CN119139300A - Nanometer medicine of electric response controlled release fenfluramine and preparation method and application thereof - Google Patents
Nanometer medicine of electric response controlled release fenfluramine and preparation method and application thereof Download PDFInfo
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Abstract
本发明涉及药物制备技术领域，具体涉及一种电响应控释芬氟拉明的纳米药物及其制备方法和应用，至少包括以下步骤：S1：将芬氟拉明与聚乙二醇加热搅拌后冷却至室温，并调节溶液的pH值为弱碱性得到溶液A；S2：向溶液A中依次添加吡咯、盐酸多巴胺和过硫酸铵水溶液，搅拌均匀反应后得到溶液B；S3：向溶液B中添加乙醇后，离心得到最终产物，即电响应控释芬氟拉明的纳米药物。本发明通过特定的反应温度、优化多巴胺与吡咯单体以及药物分子的比例，得到最优的电响应释放药物体系，有效响应癫痫神经元膜电位，可控释放癫痫药物，降低癫痫发作频率和程度。The present invention relates to the technical field of drug preparation, and specifically to a nano drug for electrically responsive controlled release of fenfluramine, and a preparation method and application thereof, which at least include the following steps: S1: heating and stirring fenfluramine and polyethylene glycol, cooling to room temperature, and adjusting the pH value of the solution to be weakly alkaline to obtain solution A; S2: sequentially adding pyrrole, dopamine hydrochloride and ammonium persulfate aqueous solution to solution A, stirring and reacting uniformly to obtain solution B; S3: adding ethanol to solution B, and centrifuging to obtain the final product, i.e., the nano drug for electrically responsive controlled release of fenfluramine. The present invention obtains the optimal electrically responsive release drug system by specifying the reaction temperature, optimizing the ratio of dopamine to pyrrole monomers and drug molecules, effectively responding to the membrane potential of epileptic neurons, controllably releasing epileptic drugs, and reducing the frequency and degree of epileptic seizures.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to an electric response controlled release fenfluramine nano-drug, a preparation method and application thereof.
Background
Epilepsy is a neurological disorder caused by abnormal firing of neurons in the brain, often repeated many attacks, with often short duration attacks. Repeated seizures cause tremendous mental stress and a heavy psychological burden on the patient and his home. Therefore, it is very important to achieve an efficient treatment of epilepsy. Fenfluramine is an emerging epileptic therapeutic which can be used to treat the Dravet syndrome (a rare childhood epilepsy) in children aged 2 and older, and the novel mechanism of action is to modulate serotonin receptor and sigma-1 receptor activity to reduce seizure frequency. However, since the fenfluramine drug, if used improperly, may have side effects that cause cardiovascular diseases such as heart valves. Therefore, how to realize the controllable release of the medicament for treating epilepsy has important significance for efficiently treating epilepsy.
The electric field response material generally has the characteristics of higher conductivity, smaller electrical impedance, better electrochemical stability and the like, and is widely used in medicine carrying, sensing application and microelectronic devices. Seizures are accompanied by abnormal discharges of neurons upon onset. The prior art CN115350193A discloses a preparation method and application of an electric field response lamotrigine composite preparation, wherein the electric field response lamotrigine composite preparation is prepared from an electric field response nano carrier and lamotrigine, the electric field response nano carrier uses FeCl 3 as an oxidant, a diaminopyridine monomer is subjected to polymerization reaction, a subsequent treatment is carried out, a nanogel freeze-dried sample is obtained, and the electric field response nano carrier is used for preparing the electric field response lamotrigine composite preparation and a medicament for preparing antiepileptic, so that the antiepileptic efficacy of the lamotrigine is improved. However, there are few studies in the prior art on controlled release of fenfluramine. Therefore, if an electrically responsive material in response to seizures could be developed for the controlled release of fenfluramine, there would be a great potential for exerting pharmaceutical efficacy while reducing side effects.
Disclosure of Invention
In order to solve the problems in the prior art, the first aspect of the invention provides a preparation method of an electric response controlled release fenfluramine nano-drug, which at least comprises the following steps:
S1, heating and stirring fenfluramine and polyethylene glycol, cooling to room temperature, and regulating the pH value of the solution to be alkalescent to obtain a solution A;
S2, sequentially adding pyrrole, dopamine hydrochloride and ammonium persulfate aqueous solution into the solution A, and uniformly stirring for reaction to obtain a solution B;
S3, adding the ethanol with the same volume into the solution B, and centrifuging to obtain a final product, namely the electric response controlled release nano-drug of the fenfluramine.
