims 1 to 4 is used for preparing a medicament for treating rheumatoid arthritis, osteoarthritis, inflammation-related cardiovascular disease, inflammatory bowel disease, allergic asthma, anticancer, antiviral, antibacterial, antidiabetic, antioxidant, or pain.

10. The use according to claim 9, wherein the pain is selected from any one of abdominoplasty pain, colorectal surgery pain, bunionectomy pain, total knee replacement pain, and pain after arthroscopic surgery.

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