Composition for promoting delivery of diabetes drugs and preparation method thereof

Abstract

The invention relates to the field of medicines, in particular to a composition for promoting delivery of diabetes drugs and a preparation method thereof, and the composition is prepared from the following raw materials: Eu-coated UiO-66, modified nanocellulose crystals, parthenolide phosphorylate, metformin hydrochloride, sodium citrate, D-sorbitol, sodium carboxymethyl starch, magnesium stearate and polyethylene glycol. The Eu-coated UiO-66, the modified nanocellulose crystal and the parthenolide phosphorylate play a role through a synergistic effect, the Eu-coated UiO-66 serves as a drug encapsulation carrier and protects a drug, the modified nanocellulose crystal accurately delivers the drug to the intestinal epithelial cell substrate side, and finally the parthenolide phosphorylate promotes absorption of cells to the drug. A dynamic balance system is formed by the three components, the functions of gastric acid environment stabilization protection, intestinal epithelium targeted penetration and response drug release are sequentially exerted in the delivery process of the diabetes drugs, and the composition beneficial to human health and capable of promoting delivery of the diabetes drugs is provided.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and specifically to a composition for promoting the delivery of diabetes drugs and a preparation method thereof. Background Art

[0002] Diabetes, as a global chronic metabolic disease, its treatment relies on long-term drug intervention. Metformin hydrochloride, as a widely used oral hypoglycemic drug, its hypoglycemic mechanism is mainly achieved by inhibiting hepatic gluconeogenesis and enhancing the uptake and utilization of glucose by peripheral tissues. Metformin hydrochloride is rapidly released in the gastrointestinal tract, which may lead to too high local concentration and stimulate the gastrointestinal mucosa. Therefore, Metformin hydrochloride often accompanies gastrointestinal side effects such as diarrhea, nausea, vomiting, and abdominal distension during clinical use, which is likely to cause discomfort to patients and may seriously affect the bioavailability of the drug. Frequent diarrhea will cause Metformin hydrochloride to quickly pass through the intestine, and the unabsorbed drug components cannot exert their hypoglycemic effect, resulting in poor blood glucose control and affecting the medication compliance and quality of life of patients. At present, solving the diarrhea side effect caused by Metformin hydrochloride in patients will significantly improve the quality of life of hundreds of millions of diabetes patients. Innovative strategies such as improving the drug delivery system and optimizing the dosage regimen can not only maximize the therapeutic value of Metformin hydrochloride. Therefore, prolonging the residence time of Metformin hydrochloride in the intestine can not only relieve gastrointestinal discomfort, but also is of great significance for improving the curative effect of diabetes and the quality of life of patients. Summary of the Invention

[0003] (1) Technical Problems to be Solved

[0004] The purpose of the present invention is to provide a composition for promoting the delivery of diabetes drugs and a preparation method thereof. By finely screening a composition that can promote the delivery of diabetes drugs, not only a variety of chemical substances are incorporated into the diabetes drugs, but also the efficient utilization of diabetes drugs during the delivery process is ensured, thereby greatly enhancing the medical effect of diabetes drugs. Finally, a composition for promoting the delivery of diabetes drugs that is both safe and effective is provided.

[0005] (2) Technical Solutions

[0006] To achieve the above purpose, on the one hand, the present invention provides a composition for promoting the delivery of diabetes drugs, comprising the following raw materials in parts by weight: 10 - 20 parts of Eu@UiO-66, 5 - 15 parts of D-sorbitol, 1 - 3 parts of sodium carboxymethyl starch, 20 - 40 parts of parthenolide phosphorylated compound, 20 - 40 parts of Metformin hydrochloride, 5 - 15 parts of sodium citrate, 100 - 200 parts of magnesium stearate, 20 - 30 parts of polyethylene glycol;

[0007] The composition for promoting the delivery of diabetes drugs further comprises:

[0008] Modified nanocrystalline cellulose

[0009] The weight ratio of the modified nanocrystalline cellulose to parthenolide phosphorylated compound is 1:(3 - 6);

[0010] The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface using nanocrystalline cellulose as a carrier.

[0011] Furthermore, the preparation method of the modified nanocrystalline cellulose includes:

[0012] S11. Dissolve nanocrystalline cellulose in phosphate buffer at room temperature to prepare a nanocrystalline cellulose solution with a concentration of 1.0 - 1.5 mg / mL, and then treat the nanocrystalline cellulose solution with ultrasonic waves;

[0013] S12. Suspend the nanocrystalline cellulose solution in anhydrous dimethyl sulfoxide, and then add 3-aminopropyltriethoxysilane. The molar ratio of 3-aminopropyltriethoxysilane to nanocrystalline cellulose is 1:(3 - 5), and react at 80 - 85 °C for 6 - 7 h under nitrogen protection to obtain a first mixed solution;

[0014] S13. Wash the first mixed solution with ethanol, centrifuge at 3000 - 4000 rpm for 3 - 5 min, and then dry it under vacuum to obtain amino-functionalized nanocrystalline cellulose, which is marked as the second mixed solution;

[0015] S14. Disperse the second mixed solution in a phosphate buffer with pH = 7.0 - 8.0, add TAT peptide and carbodiimide (EDC) / N-hydroxysuccinimide (NHS) activator. The mass ratio of EDC:NHS is = 1:(2 - 4), and react at 25 - 30 °C for 12 - 15 h under nitrogen protection to obtain a third mixed solution;

[0016] S15. Ultrafilter and centrifuge the third mixed solution, dialyze it using a dialysis bag, and then lyophilize to obtain the modified nanocrystalline cellulose.

