Biological device for simulating absorption, distribution, metabolism and excretion of medicine in human body
By designing a multi-organ simulation device, the problems of poor predictability and high cost in drug development in the prior art are solved, and dynamic integration of full-process pharmacokinetics and personalized drug use simulation are achieved, which improves predictability and reduces costs.
Patent Information
- Application Number
- CN202510750765.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-06
- Publication Date
- 2025-08-12
AI Technical Summary
In the existing drug development, animal experiments and two-dimensional cell models have poor predictability across species, high cost, long cycles, and lack the ability to simulate the entire process of multiple organs.
A biological device consisting of an absorption chamber, a metabolic chamber, a distribution chamber, an excretion chamber and a circulation chamber was designed. Combined with temperature control and electronic control systems, it simulates the absorption, distribution, metabolism and excretion process of human drugs, and uses human-related biological materials and intelligent control to realize dynamic simulation of the entire process of multiple organs.
It realizes dynamic integration of full-process pharmacokinetics, improves predictability, reduces costs, and supports personalized drug use simulation.
Smart Images
Figure CN120468384A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of drug metabolism dynamics simulation, and in particular to a biological device for simulating the absorption, distribution, metabolism and excretion of drugs in the human body. Background Art
[0002] Traditional drug development relies on animal experiments and two-dimensional cell models, which have problems such as poor cross-species predictability, high costs, and long cycles. In recent years, the combination of organ chips, organoids, and artificial intelligence technologies has promoted the innovation of in vitro pharmacokinetic models. However, existing systems mostly focus on a single organ or part of the metabolic process, and lack the ability to dynamically simulate the entire process of multiple organs. The present invention fills this technological gap by integrating multi-organ modules, bionic circulatory systems, and intelligent control. Summary of the Invention
[0003] 1. Overall structure of the device The device consists of five parts: absorption chamber, metabolism chamber, distribution chamber, excretion chamber and circulation chamber. It realizes the dynamic transport of drugs through fluid connection and semipermeable membrane separation. Figure 1 The temperature control system maintains a constant temperature of 37°C, and the electronic control system coordinates the liquid flow rate and peristaltic pump action to simulate the human physiological environment; 2. Functional module design (1) Absorption chamber Simulated gastric chamber: contains artificial gastric acid (pH 1.5-3.5) and pepsin, with two outlets: Path 1: Connect to the simulated intestinal chamber via an adjustable flow rate switch (flow rate 0.5-5 mL / min, simulating gastric emptying rate); Path 2: Direct connection to the metabolic chamber (simulating direct drug absorption in the stomach); Simulated intestinal chamber: The core is a porous polyester columnar scaffold (pore size 5-20 μm), covered with a porcine intestinal mucosa layer and filled with a semi-solid matrix (containing a phospholipid / bile salt mixture); The peristaltic pump drives the intestinal cavity to contract (frequency 3-12 times / minute) to simulate intestinal peristalsis; The outer liquid chamber is connected to the metabolic chamber to simulate the enterohepatic circulation; (2) Metabolic chamber Structure: 96-well plate-based metabolic chamber array, each chamber loaded with human liver microsomes or S9 enzyme, separated from the main chamber by a semipermeable membrane (molecular weight cutoff 10 kDa); Dynamic metabolism: drugs diffuse into the metabolic chamber, and metabolites diffuse back into the main chamber; Multi-entry design: Entrance 1: receiving gastric drugs; Entrance 2: receiving intestinal drugs; Entrance 3: Receives drugs refluxed from the circulation chamber (simulating systemic metabolism); (3) Distribution