Application of curcumin in preparation of preparation for treating traumatic hemorrhagic shock in desert dry-hot environment

Abstract

The invention relates to the technical field of medicines, in particular to application of curcumin in preparation of a preparation for treating traumatic hemorrhagic shock in a desert dry-hot environment. Curcumin is used for preparing the preparation for treating the traumatic hemorrhagic shock in the desert dry-hot environment, and a patient suffering from the traumatic hemorrhagic shock in the desert dry-hot environment can be protected in a targeted manner, so that the survival rate of the traumatic hemorrhagic shock in the desert dry-hot environment is increased, the prognosis is improved, and the curcumin has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the application of curcumin in the preparation of a formulation for treating traumatic hemorrhagic shock in a hot and dry desert environment. Background Technology

[0002] Shock is not a disease, but a pathophysiological state. It primarily refers to a severe condition caused by a rapid decrease in blood circulation due to various reasons, leading to insufficient perfusion of tissues and organs, resulting in ischemia and hypoxia of tissue cells, metabolic disorders, and functional impairment, ultimately causing multi-organ failure and death. Common symptoms of shock include decreased blood pressure, rapid heart rate, weak pulse, pallor, cold extremities, and confusion. The causes of shock are numerous, including hemorrhagic loss, fluid loss, infection, allergies, burns, and trauma. The mechanism of shock is mainly due to reduced blood volume, vasodilation, and increased permeability, leading to decreased blood circulation and consequently ischemia and hypoxia of all tissues and organs.

[0003] Shock is essentially caused by insufficient perfusion of the body and hypoxia of tissue cells. (Yan Jing. Guidelines for the resuscitation of hypovolemic shock) For patients with hemorrhagic shock, fluid resuscitation should be the first-line treatment. Specifically, for hemorrhagic shock with uncontrolled bleeding, restrictive fluid resuscitation should be initiated first; for patients with effectively controlled bleeding, aggressive fluid resuscitation should be performed. (Cheng Yujia. Application of restrictive fluid resuscitation and routine fluid resuscitation in patients with multiple traumatic hemorrhagic shock in the intensive care unit) Restrictive fluid resuscitation for traumatic hemorrhagic shock can effectively improve patient survival rates and ensure treatment efficacy. The above guidelines and treatment plans are all based on normothermic environments, and the occurrence of traumatic hemorrhagic shock in patients also occurs in normothermic environments. However, no treatment guidelines have been published for traumatic hemorrhagic shock occurring in hot and dry desert environments. However, the treatment of hemorrhagic shock is essentially limited to aggressive fluid resuscitation and restrictive fluid resuscitation. In both cases, the focus is on treating the shock itself, neglecting the impact of heat on the body. When the body is exposed to heat radiation, it will develop corresponding response mechanisms to adapt, such as increased inflammation and damage to the nervous system. Therefore, when treating traumatic hemorrhagic shock in a hot, dry desert environment, in addition to considering hemorrhagic shock, the damage caused by heat stress must also be considered. Furthermore, regardless of whether aggressive or restrictive fluid resuscitation is performed, the damage caused by ischemia-reperfusion has not been effectively prevented and controlled.

[0004] In summary, while routine fluid resuscitation (using aggressive and restrictive fluid resuscitation as needed) can be used to treat traumatic hemorrhagic shock in the dry, hot desert environment, the lack of specific protection against the thermal effects and ischemia-reperfusion damage of the environment results in less than ideal long-term prognosis for patients. Therefore, there is an urgent need for drugs that can effectively reduce the associated damage.

