CN111617036A - Targeted controlled-release anti-arthritis medicinal preparation and preparation method thereof - Google Patents
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Abstract
The invention belongs to the technical field of polymer chemistry, biomedical materials and pharmacy, and discloses a targeted controlled-release anti-arthritis medicinal preparation and a preparation method thereof. The medicine preparation is a medicine carrying micelle, the medicine carrying micelle consists of a block copolymer PEG-PPS and tripterine, and the tripterine is loaded in the micelle formed by the block copolymer PEG-PPS. The preparation method comprises the following steps of (by mass parts) mg and mL: (1) dissolving 20-80 parts by mass of PEG-PPS and 1-10 parts by mass of tripterine in 5-10 parts by volume of tetrahydrofuran; (2) and (2) adding the solution obtained in the step (1) into 50-100 parts by volume of water under ultrasonic dispersion, carrying out vacuum distillation to remove tetrahydrofuran, repeating ultrafiltration, and filtering by using a sterile microporous filter membrane to obtain the anti-arthritis nano pharmaceutical preparation. The medicinal preparation is sensitive to rheumatoid arthritis, can realize the controllable release of the medicament, and obviously inhibits the joint synovitis and bone erosion.
Description
Technical Field
The invention belongs to the technical field of polymer chemistry, biomedical materials and pharmacy, and particularly relates to a targeted controlled-release anti-arthritis medicinal preparation and a preparation method thereof.
Background
Rheumatoid Arthritis (RA) is a systemic autoimmune disease that is primarily manifested as joint involvement. According to latest epidemiological survey data, the incidence rate of RA in continental areas of China is about 0.42%, the disability rate in the course of more than 15 years reaches 61.3%, and RA is accompanied with complications such as cardiovascular and cerebrovascular diseases, pulmonary diseases, bones and the like, so that heavy burden is brought to families and society. The therapeutic goal of rheumatoid arthritis is to reduce disability rate and complications. However, there is still about 30% of patients who respond poorly to existing antirheumatic drugs. Therefore, a great deal of research is carried out on rheumatism workers, celastrol (Cel) is injected into the abdominal cavity repeatedly to reduce RA joint synovitis and bone erosion, and the possibility of further clinical application is greatly limited due to fast drug metabolism and organ toxicity.
The nanotechnology shows good application prospect in the medical field and shows good safety application potential. The nano drug-carrying system is expected to solve the problems of poor solubility of Cel and drug release, prolong the detention time of the drug in vivo and change the distribution of the Cel in vivo, thereby achieving the purposes of targeting, controlled release and slow release, improving the bioavailability and reducing the side effects of the drug.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a targeted controlled-release anti-arthritis medicinal preparation and a preparation method thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a targeted controlled-release anti-arthritis medicinal preparation is a medicine-carrying micelle, wherein the medicine-carrying micelle consists of a block copolymer PEG-PPS and tripterine, and the tripterine is loaded in the micelle formed by the block copolymer PEG-PPS.
The preparation method of the targeted controlled-release anti-arthritis medicinal preparation comprises the following steps of (by mass parts) mg and mL:
(1) dissolving 20-80 parts by mass of block copolymer PEG-PPS and 1-10 parts by mass of tripterine in 5-10 parts by volume of tetrahydrofuran;
(2) adding the solution obtained in the step (1) into 50-100 parts by volume of water under ultrasonic dispersion, vacuum distilling to remove tetrahydrofuran, repeating ultrafiltration (aiming at removing large polymer and free tripterine), and filtering with sterile microporous membrane to obtain the anti-arthritis nano-drug preparation.
Preferably, the molecular weight cut-off of the membrane during ultrafiltration is 1 ten thousand Da.
Preferably, the pore size of the microfiltration membrane is 0.22 μm or 0.45. mu.m.
In the present invention, the block copolymer PEG-PPS can be prepared according to the prior art, such as references Wu T, ChenX, Wang Y, et al, orthogonal plane-targeted and horizontal graft delivery with oxidation-sensitive microbial effects, and 14(7) 2215-26.
Has the advantages that: the medicinal preparation is sensitive to rheumatoid arthritis, can realize the controllable release of the medicament, and obviously inhibits the joint synovitis and bone erosion.
Drawings
FIG. 1: atomic force microscopy images of drug loaded micelles C-PEPS prepared in example 1.
FIG. 2: particle size distribution of drug-loaded micelle C-PEPS prepared in example 1.
FIG. 3: the influence of different concentrations of drug-loaded micelle C-PESP and blank micelle PEPS on the cell survival rate is calculated by Cel and the unit ng/mL.
FIG. 4: LPS-induced macrophages were treated with different concentrations of the drug-loaded micelle C-PESP, calculated as Cel, in ng/mL.
