CN110974777B - Craniocerebral trauma postoperative injectable hydrogel with response release and nerve nutrition functions - Google Patents

Craniocerebral trauma postoperative injectable hydrogel with response release and nerve nutrition functions Download PDF

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CN110974777B
CN110974777B CN201910274328.5A CN201910274328A CN110974777B CN 110974777 B CN110974777 B CN 110974777B CN 201910274328 A CN201910274328 A CN 201910274328A CN 110974777 B CN110974777 B CN 110974777B
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craniocerebral trauma
injectable hydrogel
hydrogel
pps
trauma
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CN110974777A (en
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刘洪梅
于如同
钱峰
叶成坤
韩宇涵
徐浩月
赵宗仁
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Xuzhou Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention provides a preparation method of an injectable hydrogel with the functions of responding release and nourishing nerves after craniocerebral trauma operation. The research carries the PPS with active oxygen phase response by hydrophilic and hydrophobic effects on triglycerol monostearate (TGMS) which can be self-assembled into injectable hydrogel and matrix metalloproteinase response decomposition after craniocerebral trauma operation120-OH and neurotrophin; the injection is locally injected at the postoperative part of the cerebral trauma to achieve the effects of quick response and release and play the roles of anti-inflammation and nourishing nerves; through hydrogel injection administration, the blood circulation degradation of the whole body and the influence of a blood brain barrier are avoided, and the specific microenvironment for responding to the wound is achieved, and the medicine is responded and released layer by layer to further play the dual functions of resisting inflammation and nourishing nerves. Has clinical application and practical therapeutic significance.

Description

Craniocerebral trauma postoperative injectable hydrogel with response release and nerve nutrition functions
Technical Field
The invention relates to an injectable hydrogel with functions of response release and nerve nutrition after craniocerebral trauma operation, belonging to the field of preparation of craniocerebral trauma medicaments.
Background
Craniocerebral Trauma (TBI) has become a serious public health problem worldwide due to its high incidence, mortality and disability rate. Although the understanding of the pathogenesis of craniocerebral injury is continuously deepened, and the treatment of patients with craniocerebral trauma is obviously improved along with the continuous increase of new medicines and the continuous application of new technologies, in the process of treating TBI patients, the prominent problem is how to resist the limited or diffuse encephaledema after injury and the deficiency problem of the nerve function after injury. Therefore, it is very important to develop safe and reliable brain protection drugs.
The free radical scavenger is a substance effective in resisting neuroinflammation, and has the function of specifically depleting Reactive Oxygen Species (ROS) mediators in inflammatory tissues and playing a role in blocking inflammatory reaction. Both Tirilazad and superoxide dismutase have been used as free radical scavengers, but due to intravenous administration and the blood-brain barrier effect, sufficient concentrations in brain tissue have not been achieved, and the prognosis improvement for patients has not been achieved to the desired effect, leading to experimental failure. Curcumin as a multi-class compound extracted from plants can effectively regulate the differentiation of neural stem cells. Its extremely low solubility in water, and the associated unstable nature, extremely low bioavailability, limits its use as a neuroprotective agent. Research into increasing drug concentrations in brain tissue in the wound area has become a major challenge in the preparation of such drug delivery systems.
Disclosure of Invention
In order to overcome the defects of lack of craniocerebral trauma medicament treatment and poor effectiveness, the invention provides a craniocerebral trauma postoperative injectable hydrogel with the functions of response release and nerve nutrition; the injectable hydrogel after craniocerebral trauma operation can be injected at the position of craniocerebral trauma in situ, and can play the role of early anti-inflammation and trophic nerve by responding to the excessive matrix metalloproteinase and active oxygen in the local microenvironment of the craniocerebral trauma and finally releasing the trophic nerve substance curcumin. The mode of in-situ injection administration can avoid the toxic and side effects of blood viscera of the whole body, improve the local concentration of the medicine in the cerebral trauma, effectively improve the effect of the cerebral trauma treatment in time and improve the level of the treatment of the craniocerebral trauma.
