Therapeutic formulations, perfusion apparatus and methods for body cavity hyperthermic perfusion therapy based on phase change microcapsule suspensions

Abstract

The application provides a body cavity hyperthermia treatment preparation based on phase change microcapsule suspension, which comprises a hyperthermia base liquid and phase change microcapsules uniformly dispersed in the hyperthermia base liquid, wherein the phase change temperature of the phase change microcapsules is between 42.5 DEG C and 43.5 DEG C, the particle size of the phase change microcapsules is between 50 mu m and 500 mu m, and the hyperthermia base liquid is selected from physiological saline, peritoneal dialysis fluid or Ringer's solution. The application utilizes the characteristics that the microcapsules absorb / release latent heat near the phase change point without changing the temperature of the microcapsules, so that adaptive and uniform heat energy transmission and distribution in the body cavity are realized.

Description

Technical Field

[0001] This invention relates to the fields of biomedical engineering and thermotherapy, specifically to a body cavity hyperthermic perfusion therapy preparation, device, and method based on phase change microcapsule suspension. Background Technology

[0002] Hyperthermic intracavitary perfusion therapy involves circulating heated drug-containing perfusion fluid within a body cavity, utilizing the synergistic effect of 43°C heat energy and chemotherapy drugs to kill cancer cells. Current technology relies primarily on macroscopic convection heat transfer, where the perfusion fluid is heated to a target temperature (e.g., 43°C) and then heat is transferred through fluid circulation.

[0003] CN116731679A discloses an intelligent constant-temperature patch, including a heating patch body composed of iron powder heating material, solid-solid phase change energy storage material, and a heating patch coating layer. This invention regulates the temperature of the heating patch through the heat absorption and release effect of the phase change material near its phase change point, achieving self-temperature control. However, this patent still has issues with optimizing the composition and ratio of the phase change material, affecting the accuracy and controllability of the phase change temperature.

[0004] CN106232064A discloses a heating device including at least one containment space for holding flowable material, wherein the containment space is at least partially formed by a flexible wall that can at least indirectly contact a living organism. The device also includes a latent heat storage unit to ensure that the flowable material is temperature-controlled for at least a certain period of time. This invention uses sodium acetate as a phase change material, absorbing heat and releasing energy in an exothermic state. However, this patent still has issues with optimizing the structure and size of the latent heat storage unit, affecting its energy storage capacity and heat release rate.

[0005] The existing technology system has the following inherent defects: 1) Uneven temperature field. Due to the complex anatomical structure of body cavities and the flow field obstruction caused by internal organs, the fluid distribution is uneven. This leads to significant differences in the actual temperature distribution of tissues, with both overheated and underheated areas coexisting, affecting the therapeutic effect and safety window.

[0006] 2) The dynamic thermal control response is lagging. The thermal inertia of the system is mainly concentrated in the large amount of perfusion fluid itself. Adjusting its overall temperature requires a large energy input and time, making it difficult to make rapid and accurate compensation for dynamic thermal disturbances caused by local changes.

[0007] 3) Effective thermal dose is difficult to control. Clinically, the inlet temperature of the perfusion fluid is usually used as the temperature control target. This is significantly different from the actual thermal dose at the tissue-drug interface in complex cavities, making precise control of thermal dosimetry difficult to achieve. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a body cavity hyperthermic perfusion therapy preparation, device and method based on phase change microcapsule suspension, so as to solve the problem that existing hyperthermic perfusion preparations cannot accurately control temperature.

[0009] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: According to one aspect of the present invention, a intracavitary hyperthermic perfusion therapy formulation based on a phase change microcapsule suspension is provided, comprising a hyperthermic perfusion base solution and phase change microcapsules uniformly dispersed in the hyperthermic perfusion base solution, wherein the phase change temperature of the phase change microcapsules is 42.5℃~43.5℃, the particle size of the phase change microcapsules is between 50μm and 500μm, and the hyperthermic perfusion base solution is selected from physiological saline, peritoneal dialysis fluid, or Ringer's solution; the volume concentration of the phase change microcapsules in the hyperthermic perfusion base solution is 5%~20%.