[0017] Furthermore, the Eu@UiO-66 is a UiO-66 type MOF doped with rare earth element Eu (Eu@UiO-66), and its specific surface area is 1500 - 1600 m 2 / g.

[0018] Furthermore, the mass ratio of the Eu@UiO-66 to D-sorbitol is 1:(2 - 4).

[0019] Furthermore, the preparation method of the parthenolide phosphorylated compound includes:

[0020] S21. In a dry 250 mL three-necked flask, add 5.0 - 6.0 g of feverfew, 0.15 - 0.2 g of DMAP, and 100 - 120 mL of anhydrous THF. Stir and dissolve under nitrogen protection, and record it as the first mixture;

[0021] S22. Cool down the system of the first mixture, control the temperature at -10 to -15 °C, and then slowly add dropwise 1.0 - 1.2 mL of dibenzyl dichlorophosphate. After the addition is complete, raise the temperature to 45 - 50 °C and continue to react for 16 - 19 h, and record it as the second mixture;

[0022] S23. Add 200 - 220 mL of sodium hydroxide to the second mixture, stir for 30 - 40 min, control the pH = 7.0 - 7.5, then extract with 400 - 420 mL of dichloromethane. Combine the organic phases, dry with 50 - 60 g of anhydrous sodium sulfate, filter, and then remove the solvent by rotary evaporation to obtain the crude product;

[0023] S24. Purify the crude product by silica column chromatography (gradient elution with DCM:MeOH, 100:0 → 95:5 → 90:10) to obtain monophosphorylated parthenolide;

[0024] S25. Dissolve 1.0 - 2.0 g of monophosphorylated parthenolide in 20 - 30 mL of methanol, add 10 - 15 mL of deionized water, adjust the pH to 7.0 - 7.5 with 1.0 - 1.1 M sodium hydroxide solution, then remove methanol by rotary evaporation and remove water by freeze-drying to obtain parthenolide phosphorylate.

[0025] Further, the mass ratio of polyethylene glycol, magnesium stearate, and sodium carboxymethyl starch is (10 - 20):1:(3 - 9).

[0026] Further, the mass ratio of parthenolide phosphorylate, metformin hydrochloride, and sodium citrate is (1 - 20):(2 - 4):(1 - 3).

[0027] On the other hand, based on the same inventive concept, the present invention also provides a preparation method of a composition for promoting diabetes drug delivery, which is applied to the composition for promoting diabetes drug delivery as described above, and includes the following steps:

[0028] S31. Add 15 parts of Eu@UiO-66, 10 parts of D-sorbitol, 2 parts of sodium carboxymethyl starch, 30 parts of parthenolide phosphorylate, 35 parts of metformin hydrochloride, 10 parts of sodium citrate, 25 parts of polyethylene glycol, and 10 parts of modified nanocrystalline cellulose into a container, and mix to obtain a first mixture;

[0029] S32. Feed the first mixture into a high-speed shear emulsifier, mix it for 15 - 20 min under the condition of 5000 - 6000 rpm, and then sieve it through a 60 - 65 mesh sieve to obtain the second mixture;

[0030] S33. Add 20 - 25% ethanol solution to the second mixture under stirring, and then pass it through fluidized bed granulation. The inlet air temperature is 50 - 55 °C, and the wind speed is 30 - 35 m 3 / h. Control the particle moisture content ≤ 3% to obtain the third mixture;

[0031] S34. Add 150 parts of magnesium stearate to the third mixture, mix it for 10 - 12 min, and press it into a tablet core with a diameter of 8 mm (hardness ≥ 50 N, friability ≤ 0.5%) using a rotary tablet press. After cooling, it is packaged to obtain the composition for promoting diabetes drug delivery.

[0032] The mechanism of action of the above raw material components is as follows:

[0033] Modified nanocellulose crystals are formed by modifying nanocellulose with cell-penetrating peptides (CPPs, such as TAT peptide). Cell-penetrating peptides can efficiently penetrate cell membranes (even the blood-brain barrier) and help macromolecular drugs or nanoparticles enter cells. The cell-penetrating peptides are anchored on the surface of nanocellulose through chemical coupling (such as amino-carboxyl reaction) to form a composite carrier system. Modified nanocellulose crystals can form electrostatic interactions with negatively charged glycoproteins (such as mucin MUC2) on the surface of intestinal mucosa, prolong the residence time of drugs in the intestine, and bypass the efflux transporters (such as P-glycoprotein) in intestinal epithelial cells to avoid the drug being pumped back into the intestinal lumen.