The invention is realized by the following technical scheme, and the craniocerebral trauma postoperative injectable hydrogel with the functions of responding to release and nourishing nerves is characterized in that: the injectable hydrogel after craniocerebral trauma operation at least contains: triglycerol monostearate (TGMS), PPS120OH and curcumin (Cur), wherein the substances are subjected to hydrophilic and hydrophobic self-assembly in a heating mode to form the injectable hydrogel after craniocerebral trauma operation.
The invention relates to an optimized scheme of the craniocerebral trauma postoperative injectable hydrogel with the functions of responding release and nourishing nerves, which comprises the following steps: the injectable hydrogel used after craniocerebral trauma operation is prepared from TGMS and PPS120-OH, Cur species are composed by a hydrophilic-hydrophobic self-assembly form;
wherein the injectable hydrogel after craniocerebral trauma operation has a volume of 1mL and is prepared from 800 μ L, water, 200 μ L, and mixed solvent composed of dimethyl sulfoxide (DMSO), and TGMS (100mg) and PPS120OH, (16mg) and Cur (4mg), heating to 65 ℃ in a water bath, keeping for 5min, and cooling at room temperature to form the injectable hydrogel after craniocerebral trauma surgery.
The invention relates to an optimized scheme of the craniocerebral trauma postoperative injectable hydrogel with the functions of responding release and nourishing nerves, which comprises the following steps: the TGMS has the function of responding to matrix metalloproteinase decomposition in a brain trauma microenvironment, and the structural formula of the TGMS is shown as follows:
Figure BDA0002019475550000021
the invention relates to an optimized scheme of the craniocerebral trauma postoperative injectable hydrogel with the functions of responding release and nourishing nerves, which comprises the following steps: the PPS120the-OH has the function of responding to active oxygen in brain trauma microenvironment and has the following structural formula:
Figure BDA0002019475550000022
wherein n is 120.
The invention has the beneficial effects that:
1. the invention relates to a craniocerebral trauma postoperative injectable hydrogel with the functions of response release and nerve nourishment, wherein the used triglycerol monostearate is a substance which is approved by FDA and has an amphiphilic segment, and the hydrogel is safeLeaning on; PPS120-OH is a hydrophobic substance with active oxygen consumption, and curcumin is a traditional Chinese medicine extract with low toxic and side effects on human body.
2. The invention relates to craniocerebral trauma postoperative injectable water condensation with response release and nerve nutrition functions, which can be self-assembled into injectable hydrogel due to the introduction of TGMS, and can wrap PPS (polyphenylene sulfide) due to hydrophilic and hydrophobic effects120-OH and Cur. So that the injection can be performed in situ of craniocerebral trauma.
3. The invention relates to an injectable hydrogel with the functions of responding to release and nourishing nerves after craniocerebral trauma operation, which is caused by TGMS and PPS120The introduction of-OH can in turn respond to matrix metalloproteases, ROS, in the wound environment, thereby accelerating hydrogel cleavage.
4. The invention relates to a craniocerebral trauma postoperative injectable hydrogel with the functions of responding release and nourishing nerves, which comprises PPS120the-OH can consume active oxygen in a brain trauma wound microenvironment to play an anti-inflammatory role, and Cur is released after the hydrogel is cracked to have a nerve nourishing function.