[0010] Optionally, in the above-mentioned intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension, the core material of the phase change material microcapsule is a phase change material, which is selected from at least one of fatty acid eutectic mixture and distilled paraffin.

[0011] Optionally, in the above-mentioned intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension, the fatty acid eutectic mixture includes lauric acid and myristic acid, wherein the mass ratio of lauric acid to myristic acid is 65:35 to 75:25.

[0012] Optionally, in the above-mentioned intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension, the mass ratio of lauric acid to myristic acid is 66:34.

[0013] Optionally, in the above-mentioned intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension, the distilled paraffin is medical-grade distilled paraffin that meets the standards of the Chinese Pharmacopoeia or USP, with a purity of ≥99%, a carbon chain distribution concentrated in the C21-C23 range, no fluorescent substances, and heavy metal content that meets pharmaceutical standards.

[0014] Optionally, in the above-mentioned intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension, the wall material of the phase change microcapsules is a gelatin-gum arabic system or a polylactic acid-glycolic acid copolymer prepared by solvent evaporation or emulsification-solvent evaporation.

[0015] According to another aspect of the present invention, an infusion device for the above-mentioned intracavitary hyperthermic perfusion therapeutic preparation based on phase change microcapsule suspension is provided, comprising a liquid storage heating unit, a circulation drive unit, and a separation and recovery module, wherein the liquid storage heating unit is connected to the intracavitary inlet of the intracavitary treatment area, the circulation drive unit is disposed on a pipeline between the liquid storage heating unit and the intracavitary treatment area, the intracavitary treatment area is connected to the separation and recovery module, and the separation and recovery module is connected to the liquid storage heating unit to form a complete closed loop.

[0016] Optionally, in the above-mentioned device, the liquid storage heating unit includes a heater, and the circulation drive unit includes a peristaltic pump or a centrifugal pump.

[0017] According to another aspect of the present invention, a control method for the above-mentioned device is provided, comprising the following steps: S1. Preheating the preparation in the liquid storage heating unit to 43°C and adding chemotherapy drugs; S2. Starting the peristaltic pump or centrifugal pump of the circulation drive unit to infuse the preparation into the body cavity treatment area, in which the phase change microcapsule suspension circulates and autonomously controls the temperature, maintaining the temperature at 43°C ± 0.5°C, establishing a closed loop, and maintaining the loop for 60 to 90 minutes; S3. Draining the liquid in the body cavity treatment area and collecting it through a porous drainage tube to the separation and recovery module, recovering the microcapsules, and returning them to the liquid storage heating unit to form a complete closed loop.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: The intracavitary hyperthermic perfusion therapy formulation of the present invention is used for intracavitary hyperthermic perfusion chemotherapy (HIPEC / HITOC) in the peritoneum, pleura, bladder, etc. It is a suspension containing microcapsules with precise phase change temperature. Through its latent heat of solid-liquid phase change, it achieves adaptive and uniform heat transfer and distribution within the body cavity, and has the following advantages: 1) As a core component of innovative functional medical preparations or drug-device combination products, it can be used in conjunction with existing or new hyperthermic perfusion equipment; it can improve the therapeutic effect, ensure that the tissues in the entire targeted body cavity volume are in the most optimized and uniform treatment temperature window, and maximize the synergistic killing effect of thermochemotherapy.

[0019] 2) Enhance treatment safety. By using the isothermal principle of phase change process, the risk of tissue damage caused by local overheating is fundamentally eliminated, and the perfusion flow rate and pressure required to achieve uniform temperature are reduced, which helps to reduce fluid dynamics-related complications such as intra-abdominal hypertension syndrome.

[0020] 3) It simplifies clinical procedures, reduces the extreme requirements on the response speed and accuracy of heating control equipment, and makes the system more robust.

[0021] 4) It has good universality and versatility, and its core thermodynamic principles can be extended to other intracavitary treatment fields that require precise and uniform heating. Attached Figure Description

[0022] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below.