[0034] Eu@UiO-66 is a material based on zirconium metal-organic framework (MOF), which is prepared by doping Eu 3+ (Eu ions) into the UiO-66 framework. UiO-66 is a porous crystalline material formed by connecting zirconium metal ions (Zr 4+ ) and 1,4-benzenedicarboxylic acid (BDC) ligands through coordination bonds, and has high chemical stability, thermal stability and water stability. Among them, the doping of Eu 3+ can make Eu@UiO-66 have a high specific surface area and porous structure, which can efficiently load diabetes treatment drugs (such as insulin or polypeptide drugs) and protect the drugs from degradation during in vivo transmission. At the same time, Eu@UiO-66 can achieve intelligent regulation of drug release through surface modification or composite with other materials.

[0035] Matricin Phosphorylate (MP) is a phosphorylated derivative of the active ingredient matricin in white chrysanthemum. Matricin is mainly derived from plants of the Compositae family, especially plants of the genus Hypericum, such as St. John's Wort. Matricin is a sesquiterpene lactone compound in white chrysanthemum. Its molecular structure has natural insulin-mimicking activity, can effectively penetrate the cell membrane barrier and precisely target the insulin β-cell receptor. The molecular structure of Matricin Phosphorylate contains a stilbene skeleton and a strategically introduced phosphate group, with a molecular weight of about 340 - 360 Da, being weakly acidic and partially ionized under intestinal pH conditions, increasing water solubility. After phosphorylation, Matricin Phosphorylate carries a negative charge and can chelate with metal cations (such as calcium and iron) in the intestinal lumen, thereby reducing the interference of these ions on the drug and decreasing their inhibitory effect on drug absorption. By creating a microenvironment more conducive to drug dissolution and absorption, phosphorylation modification can particularly enhance the absorption efficiency of drugs whose bioavailability is reduced due to being affected by metal ions such as iron and calcium.

[0036] D-Sorbitol is a hexitol (C6H 14 O6), which is the reduction product of glucose and belongs to naturally occurring polyols. It is also known as sorbitol, sorbitol alcohol. It is a white crystalline powder with a sweet taste and is naturally present in many fruits, such as apples, pears, apricots, cherries, etc. D-Sorbitol can be used in diabetes drug tablets (such as metformin hydrochloride, acarbose) to improve the taste without affecting blood sugar (because its metabolism does not depend on insulin). It protects the active ingredient of the drug (such as peptide hypoglycemic drugs) from moisture through hygroscopicity. It is used in insulin injections to adjust the osmotic pressure to enhance stability (such as synergistically with zinc ions).

[0037] Sodium citrate is an organic sodium salt with the chemical formula Na3C6H5O7, formed by the combination of citric acid and sodium ions. It is a white crystalline or crystalline powder, easily soluble in water and has a slightly salty taste. Sodium citrate is often used as a pH buffer in diabetes drug formulations to help maintain the acid-base balance of the drug solution, ensuring the stability and effectiveness of the drug. Sodium citrate can bind to calcium ions in the blood, thus playing an anticoagulant role. In some injectable diabetes drugs, it helps prevent blood clotting at the injection site. At the same time, it can also be used as a stabilizer in drug preparations to extend the shelf life of the drug and maintain the stability of the active ingredient.

[0038] Metformin hydrochloride is the hydrochloride form of metformin. It is a white crystalline or crystalline powder with no odor. It is readily soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform or ether. It is a widely used drug for treating diabetes. By inhibiting the key enzymes in the process of hepatic gluconeogenesis, it reduces the conversion of non-carbohydrate substances into glucose by the liver, thereby lowering the fasting blood glucose level. At the same time, it increases the uptake and utilization of glucose by peripheral tissues (such as muscle, fat, etc.), improves the efficiency of insulin action, enables cells to better utilize glucose in the blood, and reduces postprandial blood glucose. It can also delay the absorption rate of glucose in the small intestine, slow down the rising rate of postprandial blood glucose, and reduce blood glucose fluctuations. Sodium carboxymethyl starch is a water-soluble high-molecular compound and mainly acts as a disintegrant in diabetes drugs. It can cause the drug to disintegrate rapidly in the body, facilitating absorption and thus enabling the drug to exert its efficacy more quickly. Magnesium stearate is a white fine powder and is often used as a lubricant in diabetes drugs. It can reduce the friction between drug particles and between the drug and equipment such as tablet presses, making the tableting process smoother, ensuring the formation and appearance quality of the drug, and not affecting the drug efficacy. Polyethylene glycol is a high-molecular polymer and has various uses in diabetes drugs. It can be used as a solubilizer to help dissolve poorly soluble drugs and improve bioavailability. It can also be used as a coating material to improve the appearance and stability of the drug. It can also be used as a sustained-release material to control the drug release rate, enabling the drug to be slowly released in the body, maintaining an effective blood drug concentration for a long time, and controlling blood glucose steadily.

