Application of ginkgolide B in plateau environment cognitive dysfunction protection

Abstract

The invention relates to the technical field of biology, and particularly discloses application of bilobalide B in plateau environment cognitive dysfunction protection. The application comprises the steps that a pharmaceutical composition containing bilobalide B is mixed with a low-concentration oxygen adaptation regulating agent to be used for regulating the pharmaceutical composition, and an intermediate product with the nerve protection enhancing effect is obtained; carrying out nano-carrier packaging and functionalization treatment on the intermediate product with the effect of enhancing neuroprotection, so as to realize brain-targeted controlled release of the drug to obtain a composite controlled release drug; the compound controlled-release medicine is administrated by adopting an administration dosage optimization method based on reinforcement learning, so that long-term prevention and improvement of cognitive impairment in a plateau environment are realized, and a final cognitive function protection effect is obtained; the whole formula is regulated and controlled by a nano controlled release technology, and all the components can be continuously released and uniformly distributed, so that the optimal balance between the drug effect and the safety is realized, and the problem of cognitive impairment caused by high altitude hypoxia is comprehensively improved.

Description

Technical Field

[0001] The present invention belongs to the field of biotechnology, and particularly relates to an application of ginkgolide B in the protection of cognitive dysfunction in a plateau environment. Background Art

[0002] The plateau environment, characterized by low oxygen levels, high radiation, and extreme climatic conditions, significantly impacts human physiological systems, particularly the central nervous system. Studies have shown that long-term exposure to the plateau hypoxic environment can lead to cognitive impairment, including memory loss, reduced learning ability, and difficulty concentrating. These symptoms are closely related to the inflammatory response, oxidative stress, and neuronal damage triggered by hypoxia.

[0003] At present, the main protective measures against cognitive dysfunction in plateau environments include:

[0004] Oxygen supplementation: Oxygen inhalation or hyperbaric oxygen chamber treatment can temporarily relieve hypoxia symptoms, but it cannot fundamentally solve the problem of cognitive dysfunction.

[0005] Drug intervention: Use anti-inflammatory drugs, antioxidants or neuroprotective agents, but existing drugs have the following shortcomings:

[0006] Single target: Most drugs target only a single pathological mechanism (such as inflammation or oxidative stress) and lack multi-target synergy.

[0007] Low bioavailability: Many drugs have low bioavailability due to poor water solubility or rapid metabolism, and cannot reach effective concentrations in the brain.

[0008] Obvious side effects: Long-term use of certain drugs may cause serious side effects, such as liver and kidney damage, gastrointestinal reactions, etc.

[0009] Lack of personalized treatment: Existing treatment options are mostly "one-size-fits-all" and cannot be precisely adjusted according to individual differences.

[0010] Ginkgolide B is a diterpene lactone compound extracted from Ginkgo biloba leaves. It has significant anti-platelet activating factor (PAF) effects, as well as anti-inflammatory, antioxidant, and neuroprotective activities. In recent years, Ginkgolide B has shown promising results in the treatment of cardiovascular disease, ischemic stroke, and neurodegenerative diseases. However, its application in the prevention of cognitive dysfunction in high-altitude environments still faces the following challenges:

[0011] Limited efficacy in hypoxic environment: The high altitude hypoxic environment may lead to changes in the pharmacokinetics of ginkgolide B, reducing its bioavailability and efficacy.

[0012] Lack of brain targeting: Ginkgolide B has difficulty passing through the blood-brain barrier, resulting in insufficient concentration in the brain and inability to fully exert its neuroprotective effects.

[0013] Limitations of a single ingredient: When used alone, Ginkgolide B is difficult to fully respond to the multi-factor damage caused by the plateau environment (such as hypoxia, inflammation, and oxidative stress).

[0014] In this regard, the inventors proposed an application of Ginkgolide B in the protection of cognitive dysfunction in plateau environments to solve the above problems. Summary of the Invention

[0015] The purpose of the present invention is to provide an application of ginkgolide B in the protection of cognitive dysfunction in a plateau environment, so as to solve the problems raised in the above background technology.

[0016] To achieve the above object, the present invention provides the following technical solutions:

[0017] An application of Ginkgolide B in the protection of cognitive dysfunction in plateau environments, comprising:

[0018] A pharmaceutical composition comprising ginkgolide B, which is used to prevent or alleviate cognitive dysfunction caused by hypoxia, inflammation, and oxidative stress in a high-altitude environment, is mixed with a low-concentration oxygen adaptation regulator to regulate the pharmaceutical composition to obtain an intermediate product with enhanced neuroprotective effect;

[0019] The intermediate product with enhanced neuroprotective effect is packaged in a nanocarrier and functionalized to achieve brain-targeted controlled release of the drug, thereby obtaining a composite controlled-release drug;

[0020] The composite controlled-release drug is administered using a dosage optimization method based on reinforcement learning to achieve long-term prevention and improvement of cognitive dysfunction in a plateau environment, thereby obtaining the ultimate cognitive function protection effect.