[0005] Turmeric has a long history of medicinal and culinary use, and curcumin, as the active ingredient in the traditional Chinese medicine turmeric, also possesses various medicinal values, showing certain effects against tumors and tuberculosis. Our previous research found that curcumin has a certain effect on bodily damage caused by extreme environments, such as liver damage caused by rapid ascent to high altitudes and multi-organ protection against heatstroke. Therefore, we believe that curcumin is a potential protective drug preparation against bodily damage caused by extreme environments. However, there are currently no literature reports on the protective effect of curcumin nanocrystal intravenous injection against traumatic hemorrhagic shock in hot and dry desert environments. Summary of the Invention

[0006] The purpose of this invention is to address the problem that while conventional fluid resuscitation can be used for traumatic hemorrhagic shock in hot and dry desert environments, the lack of targeted protection against the thermal effects and ischemia-reperfusion damage of the environment leads to less than ideal long-term prognosis for patients. This invention provides an application of curcumin in the preparation of formulations for treating traumatic hemorrhagic shock in hot and dry desert environments. Using curcumin in the preparation of such formulations can provide targeted protection for patients with this condition, thereby improving survival rates and prognosis, and has broad application prospects.

[0007] To achieve the above objectives, the present invention provides the application of curcumin in the preparation of a formulation for treating traumatic hemorrhagic shock in a hot and dry desert environment.

[0008] Furthermore, the conditions of the hot and dry desert environment include: a temperature of 40-45℃ and a humidity of 10-20%.

[0009] Furthermore, the formulation is an intravenous injection formulation.

[0010] Furthermore, the concentration of curcumin in the injectable formulation is 20-40 mg / mL.

[0011] Furthermore, the concentration of curcumin used is 2.0-3.0 mg / mL.

[0012] Furthermore, the curcumin in the formulation exists in the form of curcumin nanocrystals.

[0013] Furthermore, the curcumin nanocrystals are ground using Tween 80 as the medium, and the particle size of the curcumin nanocrystals is ≤79nm.

[0014] In the above-mentioned technical solution, this invention, through a series of experiments, explored in depth the potential role of curcumin in the treatment of traumatic hemorrhagic shock in a hot and dry desert environment. Experimental results showed that curcumin nanocrystal intravenous injection can reduce the inflammatory response during restrictive and active fluid resuscitation in traumatic hemorrhagic shock in a hot and dry desert environment, alleviate secondary multi-organ damage in experimental pigs, and provide a new drug for improving the long-term prognosis of this type of trauma.

[0015] Curcumin, a natural compound with diverse pharmacological activities, has shown potential in the targeted protection of patients with traumatic hemorrhagic shock in hot and dry desert environments. It has improved the survival rate and prognosis of patients with traumatic hemorrhagic shock in hot and dry desert environments. This discovery not only provides strong support for curcumin as a potential protective drug against damage to the body in extreme environments, but also offers new ideas for the further development of protective drug formulations against damage to the body in extreme environments, showing broad application prospects.

[0016] Other features and advantages of the present invention will be described in detail in the following detailed description section. Attached Figure Description

[0017] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the following detailed description to explain the invention, but do not constitute a limitation thereof. In the drawings: Figure 1 The figures show the changes in inflammatory cells (leukocytes, neutrophils) and liver, kidney, and cardiac enzymes at different stages in the Aggressive Fluid Resuscitation (AFR) group and the Aggressive Fluid Resuscitation + Curcumin (CAFR) group in Example 1. For example, #P<0.05 compared to the T0 time point of the same group; *P<0.05 compared to the fluid resuscitation group at the same time point. Figure 2 These are HE sections and pathological damage scores of the kidneys in the AFR and CAFR groups in Example 1. Figure 3 The images show liver HE sections and pathological damage scores for the AFR and CAFR groups in Example 1. Figure 4 These are lung HE sections and pathological damage scoring images from the AFR and CAFR groups in Example 1. Figure 5 These are cardiac HE slices and pathological damage scoring images from the AFR and CAFR groups in Example 1. Figure 6 The images show the hippocampal HE sections and pathological damage scores of the AFR and CAFR groups in Example 1. Figure 7 The figures show the changes in inflammatory cells (leukocytes, neutrophils) and liver, kidney, and cardiac enzymes at different stages in the restricted fluid resuscitation (RFR) group and the restricted fluid resuscitation + curcumin (CRFR) group in Example 2. # Compared with the same group at time T0, # P < 0.05; * Compared with the same time point in the fluid resuscitation group, * P < 0.05. Figure 8 These are cardiac HE slices and pathological damage scores from the RFR and CRFR groups in Example 2. Figure 9 These are HE sections and pathological damage scores of the kidneys in the RFR and CRFR groups in Example 2. Figure 10 The images show the hippocampal HE sections and pathological damage scores of the RFR and CRFR groups in Example 2. Figure 11 These are lung HE sections and pathological damage scoring images from the RFR and CRFR groups in Example 2. Figure 12 The images show liver HE sections and pathological damage scores for the RFR and CRFR groups in Example 2. Figure 13 This is a flowchart of the experimental process of the present invention. Detailed Implementation

[0018] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0019] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0020] This invention provides the application of curcumin in the preparation of formulations for treating traumatic hemorrhagic shock in hot and dry desert environments.