Drawings
FIG. 1 is PPS120of-OH1H-NMR detection results;
FIG. 2 is a PPS120-GPC measurement of OH;
FIG. 3 is a morphological diagram of an injectable hydrogel after craniocerebral trauma surgery prepared by the present invention;
FIG. 4 is the result of HR scanning electron microscope, which shows the surface morphology of injectable hydrogel after craniocerebral trauma operation;
FIG. 5 is a rheological examination of an injectable hydrogel after craniocerebral trauma;
FIG. 6 is the ability of the injectable hydrogel of the invention after TM/PC craniocerebral trauma to release curcumin in different simulated environments in vitro;
FIG. 7 is a graph showing the drug release and degradation of DiR encapsulated in injectable hydrogel after craniocerebral trauma surgery in rats in injury and injury control groups;
FIG. 8 shows the result of a statistical analysis of the fluorescence values of FIG. 7;
FIG. 9 is a diagram showing that the injectable hydrogel after craniocerebral trauma can improve the cerebral edema degree in early craniocerebral trauma;
FIG. 10 shows that the injectable hydrogel of the present invention can improve the blood brain barrier penetration degree after craniocerebral trauma operation;
FIG. 11 shows that the injectable hydrogel of the invention has anti-inflammatory effect after craniocerebral trauma operation;
FIG. 12 the injectable hydrogel after craniocerebral trauma operation of the invention can change the neuron regeneration of craniocerebral trauma.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1: PPS120Synthesis route and characterization of-OH
PPS120The synthetic route for-OH is shown below: in the synthetic route: the Propylene sulfide is Propylene sulfide and C4H9SH is 1-butanethiol, 2-iodoethanol is 2-iodoethanol, DBU: 1, 8-diazabicyclo [5.4.0]]Undec-7-ene;
propylene sulfide; 1, 8-diazabicyclo [5.4.0] undec-7-ene; 1-butanethiol; 2-iodoethanol was purchased from Taishiai (Shanghai) chemical industry development Co., Ltd.
Figure BDA0002019475550000041
The preparation method comprises the following steps:
the preparation method of the degassed propylene sulfide comprises the following steps: adding propylene sulfide into a flask, placing the flask on a rotary evaporator, obliquely immersing the flask in about one third of water, and keeping the water temperature at 4 +/-2 ℃; starting a vacuum pump to exhaust air in the device, and starting the condenser and a water inlet valve thereof, wherein the process is carried out for 30 min.
The preparation method of the degassed tetrahydrofuran comprises the following steps: adding tetrahydrofuran into a flask, placing the flask on a rotary evaporator, obliquely immersing the flask in about one third of water, and keeping the water temperature at 4 +/-2 ℃; starting a vacuum pump to exhaust air in the device, and starting the condenser and a water inlet valve thereof, wherein the process is carried out for 30 min.
Adding 1, 8-diazabicyclo [5.4.0] undec-7-ene (258 mg in amount, 1.5mmol) and degassed tetrahydrofuran (1.5 mL) into a round-bottom flask, and degassing at 0 ℃ for 30min to obtain a degassed DBU tetrahydrofuran solution;
dropwise adding 1-butanethiol (45 mg,0.5mmol) into degassed DBU tetrahydrofuran solution, reacting for 30min, and maintaining the temperature at 0 deg.C to obtain reaction system mixture;
degassed propylene sulfide (2.96 g,40mmol) was added to the reaction mixture and reacted at 0 ℃ for 2 hours; adding 2-iodoethanol (172 mg,1mmol), stirring at room temperature for 12 hr, terminating the reaction, filtering the polymer solution to remove precipitated salt, precipitating with cold methanol for three times for further purification, and vacuum drying to obtain colorless viscous polymer, i.e. PPS product120-OH。
PPS120of-OH1The results of H-NMR measurements are shown in FIG. 1; PPS120The GPC measurement of-OH is shown in FIG. 2.
Example 2: the morphological diagram, the high resolution electron microscope examination and the rheological examination of the craniocerebral trauma postoperative injectable hydrogel with the functions of responding to release and nourishing nerves.
Weighing 100mg of TGMS; 16mg PPS120OH and 4mg Cur, respectively dissolved in a mixed solvent of 800. mu.L water and 200. mu.L dimethyl sulfoxide, and heated to 65 deg.C until TGMS and PPS120the-OH and the Cur are uniformly dissolved, and then the solution is cooled at room temperature for 30min to be converted into viscous gel, namely the injectable hydrogel after the craniocerebral trauma operation, as shown in figure 3, the right side II in figure 3 is a liquid bottle which is placed in an inverted mode, the hydrogel does not fall, and the success of preparing the injectable hydrogel after the craniocerebral trauma operation is shown.