[0039] In the composition for promoting diabetes drug delivery, Eu@UiO-66, modified nanocrystalline cellulose, and parthenolide phosphide act through a synergistic effect. In the preparation process of the composition for diabetes drug delivery, Eu@UiO-66 serves as a primary protective carrier. Using its nanopores with a high specific surface area, it physically encapsulates drugs such as metformin hydrochloride. The fluorescence label formed by Eu doping on the crystal surface can track the drug position in real time, enabling it to enter the intestine completely. Subsequently, the pores of the UiO-66 framework open to release the drug. At this time, for the modified nanocrystalline cellulose, the TAT transmembrane peptide grafted on its surface adsorbs through positive charges to extend the residence time of the drug in the intestinal mucosa. At the same time, it activates the transmembrane transport mediated by caveolae-mediated endocytosis, directly delivering the drug to the basolateral side of intestinal epithelial cells, avoiding the decomposition of the drug by intestinal cell metabolic enzymes or clearance by efflux pumps, enabling intestinal cells to accurately receive diabetes drugs. Subsequently, the diabetes drugs released into the blood circulation are captured by parthenolide phosphide. The phosphate groups inside it have an electrostatic interaction with the phosphate heads of the phospholipid bilayer on the cell membrane surface, temporarily changing the membrane fluidity and permeability, strengthening drug delivery and transmission, improving the absorption of the drug by intestinal cells, and reducing the number of them free in the intestinal environment. At the same time, the hydroxyl groups on the parthenolide molecule form a hydrogen bond network with cell membrane proteins, extending the drug-membrane interaction time and ensuring the continuous and stable release of the drug.

[0040] (3) Beneficial effects

[0041] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0042] 1. Eu@UiO-66 is used as the core encapsulation material, and diabetic drug molecules are encapsulated through its crystal pores to maintain the integrity of the drug, enabling it to reach the intestine intact and reducing drug loss;

[0043] 2. Parthenolide phosphorylates can increase the permeability of cell gaps without damaging the integrity of the barrier function, accelerate the absorption of drugs by cells, thereby achieving precise drug delivery and reducing the free state of diabetic drugs in the intestinal environment;

[0044] 3. Using Eu@UiO-66, modified nanocrystalline cellulose, and parthenolide phosphorylates as the core functional units, the bioavailability and controlled release efficacy of the drug are significantly improved through synergistic effects. Description of the drawings

[0045] Figure 1 This is the SEM image of Eu@UiO-66 in Example 1 of the present invention. Detailed implementation manners

[0046] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0047] The test equipment and preparations in the following embodiments are as follows: electronic balance (Sartorius, Germany), electrothermal constant temperature water bath (Kedao, Jiangsu), magnetic stirrer (Meiyingpu, Shanghai), ultrasonic instrument (Yixin, Shanghai), high-speed centrifuge (Jidi, Guangzhou), vacuum drying oven (Jiecheng, Shanghai), scanning electron microscope (Zeiss, Germany), specific surface area analyzer (Beijing Beishide Instrument Technology), Schlenk reaction device and vacuum pump system, rotary evaporator (BUCHI R-300), freeze dryer (Pudong Freeze Drying, Shanghai), pH meter (Shanghai Yidian), ultrasonic vibrator (ELMA-E5K); chemical drugs and reagents are purchased from Sigma-Aldrich.

[0048] Example 1: This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 10 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 20 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:3. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier.