[0021] In a preferred embodiment of the present invention, the conditions of the hot and dry desert environment include: a temperature of 40-45°C and a humidity of 10-20%.

[0022] In a preferred embodiment of the present invention, the preparation is an injectable preparation.

[0023] In a preferred embodiment of the present invention, the concentration of curcumin in the injectable preparation is 20-40 mg / mL, preferably 30 mg / mL.

[0024] In a preferred embodiment of the present invention, the concentration of curcumin used is 2.0-3.0 mg / mL.

[0025] In a preferred embodiment of the present invention, the curcumin in the preparation exists in the form of curcumin nanocrystals.

[0026] In a preferred embodiment of the present invention, the curcumin nanocrystals are ground using Tween 80 as the medium, and the particle size of the curcumin nanocrystals is ≤79nm.

[0027] The present invention will be described in detail below through examples. In the following examples, the pharmaceuticals and agents are all conventional commercially available products.

[0028] Experimental materials: Laboratory animals: Forty ordinary, clean-grade Landrace pigs, 3-4 months old, weighing 30-35kg, were purchased from Xinjiang Taikun Agricultural and Animal Husbandry Technology Co., Ltd.

[0029] • Reagents and instruments are shown in Table 1: Table 1 name Source / Model Curcumin Nanocrystal Injection Provided by the Academy of Military Medical Sciences; concentration: 30 mg / ml; particle size: 70 nm physiological saline - Atropine sulfate Tianjin Jinyao, batch number: 2205101 Ketamine hydrochloride injection Jiangsu Hengrui, batch number: 11020BL Propofol medium / long chain fat emulsion injection Xi'an Libang, Batch No.: 12111262-1 Rocuronium bromide injection Emeishan Tonghui, approval number: 22071801 Northwest Special Environment Artificial Test Chamber Xinjiang Military Region General Hospital, China Fully automated biochemical analyzer Mindray electrocardiogram monitor T8, Mair Example 1

[0030] This embodiment illustrates the effects of curcumin nanocrystal injection on inflammatory cells, heart, kidneys, brain, lungs, and liver during active fluid resuscitation in traumatic hemorrhagic shock in a hot and dry desert environment.