[0023] Figure 1This is a schematic diagram of the infusion device for the intracavitary hyperthermic perfusion therapy preparation based on phase change microcapsule suspension of the present invention. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0025] The intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension of the present invention includes a hyperthermic perfusion base solution and phase change microcapsules uniformly dispersed in the hyperthermic perfusion base solution, wherein the phase change temperature of the phase change microcapsules is 42.5℃~43.5℃, preferably 43℃, the particle size of the phase change microcapsules is between 50μm and 500μm, and the hyperthermic perfusion base solution is selected from physiological saline, peritoneal dialysis fluid or Ringer's solution.

[0026] The working principle of the intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension of the present invention is as follows: During use, the therapy formulation is preheated to a target temperature (e.g., 43°C), then perfused into the body cavity and circulation is established. During circulation: When the phase change microcapsule moves with the fluid to a region where the local temperature is higher than its phase change point (e.g., 43°C), the phase change microcapsule absorbs heat from the environment and undergoes a solid-to-liquid phase change, but the temperature does not change, thus effectively buffering and preventing local overheating.

[0027] When the phase change microcapsules move with the fluid to a region where the local temperature is lower than their phase change point (e.g., 43°C), the phase change microcapsules release latent heat into the environment to generate a liquid-to-solid phase change, acting as a distributed, mobile micro heat source without significant temperature change, actively and directly replenishing heat to the region.

[0028] This endothermic / exothermic process is driven by the physicochemical properties of the phase change microcapsules themselves, without the need for external active intervention. This ensures that the temperature of the hot perfusion base fluid remains unchanged throughout the entire circulation process, precisely stabilizing at the target temperature. As a result, a uniform and stable temperature field is established throughout the entire treatment cavity, and the core temperature is precisely anchored near the phase change temperature point of the phase change microcapsules.

[0029] The core material (i.e., the filling material) of the phase change material microcapsule is selected from phase change materials. Phase change materials have a phase change temperature (melting point) of 42.5℃~43.5℃ and excellent biocompatibility and chemical stability, and can maintain stable performance in repeated phase change cycles.

[0030] Preferably, the phase change material is selected from at least one of fatty acid eutectic mixtures and distilled paraffin.

[0031] A fatty acid eutectic mixture, comprising lauric acid and myristic acid, wherein the mass ratio of lauric acid to myristic acid is 65:35 to 75:25, forms a binary composite phase change material to obtain a stable eutectic with a melting point of 42.5℃ to 43.5℃; preferably, when the mass ratio of lauric acid to myristic acid is 66:34, a stable eutectic with a melting point of 43.0℃ is obtained. The fatty acid eutectic mixture is non-toxic, biodegradable, has a high latent heat value, and is chemically stable.

[0032] The distilled paraffin is a medical-grade distilled paraffin that conforms to the Chinese Pharmacopoeia or USP standards, with a purity of ≥99%, a carbon chain distribution concentrated in the C21-C23 range, no fluorescent substances, and heavy metal content meeting pharmaceutical standards. Using highly purified and precisely fractionated paraffin allows for an extremely narrow melting range, such as 42.5℃~43.5℃, enabling precise temperature control.

[0033] The wall material of phase change microcapsules possesses excellent biocompatibility, exhibiting structural integrity and stable performance under therapeutic temperatures and physiological environments, and providing a reliable seal for the core phase change material. Furthermore, the surface properties of this wall material are tunable, effectively improving the dispersion and suspension stability of the microcapsules in the hot perfusion base solution. The wall material for phase change microcapsules can be a gelatin-gum arabic system prepared using a composite coagulation method; alternatively, polylactic acid-glycolic acid copolymer (PLGA) can be used, prepared via solvent evaporation or emulsification-solvent evaporation methods. Both of these microcapsule preparation processes are existing mature technologies with a foundation for industrial application.