[0049] In the present invention, Eu@UiO-66, the modified nanocrystalline cellulose and the parthenolide phosphorylated compound construct a closed-loop delivery system from drug protection to targeted penetration and finally to dynamic regulation through a three-level progressive synergistic mechanism. In the gastric acid environment, the core function of Eu@UiO-66 as the primary protection carrier stems from its unique crystal structure - the nanopores constructed by zirconium oxide clusters and terephthalic acid ligands can physically encapsulate metformin hydrochloride molecules. Figure 1 The SEM of Eu@UiO-66 can be observed, and it can be seen that Eu@UiO-66 presents a typical UiO-66 structure. Eu is loaded on very small particles on the surface. Eu ions form stable fluorescent labels through coordination, which not only enhances the mechanical strength of the crystal framework but also can track the distribution trajectory of drugs in the gastrointestinal tract in real time through in vivo imaging. Under gastric acid conditions (pH ≤ 3), protonation forms Zr-OH2 +The group contracts the pore diameter to less than 0.8 nm, effectively blocking the penetration attack of pepsin. When it enters the alkaline environment of the intestine (pH≥6.5), the coordination bond breaks, resulting in the expansion of the pore diameter. At this time, the drug release rate is increased compared with that in the gastric environment, precisely matching the intestinal absorption window. The released drug immediately interacts with the modified nanocellulose crystals. The surface-grafted TAT transmembrane peptide (sequence YGRKKRRQRRR) forms an electrostatic adsorption with the negatively charged mucosal protein (such as mucin MUC2) in the intestinal mucus layer through the Zeta potential generated by arginine residues, extending the drug residence time to more than 6 hours. At the same time, the cell-penetrating functional domain of the TAT peptide activates the endocytic pathway of caveolae in the intestinal epithelial cell membrane, directly transporting the drug to the basolateral side of the cell through a clathrin-independent mechanism, bypassing the efflux effect of multidrug resistance proteins (such as P-gp). Finally, the phosphate group in parthenolide phosphorylate undergoes an electrostatic interaction with the phosphate head of the phospholipid bilayer on the cell membrane surface, changing the membrane fluidity and permeability, while the stilbene hydrophobic skeleton of parthenolide can insert into the lipid bilayer of the cell membrane, further enhancing the membrane permeability. When it reaches the intestinal epithelial cells, the phosphorylate reversibly regulates the phosphorylation level of tight junction proteins (such as occludin and ZO-1), transiently increasing the permeability of the intercellular space without destroying the complete function of the barrier, prolonging the residence time of the diabetes drug in the intestine, reducing its loss, and also inducing the formation of transient invaginations in the cell membrane to create a drug transmembrane channel. At the same time, the molecules in parthenolide phosphorylate can activate the calcium-dependent endocytosis on the apical membrane to form endocytic vesicles carrying the drug. These vesicles are directionally transported to the basolateral side through the microtubule network, bypassing the efflux effect of multidrug resistance proteins (such as P-glycoprotein). In addition, parthenolide phosphorylate can regulate the intracellular pH gradient and ionic environment, reducing the risk of the drug being captured by other components in the cell and mildly inhibiting the cytochrome P450 enzyme system, reducing the metabolism of the drug in the cell. The three functions are closely linked to form a dynamic balance, creating an efficient drug transport channel from the intestinal lumen to the blood circulation, significantly improving the bioavailability of oral administration. In addition, the unique three-dimensional structure of parthenolide phosphorylate can specifically bind to the mucin on the surface of intestinal epithelial cells, enhancing the residence time of the drug complex on the intestinal wall, creating more sufficient opportunities for drug absorption, significantly reducing the ineffective degradation and excretion of the drug in the intestinal environment, and reducing systemic adverse reactions.

[0050] The preparation method of the modified nanocellulose crystals includes:

[0051] S11. Dissolve the nanocellulose crystals in a phosphate buffer at room temperature to prepare a nanocellulose crystal solution with a concentration of 1.0 - 1.5 mg / mL, and then treat the nanocellulose crystal solution with ultrasonic waves;

[0052] S12. Suspend the nanocellulose crystal solution in anhydrous dimethyl sulfoxide, and then add 3-aminopropyltriethoxysilane. The molar ratio of 3-aminopropyltriethoxysilane to nanocellulose crystals is 1:(3 - 5). React at 80 - 85 °C for 6 - 7 h under nitrogen protection, and label it as the first mixture;

[0053] S13. Wash the first mixture with ethanol, centrifuge at 3000 - 4000 rpm for 3 - 5 min, and then dry it under vacuum to obtain amino-functionalized nanocellulose crystals, which are labeled as the second mixture;

[0054] S14. Disperse the second mixture in a phosphate buffer solution with pH = 7.0 - 8.0, add TAT peptide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) / N-hydroxysuccinimide (NHS) activator. The mass ratio of EDC:NHS is = 1:(2 - 4). React at 25 - 30 °C for 12 - 15 h under nitrogen protection, and label it as the third mixture;

[0055] S15. Ultrafilter and centrifuge the third mixture, then dialyze it using a dialysis bag, and finally lyophilize to obtain modified nanocellulose crystals.

[0056] The Eu@UiO-66 is a UiO-66 type metal-organic framework doped with rare earth element Eu (Eu@UiO-66), and its specific surface area is 1500 - 1600 m 2 / g.

[0057] The mass ratio of Eu@UiO-66 to D-sorbitol is 1:2.

[0058] The preparation method of the parthenolide phosphide includes:

[0059] S21. In a dry 250 mL three-necked flask, add 5.0 - 6.0 g of parthenolide, 0.15 - 0.2 g of DMAP, and 100 - 120 mL of anhydrous THF. Stir and dissolve it under nitrogen protection, and label it as the first mixture;

[0060] S22. Cool down the system of the first mixture to -10 - -15 °C, and then slowly add 1.0 - 1.2 mL of dibenzyl phosphorochloridate. After the addition is completed, raise the temperature to 45 - 50 °C and continue to react for 16 - 19 h, and label it as the second mixture;

[0061] S23. Add 200 - 220 mL of sodium hydroxide to the second mixture, stir for 30 - 40 min, control the pH = 7.0 - 7.5, then extract with 400 - 420 mL of dichloromethane. Combine the organic phases, dry with 50 - 60 g of anhydrous sodium sulfate, filter, and then rotary evaporate to remove the solvent to obtain the crude product;

[0062] S24. The crude product was purified by silica gel column chromatography (gradient elution with DCM:MeOH, 100:0 → 95:5 → 90:10) to obtain monophoresyl parthenolide;

[0063] S25. Dissolve 1.0 - 2.0 g of monophoresyl parthenolide in 20 - 30 mL of methanol, add 10 - 15 mL of deionized water, adjust the pH to 7.0 - 7.5 with 1.0 - 1.1 M sodium hydroxide solution, then remove methanol by rotary evaporation and remove water by freeze-drying to obtain parthenolide phosphorylate.