[0031] S1. Twenty experimental pigs were randomly divided into an active fluid resuscitation group (AFR) and an active fluid resuscitation + curcumin group (CAFR). The experimental animals were placed in a pre-set phase environment (desert dry and hot environment: temperature 40.5±0.5℃, humidity 10%±2%) experimental chamber for 3 hours. S2. Ketamine 20mg / kg and atropine 0.05mg / kg were injected intramuscularly to induce anesthesia. The experimental pigs were placed supine on the operating table, their limbs were fixed, and tracheal intubation was performed. After successful intubation, the respiratory anesthesia machine was connected. After the muscle relaxant was injected, the machine was switched to machine-controlled mode when breathing stopped. The tidal volume was set to (10±2)mL / kg, the respiratory rate was (20±2) breaths per minute, the oxygen flow rate was (1.5±0.5)L per minute, and the inspiratory to expiratory ratio was 1:2. S3. Establish an intravenous access through the marginal ear vein, and maintain anesthesia by intravenous infusion of propofol injection at 8-10 mg / (kg·h), connect to ECG monitor, and monitor body temperature; after satisfactory anesthesia, isolate and expose the right external jugular vein, collect mixed venous blood samples and rehydration fluid, and insert a cannula in the right femoral artery to monitor arterial blood pressure, while the left femoral artery is used for phlebotomy and blood sample collection. S4. Midline laparotomy was performed, followed by splenectomy and partial resection of the left lower lobe of the liver. The patient was weighed and given lactated Ringer's solution at 3 times the weight of the spleen. Then, a cystostomy was performed. S5. The shock model uses moderate traumatic hemorrhagic shock with fixed blood pressure. Rapid bloodletting is performed from the external iliac artery to achieve a mean arterial pressure (MAP) of 45±5 mmHg. After stabilization for 60 minutes, it is recorded as shock 0h. During the stabilization period, the target blood pressure can be stabilized by re-bleeding or intravenous infusion of lactated Ringer's solution. S6. When shock reaches 0, begin aggressive fluid resuscitation to quickly reach the target resuscitation MAP blood pressure of 90 mmHg. Once the target blood pressure is reached at resuscitation 0, maintain blood pressure by controlling the infusion rate and volume. Blood is drawn every hour thereafter. After 4 hours of resuscitation, resuscitation is considered successful. Propofol sedation is gradually discontinued, and anesthesia resuscitation is performed followed by extubation. Blood is drawn at 6, 8, 12 and 24 hours of resuscitation. The experimental pigs are then euthanized under anesthesia for sampling. The use of curcumin nanocrystal intravenous injection solution began at the start of fluid resuscitation, with an infusion dose of 20 mg / kg, a concentration of 2.4 mg / ml, and an infusion rate of 60 drops / min. After the infusion was completed, the same dose of curcumin nanocrystal intravenous injection solution was infused again 12 hours after resuscitation.

[0032] S7. White blood cells and neutrophils were detected in the blood at relevant time points. Serum was separated at each time point, and CK, CK-MB, LDH, ALT, AST, CREAM, and BUN were detected using a whole-body biochemical analyzer (Mindray). Heart, liver, spleen, lung, and kidney tissue samples taken at the final time point were stained with hematoxylin and eosin (HE) and eosin (H&E) for relevant pathological damage scoring. Experimental results are shown in […]. Figure 1-6 .

[0033] Note: T0 (before environmental exposure), T1 (3 hours after environmental exposure), T2 (0 hours after shock), T3 (1 hour after shock), T4 (0 hours after resuscitation), T5 (1 hour after resuscitation), T6 (2 hours after resuscitation), T7 (3 hours after resuscitation), T8 (4 hours after resuscitation), T9 (6 hours after resuscitation), T10 (8 hours after resuscitation), T11 (12 hours after resuscitation), T12 (24 hours after resuscitation).

[0034] Depend on Figure 1The content indicates that, in aggressive fluid resuscitation protocols, curcumin nanocrystal injection can reduce multi-organ damage by decreasing the expression of inflammatory cells (leukocytes, neutrophils) and lowering the expression of liver, kidney, and cardiac function-related indicators; Figure 2-6 It is known that, in aggressive fluid resuscitation regimens, curcumin nanocrystal injection can reduce damage to the hippocampus, myocardium, liver, lungs, and kidneys, lower pathological damage scores in the brain, heart, liver, lungs, and kidneys, and improve long-term prognosis.

[0035] from Figure 2-6 HE sections revealed the following: Kidneys: glomerular capsule narrowing and congestion, renal tubular epithelial cell edema; pathological changes were less pronounced in the curcumin group compared to the simple resuscitation group. Liver: Hepatocyte edema, eosinophilic degeneration, and nuclear pyknosis were observed in the simple fluid resuscitation group; eosinophilic degeneration was significantly reduced in the curcumin group, with only a small amount of nuclear pyknosis. Lungs: Alveolar collapse, inflammatory cell infiltration in the alveoli and interstitium, and alveolar thickening were observed in the simple fluid resuscitation group; no alveolar wall thickening, capillary dilation, or congestion were observed in the curcumin group. Heart: Extensive myocardial disorder, intermyocardial vascular dilation, and hemorrhage were observed in the simple fluid resuscitation group; no significant myocardial disorder was observed in the curcumin group, but scattered eosinophilic degeneration was visible. Brain: Hippocampal interstitial edema and partial pyramidal cell nuclear condensation were observed in the simple fluid resuscitation group; hippocampal interstitial edema was significantly reduced in the curcumin group.

