Nicardipine delivery system and application thereof in resisting post-traumatic stress disorder

Abstract

The invention discloses a nicardipine delivery system and application of the nicardipine delivery system in resisting post-traumatic stress disorder. According to the present invention, the functional modification is performed on the PLGA-PEG to develop the brain enrichment type PLGA-PEG-MANNOse molecule, the nicardipine is subjected to nanometer modification, the blood brain barrier permeability is enhanced, and the fear memory disorder of the post-traumatic stress disorder model animal can be effectively relieved; research finds that when PPM-N is used for treating mice related to electric shock complicated post-traumatic stress disorder, indexes of multiple experimental results are equivalent to serotonin reuptake inhibitor medicine sertraline. Related experiments show that PPM-N has the effect of treating and / or relieving post-traumatic stress disorder and has a good clinical application prospect.

Description

Technical Field

[0001] This invention belongs to the field of biotechnology, specifically relating to a nicardipine delivery system based on PLGA-PEG-Mannose nanocarriers and its use in treating post-traumatic stress disorder. Background Technology

[0002] Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness caused by life-threatening events or catastrophic psychological trauma, such as war trauma, death threats, serious injury, or sexual violence. Statistics show that one in ten people who have experienced traumatic events will develop PTSD symptoms, and the estimated annual prevalence of PTSD worldwide is 3%-4%. The Diagnostic and Statistical Manual of Mental Disorders (5th edition) identifies the core symptoms of PTSD as re-experiencing trauma, avoidance or numbness, negative cognition and mood, and increased vigilance. Fear memory regression disorder is considered a hallmark of the mood disorder in PTSD, with recurrent fears severely interfering with patients' daily work and life. Currently, serotonin reuptake inhibitors (SRIs) are the primary clinical treatment for PTSD. However, these medications often cause side effects, with gastrointestinal discomfort and central nervous system effects being the most common and relatively frequent. Furthermore, these medications carry a slight risk of increased bleeding tendency.

[0003] Excessive consolidation of trauma-related fear memories is a core behavioral feature of post-traumatic stress disorder (PTSD), playing a crucial role in maintaining neurobehavioral homeostasis and disease progression. Phenotypic, animal models of PTSD typically exhibit significant generalization of conditioned fear responses. Previous studies have shown that under acute stress exposure, animal models exhibit persistent impairment in fear memory extinction and spatial exploration avoidance behaviors. Under physiological conditions, the fear extinction capacity and exploratory behavior in adult individuals maintain a relatively dynamic balance; however, in conditioned fear-induced PTSD models, re-exposure to trauma induces intense rigidity (conditioned fear test).

[0004] Currently, there are no effective drugs with low side effects for treating post-traumatic stress disorder (PTSD). Given that PTSD can lead to persistent functional impairments at the cognitive, emotional, behavioral, and physiological levels, and significantly increase the risk of comorbidities and suicide, it is crucial to conduct drug target research and develop a drug that can effectively alleviate PTSD caused by electric shock. Summary of the Invention

[0005] The purpose of this invention is to provide a nicardipine delivery system and its use in treating post-traumatic stress disorder.

[0006] Nicardipine, also known as Perdipine, has the molecular formula C0. 26 H 29 N3O6, molecular weight: 479.525, chemical structure formula is shown below:

[0007]

[0008] Application of nicardipine delivery system based on PLGA-PEG-Mannose nanocarrier in the preparation of drugs for the prevention and / or treatment of post-traumatic stress disorder.

[0009] The post-traumatic stress disorder mentioned refers to post-traumatic stress disorder caused by electric shock.

[0010] The delivery system can alleviate the duration of motion sickness in mice during scene-fear experiments.

[0011] A medicament for the prevention and / or treatment of post-traumatic stress disorder caused by electric shock, wherein the active ingredient of the medicament comprises the nicardipine delivery system based on PLGA-PEG-Mannose nanocarrier, in a content of 0.01wt%-99.99wt%.

[0012] The drug also includes a pharmaceutically acceptable carrier, including one or more of solvents, excipients, preservatives, stabilizers, emulsifiers, salts for adjusting osmotic pressure, and buffers.

[0013] The dosage form of the drug is powder for injection, injection solution, tablet, pill, capsule, spray or dispersion.

[0014] The routes of administration of the drug include oral, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, nasal inhalation, or oral inhalation.

[0015] The beneficial effects of this invention are as follows: Firstly, this invention functionalizes PLGA-PEG, a polymer material, to develop a brain-enriched PLGA-PEG-Mannose molecule. Secondly, it nano-modifies nicardipine to enhance blood-brain barrier permeability. A mouse model of post-traumatic stress disorder induced by electric shock was constructed, and scene fear analysis was performed on days 3 and 8 after the shock. The drug provided by this invention for the prevention and / or treatment of post-traumatic stress disorder induced by electric shock contains a pharmacodynamic dose of PPM-N and pharmaceutically acceptable carriers or excipients. It can be formulated into a drug dosage form that is convenient for clinical use and can achieve optimal efficacy, possessing good pharmaceutical prospects and high economic value. Attached Figure Description

[0016] Figure 1 These are in vivo images of the nanomaterial PPM@P18 taken at different time points in the experimental example.

[0017] Figure 2 In this experimental case, in vivo imaging of isolated brain tissue and organs was taken 4 hours after PPM@P18 administration.