[0064] The polyethylene glycol, magnesium stearate and sodium carboxymethyl starch are in a mass ratio of 10:1:3.

[0065] The mass ratio of parthenolide phosphorylate, metformin hydrochloride and sodium citrate is 1:3:1.

[0066] A preparation method of a composition for promoting diabetes drug delivery, applied to the composition for promoting diabetes drug delivery as described above, includes the following steps:

[0067] S31. Add 15 parts of Eu@UiO-66, 10 parts of D-sorbitol, 2 parts of sodium carboxymethyl starch, 30 parts of parthenolide phosphorylate, 35 parts of metformin hydrochloride, 10 parts of sodium citrate, 25 parts of polyethylene glycol and 10 parts of modified nanocrystalline cellulose into a container and mix to obtain a first mixture;

[0068] S32. Put the first mixture into a high-speed shear emulsifier, mix at 5000 - 6000 rpm for 15 - 20 min, and then pass through a 60 - 65 mesh sieve to obtain a second mixture;

[0069] S33. Add a 20 - 25% ethanol solution to the second mixture under stirring, then carry out fluidized bed granulation, with an inlet air temperature of 50 - 55 °C and an air velocity of 30 - 35 m 3 / h, and control the particle moisture ≤ 3% to obtain a third mixture;

[0070] S34. Add 150 parts of magnesium stearate to the third mixture, mix for 10 - 12 min, and press into a tablet core with a diameter of 8 mm (hardness ≥ 50 N, friability ≤ 0.5%) using a rotary tablet press, and then carry out packaging after cooling to obtain the composition for promoting diabetes drug delivery.

[0071] Example 2: This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 10 parts of Eu@UiO-66, 10 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 20 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:4. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation methods of the modified nanocrystalline cellulose and the parthenolide phosphorylated compound in this example are the same as those in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0072] Example 3: This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 10 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 30 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:6. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation methods of the modified nanocrystalline cellulose and the parthenolide phosphorylated compound in this example are the same as those in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0073] Example 4: This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 15 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 20 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 40 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:3. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation methods of the modified nanocrystalline cellulose and the parthenolide phosphorylated compound in this example are the same as those in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0074] Example 5: This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 20 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 30 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:3. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation methods of the modified nanocrystalline cellulose and the parthenolide phosphorylated compound in this example are the same as those in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0075] Example 6: This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 20 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 30 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:6. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation methods of the modified nanocrystalline cellulose and the parthenolide phosphorylated compound in this example are the same as those in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0076] Example 7: This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 20 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 30 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:3. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation methods of the modified nanocrystalline cellulose and the parthenolide phosphorylated compound in this example are the same as those in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0077] Example 8: This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 20 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 10 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:6. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation methods of the modified nanocrystalline cellulose and the parthenolide phosphorylated compound in this example are the same as those in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0078] Control Group 1: The difference between this example and Example 1 is that it does not contain modified nanocrystalline cellulose. This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 10 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 20 parts of parthenolide phosphorylated compound, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The preparation method of the parthenolide phosphorylated compound in this example is the same as that in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0079] Control Group 2: The difference between this example and Example 1 is that it does not contain parthenolide phosphorylated compound. This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 10 parts of Eu@UiO-66, 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation method of the modified nanocrystalline cellulose in this example is the same as that in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0080] Control Group 3: The difference between this example and Example 1 is that it does not contain Eu@UiO-66. This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 5 parts of D-sorbitol, 3 parts of sodium carboxymethyl starch, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The composition for promoting the delivery of diabetes drugs further comprises modified nanocrystalline cellulose. The weight ratio of the modified nanocrystalline cellulose to parthenolide phosphide is 1:3. The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface of nanocrystalline cellulose as a carrier. The preparation methods of the modified nanocrystalline cellulose and parthenolide phosphide in this example are the same as those in Example 1. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0081] Control Group 4: The difference between this example and Example 1 is that it does not contain Eu@UiO-66, modified nanocrystalline cellulose, and parthenolide phosphide. This example discloses a composition for promoting the delivery of diabetes drugs, which comprises the following raw materials in parts by weight: 3 parts of sodium carboxymethyl starch, 20 parts of metformin hydrochloride, 5 parts of sodium citrate, 5 parts of D-sorbitol, 100 parts of magnesium stearate, and 20 parts of polyethylene glycol. The preparation method of the composition for promoting the delivery of diabetes drugs in this example is the same as that in Example 1.

[0082] Blank Group 1: The composition for promoting the delivery of diabetes drugs is not added to the diabetes drugs.