room Multi-cavity structure: contains simulated cavities of organs such as brain, fat, and muscle, each separated by a semipermeable membrane; Tissue homogenate: One side of the cavity is filled with animal tissue homogenate (e.g. brain tissue homogenate containing lipid content > 60%) to simulate drug tissue distribution; Dynamic balance: drugs in the central cavity enter the cavities of various organs by diffusion, and the outlet is connected to the circulation chamber; (4) Excretion chamber Bile excretion cavity: It has a double-layer structure, with the inner layer containing ox bile (pH 8.0-8.5) and the outer layer connected to the circulation chamber via a semipermeable membrane; The drug enters the bile via active transport, simulating enterohepatic circulation; Renal excretory cavity: Aqueous phase flow rate 0.1-2 mL / min (simulating glomerular filtration rate); The semipermeable membrane retains large molecule drugs, while small molecule metabolites are discharged with the water flow; (5) Circulation room Plasma circulation: filled with human plasma (containing 40 g / L albumin) and driven by a peristaltic pump (flow rate 5-20 mL / min); Multi-directional connection: forms a closed loop with the metabolism chamber, distribution chamber, and excretion chamber to simulate systemic circulation and enterohepatic circulation; 3. Control system Temperature control module: PID temperature control chip, accuracy ±0.5℃; Electronic control module: PLC controls peristaltic pump and valve opening and closing (response time <50 ms); Real-time monitoring of pH, dissolved oxygen, and pressure parameters; Compared with the prior art, the present invention has the following beneficial effects: 1. Full-process simulation: For the first time, dynamic integration of the entire ADME process is achieved, breaking through the limitations of a single organ chip; 2. Optimized human relevance: Using primary hepatocytes, human plasma and other biological materials, the predictive power is significantly improved compared to animal models; 3. Intelligent regulation: Microfluidics + AI algorithms adjust flow rate / metabolic conditions in real time to support personalized medication simulation (such as liver and kidney dysfunction models); The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS
[0004] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.
[0005] Figure 1 It is a combination diagram of different functional modules of the entire device. DETAILED DESCRIPTION
[0006] Example 1: Drug absorption and first-pass metabolism simulation (1) Drug administration: Midazolam (10 mg) was administered into the simulated gastric chamber, and the pH of artificial gastric acid was set to 2.0; (2) Gastric emptying control: The adjustable flow rate switch delivers the unabsorbed drug to the simulated intestinal chamber at a rate of 1 mL / min, and the remaining 20% directly enters the metabolic chamber; (3) Intestinal absorption: The frequency of simulated intestinal peristalsis was set at 8 times / min, the semi-solid matrix contained 5% bile salt, and the permeability coefficient of the pig intestinal mucosa was 1×10 -4 cm / s; (4) Hepatic metabolism: CYP3A4 human liver microsomes (activity unit ≥ 20 pmol / mg) are added to the metabolic chamber. The drug diffuses into the chamber through the semipermeable membrane, and the metabolite (1-hydroxymidazolam) diffuses back into the main chamber. (5) Circulation and distribution: The plasma flow rate in the circulation chamber is 15 mL / min. When the drug is distributed through the ventricular and cerebral cavity, the lipid adsorption rate reaches 85%; (6) Excretion monitoring: renal excretion cavity water flow rate 0.5 mL / min, clearance rate 92% within 24 hours; (7) Data analysis: LC-MS / MS was used to detect the drug concentration in each cavity, and the calculated AUC was 1200 ng·h / mL, Cmax was 150 ng / mL, and Tmax was 2 hours.
[0007] Example 2: Special Population Simulation (Hepatic Insufficiency) (1) Adjust the metabolic compartment liver microsomal activity to 5 pmol / mg (simulating CYP3A4 inhibition); (2) Results: The metabolic rate of midazolam decreased by 60%, the AUC increased to 3200 ng·h / mL, and the Cmax increased to 280 ng / mL, verifying that the device can be customized to simulate pathological conditions.