[0018] Figure 3 The fluorescence intensity of PPM@P18 in the brain at different time points was statistically analyzed in the experimental case.

[0019] Figure 4 This is a laser confocal image showing the distribution of PPM@P18 and PP@P18 in isolated brain tissue in the experimental example. Blue represents DAPI, and red represents nanomaterials.

[0020] Figure 5 The image shows the fluorescence intensity of PPM@P18 and PP@P18 crossing the blood-brain barrier in the experimental case.

[0021] Figure 6 The time PPM-N effectively alleviated the rigidity caused by scene-fear experiment in mice on day 3 after modeling.

[0022] Figure 7 The duration of rigidity in mice after a scene-fear experiment was measured by the effectiveness of PPM-N in alleviating this effect on day 8 post-modeling. Detailed Implementation

[0023] To facilitate understanding of the present invention, a more comprehensive description will be given below. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0024] Example 1

[0025] Establishment of a post-traumatic stress disorder model: C57 male mice were randomly divided into four groups: control group, model group, sertraline group, and PPM-N group. On the first day of electric shock, the mice were placed in the electric shock chamber for 5 minutes to adapt to white light. On the second and third days, the model group, sertraline group, and PPM-N group were placed in the electric shock chamber for 10 minutes. White light stimulation was given for the first 5 minutes, followed by electric shock for 10 seconds for the next 5 minutes, with a 10-second interval, and the cycle was repeated 14 times.

[0026] Conditioned fear measurement in mice: On the 3rd and 8th days after the electric shock fear, the mice in the above four groups were placed in the mouse fear test system. The movement trajectory of the mice within 10 minutes was recorded using Shanghai Jiliang software, and the percentage of time the mice remained still in the last 5 minutes was calculated.

[0027] Experimental results:

[0028] The loading rate of the nano-modified drug (PPM-N) was statistically analyzed (Table 1).

[0029] Table 1

[0030]

[0031] Analysis of the brain enrichment results of nanomaterials ( Figure 1-4 ); Analysis of the fluorescence intensity of PPM@P18 and PP@P18 across the in vitro blood-brain barrier ( Figure 5 A post-traumatic stress disorder model was established in C57BL / 6J mice, and behavioral assessments were performed 3 and 8 days after conditioned fear stress.

[0032] The duration of rigidity in trauma re-exposure situations was detected using a conditioned fear experiment. Figure 6 , 7 The results showed that after PLGA-PEG-Mannose molecular nanofiber modification, the average particle size of nicardipine was 153.3 nm, the DPI was 0.128, the loading rate was 59.99%, and the encapsulation rate was 80.65%. In vivo animal validation showed that the brain-enriched PLGA-PEG-Mannose nanosystem could effectively promote the penetration of nanomedicines through the BBB and deliver fluorescent molecules to the brains of healthy mice. The penetration rate of the brain-enriched PLGA-PEG-Mannose nanosystem in the in vitro BBB model was 7%. The model group mice showed significant fear memory consolidation on days 3 and 8 after stress (*p<0.05, **p<0.01, ***p<0.001).

[0033] To verify the therapeutic effect of PPM-N, a systematic behavioral analysis was conducted on the model group and the PPM-N treatment group: Conditioned fear experiments showed that the rigidity time in the treatment group was significantly shorter than that in the model group. Figure 6 , 7 ).

[0034] To verify the efficacy of PLGA-PEG-Mannose molecular nanocompositing in modifying nicardipine, the drug loading rate of PPM-N was statistically analyzed, and the blood-brain barrier penetration test and brain enrichment results of PPM@P18 were statistically analyzed. The results showed that PLGA-PEG-Mannose molecular nanocompositing increased blood-brain barrier permeability and enabled the material to reach the brains of healthy mice. Figure 1-5 ).

[0035] Based on the above evidence, we can conclude that PLGA-PEG-Mannose molecular nanocompositing results in a higher nicardipine loading rate, increases the blood-brain barrier permeability of nicardipine, and delivers fluorescent molecules to the brains of healthy mice. Traumatic stress induces core behavioral symptoms: solidified fear memories (conditioned fear test); PPM-N significantly and effectively promotes the extinction of fear memories.

[0036] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. Application of PLGA-PEG-Mannose nanocarrier-based nicardipine delivery system in the preparation of drugs for the prevention and / or treatment of post-traumatic stress disorder.

2. The application according to claim 1, wherein the post-traumatic stress disorder is electric shock-induced post-traumatic stress disorder.

3. According to claim 1, the delivery system can alleviate the rigidity time in mice caused by scene-fear experiments.

4. A drug for the prevention and / or treatment of post-traumatic stress disorder caused by electric shock, characterized in that: The active ingredient of the drug includes the nicardipine delivery system based on PLGA-PEG-Mannose nanocarrier as described in claim 1, with a content of 0.01wt%-99.99wt%.

5. The drug according to claim 4, characterized in that, The drug also includes a pharmaceutically acceptable carrier, including one or more of solvents, excipients, preservatives, stabilizers, emulsifiers, salts for adjusting osmotic pressure, and buffers.

6. The drug according to claim 4, characterized in that, The dosage form of the drug is powder for injection, injection solution, tablet, pill, capsule, spray or dispersion.

7. The drug according to claim 4, characterized in that, The routes of administration of the drug include oral, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, nasal inhalation, or oral inhalation.

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