[0083] Effect evaluation: 10 male diabetic rats with a body weight of 170-220 g were selected for each test group. After 1 week of adaptive feeding, they were fasted for 12 hours, and their fasting blood glucose was measured through the tail vein and their body weight was recorded. Subsequently, STZ (dissolved in 0.1 mol / L citric acid buffer solution with pH = 4-5) was intraperitoneally injected at a dose of 60 mg / kg body weight once to induce a type 1 diabetes model. After injection, sufficient water and food were given daily to keep the breeding environment dry. Fasting blood glucose was measured on the 1st, 7th, and 10th days after STZ injection. Subsequently, each test group was administered orally once at a dose of 50 mg / kg. After administration, the blood drug concentration and blood glucose changes were continuously monitored for 0-24 h, and measured every 3 hours. Their blood glucose was measured to evaluate the drug delivery efficiency and hypoglycemic effect of each composition. Using AUC 0-24 , the blood drug concentration-time curve from 0 hour to 24 hours after administration, and blood glucose fluctuations were used to evaluate the diabetes drug delivery effect.

[0084] Table 1 shows the measurement and statistical results of the conditions of diabetic rats in each experimental group

[0085] Sample Blood glucose fluctuation (SD, mmol / L) <![CDATA[AUC 0-24 (μg·h / mL)]]> Example 1 1.3±0.2 120.3±10.7 Example 2 1.8±0.3 110.3±8.9 Example 3 1.8±0.5 119.1±8.7 Example 4 2.0±0.9 115.1±8.0 Example 5 1.9±1.1 111.0±8.3 Example 6 2.1±0.4 117.1±7.7 Example 7 2.3±1.0 116.4±8.0 Example 8 2.2±0.8 118.3±8.8 Control Group 1 3.4±0.9 101.1±5.6 Control Group 2 3.0±1.5 103.1±5.1 Control Group 3 3.9±1.2 107.1±6.0 Control Group 4 3.8±1.3 105.1±6.1 Blank Group 1 9.1±0.9 61.8±5.6

[0086] Table 1 shows the measurement and statistical results of the conditions of diabetic rats in each experimental group. As can be seen from Table 1, after the rats prepared in each experimental group were fed with the composition for promoting the delivery of diabetes drugs, the AUC 0-24 and the SD value of blood glucose fluctuation changed significantly. AUC 0-24 can quantify the total exposure of the drug in the body, is proportional to the dose of the drug, and the higher the value, the greater the exposure of the drug in the body and the higher the bioavailability, which can be used to evaluate the absorption efficiency and bioavailability of the drug. And the smaller the SD value of blood glucose fluctuation, the smaller the blood glucose fluctuation and the more stable the blood glucose control. By comparing the blood glucose evaluation indexes of the diabetic rats in Examples 1-8 with those in Control Groups 1-4, it can be seen that overall, the compositions for promoting the delivery of diabetes drugs prepared in Examples 1-8 can make the blood glucose control of diabetic rats more stable, and the effects are better than those of the control group and the blank group. This shows that the compositions for promoting the delivery of diabetes drugs prepared in Examples 1-7 have good effects. Among them, the SD of blood glucose fluctuation in Example 1 is the lowest, and AUC 0-24 is the highest, indicating that the composition for promoting the delivery of diabetes drugs prepared in Example 1 has the best effect. And the SD values prepared in Control Groups 1-4 are all higher than those in the experimental group, which shows that by adding Eu@UiO-66, modified nanocrystalline cellulose and parthenolide phosphide simultaneously during the preparation of the feed additive, a composition with excellent promotion of diabetes drug delivery can be obtained. Through the above limited experiments, the application effect of the composition for promoting the delivery of diabetes drugs in Example 1 of the present invention is remarkable. By adding Eu@UiO-66, modified nanocrystalline cellulose and parthenolide phosphide simultaneously during the production process, the utilization rate of diabetes drugs can be significantly improved, the delivery effect of diabetes drugs can be enhanced, and the blood glucose can be effectively reduced. The three form a dynamic balance system to jointly maintain the efficacy of a composition for promoting diabetes delivery.

[0087] Finally, it should be noted that although the present invention has been described in detail with reference to the foregoing embodiments, for those skilled in the art, it is still possible to modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A composition for promoting the delivery of diabetes drugs, characterized in that, It includes the following raw materials in parts by weight: 10 - 20 parts of Eu@UiO-66, 5 - 15 parts of D-sorbitol, 1 - 3 parts of sodium carboxymethyl starch, 20 - 40 parts of parthenolide phosphorylated compound, 20 - 40 parts of metformin hydrochloride, 5 - 15 parts of sodium citrate, 100 - 200 parts of magnesium stearate, and 20 - 30 parts of polyethylene glycol; The composition for promoting the delivery of diabetes drugs further includes: Modified nanocrystalline cellulose; The weight ratio of the modified nanocrystalline cellulose to the parthenolide phosphorylated compound is 1:(3 - 6); The modified nanocrystalline cellulose is obtained by grafting TAT transmembrane peptide on the surface using nanocrystalline cellulose as a carrier.

