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CN-121983348-A - Transdermal drug delivery preparation rheology parameter self-adaptive regulation and control method and system based on biofeedback signals

CN121983348ACN 121983348 ACN121983348 ACN 121983348ACN-121983348-A

Abstract

The invention discloses a transdermal drug delivery preparation rheology parameter self-adaptive regulation and control method and system based on biofeedback signals. The method comprises the steps of acquiring radial artery pressure waveforms, calculating target pH, viscosity and surface tension by using a deep neural network model, and controlling the precise proportion of four types of functional media of A/B/C/D in a closed loop mode. The system introduces on-line viscosity/pH monitoring and feedback correction, ensures that the permeation characteristic of the preparation is highly matched with the physiological state of an individual (CV is less than or equal to 12 percent), and solves the industrial problem of large individual difference of the bioavailability of the traditional transdermal administration preparation.

Inventors

  • LI ZHEN
  • WU BAICHAO
  • LI CHENGJUN

Assignees

  • 李臻

Dates

Publication Date
20260505
Application Date
20260125

Claims (8)

  1. 1. A method for adaptively regulating and controlling rheological parameters of a transdermal drug delivery preparation based on biofeedback signals, which is characterized by comprising the following steps: S1, data acquisition and feature extraction, namely acquiring hemodynamic pressure waveform data of a tested object through a digital radial artery pressure sensor at a sampling frequency of more than or equal to 500Hz, and extracting waveform feature parameters at least comprising a main frequency, an amplitude variation coefficient and a waveform tension index by adopting fast Fourier transformation; S2, parameter mapping and modeling, namely inputting the characteristic parameters into a preset 'biological signal-preparation physical property' deep neural network mapping model trained by not less than 5000 cases of clinical data, and calculating physical and chemical control indexes of a target preparation, wherein the indexes at least comprise a target pH value, a target viscosity coefficient and a target surface tension; S3, generating a deployment instruction, namely generating a flow velocity instruction of the medium distribution unit and a shear rate instruction of the stirring unit by a central control unit through a proportional-integral-derivative closed-loop control algorithm according to the target index; s4, dynamically adjusting and mixing, namely mixing the A/B/C/D functional liquid media and the standardized solid matrix by an executing mechanism according to instructions at a constant temperature of 37+/-0.5 ℃; S5, closed loop feedback correction, namely monitoring the rheological state of the mixture in real time through an online viscometer or an online pH meter in the mixing process, and if the deviation between the detection value and the target index exceeds a preset threshold value +/-5%, automatically fine-adjusting the medium addition amount or stirring time by the system until the preparation parameter converges to the target range and the variation coefficient CV value is less than or equal to 12%.
  2. 2. The method of claim 1, wherein the logic of the "bio-signal-property" multidimensional mapping model is constructed as: when the main frequency of the pressure waveform is less than 0.8Hz and the amplitude variation coefficient is less than 0.3, the model outputs instructions for reducing the pH value of the preparation to 3.5-4.0 and increasing alcohol-soluble components, and the transdermal penetration resistance is reduced by 30-50% by utilizing the stratum corneum lipid disturbance effect of acidic environment or ethanol.
  3. 3. The method according to claim 1, wherein the functional liquid medium used in step S4 is physically and chemically encoded as: A class A medium (acid electrolyte regulating solution) which is an acetic acid-sodium acetate buffer system with pH of 3.0-4.5 and is used for regulating the pH value of the microenvironment of the preparation; class B medium (alcohol permeation promoting carrier) is alcohol-water cosolvent system with ethanol volume fraction of 40-70%, and is used for regulating polarity and solubility of the preparation; Class C medium (vanillamide receptor agonist solution) an active solution containing 6-gingerol or 8-gingerol at a standardized concentration of 0.5-2.0% for activating cutaneous TRPV1 thermo-sensitive receptors; And D-type medium (polysaccharide thixotropic matrix) which is sodium hyaluronate or supersaturated chitosan solution with mass fraction of 15-25% and is used for regulating the adhesiveness and slow-release rate of preparation.
  4. 4. The method according to claim 1, wherein the preset threshold value in the step S5 is set based on a deviation range of + -5% determined based on an orthogonal experimental design, which ensures a level of cumulative permeability coefficient (CV value) of 12% or less, superior to the CV >40% of the prior art, in the final in vitro transdermal test.
  5. 5. The method of claim 1, wherein the final pharmaceutical composition is characterized by a 24 hour cumulative permeation increase of greater than or equal to 200% relative to control and a CV value between batches of greater than or equal to 12% in a Franz diffusion cell in vitro transdermal test.
  6. 6. An intelligent manufacturing system that implements the method of any of claims 1-5, comprising: the biological signal acquisition terminal comprises a medical-grade piezoelectric film pulse sensor and a 24-bit ADC analog-to-digital conversion module, and the sampling precision is more than or equal to 0.1kPa; The edge calculation control center is internally provided with a mapping model database and a self-adaptive PID closed-loop control algorithm module which are clinically verified, and the response time is less than or equal to 200ms; The precise fluid workstation comprises 4 independent temperature control liquid storage tanks, a microscale sample pump and a homogenizing mixer; The online quality inspection module is arranged in the physical and chemical parameter probe in the stirring container; And the man-machine interaction interface displays real-time waveform characteristics, target parameter curves and preparation quality judgment results.
  7. 7. The system of claim 6, wherein the mapping model database of the edge computing control center is updated monthly by the cloud server, the updated content comprises newly added clinical case data and corresponding optimal formulation parameter combinations, and the model iteration period is no more than 30 days.
  8. 8. The system of claim 6, wherein the homogenizing mixer of the precise fluid workstation is provided with a micro-fluidic chip mixing unit, so that laminar flow ordered mixing of four types of media of A/B/C/D under the micron scale can be realized, and the mixing efficiency is improved by more than 40%.