[0021] Preferably, the composition percentage of the pharmaceutical composition containing ginkgolide B is:

[0022] Ginkgolide B 3.0%;

[0023] Nano perfluorooctane emulsion 0.5%;

[0024] N-acetylcysteine ​​NAC nanoparticles 0.3%;

[0025] Vitamin E liposomes 0.2%;

[0026] Rhodiola rosea high polarity extract 1.0%;

[0027] Ultrapure conifer resin derivative 0.5%;

[0028] Hydroxypropyl methylcellulose HPMC 1.0%;

[0029] Glycerin regulator 25%;

[0030] The remainder is high-purity water.

[0031] Preferably, the preparation method of the pharmaceutical composition containing ginkgolide B is:

[0032] S1. Weigh each component according to the above formula requirements, dissolve Ginkgolide B in ethanol to fully dissolve it to obtain a uniform solution; dissolve the Rhodiola rosea high-polarity extract in high-purity water, and mix thoroughly to obtain a Rhodiola rosea extract solution for use.

[0033] S2. Add perfluorooctane to a pre-weighed amount of solvent, dissolve it together with lecithin, and mix well.

[0034] Slowly add the oil phase dropwise into the water phase containing high-purity water and a certain proportion of glycerin regulator while stirring;

[0035] After mixing for 2–3 minutes using a high-speed stirrer, ultrasonic vibration treatment was performed using an ultrasonic emulsifier at 40 kHz for 10 minutes to obtain a uniform emulsion with nanoparticles less than 200 nm in size;

[0036] The nano-perfluorooctane emulsion after ultrasonic emulsification was added to the pre-filtered coniferous resin derivative solution, and the mixture was gently stirred for 5 minutes to obtain an oxygen carrier nano-system;

[0037] S3, dissolving NAC in ethanol and adjusting to the target concentration using ultrasound-assisted dissolution technology;

[0038] Using reverse microemulsification or high-pressure homogenization equipment at 800–1000 bar, nano-processing is performed to form NAC nanoparticles with a controlled particle size of 50–150 nm.

[0039] The larger particles that were not nanosized were removed by filtration, and the uniformly dispersed NAC nanosuspension was collected;

[0040] Mix vitamin E and lecithin and dissolve them in chloroform, then pour into a round-bottom flask;

[0041] The organic solvent was evaporated using a rotary evaporator at 40 °C to form a uniform film;

[0042] Add appropriate amount of high-purity water to the film to slowly hydrate it, and at the same time, use a slight ultrasonic water bath to fully disperse the film to form uniform liposomes;

[0043] The liposome particle size was adjusted to less than 200 nm by extrusion through a fine-pore extruder;

[0044] S4. Slowly add the ginkgolide B pre-solution into the Rhodiola rosea extract solution and mix thoroughly;

[0045] Add the prepared perfluorooctane nanoemulsion and homogenize by magnetic stirring or low-speed stirring to ensure that all components are fully integrated;

[0046] NAC nanoparticles and vitamin E liposomes were added to the mixed solution separately and continuously mixed with mechanical stirring or light ultrasound (to avoid destroying the liposome structure) for 5–10 minutes to uniformly disperse them in the matrix.

[0047] Gradually add hydroxypropyl methylcellulose (HPMC) in the form of an aqueous solution, stirring slowly throughout the process to prevent agglomeration; adjust the viscosity and rheological properties of the mixture to ensure that the drug component can form a sustained and uniform release film in the body; adjust the pH of the composition using citric acid or sodium hydroxide solution to a pH range of 7.2 to 7.4;

[0048] The entire system is homogenized again using a high-pressure homogenizer or ultrasonic treatment to ensure that each nanocomponent is evenly distributed in the entire system, thereby obtaining a pharmaceutical composition of ginkgolide B.