FIG. 5: animal experiment flow chart.
FIG. 6: collagen-induced arthritis CIA animal model, fluorescent DIR-marked blank micelle injection, and fluorescence intensity results at different times.
FIG. 7: weight, arthritis score, left ankle diameter, right ankle diameter change profile, Normal group of mice in different groups; CIA model, group of CIA models; PEPS, blank micelle group; C-PEPS, group of drug-loaded micelles.
FIG. 8: different groups of mice had gross joint illumination, joint CT, H & E, T & B, SO-FG staining, T & B for toluidine blue staining, SO-FG staining for safranin O-fast green staining; CIA, CIA model set; PEPS, blank micelle group; C-PEPS, group of drug-loaded micelles.
FIG. 9: different groups of mice joint synovitis, bone erosion and cartilage destruction score chart; CIA, CIA model set; PEPS, blank micelle group; C-PEPS, group of drug-loaded micelles.
FIG. 10: evaluating the safety of different groups of mice, (A) H & E staining of heart, liver, spleen, lung and kidney of different groups, and (B) a serum liver and kidney function chart of different groups; CIA, CIA model set; PEPS, blank micelle group; C-PEPS, group of drug-loaded micelles.
Detailed Description
The present invention will be further described with reference to the following specific examples. It should be understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.
Example 1
A preparation method of a targeted controlled-release anti-arthritis medicinal preparation comprises the following steps:
(1) dissolving 50 mg of PEG-PPS and 5 mg of tripterine (Cel) in 5 mL of tetrahydrofuran;
(2) and (2) adding the solution obtained in the step (1) into 50 mL of deionized water under ultrasonic dispersion, distilling in vacuum to remove tetrahydrofuran, repeating ultrafiltration for 3 times to remove large polymers and free tripterine, and filtering by using a 0.22-micron sterile microporous membrane to obtain the anti-arthritis nano-drug preparation with the concentration of 1 mg/mL (calculated by Cel).
An atomic force microscope image of the nano-drug formulation prepared in this example is shown in fig. 1. As can be seen from fig. 1: the obtained nano-drug preparation is spherical and nano-shaped.
The particle size distribution of the nano-drug formulation prepared in this example is shown in fig. 2. As can be seen from fig. 2: the obtained nanometer medicinal preparation has particle diameter of 60-220 nm and average particle diameter of 110 nm. The particle size range of the nano-drug preparation is consistent with that of the micelle, and the nano-drug preparation prepared by the invention is a drug-loaded micelle and is marked as C-PEPS.
Comparative example 1
The difference from example 1 is that: in the step (1), the addition amount of Cel is 0, the rest is the same as that in the example 1, and finally, a blank micelle is prepared and is marked as PEPS.
The drug-loaded micelle C-PEPS prepared in example 1 with the concentration of 1 mg/mL is subjected to gradient dilution by deionized water to obtain the drug-loaded micelle C-PEPS with the concentrations of 452ng/mL, 226 ng/mL, 113 ng/mL, 57 ng/mL and 28 ng/mL (the concentration is calculated by Cel) respectively, so as to be prepared for the following experiments.
Cell experiments
Mouse macrophage line RAW264.7 was cultured in complement-inactivated DMEM medium (10% FCS + 1% penicillin, the percentages of FCS and penicillin being in% by volume) at 37 ℃ and 5 v% CO2Changing the culture solution every other day in an incubator, digesting and subculturing 0.25% of pancreatin (mass/volume percentage, namely 0.25 g of pancreatin is dissolved in 100 mL of PBS), adding 100 mu L of cell culture solution (containing 3000 cells) into each hole of a 96-hole plate, after the cells are attached to the wall, respectively adding 10 mu L of blank micelles (PEPS) and drug-loaded micelles (C-PEPS) with different concentrations at 37 ℃ and 5 v% CO2After 24 h incubation in an incubator, 10 μ LCCK-8 (CCK-8, Dojindo Molecular Technologies, Shanghai, China) was added to each well, absorbance at 450 nm was measured with a microplate reader (SydergyH1, BioTek, USA), while a blank control well and a 0-dose control well were placed, and cell viability was calculated according to the following calculation formula (see below for calculation), and the results are shown in fig. 3 (abscissa concentration represents the concentration of drug-loaded micelle C-PEPS, concentration is calculated as Cel, unit ng/mL).
Cell viability = [ A (dosed) -A (blank) ]/[ A (0 dosed) -A (blank) ] × 100%
A (dosing): absorbance of wells with cells, medium, CCK-8 and micelles (100. mu.L cell culture medium + 10. mu.L CCK-8+ 10. mu.L PEPS/C-PEPS);
a (blank): absorbance of wells with media and CCK-8 without cells, micelles (100 μ L DMEM media +10 μ L CCK-8);
a (0 dosing): absorbance of wells with cells, media, CCK-8 but no micelles (100. mu.L cell culture + 10. mu.LCCK-8).