The nano-drug of the electrically responsive controlled release fenfluramine is named as PPY-PDA-FFM in the invention.
In one embodiment, the polyethylene glycol has a molecular weight of 2000.
In one embodiment, the mass ratio of fenfluramine to polyethylene glycol in step S1 is 1-10:20-100.
In one embodiment, the mass ratio of fenfluramine to polyethylene glycol in step S1 is 1:10.
In one embodiment, the heating conditions in step S1 are 40-60 ℃ for 1h.
In one embodiment, the heating conditions in step S1 are 50 ℃ and stirring is performed for 1h.
In one embodiment, the pH value is adjusted in the step S1 by adopting a hydrochloric acid solution, wherein the concentration of the hydrochloric acid solution is 1.0mol/L, and the adding amount is 100 mu L.
In one embodiment, the pH of solution a in step S1 is 8.0.
In one embodiment, the step S2 specifically includes:
And (3) firstly adding pyrrole and dopamine hydrochloride into the solution A, uniformly stirring, then adding ammonium persulfate aqueous solution, uniformly stirring, and reacting for 12 hours under the condition of light shielding to obtain a solution B.
In one embodiment, the ammonium persulfate aqueous solution has a mass concentration of 10mg/mL
In one embodiment, the ratio of the usage amount of the pyrrole, the dopamine hydrochloride and the ammonium persulfate aqueous solution is 10-100 mu L and 1-10mg to 100mg.
In one embodiment, the ratio of the amount of the pyrrole, the dopamine hydrochloride and the ammonium persulfate aqueous solution is 50 mu L, 5mg and 100mg.
In one embodiment, the dosage ratio of the fenfluramine, the pyrrole and the dopamine hydrochloride is 5-50 mg/10-100 mu L/1-10 mg.
In one embodiment, the ratio of the amounts of the fenfluramine, the pyrrole and the dopamine hydrochloride is 25mg to 50 mu L to 5mg.
In one embodiment, the centrifugal speed in the step S3 is 18000r/min.
The second aspect of the invention provides a nano-drug obtained by the preparation method of the nano-drug of the electric response controlled release fenfluramine.
The third aspect of the invention provides an application of the preparation method of the nano-drug of the electric response controlled release fenfluramine in preparing antiepileptic drugs.
Advantageous effects
1. According to the invention, the optimal electric response release drug system is obtained by optimizing the proportion of dopamine to pyrrole monomers and drug molecules, and the epileptic drugs can be released in an electric response controllable way.
2. The influence of temperature on the morphology and the drug loading capacity of the material is explored, and the morphology and the drug loading capacity of the prepared drug material are optimal through a specific reaction temperature, particularly when the temperature is 40-60 ℃.
3. The invention can effectively respond to epileptic neuron membrane potential and reduce epileptic seizure frequency and degree by controlling the dosage proportion of dopamine, pyrrole monomer and drug molecule, especially when the dosage proportion of fenfluramine, pyrrole and dopamine hydrochloride is 5-50mg:10-100 mu L:1-10 mg.
4. The invention reduces the influence on the subsequent rate of polymerization of pyrrole and dopamine and the conductivity of polypyrrole by controlling the pH value of the reaction system to be alkalescent.
5. The invention adopts one-pot reaction, has simple preparation process, is expected to be applied to the preparation of antiepileptic drugs on a large scale, and has good practical value.
Drawings
FIG. 1 is a transmission electron microscope image of the PPY-PDA-FFM prepared in example 1.
FIG. 2 is a scanning electron microscope image of the PPY-PDA-FFM prepared in example 1.
FIG. 3 is an infrared spectrum of PPY-PDA-FFM and PPY-PDA prepared in example 1.
FIG. 4 is a graph showing the UV-visible absorption spectrum of the PPY-PDA-FFM prepared in example 1, releasing fenfluramine over time at a voltage of 120 mV.
FIG. 5 is an ultraviolet-visible absorption spectrum showing the change of the maximum absorption value with time at 255nm of the PPY-PDA-FFM prepared in example 1.
FIG. 6 is an NMR spectrum of PPY-PDA-FFM prepared in example 1 releasing fenfluramine over time in the brain of a mouse suffering from epilepsy.
FIG. 7 is a 19 F-MRI imaging profile of PPY-PDA-FFM prepared in example 1 in the brain of a mouse with epilepsy.
FIG. 8 is a graph showing membrane potential excitability test of the PPY-PDA-FFM, FFM and PPY-PDA prepared in example 1, wherein A is a graph showing changes in nerve cell membrane potential, B is a graph showing changes in nerve cell calcium ion influx, and C is a graph showing changes in nerve cell potassium ion efflux.