[0049] Preferably, the release rate for achieving brain-targeted controlled release of the drug is calculated using a nano-controlled release kinetic model, and the expression is:

[0050]

[0051] Wherein, R(t): the immediate release rate of ginkgolide B at time t, reflecting the drug release dynamics of the nanocarrier in vivo;

[0052] R0: Peak release rate, which indicates the initial release capacity of the drug inside the nanocarrier; this parameter is closely related to the preparation process and drug loading of the nanoparticles;

[0053] μ: Peak release time, that is, the time point when drug release reaches its maximum value. This parameter helps to determine the optimal efficacy window;

[0054] σ: time diffusion parameter of the drug release process, reflecting the smoothness of drug release; a smaller σ value indicates a short and concentrated release time, while a larger σ value indicates a smoother release process;

[0055] η(t): Adjustment term, representing the fine-tuning term affected by physiological status (such as individual metabolic differences and ambient temperature) and real-time data feedback in the actual plateau hypoxic environment. This part can be adaptively corrected using machine learning algorithms (such as online regression models).

[0056] Preferably, the cumulative cognitive improvement contribution calculation function for the long-term prevention and improvement of cognitive dysfunction in plateau environment is expressed as:

[0057]

[0058] Wherein, F: the cumulative contribution of drug release to the improvement of cognitive function during the entire treatment period T;

[0059] a: Proportional coefficient, indicating the intensity of the neuroprotective effect of ginkgolide B. This value can be adjusted based on in vivo inflammatory indicators, oxidative stress data, and individual genetic background;

[0060] R(t): immediate release rate of ginkgolide B at time t;

[0061] Rref: reference release rate, used to normalize data from different individuals or at different time points to ensure numerical stability;

[0062] T: Total treatment time, which here represents the duration of the entire intervention process.

[0063] Preferably, the formula of the dosage optimization method based on reinforcement learning is:

[0064]

[0065] Where Q(st,at) is the expected cumulative benefit after taking the medication action at at time t in state st.

[0066] r(st,at): The immediate reward function, which is designed to balance the improvement of cognitive function (such as improved behavioral test scores) and side effects (such as adverse reactions caused by excessive drug concentrations).

[0067] γ: Discount factor, used to weigh the importance of current rewards and future rewards, with a value between 0 and 1;

[0068] st: state vector, including the current drug concentration in the brain, cognitive assessment indicators (such as memory and learning ability scores), and environmental hypoxia indicators;

[0069] at: action or decision, indicating the specific dosage or dosing interval selected at time t;

[0070] Represents the maximum expected benefit that can be obtained in the next state.

[0071] Compared with the prior art, the present invention has the following beneficial effects:

[0072] (1) The pharmaceutical composition of the present invention forms a multi-layered protective system through the synergistic effect of ginkgolide B with perfluorooctane emulsion, nanosized N-acetylcysteine, vitamin E liposomes, and Rhodiola rosea extract. In the low-oxygen environment of the plateau, the perfluorooctane emulsion provides efficient oxygen supply, alleviating local hypoxia; N-acetylcysteine ​​and vitamin E liposomes provide dual antioxidant protection, reducing cell damage caused by oxidative stress; ginkgolide B provides significant neuroprotective and anti-inflammatory effects; and at the same time, the Rhodiola rosea extract activates the body's hypoxia adaptation mechanism, improving tolerance.

[0073] (2) The entire formula of the present invention is regulated by nano-controlled release technology, and each component can be continuously released and evenly distributed, thereby achieving an optimal balance between efficacy and safety, and comprehensively improving the cognitive dysfunction caused by plateau hypoxia. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 The present invention is a flowchart of the application of Ginkgolide B in the protection of cognitive dysfunction in plateau environment. DETAILED DESCRIPTION

[0075] The following will provide a clear and complete description of the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0076] Example 1:

[0077] A pharmaceutical composition comprising ginkgolide B, which is used to prevent or alleviate cognitive dysfunction caused by hypoxia, inflammation, and oxidative stress in a high-altitude environment, is mixed with a low-concentration oxygen adaptation regulator to regulate the pharmaceutical composition to obtain an intermediate product with enhanced neuroprotective effect;

[0078] The intermediate product with enhanced neuroprotective effect is packaged in a nanocarrier and functionalized to achieve brain-targeted controlled release of the drug, thereby obtaining a composite controlled-release drug;

[0079] The composite controlled-release drug is administered using a dosage optimization method based on reinforcement learning to achieve long-term prevention and improvement of cognitive dysfunction in a plateau environment, thereby obtaining the ultimate cognitive function protection effect.

[0080] The release rate for achieving brain-targeted controlled release of the drug is calculated using a nano-controlled release kinetic model, and the expression is:

[0081]

[0082] Wherein, R(t): the immediate release rate of ginkgolide B at time t, reflecting the drug release dynamics of the nanocarrier in vivo;

[0083] R0: Peak release rate, which indicates the initial release capacity of the drug inside the nanocarrier; this parameter is closely related to the preparation process and drug loading of the nanoparticles;

[0084] μ: Peak release time, that is, the time point when drug release reaches its maximum value. This parameter helps to determine the optimal efficacy window;

[0085] σ: time diffusion parameter of the drug release process, reflecting the smoothness of drug release; a smaller σ value indicates a short and concentrated release time, while a larger σ value indicates a smoother release process;

[0086] η(t): Adjustment term, representing the fine-tuning term based on physiological status (such as individual metabolic differences, ambient temperature, etc.) and real-time data feedback in the actual plateau hypoxic environment. This part can be adaptively corrected using machine learning algorithms (such as online regression models).