As can be seen from fig. 3: the cell survival rate of the PEPS group is over 95 percent along with the increase of the concentration, which shows that the PEPS group has almost no influence on the cell survival rate; the C-PEPS group is similar to the PEPS group in the aspect that the cell survival rate is below 226 ng/mL along with the increase of the Cel concentration, and has no statistical difference, and has the statistical difference with the PEPS at the concentration of 452ng/mL, which indicates that the concentration of the drug therapy should be below 452 ng/mL.
Experiment of
Macrophages in a resting state become M1 type macrophages in an activated state after being stimulated by adding LPS, are characteristic of a cell inflammation model, and are common in vitro models for researching anti-inflammation of medicaments.
Macrophages were pretreated by adding 10 μ L blank micelles (PEPS) and drug-loaded micelles (C-PEPS) of different concentrations (113, 226, 452 ng/mL) for 6 h, then LPS of 1 μ g/mL was added/not added for 6 h to activate the macrophages, and the expression of inflammatory factors (iNOS, TNF- α, IL-6) was observed, and the results are shown in FIG. 4 (in LPS line, -represents no activation, + represents activation; in Cel line, -represents that blank micelles PEPS were added without drug addition, + represents that drug-loaded micelles C-PEPS were added; the concentration is calculated in Cel, unit ng/mL), as shown in FIG. 4: compared with macrophages (LPS-, Cel-) in a resting state, iNOS, TNF-alpha and IL-6 in the macrophage group (LPS +, Cel-) activated by LPS are obviously increased, and the statistical significance is achieved, which indicates that 1 microgram/mL LPS successfully activates the macrophages; the expression of iNOS, TNF-alpha and IL-6 is concentration-dependent within the safe concentration range of cell viability (the inhibition of inflammation is stronger in Cel 452ng/mL than in Cel 226 ng/mL and stronger in Cel 113 ng/mL, and the groups are statistically different).
Animal experiments
The animal experiment flow chart is shown in figure 5.
The mice were 8 weeks male DBA/1 mice. Adapting to the environment for one week. The method for preparing the collagen-induced arthritis (CIA) animal model by adopting two immunizations comprises the following specific steps of using Complete Freund's Adjuvant (CFA) and bovine type II Collagen (CII) for emulsification and immunization for the first time and using CII for immunization for the second time: equal volumes of complete Freund's adjuvant (4 mg/mL in PBS) and bovine type II collagen (2 mg/mL in PBS) were mixed well using an electric homogenizer, and a first immunization was performed with 100. mu.L of CII and CFA emulsion injected intradermally on day 0 and a second immunization with 100. mu.g of CII booster injection on day 21. After the model is successfully made, injecting a blank micelle PEPS marked by fluorescein DIR at different time points, and collecting the in-vivo fluorescence intensity by a small animal living body imager. Body weight, arthritis clinical score, left ankle diameter, right ankle diameter measurements were taken every 3 days from day 21. On the 30 th day and the 40 th day, 10 mug (Cel equivalent dose)/g (mouse weight) of drug-loaded micelle (C-PEPS) is injected into tail vein respectively to treat the arthritis model, and meanwhile, a normal group (no model is formed and no drug is administered), a CIA model group (model is formed and no drug is administered but normal saline is injected, the dosage of the normal saline is equal to that of the C-PEPS, and the dosage of the PEPS is equal to that of the C-PEPS), and a blank micelle (model is formed and PEPS treatment and the dosage of the PEPS is equal to that of the C-PEPS) are used as controls. Joint gross illumination, joint CT, H & E, T & B, SO-FG staining were performed on day 51, and safety assessments including heart, liver, spleen, lung, kidney pathology and serum liver function, creatinine, urea levels were performed.
The preparation process of the fluorescein DIR-labeled blank micelle PEPS comprises the following steps: (1) 50 mg of PEG-PPS and 0.1mg of DIR were dissolved in 5 mL of tetrahydrofuran; (2) and (2) adding the solution obtained in the step (1) into 50 mL of deionized water under ultrasonic dispersion, carrying out vacuum distillation to remove tetrahydrofuran, repeating ultrafiltration for 3 times to remove large polymers and free DIR, and filtering by using a 0.22-micron sterile microporous membrane to obtain the blank micelle PEPS labeled by the fluorescein DIR.