The prepared injectable hydrogel after the craniocerebral trauma operation is injected into a small hole of a special sample stage for freezing and transmission by an injector, then is transferred into liquid nitrogen mud for rapid freezing to-210 ℃, and is transferred into a preparation chamber by a transmission rod; adjusting the indoor temperature, increasing the temperature from-140 deg.C to-90 deg.C, sublimating for 3min, and spraying platinum film on the surface of injectable hydrogel after craniocerebral trauma operation for 50 s; the treated injectable hydrogel after craniocerebral trauma surgery was transferred to an HR scanning electron microscope (Zeiss Merlin High resolution SEM) for observation and photographing, and the figure is shown in figure 4.
The samples were tested for dynamic rheological properties using a Discovery HR-2 rotary rheometer manufactured by TA Instruments, USA. The diameter of the parallel plates is 40mm, the plate spacing is 500 μm, and the instrument selects the "oscillatory test" mode during testing. The frequency sweep range was 0.0398-628.319rad/s, strain 5%, temperature 37 ℃, and the storage modulus (G '), loss modulus (G') versus angular frequency (ω) for the sample was obtained, see FIG. 5, where: TM represents TGMS hydrogel group; TM/C represents a TGMS Cur-loaded hydrogel group; TM/P stands for TGMS Encapsulated PPS120-a hydrogel group of OH; TM/PC stands for TGMS Encapsulated PPS120-OH and Cur. From fig. 5, it can be obtained that the injectable hydrogel after craniocerebral trauma operation has hydrogel rheological properties.
Example 3: the craniocerebral trauma postoperative injectable hydrogel with the functions of responding to release and nourishing nerves has the capability of releasing curcumin in different simulated environments in vivo and in vitro.
TM/PC (representing TGMS entrapping PPS) detection by using multifunctional microplate reader120-hydrogel group of OH and Cur, i.e. injectable hydrogel after craniocerebral trauma surgery), Cur release rate in different simulated environments in vitro; taking 200 mu L of craniocerebral trauma postoperative injectable hydrogel, adding 10mL of Phosphate Buffer Saline (PBS), setting different in-vitro environments, adding 10 mu L of different solvents every three days, standing in a 37 ℃ incubator, sampling at different time points, detecting the concentration of Cur in a supernatant by using a multifunctional microplate reader, and calculating the cumulative release amount of the drug, wherein the figure is 6; the results in the figure show that Cur is released most rapidly under the dual action of hydrogen peroxide and matrix metalloproteinase.
Adding 10 mu L of different solvents every three days, wherein the specific names and the concentrations of the different solvents are as follows:
1) PBS denotes: phosphate buffered saline solution;
2)、H2O2represents: hydrogen peroxide (concentration 1 mol/L);
3) MMP-2 represents: matrix metalloproteinase 2 (concentration 100 ng/. mu.L);
4)、H2O2+ MMP-2 represents: hydrogen peroxide (concentrated)Degree 2mol/L) + matrix metalloproteinase 2 (concentration 200 ng/. mu.l), each at a volume ratio of 1: 1, mixing and preparing;
5) MMP-2+ Inhibitor, for: matrix metalloproteinase 2 (concentration 200 ng/. mu.L) + matrix metalloproteinase inhibitor (concentration 2mmol/L), each at a volume ratio of 1: 1, mixing and preparing;
6)、H2O2+ MMP-2+ Inhibitor denotes: hydrogen peroxide (concentration 3mol/L) + matrix metalloproteinase 2 (concentration 300 ng/. mu.l) + matrix metalloproteinase inhibitor (concentration 3mmol/L), each at a volume ratio of 1: 1: 1, mixing and preparing.