[0087] This formula uses a Gaussian distribution to describe the basic release curve of a nano-controlled release system. Incorporating the real-time environmental feedback term η(t), this allows the system to automatically adjust based on this information, enhancing effective drug delivery and controlled release in the brain. By fitting the parameters R0, μ, and σ to experimental data, dynamic adjustments can be made to address different plateau environments and individual differences, enabling a safe and efficient drug delivery strategy.

[0088] The cumulative cognitive improvement contribution calculation function expression for the long-term prevention and improvement of cognitive dysfunction in plateau environment is:

[0089]

[0090] Wherein, F: the cumulative contribution of drug release to the improvement of cognitive function during the entire treatment period T;

[0091] a: Proportional coefficient, indicating the intensity of the neuroprotective effect of ginkgolide B. This value can be adjusted based on in vivo inflammatory indicators, oxidative stress data, and individual genetic background;

[0092] R(t): immediate release rate of ginkgolide B at time t;

[0093] Rref: reference release rate, used to normalize data from different individuals or at different time points to ensure numerical stability;

[0094] T: total treatment time, which here represents the duration of the entire intervention process;

[0095] Through integration and logarithmic processing, the nonlinear effect of sudden release on cognitive improvement is smoothed, making the model more consistent with the actual situation of gradual accumulation of physiological effects; the introduction of parameter a enables the model to be personalized according to individual and environmental conditions (such as plateau hypoxic stress), thereby achieving accurate evaluation and prediction of therapeutic efficacy.

[0096] The formula of the drug dosage optimization method based on reinforcement learning is:

[0097]

[0098] Where Q(st,at) is the expected cumulative benefit after taking the medication action at at time t in state st.

[0099] r(st,at): The immediate reward function, which is designed to balance the improvement of cognitive function (such as improved behavioral test scores) and side effects (such as adverse reactions caused by excessive drug concentrations).

[0100] γ: Discount factor, used to weigh the importance of current rewards and future rewards, with a value between 0 and 1;

[0101] st: state vector, including the current drug concentration in the brain, cognitive assessment indicators (such as memory and learning ability scores), and environmental hypoxia indicators;

[0102] at: action or decision, indicating the specific dosage or dosing interval selected at time t;

[0103] Represents the maximum expected benefit that can be obtained in the next state;

[0104] This formula utilizes the Q-learning method from reinforcement learning, continuously updating the dosing strategy based on real-time status data to ensure that each subject achieves a balance between optimal efficacy and minimal side effects in the complex high-altitude environment. This algorithm enables personalized, precise dosing. The system dynamically adjusts based on continuous feedback, ensuring optimal long-term operation and ultimately improving cognitive function.

[0105] Example 2:

[0106] The composition percentage of the pharmaceutical composition containing Ginkgolide B is:

[0107] Ginkgolide B 3.0%;

[0108] Nano perfluorooctane emulsion 0.5%;

[0109] N-acetylcysteine ​​NAC nanoparticles 0.3%;

[0110] Vitamin E liposomes 0.2%;

[0111] Rhodiola rosea high polarity extract 1.0%;

[0112] Ultrapure conifer resin derivative 0.5%;

[0113] Hydroxypropyl methylcellulose HPMC 1.0%;

[0114] Glycerin regulator 25%;

[0115] The remainder is high-purity water.

[0116] Specifically, the preparation method of the pharmaceutical composition containing ginkgolide B is:

[0117] S1. Weigh each component according to the above formula requirements, dissolve Ginkgolide B in ethanol to fully dissolve it to obtain a uniform solution; dissolve the Rhodiola rosea high-polarity extract in high-purity water, and mix thoroughly to obtain a Rhodiola rosea extract solution for use.

[0118] S2. Add perfluorooctane to a pre-weighed amount of solvent, dissolve it together with lecithin, and mix well.