FIG. 9 is a graph for testing the anti-epileptic effect of PPY-PDA-FFM prepared in example 1 in the brain of a mouse suffering from epileptic, wherein A-D is the expression amount of MCP-1, TNF-alpha, IL-1 beta and IL-6 in brain tissues after QPCR detection of materials, E-G is the behavioral observation of the mouse after different materials act, H is the survival rate analysis of the mouse after different materials act, I is the fluorescence graph of GFAP and FJB in the DG region of the hippocampus after materials act, and J-K is the quantitative result analysis graph of GFAP and FJB.
Detailed Description
The present invention will be described in further detail with reference to the following examples and drawings in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. The experimental procedure, in which no specific conditions are noted in the examples, was performed according to conventional conditions or conditions suggested by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
The first aspect of the present embodiment provides a method for preparing an electrically responsive controlled release nano-drug of fenfluramine, comprising the steps of:
s1, heating and stirring 25mg of fenfluramine and 250mg of polyethylene glycol, cooling to room temperature, and regulating the pH value of the solution to 8.0 to obtain a solution A;
S2, firstly adding 50 mu L of pyrrole and 5mg of dopamine hydrochloride into the solution A, uniformly stirring, then adding 100mg of ammonium persulfate aqueous solution, uniformly stirring, and reacting for 12 hours under the condition of avoiding light to obtain a solution B;
and S3, adding ethanol into the solution B, and centrifuging to obtain a final product, namely the electric response controlled release nano-drug of fenfluramine.
The heating condition in the step S1 is that stirring is carried out for 1h at 50 ℃.
And in the step S1, a hydrochloric acid solution is adopted to adjust the pH value, the concentration of the hydrochloric acid solution is 1.0mol/L, and the addition amount is 100 mu L.
And in the step S3, the centrifugal rotating speed is 18000r/min.
The second aspect of the present embodiment provides a nano-drug obtained according to the above method for preparing an electrically responsive controlled release nano-drug of fenfluramine.
In a third aspect, the embodiment provides an application of the preparation method of the nano-drug of the electric response controlled release fenfluramine in preparing antiepileptic drugs.
Performance testing
In the application, PPY is polypyrrole, PPY-PDA is polypyrrole-polydopamine, and FFM is fenfluramine.
1. FIG. 1 is a transmission electron microscope image of the PPY-PDA-FFM prepared in example 1, and FIG. 2 is a scanning electron microscope image of the PPY-PDA-FFM prepared in example 1. Transmission electron microscopy and scanning electron microscopy pictures can show successful preparation of the drug.
2. FIG. 3 shows the IR spectra of PPY-PDA-FFM and PPY-PDA prepared in example 1. From the figure, the PPY-PDA-FFM prepared in the example has the same characteristic peak as that of the fenfluramine, which shows the successful loading of the fenfluramine.
3. Ultraviolet absorption spectrum chart fig. 4 is an ultraviolet visible absorption spectrum chart of the PPY-PDA-FFM prepared in example 1 releasing fenfluramine with time under 120mV voltage, and fig. 5 is a graph of the maximum absorption value of the PPY-PDA-FFM prepared in example 1 at 255nm with time. From the graph, the nano-drug prepared according to the embodiment can controllably release the fenfluramine under the stimulation of 120mV voltage, which shows that the nano-drug prepared by the invention has the effect of releasing the fenfluramine in an electric response.
4. Nuclear magnetic resonance F spectrogram FIG. 6 is an NMR spectrum of the PPY-PDA-FFM prepared in example 1 releasing fenfluramine with time in the brain of a mouse suffering from epilepsy, wherein the medicine is fenfluramine pure product, and the material is the PPY-PDA-FFM prepared in example 1. As can be seen from the figure, the PPY-PDA-FFM (5 mu L,20 mg/mL) is injected into the brain of a mouse suffering from epilepsy for 10 minutes, and F-MRI imaging is obvious, so that the PPY-PDA-FFM prepared in the embodiment can respond to the brain voltage of the mouse suffering from epilepsy and successfully release the fenfluramine drug.
5. Magnetic resonance spectrum fig. 7 shows 19 F-MRI imaging spectrum of the PPY-PDA-FFM prepared in example 1 in brain of a mouse suffering from epilepsy, from which it is known that the PPY-PDA-FFM prepared in this example can be used for epilepsy treatment under image monitoring.