Description

Transdermal drug delivery preparation rheology parameter self-adaptive regulation and control method and system based on biofeedback signals Technical Field The invention belongs to the field of intelligent pharmaceutical technology and biomedical engineering, and particularly relates to a manufacturing method and a manufacturing system for adaptively regulating and controlling rheological parameters of a transdermal drug delivery preparation based on individual biofeedback signals, which are particularly suitable for precise and standardized production of the individual transdermal drug delivery preparation. Background The existing percutaneous administration preparations are produced in batches by adopting fixed formulas, and the fundamental defect is to ignore the dynamic difference of individual physiological states. Clinical researches show that the skin barrier strength obviously fluctuates along with the autonomic nerve tension, the compactness of the stratum corneum is improved by 30-50% when the sympathetic nerve is excited, and the drug permeation resistance is obviously increased. This individual variability results in bioavailability Coefficient of Variation (CV) of commercial transdermal formulations often exceeding 40%, severely affecting the reproducibility of the therapeutic effect. The existing personalized blending technology relies on manual experience of pharmacists to blend, and has three pain points, namely low ① precision (pH adjustment error + -0.5 unit), large difference among ② batches (viscosity CV > 25%), and ③ failure to realize industrialized continuous production. These problems are not overcome in the related technology (application number 2026100810177, a meridian-returning medicine acupoint application device with body surface positioning marks and personalized loading method), although the device realizes the spatial correspondence between medicine and body surface positioning points, the medium formula is fixed, and the device cannot adapt to the real-time physiological state difference of patients with different physique. The core research and development motivation of the invention is to fill the conversion gap between individual physiological state difference and industrial automation control parameters, and realize the industrialized production of one person by directly regulating and controlling the microscopic physical property of the preparation through a biofeedback signal. Disclosure of Invention The invention is characterized in that a digital twin system of 'biological signal perception-preparation parameter calculation-medium closed loop allocation' is constructed, and all technical characteristics are structurally or flowsheet embodied in the attached drawings. The invention aims to provide a transdermal drug delivery preparation rheology parameter self-adaptive regulation and control method and system based on biofeedback signals. The accurate proportioning and on-line correction of four types of functional media are realized by collecting radial artery pressure waveforms in real time and utilizing a deep neural network mapping model and PID closed-loop control, so that the physicochemical parameters of the preparation are highly matched with the physiological states of individuals, and finally, the inter-individual variation coefficient of the in-vitro transdermal penetration is controlled within 12%. The specific composition of the A/B/C/D type functional liquid medium is shown in claim 3, the classification system is constructed based on the mapping relation between the physicochemical properties of the medium and the pulse condition signals, wherein the A type is an acidic regulating liquid, the B type is an alcohol permeation promoting carrier, the C type is a receptor agonist solution, the D type is a thixotropic matrix, and the four types of mediums act synergistically as a basic allocation unit in the step S4. The method has the technical effects that subjective judgment such as 'floating/sinking weak' based on self-adaptive logic of peripheral hemodynamic characteristics is converted into quantifiable pH, viscosity and surface tension control indexes, and the industrial problems of poor precision and large batch-to-batch difference of traditional manual blending are solved. When the preparation is applied to a body surface locating point applying device, triple accurate matching of dosage form, body surface locating point and physique can be realized, so that the bioavailability is improved by 2-3 times. The invention realizes the cross-scale multi-parameter coupling regulation and control for the first time aiming at single steady-state physical quantity (such as constant temperature) by the traditional PID control, and needs to synchronously coordinate pH (chemical quantity), viscosity (rheological quantity) and surface tension (interfacial physical quantity), and the input end is an unsteady-state waveform signal. Dynamic balance of microscopic p