[0036] Example 2

[0037] This embodiment illustrates the effects of curcumin nanocrystal injection on inflammatory cells, heart, kidneys, brain, lungs, and liver during fluid-restricted resuscitation in traumatic hemorrhagic shock in a hot and dry desert environment.

[0038] S1. Twenty experimental pigs were randomly divided into a restricted fluid resuscitation group (RFR) and a restricted fluid resuscitation + curcumin group (CRFR). The experimental animals were placed in a pre-set phase environment (desert dry and hot environment: temperature 40.5±0.5℃, humidity 10%±2%) experimental chamber for 3 hours. S2. Ketamine 20mg / kg and atropine 0.05mg / kg were injected intramuscularly to induce anesthesia. The experimental pigs were placed supine on the operating table, their limbs were fixed, and endotracheal intubation was performed. After successful intubation, the respiratory anesthesia machine was connected. After the muscle relaxant was injected, the machine was switched to machine-controlled mode when breathing stopped. The tidal volume was set to (10±2)mL / kg, the respiratory rate was (20±2) breaths per minute, the oxygen flow rate was (1.5±0.5)L per minute, and the inspiratory to expiratory ratio was 1:2. S3. Establish an intravenous access through the marginal auricular vein, and maintain anesthesia with propofol injection at 8-10 mg / (kg·h) via intravenous pump. Connect the cardiac monitor and monitor body temperature. After satisfactory anesthesia, isolate and expose the right external jugular vein, collect mixed venous blood samples and administer fluids, and insert a cannula in the right femoral artery to monitor arterial blood pressure. The left femoral artery is used for phlebotomy and blood sample collection. S4. Midline laparotomy was performed, followed by splenectomy and partial resection of the left lower lobe of the liver. The patient was weighed and given lactated Ringer's solution at 3 times the weight of the spleen. Then, a cystostomy was performed. S5. The shock model uses moderate traumatic hemorrhagic shock with fixed blood pressure. Rapid bloodletting is performed from the external iliac artery to achieve a mean arterial pressure (MAP) of 45±5 mmHg. After stabilization for 30 minutes, it is recorded as shock 0h. During the stabilization period, the target blood pressure can be stabilized by re-bleeding or intravenous infusion of lactated Ringer's solution. S6. When shock 0 is reached, restrictive fluid resuscitation is initiated to quickly reach the target resuscitation MAP blood pressure between 60 and 80 mmHg. The target blood pressure is maintained for 30 minutes, and then fluid resuscitation is continued until the MAP reaches 90 mmHg, which is recorded as resuscitation 0. Blood pressure is maintained by controlling the infusion rate and volume. Blood is drawn every hour thereafter. After 4 hours of resuscitation, resuscitation is considered successful. Propofol sedation is gradually discontinued, and anesthesia resuscitation is performed and the trachea is extubated. Blood is drawn at 6, 8, 12 and 24 hours of resuscitation. The experimental pigs are then sacrificed under anesthesia for sampling. The use of curcumin nanocrystal intravenous injection solution began at the start of fluid resuscitation, with an infusion dose of 20 mg / kg, a concentration of 2.4 mg / ml, and an infusion rate of 60 drops / min. After the infusion was completed, the same dose of curcumin nanocrystal intravenous injection solution was infused again 12 hours after resuscitation.

[0039] S7. White blood cells and neutrophils were detected in the blood at relevant time points. Serum was separated at each time point, and CK, CK-MB, LDH, ALT, AST, CREAM, and BUN were detected using a whole-body biochemical analyzer (Mindray). Heart, liver, spleen, lung, and kidney tissue samples taken at the final time point were stained with hematoxylin and eosin (HE) and eosin (H&E) for relevant pathological damage scoring. Experimental results are shown in […]. Figure 7-12 .