2. The composition for promoting diabetes drug delivery according to claim 1, wherein The preparation method of the modified nanocrystalline cellulose includes: S11. Dissolve nanocrystalline cellulose in phosphate buffer at room temperature to prepare a nanocrystalline cellulose solution with a concentration of 1.0 - 1.5 mg / mL, and then treat the nanocrystalline cellulose solution with ultrasonic waves; S12. Suspend the nanocrystalline cellulose solution in anhydrous dimethyl sulfoxide, and then add 3-aminopropyltriethoxysilane. The molar ratio of 3-aminopropyltriethoxysilane to nanocrystalline cellulose is 1:(3 - 5), and react at 80 - 85 °C for 6 - 7 h under nitrogen protection, marked as the first mixture; S13. Wash the first mixture with ethanol, centrifuge at 3000 - 4000 rpm for 3 - 5 min, and then dry it under vacuum to obtain amino-functionalized nanocrystalline cellulose, marked as the second mixture; S14. Disperse the second mixture in phosphate buffer with pH = 7.0 - 8.0, add TAT peptide and carbodiimide (EDC) / N-hydroxysuccinimide (NHS) activator. The mass ratio of EDC:NHS is = 1:(2 - 4), and react at 25 - 30 °C for 12 - 15 h under nitrogen protection, marked as the third mixture; S15. Ultrafilter and centrifuge the third mixture, and dialyze it using a dialysis bag, and then lyophilize to obtain the modified nanocrystalline cellulose.

3. The composition for promoting diabetes drug delivery according to claim 1, wherein The Eu@UiO-66 is a UiO-66 type MOF doped with rare earth element Eu (Eu@UiO-66), and its specific surface area is 1500-1600 m 2 / g.

4. A composition for promoting diabetes drug delivery according to claim 1, wherein, The mass ratio of Eu@UiO-66 to D-sorbitol is 1:(2 - 4).

5. A composition for promoting diabetes drug delivery according to claim 1, characterized in that, The preparation method of the parthenolide phosphorylated compound includes: S21. Add 5.0 - 6.0 g of parthenolide, 0.15 - 0.2 g of DMAP, and 100 - 120 mL of anhydrous THF into a dry 250 mL three-necked flask, stir and dissolve under nitrogen protection, and stir for 30 - 40 min, recorded as the first mixture; S22. Cool down the system of the first mixture, control the temperature at -10 - -15 °C, and then slowly dropwise add 1.0 - 1.2 mL of dibenzyl dichlorophosphate. After the addition is completed, raise the temperature to 45 - 50 °C and continue to react for 16 - 19 h, recorded as the second mixture; S23. Add 200 - 220 mL of sodium hydroxide to the second mixture, stir for 30 - 40 min, control pH = 7.0 - 7.5, then extract with 400 - 420 mL of dichloromethane, combine the organic phases, dry with 50 - 60 g of anhydrous sodium sulfate, filter and then rotary evaporate to remove the solvent to obtain the crude product; S24. The crude product was purified by silica gel column chromatography (gradient elution with DCM:MeOH, 100:0 → 95:5 → 90:10) to obtain monophenylphosphorylated parthenolide; S25. 1.0 - 2.0 g of monophenylphosphorylated parthenolide was dissolved in 20 - 30 mL of methanol, 10 - 15 mL of deionized water was added, the pH was adjusted to 7.0 - 7.5 with 1.0 - 1.1 M sodium hydroxide solution, then methanol was removed by rotary evaporation and water was removed by freeze-drying to obtain parthenolide phosphorylate.

6. The composition for promoting diabetic drug delivery according to claim 1, wherein, The mass ratio of the polyethylene glycol, magnesium stearate and sodium carboxymethyl starch is (10 - 20):1:(3 - 9).

7. A composition for promoting the delivery of diabetes drugs according to claim 1, characterized in that, The mass ratio of the parthenolide phosphorylate, metformin hydrochloride and sodium citrate is (1 - 20):(2 - 4):(1 - 3).

8. A method for preparing a composition for promoting diabetes drug delivery, which is applied to prepare a composition for promoting diabetes drug delivery as described in any one of claims 1 to 7, characterized in that, The method comprises the following steps: S31. 15 parts of Eu@UiO-66, 10 parts of D-sorbitol, 2 parts of sodium carboxymethyl starch, 30 parts of parthenolide phosphorylate, 35 parts of metformin hydrochloride, 10 parts of sodium citrate, 25 parts of polyethylene glycol and 10 parts of modified nanocrystalline cellulose were added to a container and mixed to obtain a first mixture; S32. The first mixture was put into a high-speed shear emulsifier and mixed at 5000 - 6000 rpm for 15 - 20 min, and then passed through a 60 - 65 mesh sieve to obtain a second mixture; S33. Add a 20-25% ethanol solution to the second mixture under stirring, and then introduce it into fluidized bed granulation. The inlet air temperature is 50-55°C, and the air velocity is 30-35 m 3 / h. Control the particle moisture content ≤ 3% to obtain the third mixture; S34. 150 parts of magnesium stearate was added to the third mixture and mixed for 10 - 12 min, and then compressed into a tablet core with a diameter of 8 mm (hardness ≥ 50 N, friability ≤ 0.5%) by a rotary tablet press, and after cooling, it was packaged to obtain a composition for promoting diabetes drug delivery.

Images