[0034] The phase change microcapsules have a particle size ranging from 50 μm to 500 μm, preferably from 50 μm to 300 μm. This size design ensures that the phase change microcapsule particles are small enough to form a stable suspension in the hyperthermic perfusion base solution and can enter the interstitial micro-gap with the perfusion solution. Furthermore, this size design provides sufficient heat capacity units, with significant latent heat per particle, and also facilitates effective separation from the drainage fluid after treatment via filtration or other methods.

[0035] Regarding formulation concentration, the preferred volume concentration of phase change microcapsules in the thermoperfusion base solution is 5% to 20%. This concentration is crucial for the stable regulation of the perfusion fluid temperature when the phase change microcapsules are infused into the body cavity treatment area. It has been verified that if the concentration is too low, the thermal homogenization effect is insufficient, and the temperature change may exceed the phase transition point, resulting in a significant temperature drop. Therefore, from the perspective of thermal homogenization, a higher volume concentration of phase change microcapsules in the thermoperfusion base solution is better. If the concentration is too high, it may lead to a significant increase in suspension viscosity, affecting perfusion smoothness. Therefore, from the perspective of perfusion smoothness, a lower volume concentration of phase change microcapsules in the thermoperfusion base solution is better. 5% to 20% represents a balance range that ensures both thermal homogenization and perfusion smoothness.

[0036] The intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension of the present invention requires the addition of the required therapeutic drugs to the intracavitary hyperthermic perfusion therapy formulation according to relevant medical experience and clinical protocols, as shown in Table 1. The formulation needs to be prepared in a sterile and pyrogen-free form and can be directly applied in clinical practice.

[0037] Table 1. Formulation of intracavitary hyperthermic perfusion therapy preparations based on phase change microcapsule suspensions like Figure 1 As shown, the infusion device for intracavitary thermal perfusion therapy based on phase change microcapsule suspension includes a liquid storage and heating unit 1, a circulation drive unit 2, a separation and recovery module 4, and pipelines. The liquid storage and heating unit 1 is connected to the intracavitary infusion port of the intracavitary treatment area 3 through pipelines. The circulation drive unit 2 is located on the pipeline between the liquid storage and heating unit 1 and the intracavitary treatment area 3. The intracavitary treatment area 3 is connected to the separation and recovery module 4 through a porous drainage tube. The separation and recovery module 4 is connected to the liquid storage and heating unit 1 to form a complete closed loop.

[0038] The liquid storage heating unit 1 is used to contain and heat the preparation to a target temperature; the liquid storage heating unit 1 includes a heater for stabilizing the intracavitary hyperthermic perfusion therapy preparation at a preset base set temperature.

[0039] The circulation drive unit 2 is used to drive the formulation to circulate within the closed loop of the entire infusion device. The circulation drive unit uses a peristaltic pump or centrifugal pump with low shear force to avoid damaging the structural integrity of the microcapsules during pumping.

[0040] The tubing includes an infusion tube for introducing the preparation into the body cavity treatment area 3 and a porous drainage tube for leading out the preparation; Separation and recovery module 4 is used for material reflux, filtration, or recovery functions. Separation and recovery module 4 includes a terminal filter for separating and recovering microcapsules from the drainage fluid at the end of or during the treatment cycle, enabling potential heavy use or safe disposal. Preferably, the terminal filter is located downstream of the porous drainage tube, on the reflux or drain line, and more preferably in the terminal recovery branch connected after treatment. The pore size of the terminal filter is smaller than the minimum microcapsule particle size.

[0041] The infusion device for intracavitary hyperthermic perfusion therapy based on phase change microcapsule suspension of this invention utilizes the endothermic / exothermic process of the microcapsules, requiring no external active intervention. This achieves minimal temperature change in the base fluid throughout the entire circulation process, precisely stabilizing it at the target temperature. This establishes a uniform and stable temperature field within the entire treatment cavity, accurately anchoring the core temperature at the phase change temperature point of the phase change microcapsules. Compared to traditional technologies that control and adjust the perfusion fluid temperature through temperature feedback, the infusion device for intracavitary hyperthermic perfusion therapy of this application adjusts the temperature within the body cavity, rather than through a liquid storage heating unit. This allows for timely temperature compensation during heat exchange, resulting in a faster response than traditional technologies. Therefore, the system eliminates the need for a temperature monitoring unit, simplifying the system.