[0040] Note: T0 (before environmental exposure), T1 (3 hours after environmental exposure), T2 (0 hours after shock), T3 (1 hour after shock), T4 (0 hours after resuscitation), T5 (1 hour after resuscitation), T6 (2 hours after resuscitation), T7 (3 hours after resuscitation), T8 (4 hours after resuscitation), T9 (6 hours after resuscitation), T10 (8 hours after resuscitation), T11 (12 hours after resuscitation), T12 (24 hours after resuscitation).

[0041] Depend on Figure 7The content indicates that, in restrictive fluid resuscitation protocols, curcumin nanocrystal injection can reduce the levels of inflammatory cells (leukocytes, neutrophils) and inflammatory factors, decrease the expression of liver, kidney, and cardiac function-related indicators, and reduce multi-organ damage. Figure 8-12 According to the information provided, curcumin nanocrystal injection can reduce the pathological damage scores of the brain, heart, liver, lungs and kidneys, and improve long-term prognosis.

[0042] from Figure 8-12 HE sections revealed the following: Kidneys: In the fluid resuscitation group, the glomerular capsule was narrowed, with some vessels showing congestion and dilation, and renal tubular epithelial cells showing edema. In the curcumin group, some renal corpuscles showed mild congestion and swelling, with occasional vascular congestion. Liver: In the fluid resuscitation group, focal necrosis of hepatocytes, sinusoidal congestion, and significant eosinophilic changes were observed. In the curcumin group, eosinophilic changes were significantly reduced, with a small amount of nuclear pyknosis and minor hemorrhage. Lungs: In the fluid resuscitation group, inflammatory cell infiltration in the alveoli and interstitium was observed, with alveolar thickening and a small amount of exudate around them. In the curcumin group, the alveolar walls were not thickened, there was no capillary dilation or congestion, and almost no exudate. Heart: In the fluid resuscitation group, disordered myocardium, intermyocardial vascular dilation and hemorrhage were observed, with extensive eosinophilic changes. In the curcumin group, scattered eosinophilic changes were observed, with myofibrils arranged neatly. Brain: In the fluid resuscitation group, mild edema of the hippocampal interstitium and a small amount of pyramidal cell nuclear condensation were observed. In the curcumin group, there was no significant edema of the hippocampal interstitium.

[0043] In summary, this invention, through extensive animal experimental studies, has screened and clarified the therapeutic effect of curcumin nanocrystal injection on traumatic hemorrhagic shock in arid desert environments. Curcumin nanocrystal injection is prepared by grinding curcumin to a nanoscale state using Tween 80 as a medium, which significantly increases its water solubility and bioabsorption. Intravenous injection of curcumin nanocrystals can reduce the inflammatory response during both active and restrictive fluid resuscitation in patients with traumatic hemorrhagic shock in arid desert environments, and alleviate secondary multi-organ damage in experimental pigs, providing a new drug for improving the long-term prognosis of this type of trauma. Simultaneously, curcumin has shown potential in targeted protection against traumatic hemorrhagic shock in arid desert environments, improving the survival rate and prognosis of patients with this condition. This discovery not only strongly supports the idea that curcumin is a potential protective drug against damage in extreme environments, but also provides new ideas for further development of protective drugs against damage in extreme environments, demonstrating broad application prospects.

[0044] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0045] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

[0046] Furthermore, various different embodiments of the present invention can be combined in any way, as long as they do not violate the spirit of the present invention, they should also be regarded as the content disclosed by the present invention.

Claims

1. Use of curcumin in the preparation of a preparation for treating traumatic hemorrhagic shock in a desert hot environment.

2. Use according to claim 1, characterized in that, The conditions of the desert hot environment include a temperature of 40-45℃ and a humidity of 10-20%.

3. Use according to claim 1 or 2, characterized in that, The preparation is an injection preparation.

4. Use according to claim 3, characterized in that, The concentration of curcumin in the injection preparation is 20-40 mg / mL.

5. The use according to claim 1, characterized in that, The concentration of curcumin used is 2.0-3.0 mg / mL.

6. Use according to claim 1, characterized in that, The curcumin in the preparation exists in the form of curcumin nanocrystals.

7. Use according to claim 6, characterized in that, The curcumin nanocrystals are ground in Tween 80 as a medium, and the particle size of the curcumin nanocrystals is ≤79 nm.

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