[0119] Slowly add the oil phase dropwise into the water phase containing high-purity water and a certain proportion of glycerin regulator while stirring;

[0120] After mixing for 2 minutes using a high-speed stirrer, ultrasonic vibration treatment was performed using an ultrasonic emulsifier at 40 kHz for 10 minutes to obtain a uniform emulsion with nanoparticles less than 200 nm in size;

[0121] The nano-perfluorooctane emulsion after ultrasonic emulsification was added to the pre-filtered coniferous resin derivative solution, and the mixture was gently stirred for 5 minutes to obtain an oxygen carrier nano-system;

[0122] S3, dissolving NAC in ethanol and adjusting to the target concentration using ultrasound-assisted dissolution technology;

[0123] Using reverse microemulsification or high-pressure homogenization equipment at 800 bar, nano-processing is performed to form NAC nanoparticles with a controlled particle size between 50 and 150 nm.

[0124] The larger particles that were not nanosized were removed by filtration, and the uniformly dispersed NAC nanosuspension was collected;

[0125] Mix vitamin E and lecithin and dissolve them in chloroform, then pour into a round-bottom flask;

[0126] The organic solvent was evaporated using a rotary evaporator at 40 °C to form a uniform film;

[0127] Add appropriate amount of high-purity water to the film to slowly hydrate it, and at the same time, use a slight ultrasonic water bath to fully disperse the film to form uniform liposomes;

[0128] The liposome particle size was adjusted to less than 200 nm by extrusion through a fine-pore extruder;

[0129] S4. Slowly add the ginkgolide B pre-solution into the Rhodiola rosea extract solution and mix thoroughly;

[0130] Add the prepared perfluorooctane nanoemulsion and homogenize by magnetic stirring or low-speed stirring to ensure that all components are fully integrated;

[0131] NAC nanoparticles and vitamin E liposomes were added to the mixed solution respectively, and mechanical stirring or mild ultrasound (to avoid destroying the liposome structure) was continuously used to assist mixing for 10 minutes to uniformly disperse them in the matrix;

[0132] Gradually add hydroxypropyl methylcellulose (HPMC) in the form of an aqueous solution, stirring slowly throughout the process to prevent agglomeration; adjust the viscosity and rheological properties of the mixture to ensure that the drug component can form a sustained and uniform release film in the body; adjust the pH of the composition using citric acid or sodium hydroxide solution to a pH range of 7.2 to 7.4;

[0133] The entire system is homogenized again using a high-pressure homogenizer or ultrasonic treatment to ensure that each nanocomponent is evenly distributed in the entire system, thereby obtaining a pharmaceutical composition of ginkgolide B.

[0134] Example 3:

[0135] Nanocarrier controlled release system and application of reinforcement learning individualized optimization scheme

[0136] 1. Overview of the Experimental Protocol

[0137] Utilizing the Ginkgolide B pharmaceutical composition and Ginkgolide B nano-controlled release method described in Examples 2 and 1 of this protocol, we optimized drug release within nanocarriers and personalized dosing. The goal is to achieve optimal drug concentration in the brain and improve cognitive function through dynamic control of drug release profiles and real-time feedback.

[0138] 2. Parameter determination

[0139] Drug release data collection:

[0140] A microdialysis probe was used to monitor drug concentration in the rat brain in real time, and release rate data were recorded at various time points under a hypoxic environment. The experimental acquisition time window was set from 0 to 12 hours, with a data sampling interval of 0.5 hours.

[0141] Behavioral data collection:

[0142] The water maze test and novel object recognition test were used to measure the latency, search path length and memory retention time of the rats on the 7th day after administration.

[0143] In the water maze, the time it takes for the rat to move from the starting point to the platform was recorded (in seconds);

[0144] In novel object trials, the proportion of exploration time was used as the evaluation parameter.

[0145] Initial parameter settings: Based on the previous model fitting, the initial parameter settings are as follows:

[0146] Release rate model:

[0147] R0=0.8mg / h

[0148] μ=3.0h

[0149] σ=1.0

[0150] The adjustment term η(t) was initially set to a mean of 0 and a standard deviation of 0.05 mg / h based on real-time physiological data;

[0151] Cognitive improvement contribution model:

[0152] a=1.2 (determined by previous inflammation and antioxidant experiments)

[0153] Reference release rate Rref = 0.5 mg / h

[0154] Total treatment cycle T = 12h

[0155] Reinforcement Learning Algorithms:

[0156] Discount factor γ = 0.9

[0157] The initial state vector st contains: the current drug concentration in the brain, behavioral score and hypoxia index, and the initial setting s0 = [0.5mg / L, 60s, 0.8]

[0158] The immediate reward function r(st,at) is designed as:

[0159] r(st,at)=λ1(Δcognitive score / 10)-λ2|ΔCbrain(t)|

[0160] Where λ1=1.0,λ2=0.5

[0161] Multi-objective optimization function:

[0162] Target cognitive improvement Ftarget = 15 (unit: integral quantitative value)