The experimental animal is selected from ICR male mice (16-20g), purchased from Beijing Huafukang biotech GmbH, and subjected to animal experiment after being adaptively raised for 12 days in advance. The experimental animals are raised in an independent air supply isolation cage, the room temperature is controlled at 23 +/-2 ℃, regular illumination is kept (12h day and 12h night), and the water and the grain are fully supplied.
The degradation and release capacity of the injectable hydrogel after the craniocerebral trauma in vivo is evaluated by detecting the metabolic intensity of the fluorescent dye in the craniocerebral trauma animal body by using a small animal living body imager and encapsulating the fluorescent dye in the injectable hydrogel after the craniocerebral trauma, and the degradation and release capacity of the injectable hydrogel after the craniocerebral trauma in vivo is shown in figure 7(Sham group is a Sham operation group, TBI is a brain trauma group) and figure 8 (ns: non-statistical value; P: 0.01; P: 0.001).
Example 4 post-craniocerebral trauma injectable hydrogels with responsive release and trophic neurological functions improved the extent of craniocerebral trauma in early animals.
Applying the dry-wet-weight method to the brain and evaluating the effect of the hydrogel on the edema after craniocerebral trauma, as shown in figure 9 (Cont: untreated group of brain trauma; TM/PC is treated group of the hydrogel administered to TM/PC after brain trauma; P: 0.001); using an enzyme-labeling instrument to detect the absorbance of evans blue, and evaluating the protective effect of the hydrogel on the blood brain barrier after craniocerebral trauma, as shown in figure 10 (Cont: a brain trauma untreated group; TM/PC: a treatment group for applying the TM/PC hydrogel to the brain trauma; P: 0.0001); glial Fibrillary Acidic Protein (GFAP) and microglia/macrophage specific protein (Iba-1) were detected by immunofluorescence staining to evaluate the level of neuroinflammation around the cranial lesions, as shown in FIG. 11 (Cont: untreated group of brain wounds; TM/PC: treated group of brain wounds administered with TM/PC hydrogel).
Example 5 post-traumatic craniocerebral injury injectable hydrogel with responsive release and trophic nerve functions can promote the regeneration and repair of neurons after craniocerebral injury.
The expression level of neuron indexes Nestin and neurofilament protein NF-200 around the craniocerebral trauma focus is evaluated by using an immunofluorescence staining method, and is shown in figure 12 (both Nestin and NF-200 are molecular markers for neuron regeneration and repair; Cont is a brain trauma untreated group; and TM/PC is a treatment group for applying the TM/PC hydrogel to the brain trauma).

Claims (1)

1. An injectable hydrogel with functions of responding to release and nourishing nerves after craniocerebral trauma operation, which is characterized in that: the injectable hydrogel after craniocerebral trauma operation at least comprises: triglycerol monostearate, PPS120OH and curcumin, wherein the substances are subjected to hydrophilic and hydrophobic self-assembly in a heating mode to form the craniocerebral trauma postoperative injectable hydrogel;
the injectable hydrogel used after craniocerebral trauma operation is prepared from triglycerol monostearate and PPS120OH, curcumin and a mixed solvent, wherein each substance is added into the mixed solvent and is subjected to hydrophilic-hydrophobic self-assembly by a heating mode;
wherein, the 1ml volume of the injectable hydrogel after craniocerebral trauma operation is a mixed solvent consisting of 800 muL, water, 200 muL and dimethyl sulfoxide, and is added with triglycerol monostearate, 100mg and PPS120Heating OH, 16mg and curcumin, 4mg in water bath to 65 ℃, keeping for 5min, and cooling at room temperature to form craniocerebral trauma postoperative injectable hydrogel;
the triglycerol monostearate has the function of responding to matrix metalloproteinase decomposition in a brain trauma microenvironment, and the structural formula of the triglycerol monostearate is shown as follows:
Figure 288632DEST_PATH_IMAGE001
；
the PPS120the-OH has the function of responding to active oxygen in brain trauma microenvironment and has the following structural formula:
Figure 674614DEST_PATH_IMAGE002
，
wherein n is 120.
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