The fluorescence intensity results at different times are shown in FIG. 6, and as a result, it was found that: the fluorescence intensity of the blank micelle is gradually enhanced within 8 days, which shows that the micelle formed by PEG-PPS has the characteristics of inflammation sensitivity, targeting, slow release and controlled release at the arthritis part as a drug carrier.
The weight, arthritis score (table 1), diameter of the left ankle, and diameter of the right ankle of the mice in different groups are shown in fig. 7, and it can be seen from fig. 7 that: the body weights of the CIA group, the PEPS group and the C-PEPS group are reduced 21 days after the first immunization, and the body weights of the C-PEPS group are obviously reduced in 39 d, 42 d and 45 d compared with the CIA/PEPS group, which shows that Cel has the weight reduction effect; in the aspect of arthritis scoring, after modeling, the arthritis scoring reaches a peak at 36 days and maintains the state of arthritis, the arthritis scoring of the C-PEPS group starts to decline after treatment, and the arthritis scoring has statistical significance in 36d, 42 d, 45 d, 48 d and 51 d compared with the CIA group; the diameter of the left/right ankle was smaller after C-PEPS treatment, with the diameter of the left ankle statistically significant at 39 d and the diameter of the right ankle statistically significant at 51 d. The above indexes indicate that C-PEPS is effective in treating CIA mice.
The results of the gross joint lighting, joint CT, H & E, T & B, SO-FG staining of the different groups of mice are shown in FIG. 8, T & B for toluidine blue staining and SO-FG for safranin O-fast green staining. As can be seen from fig. 8: compared with a CIA model control group, the PEPS group has similar joint general photograph, joint CT, joint H & E, T & B, SO-FG performances, and shows obvious joint swelling, inflammation, bone erosion and cartilage destruction compared with a normal group, which indicates that the PEPS group has no treatment effect on the CIA mice; compared with the CIA group/PEPS group, the C-PEPS treatment group has obviously improved joint gross photograph, joint CT and joint H & E, T & B, SO-FG. The mouse synovitis, bone erosion and cartilage destruction degrees are evaluated according to joint H & E, T & B, SO-FG staining, the details of the scores are shown in Table 2, and the scores are shown in FIG. 9. As can be seen from fig. 9: after C-PEPS treatment, the scores of arthromeningitis, bone erosion and cartilage destruction are obviously reduced, and the statistical significance is achieved.
The safety evaluation results of different groups of mice are shown in figure 10, wherein, (A) -heart, liver, spleen, lung and kidney H & E staining results, (B) -serum liver and kidney function maps, ALT (alanine aminotransferase), AST (aspartate aminotransferase) and ALP (alkaline phosphatase) are indexes reflecting liver functions, and creatinine and urea are indexes reflecting kidney functions. As can be seen from fig. 10 (a): the PEPS group and the C-PEPS group showed no pathological change of organs compared with the normal group and the CIA group. As can be seen from fig. 10 (B): the results of each group are in a reference range, which indicates that the blank micelle and the drug-loaded micelle have no serum chemical toxicity.
Claims (4)
1. A targeted controlled-release anti-arthritis pharmaceutical preparation is characterized in that: the medicine preparation is a medicine carrying micelle, the medicine carrying micelle consists of a block copolymer PEG-PPS and tripterine, and the tripterine is loaded in the micelle formed by the block copolymer PEG-PPS.
2. The preparation method of the targeted controlled-release anti-arthritis pharmaceutical preparation according to claim 1, wherein the preparation steps comprise the following steps in parts by mass in mg and parts by volume in mL:
(1) dissolving 20-80 parts by mass of block copolymer PEG-PPS and 1-10 parts by mass of tripterine in 5-10 parts by volume of tetrahydrofuran;
(2) and (2) adding the solution obtained in the step (1) into 50-100 parts by volume of water under ultrasonic dispersion, carrying out vacuum distillation to remove tetrahydrofuran, repeating ultrafiltration, and filtering by using a sterile microporous filter membrane to obtain the anti-arthritis nano pharmaceutical preparation.
3. The process for preparing a targeted controlled-release anti-arthritic pharmaceutical formulation according to claim 2, wherein: the molecular weight cut-off of the filter membrane during ultrafiltration is 1 ten thousand Da.
4. The process for preparing a targeted controlled-release anti-arthritic pharmaceutical formulation according to claim 2, wherein: the pore size of the microporous filter membrane is 0.22 μm or 0.45 μm.
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| CN113081976A (en) * | 2021-04-16 | 2021-07-09 | 烟台大学 | Nanometer preparation based on MMP-2 enzyme sensitivity and preparation method and application thereof |
| CN117982683A (en) * | 2024-04-07 | 2024-05-07 | 中国科学院苏州纳米技术与纳米仿生研究所 | Drug delivery system with reduction responsiveness and preparation method and application thereof |
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