[0163] Optimal brain concentration Copt = 1.0 mg / L

[0164] Trade-off parameters α = 0.8, β = 0.6

[0165] 3. Calculation process and optimization control

[0166] (1) Calculation of nano-controlled release kinetics model

[0167] Calculate the release rate:

[0168]

[0169] At t=3h, the release rate reaches its peak:

[0170] R(3.0)≈0.8+eta(3.0)≈0.8mg / h, where eta(3.0)≈0

[0171] At t = 2h:

[0172] R(t)=0.8exp(-0.5)+0.05≈0.535mg / h

[0173] By fitting microdialysis data, η(t) is dynamically updated to adapt to individual differences, achieving the purpose of real-time feedback correction.

[0174] (2) Calculation of cumulative cognitive improvement contribution function

[0175]

[0176] By integrating at discrete time points (numerical integration), the cumulative contribution value is approximately F≈16.8 (integral unit), which exceeds the target value Ftarget=15, indicating that the potential for cognitive improvement is sufficient.

[0177] (3) Reinforcement learning for individualized dosage control

[0178] Using the Q-learning formula:

[0179]

[0180] After multiple state transition updates, the optimal drug delivery strategy selected by the system is:

[0181] Phase 1 (0-3 hours): Initial dose adjusted to 0.8 mg / h

[0182] Phase 2 (3-6 hours): Gradually increase the dose to 1.0 mg / h based on the behavioral feedback score

[0183] Phase 3 (6-12 hours): Maintain at 1.0 mg / h with fine-tuning to ensure that the brain concentration does not exceed 1.0 mg / L.

[0184] After 20 iterations of the simulation, the optimal solution for the cumulative reward showed that the cognitive test score dropped from the initial 60 seconds to 45 seconds (water maze latency), and the proportion of exploration time in the novel object test increased by about 20%.

[0185] (4) Multi-objective optimization function calculation

[0186] Calculate the overall efficacy objective function:

[0187] F = 16.8, then (Ftarget - F) 2 =(15-16.8) 2 =3.24

[0188] The integrated deviation of brain concentration over the entire cycle:

[0189]

[0190] The final objective function value is:

[0191] J=0.8×3.24+0.6×0.03≈2.592+0.018=2.61

[0192] A lower J value indicates that both efficacy and safety have been optimized.

[0193] 4. Technical effect evaluation

[0194] The release curve is smooth and complies with the predetermined control strategy;

[0195] The cumulative contribution of cognitive improvement exceeded the target value, and behavioral tests showed significant improvement;

[0196] Reinforcement learning algorithms enable real-time personalized control and rapid system response.

[0197] As can be seen from the above, the pharmaceutical composition of the present invention forms a multi-layered protection system through the synergistic effect of ginkgolide B with perfluorooctane emulsion, nano-sized N-acetylcysteine, vitamin E liposomes, and Rhodiola rosea extract. In the hypoxic environment of the plateau, the perfluorooctane emulsion exerts a highly efficient oxygen supply, alleviating local hypoxia; N-acetylcysteine ​​and vitamin E liposomes provide dual antioxidant protection, reducing cell damage caused by oxidative stress; ginkgolide B provides significant neuroprotection and anti-inflammatory effects; and at the same time, Rhodiola rosea extract activates the body's hypoxia adaptation mechanism and improves tolerance. The entire formula is regulated by nano-controlled release technology, and each component can be continuously released and evenly distributed, thus achieving an optimal balance between efficacy and safety, and comprehensively improving the cognitive dysfunction caused by high-altitude hypoxia.

[0198] Example 4:

[0199] Traditional drug administration control group:

[0200] 1. Overview of the Experimental Protocol

[0201] The control group did not use nanocarrier controlled release and reinforcement learning algorithm optimization, but instead used traditional ginkgolide B aqueous solution for oral administration. The dosage was fixed at 0.8 mg / h, and the frequency and dosage of administration were not adjusted according to individual conditions.

[0202] 2. Data acquisition methods and parameter measurement

[0203] Drug release data collection: A microdialysis probe was also used to collect brain drug concentration data. However, due to the solution dosage form, the release rate exhibited a transient peak followed by a rapid decline, lacking continuous control. Recorded data showed an initial release rate of 1.0 mg / h at t = 0.5 hours, but dropped to 0.4 mg / h at t = 3 hours, resulting in an average release rate of less than 0.5 mg / h over 12 hours.

[0204] Behavioral data collection: The water maze and control tests were used in the same manner. On the 7th day after administration, the following data were measured:

[0205] Water maze latency: average 55 seconds;

[0206] The proportion of exploration time in novel object trials increased by approximately 10%.