[0008] Example 3: Effect of food on drug intestinal absorption (1) Use the intestinal chamber module independently, close the entrance to the gastric chamber, and close the intestinal chamber to the metabolic chamber; (2) Rabeprazole enteric-coated capsules and pulverized food were added to the intestinal compartment; another experiment without pulverized food was used as a control; (3) Sampling was performed on the food side of the intestinal compartment and the other side of the cavity at different time points from 0 to 8 hours; (4) LC-MS / MS was used to detect sample concentrations and statistically analyze the drug release curves with and without food, evaluating the effect of food on drug release and absorption. The results showed that food delayed the release rate of the drug, and the absorption rate and absorption extent AUC were similar.
[0009] It should be understood by those skilled in the art that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention (including the claims) is limited to these examples. Within the scope of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.
[0010] The present invention is intended to cover all such substitutions, modifications and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A biological device that simulates the absorption, distribution, metabolism and excretion of drugs in the human body, characterized by: (1) Absorption chamber, consisting of a simulated stomach chamber and a simulated intestinal chamber; wherein: The simulated stomach chamber contains artificial gastric acid and pepsin and has two outlets: the first outlet is connected to the simulated intestinal chamber via an adjustable flow rate switch, and the second outlet is directly connected to the metabolic chamber; The simulated intestinal chamber is composed of a porous polyester columnar scaffold, covered with a pig intestinal mucosa layer, and the inner cavity is filled with a semi-solid matrix containing phospholipids / bile salts, and is driven by a peristaltic pump; (2) Metabolic chamber, including: The main chamber and the built-in 96-well plate-type metabolic chamber array, each chamber is loaded with human liver microsomes or S9 enzymes and separated from the main chamber by a semipermeable membrane (molecular weight cut-off 10 kDa); The three inlets are connected to the simulated stomach chamber, simulated intestinal chamber and circulation chamber respectively, and the two outlets are connected to the excretion chamber and circulation chamber respectively; (3) Distribution chamber, which contains multiple simulated organ cavities, each separated by a semipermeable membrane, and one side is filled with animal tissue homogenate (e.g., brain tissue homogenate containing lipids > 60%); (4) Excretion chamber, including bile excretion cavity and renal excretion cavity: The bile excretion cavity is composed of an inner cavity containing animal bile and an outer cavity connected to a circulation chamber, separated by a semipermeable membrane in the middle; The kidney excretion cavity is connected to the circulation chamber through a semipermeable membrane and is provided with a controllable water flow channel; (5) Circulation chamber, filled with human plasma (albumin concentration 40 g / L), driven by a peristaltic pump and connected to the metabolism chamber, distribution chamber, and excretion chamber through pipes; (6) Temperature control system, maintaining the device at a constant temperature of 37°C; (7) Electronic control system, integrated PLC module to control flow rate, peristaltic pump and sensor parameters (pH, dissolved oxygen, pressure).
2. The device according to claim 1, characterized in that: The peristaltic pump control parameters of the simulated intestinal chamber include contraction amplitude and waveform (sine wave or step wave).
3. The device according to claim 1, characterized in that: The semipermeable membrane of the metabolic chamber is made of polyethersulfone or polycarbonate.
4. The device according to claim 1, characterized in that: The simulated organ cavities of the distribution chamber include brain, fat, and muscle cavities, wherein the semipermeable membrane of the brain cavity has a molecular weight cutoff of 500 Da to simulate the blood-brain barrier.
5. The device according to claim 1, characterized in that: The temperature control system adopts PID algorithm and adjusts the power of the heating module through real-time feedback from thermocouple sensors.
6. The device according to claim 1, characterized in that: Each functional chamber can be connected or isolated through valve control to simulate some pharmacokinetic characteristics separately.
7. The device according to claim 1, characterized in that: Each functional chamber has a sample addition and sampling port for drug administration and sampling. The changes of drugs in a certain functional chamber can be studied separately.
8. The device according to claim 1, characterized in that: A pH buffer zone is set between the gastric chamber and the intestinal chamber, and between the gastric chamber and the metabolic chamber, and is filled with a pH 7.4 buffer solution to prevent the liquid in the gastric chamber from affecting the pH of other functional chambers.