6. Membrane potential excitability test:
FIG. 8A is a graph showing changes in cell membrane potential of nerve cells, primary nerve cells were seeded in 24-well plates, 2X 105/well, 100 ng/. Mu.L of alginic acid was added to activate cells, different materials (PPY-PDA-FFM, FFM, PPY-PDA prepared in example 1) were used to incubate cells for 12 hours in advance, diSBAC (3) was added to the medium at a final concentration of 100nM, incubated for 30min, and changes in fluorescence intensity of cells were recorded using a flow cytometer;
FIG. 8B is a graph showing the change in calcium ion influx of neural cells, which were obtained by inoculating primary neural cells in a 24-well plate, 2X 105 cells/well, adding 100 ng/. Mu.L of alginic acid to activate cells, incubating the cells with different materials (PPY-PDA-FFM, FFM, PPY-PDA prepared in example 1) for 12 hours in advance, labeling neural cells with a calcium ion probe and performing flow analysis, and recording the change in fluorescence intensity of the cells;
FIG. 8C shows the change in potassium outflow of nerve cells, which was obtained by inoculating primary nerve cells in a 24-well plate, 2X 105 cells/well, adding 100 ng/. Mu.L of alginic acid to activate cells, incubating the cells with different materials (PPY-PDA-FFM, FFM, PPY-PDA prepared in example 1) for 12 hours in advance, labeling nerve cells with a potassium ion probe and performing flow analysis, and recording the change in fluorescence intensity of cells;
the graph shows that the PPY-PDA-FFM electroresponse controlled release fenfluramine prepared by the invention can efficiently reduce membrane potential excitability, reduce calcium inflow and potassium outflow, and effectively reduce nerve cell membrane potential.
7. Behavioural experiments and brain slice testing:
Establishment of an acute epilepsy rat model, i.e. the rats to be operated are anesthetized by intraperitoneal injection of chloral hydrate (400 mg/kg) after the same dose (5 mu L,20 mg/mL) of different materials (FFM, PPY-PDA-FFM, PPY-PDA) is administered by intraperitoneal injection. After anesthesia, the electrodes were implanted into the right cortex (AP: -3.2mm, L: -3.0mm, V: -1.8 mm) and the cannula was implanted into the left ventricle (AP: -1mm, L: -1.2mm, V: -3.6 mm) by fixing them on a stereotactic apparatus. The electrode is made of a double-stranded stainless steel wire (d: 0.05 mm) with a polytetrafluoroethylene insulating layer on the outer layer and spirally wound, the lower end is bifurcated by 0.6mm, and the insulating layer of about 0.5mm is stripped. The upper end of the electrode is welded with the miniature three-hole socket, clings to the skull as much as possible, and is fixed by red and white dental cement. Rats recovered one week after surgery. One week after the operation, the microsyringe needle slowly advanced the alginic acid (KA) (1.25 g/mL,0.65 uL/min) into the lateral ventricle within 10 minutes and the needle was placed in the cannula 5 minutes after administration before slowly retracting the needle. After KA administration, each rat was placed in a (50 cm. Times.30 cm) clear resin observation box, and the animal epileptics were observed and EEG changes were recorded. Animal epileptic behavior is classified according to the Racine standard into grade I-V, grade I representing nonselective chewing, grade II representing trembling, grade III representing unilateral forelimb lifting, grade IV representing bilateral forelimb lifting with wet dog-like trembling, grade V representing twitching, and falling back. Wherein, the stages I to III are focal attacks, and the stages IV and V are epileptic big attacks.
Animal material taking and tissue pathological section, namely, tissue material taking is carried out after an epileptic model is constructed for 30 days, a thoracic cavity is opened after a mouse is anesthetized, a heart is exposed, a coarse injection needle is inserted and fixed from a heart apex through a left ventricular incision, then a right auricle is cut off, 250mL of 0.9% physiological saline is rapidly poured, and 250mL of 4% neutral paraformaldehyde fixing solution is poured instead after the liver turns white, so that the rat is stiff. Then breaking the end of the perfused rat, opening the cranial cavity, taking out the whole brain tissue carefully, fixing overnight at 4 ℃ with 4% paraformaldehyde, immersing in 30% sucrose solution, embedding the brain tissue with embedding medium after sinking, putting into a-86 ℃ ultralow temperature refrigerator for 2 hours, starting frozen section, and pathological staining the sectioned tissue.
The test results are shown in FIG. 9, wherein FIG. 9A-D shows the measurement and test of MCP-1, TNF-alpha, IL-1 beta and IL-6 expression in brain tissue after the QPCR detection material is acted, and the level of the related expression factors is obviously lower than that of FFM and PPY-PDA group after the PPY-PDA-FFM is acted, so that the PPY-PDA-FFM has a certain immune inhibition effect on cytokine production, and further shows that the PPY-PDA-FFM can obviously inhibit epileptic seizure.