[0207] Parameter settings:

[0208] Fixed administration rate of 0.8 mg / h, no dynamic regulation;

[0209] There is no real-time algorithm feedback and no dynamic adjustment of the release curve.

[0210] 3. Comparison of calculation process

[0211] (1) Comparison of release rate calculation

[0212] The release rate measured by the traditional drug delivery method at t = 3 hours was approximately 0.4 mg / h, far lower than the peak release rate of 0.8 mg / h for nano-controlled release, and the release curve was discontinuous. The release model in the traditional method could not meet the requirements of continuous drug delivery.

[0213] (2) Calculation of cumulative cognitive improvement contribution

[0214] Using the same model, due to the lower release rate, the integral calculation is:

[0215]

[0216] The average R(t) was about 0.5 mg / h, and the integral result was about 11.2, which was far below the target Ftarget=15 (integral unit), indicating that the effect was insufficient.

[0217] (3) Problems caused by lack of individualized medication

[0218] Because the drug is fixed-dose and lacks dynamic optimization through reinforcement learning, some individuals experience large fluctuations in drug concentration or insufficient efficacy when faced with individual differences (such as metabolic rate and physiological state). Some animals experienced mild adverse reactions (such as transient behavioral inhibition) without immediate feedback or adjustments.

[0219] (4) Multi-objective optimization function calculation

[0220] Assuming that the overall brain concentration in the control group fluctuates greatly, the integral deviation is calculated as:

[0221]

[0222] And F≈11.2, so:

[0223] (Ftarget-F) 2 =(15-11.2) 2 =14.44

[0224] Then the objective function value is:

[0225] J=0.8×14.44+0.6×0.12≈11.552+0.072=11.624

[0226] It is significantly higher than the J value of Example 3 (2.61), reflecting that the overall efficacy and safety are poor.

[0227] 4. Technical effect evaluation

[0228] Discontinuous release curve: Traditional methods have problems with unstable drug delivery and large concentration fluctuations;

[0229] The cognitive improvement effect was insufficient: the average water maze latency in behavioral testing was only reduced by approximately 5 seconds, and the improvement in the control test was small;

[0230] Lack of overall optimization: Lack of real-time data feedback and individualized adjustment cannot fully respond to the complex pathological needs under the high-altitude hypoxic environment.

[0231] The comprehensive comparison data of Example 3 and Example 4 are shown in Table 1

[0232] Table 1

[0233]

[0234]

[0235] As shown above, through detailed comparative data from the two examples, the use of this solution's nano-controlled release of Ginkgolide B and individualized optimization method using reinforcement learning not only significantly improved the drug's targeted controlled release in the brain, but also significantly enhanced cognitive function through real-time feedback regulation and effectively reduced the safety risks associated with dosage fluctuations. The application of data acquisition, calculation processes, and optimization algorithms demonstrates the significant technical advantages and innovations of this solution in the prevention of cognitive dysfunction in high-altitude environments.

[0236] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. An application of Ginkgolide B in the protection of cognitive dysfunction in plateau environment, characterized in that: include: Mixing a pharmaceutical composition containing ginkgolide B with a low-concentration oxygen adaptation regulator to regulate the pharmaceutical composition to obtain an intermediate product with enhanced neuroprotective effect; The intermediate product with enhanced neuroprotective effect is packaged in a nanocarrier and functionalized to achieve brain-targeted controlled release of the drug, thereby obtaining a composite controlled-release drug; The composite controlled-release drug is administered using a dosage optimization method based on reinforcement learning to achieve long-term prevention and improvement of cognitive dysfunction in a plateau environment, thereby obtaining the ultimate cognitive function protection effect.

2. The use of ginkgolide B in the protection of cognitive dysfunction in plateau environment according to claim 1, characterized in that: The composition percentage of the pharmaceutical composition containing Ginkgolide B is: Ginkgolide B 3.0%; Nano perfluorooctane emulsion 0.5%; N-acetylcysteine ​​NAC nanoparticles 0.3%; Vitamin E liposomes 0.2%; Rhodiola rosea high polarity extract 1.0%; Ultrapure conifer resin derivative 0.5%; Hydroxypropyl methylcellulose HPMC 1.0%; Glycerin regulator 25%; The remainder is high-purity water.

3. The use of ginkgolide B in the protection of cognitive dysfunction in plateau environment according to claim 2, characterized in that: The preparation method of the pharmaceutical composition containing ginkgolide B is as follows: S1. Weigh each component according to the above formula requirements, dissolve Ginkgolide B in ethanol to fully dissolve it to obtain a uniform solution; dissolve the Rhodiola rosea high-polarity extract in high-purity water, and mix thoroughly to obtain a Rhodiola rosea extract solution for use. S2. Add perfluorooctane to a pre-weighed amount of solvent, dissolve it together with lecithin, and mix well. Slowly add the oil phase dropwise into the water phase containing high-purity water and a certain proportion of glycerin regulator while stirring; After mixing for 2–3 minutes using a high-speed stirrer, ultrasonic vibration treatment was performed using an ultrasonic emulsifier at 40 kHz for 10 minutes to obtain a uniform emulsion with nanoparticles less than 200 nm in size; The nano-perfluorooctane emulsion after ultrasonic emulsification was added to the pre-filtered coniferous resin derivative solution, and the mixture was gently stirred for 5 minutes to obtain an oxygen carrier nano-system; S3, dissolving NAC in ethanol and adjusting to the target concentration using ultrasound-assisted dissolution technology; Using reverse microemulsification or high-pressure homogenization equipment at 800–1000 bar, nano-processing is performed to form NAC nanoparticles with a controlled particle size of 50–150 nm. The larger particles that were not nanosized were removed by filtration, and the uniformly dispersed NAC nanosuspension was collected; Mix vitamin E and lecithin and dissolve them in chloroform, then pour into a round-bottom flask; The organic solvent was evaporated using a rotary evaporator at 40 °C to form a uniform film; Add appropriate amount of high-purity water to the film to slowly hydrate it, and at the same time, use a slight ultrasonic water bath to fully disperse the film to form uniform liposomes; The liposome particle size was adjusted to less than 200 nm by extrusion through a fine-pore extruder; S4. Slowly add the ginkgolide B pre-solution into the Rhodiola rosea extract solution and mix thoroughly; Add the prepared perfluorooctane nanoemulsion and homogenize by magnetic stirring or low-speed stirring to ensure that all components are fully integrated; NAC nanoparticles and vitamin E liposomes were added to the mixed solution respectively, and mechanical stirring or gentle ultrasound-assisted mixing was continuously used for 5–10 minutes to uniformly disperse them in the matrix. Gradually add hydroxypropyl methylcellulose (HPMC) in the form of an aqueous solution, stirring slowly throughout the process to prevent agglomeration; adjust the viscosity and rheological properties of the mixture to ensure that the drug component can form a sustained and uniform release film in the body; adjust the pH of the composition using citric acid or sodium hydroxide solution to a pH range of 7.2 to 7.4; The entire system is homogenized again using a high-pressure homogenizer or ultrasonic treatment to ensure that each nanocomponent is evenly distributed in the entire system, thereby obtaining a pharmaceutical composition of ginkgolide B.

4. The use of ginkgolide B in the protection of cognitive dysfunction in plateau environment according to claim 1, characterized in that: The release rate for achieving brain-targeted controlled release of the drug is calculated using a nano-controlled release kinetic model, and the expression is: Wherein, R(t): the immediate release rate of ginkgolide B at time t, reflecting the drug release dynamics of the nanocarrier in vivo; R0: peak release rate, indicating the initial capacity of drug release inside the nanocarrier; μ: peak release time, i.e., the time point when drug release reaches its maximum value; σ: time diffusion parameter of the drug release process, reflecting the smoothness of drug release; η(t): Adjustment term, which represents the fine-tuning term after physiological status and real-time data feedback in the actual plateau hypoxic environment.

5. The use of ginkgolide B in the protection of cognitive dysfunction in plateau environment according to claim 1, characterized in that: The cumulative cognitive improvement contribution calculation function expression for the long-term prevention and improvement of cognitive dysfunction in plateau environment is: Among them, F: the entire treatment period T; a: proportionality coefficient, indicating the intensity of the neuroprotective effect of ginkgolide B; R(t): immediate release rate of ginkgolide B at time t; Rref: reference release rate; T: total treatment time.

6. The use of ginkgolide B in the protection of cognitive dysfunction in plateau environment according to claim 1, characterized in that: The formula of the drug dosage optimization method based on reinforcement learning is: Where Q(st,at) is the expected cumulative benefit after taking the medication action at at time t in state st. r(st,at): The immediate reward function, which is designed to balance the improvement of cognitive function (such as improved behavioral test scores) and side effects (such as adverse reactions caused by excessive drug concentrations). γ: Discount factor, used to weigh the importance of current rewards and future rewards, with a value between 0 and 1; st: state vector, including current brain drug concentration, cognitive assessment index, and environmental hypoxia index; at: action or decision, indicating the specific dosage or dosing interval selected at time t; Represents the maximum expected benefit that can be obtained in the next state.

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