Fig. 9E-G are graphs showing the behavioral observation and test of mice after the action of different materials, and it can be seen from the graphs that FFM, PPY-PDA and PPY-PDA-FFM can reduce the seizure frequency, wherein PPY-PDA-FFM prepared in this example has the effects of significantly reducing the seizure frequency and shortening the duration of seizure.
FIG. 9H is a graph showing the survival rate of mice after the action of different materials, and the electrical response material PPY-PDA-FFM prepared in the embodiment is relatively safe.
FIG. 9I is a fluorescent image of GFAP and FJB in the hippocampal DG region after PPY-PDA-FFM and FFM are applied, and FIG. 9J-K is an analytical image of quantitative results of GFAP and FJB. From the graph, the expressions of GFAP and FJB in the DG region of the sea horse are obviously reduced after the electric response material PPY-PDA-FFM prepared by the embodiment acts, so that the PPY-PDA-FFM can obviously inhibit the seizure.
Claims (10)
1. The preparation method of the electric response controlled release fenfluramine nano-drug is characterized by at least comprising the following steps:
S1, heating and stirring fenfluramine and polyethylene glycol, cooling to room temperature, and regulating the pH value of the solution to be alkalescent to obtain a solution A;
S2, sequentially adding pyrrole, dopamine hydrochloride and ammonium persulfate aqueous solution into the solution A, and uniformly stirring for reaction to obtain a solution B;
S3, adding the ethanol with the same volume into the solution B, and centrifuging to obtain a final product, namely the electric response controlled release nano-drug of the fenfluramine.
2. The method for preparing the nano-drug for electrically responsive controlled release of fenfluramine according to claim 1, wherein the mass ratio of fenfluramine to polyethylene glycol in the step S1 is 1-10:20-100.
3. The method for preparing the nano-drug for electrically-responsive controlled release of fenfluramine according to claim 2, wherein the heating condition in the step S1 is that stirring is carried out for 1h at 40-60 ℃.
4. The method for preparing the nano-drug for electrically responsive controlled release of fenfluramine according to claim 1, wherein the pH value of the solution a in the step S1 is 8.0.
5. The method for preparing the nano-drug for electrically responsive controlled release of fenfluramine according to claim 1, wherein the step S2 is specifically:
And (3) firstly adding pyrrole and dopamine hydrochloride into the solution A, uniformly stirring, then adding ammonium persulfate aqueous solution, uniformly stirring, and reacting for 12 hours under the condition of light shielding to obtain a solution B.
6. The method for preparing the nano-drug for electrically-responsive controlled release of fenfluramine according to claim 5, wherein the dosage ratio of the pyrrole to the dopamine hydrochloride to the ammonium persulfate aqueous solution is 10-100 mu L and 1-10mg to 100mg.
7. The method for preparing the nano-drug for electrically-responsive controlled release of fenfluramine according to claim 1, wherein the dosage ratio of fenfluramine, pyrrole and dopamine hydrochloride is 5-50mg:10-100 mu L:1-10mg.
8. The method for preparing the nano-drug for electrically responsive controlled release of fenfluramine according to claim 1, wherein the centrifugal rotation speed in the step S3 is 18000r/min.
9. A nano-drug obtained by the method for preparing an electrically responsive controlled release nano-drug of fenfluramine according to any one of claims 1-8.
10. Use of a method for the preparation of an electrically responsive controlled release nano-drug of fenfluramine according to any one of claims 1-8 for the preparation of an antiepileptic drug.
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| WO2018060732A2 (en) * | 2016-09-30 | 2018-04-05 | Zogenix International Limited | Compositions and methods for treating seizure disorders |
| CN114585354A (en) * | 2019-09-17 | 2022-06-03 | 周格尼克斯国际有限公司 | Methods of treating patients with epilepsy with fenfluramine |
| CN112472684A (en) * | 2020-12-02 | 2021-03-12 | 浙江大学 | Electric field sensitive polydopamine-polypyrrole nano drug delivery system and preparation method and application thereof |
| WO2023037182A2 (en) * | 2021-08-19 | 2023-03-16 | Biophore India Pharmaceuticals Pvt Ltd | AN IMPROVED PROCESS FOR THE PREPARATION OF N-ETHYL- α -METHYL-3-(TRIFLUOROMETHYL)PHENETHYLAMINE HYDROCHLORIDE |
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