[0042] The control method of the above-mentioned perfusion equipment includes the following steps, namely, the hot perfusion operation process is as follows: S1. Preheat the preparation to 43℃ in the storage heating unit and add chemotherapy drugs; S2. Start the peristaltic pump or centrifugal pump of the circulation drive unit to infuse the preparation into the body cavity treatment area at a flow rate of 200-400mL / min. In the body cavity treatment area, the phase change microcapsule suspension circulates and controls the temperature autonomously, maintaining the temperature at 43℃±0.5℃, establishing a closed loop, and maintaining the loop for 60-90 minutes to complete the treatment. During the loop, the latent heat of phase change of the phase change microcapsules is used to homogenize and stabilize the temperature in the body cavity near the phase change temperature; S3. Stop the pump, drain the liquid in the body cavity treatment area, collect it through a porous drainage tube and send it to the separation and recovery module, recover the microcapsules through the filter, complete the treatment process, and finally return it to the storage heating unit. It should be noted that during the normal treatment cycle, the phase change microcapsules should circulate together with the formulation and should not be filtered or separated; the separation and recovery module should function during the emptying / recovery phase after treatment, or be in a bypass / non-separation state during the circulation phase.

[0043] Preferably, after treatment, the procedure further includes the step of drawing the liquid containing the phase change microcapsules out of the body cavity and performing solid-liquid separation to recover the phase change microcapsules. The separated microcapsules enter a recovery container, are processed, and then returned to the liquid storage and heating unit.

[0044] This invention fundamentally changes the heat transfer mode within the body cavity. By leveraging the characteristic that phase change materials do not experience temperature changes during heat absorption or release at the phase change point, it transforms macroscopic convection heating, which relies on the overall thermal fluid, into adaptive heating based on the latent heat of phase change.

[0045] The above embodiments are merely specific implementations of the present invention, used to illustrate the technical solutions of the present invention, and are not intended to limit it. The scope of protection of the present invention is not limited thereto. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that any person skilled in the art can still modify or improve the technical solutions described in the foregoing embodiments, or make equivalent substitutions for some of the technical features, within the scope of the technology disclosed in the present invention; and these modifications, changes, or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention, and should all be covered within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A body cavity hyperthermic perfusion therapy formulation based on phase change microcapsule suspension, characterized in that, The product comprises a hyperthermic perfusion base fluid and phase change microcapsules uniformly dispersed in the hyperthermic perfusion base fluid. The phase change temperature of the phase change microcapsules is 42.5℃~43.5℃, the particle size of the phase change microcapsules is between 50μm and 500μm, and the hyperthermic perfusion base fluid is selected from physiological saline, peritoneal dialysis fluid, or Ringer's solution. The volume concentration of the phase change microcapsules in the hyperthermic perfusion base fluid is 5%~20%.

2. The intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension according to claim 1, characterized in that, The core material of the phase change material microcapsule is a phase change material, which is selected from at least one of fatty acid eutectic mixture and distilled paraffin.

3. The intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension according to claim 2, characterized in that, The fatty acid eutectic mixture includes lauric acid and myristic acid, wherein the mass ratio of lauric acid to myristic acid is 65:35 to 75:

25.

4. The intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension according to claim 3, characterized in that, The mass ratio of lauric acid to myristic acid is 66:

34.

5. The intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension according to claim 2, characterized in that, The distilled paraffin is a medical-grade distilled paraffin that conforms to the Chinese Pharmacopoeia or USP standards, with a purity of ≥99%, a carbon chain distribution concentrated in the C21-C23 range, no fluorescent substances, and heavy metal content that meets pharmaceutical standards.

6. The intracavitary hyperthermic perfusion therapy formulation based on phase change microcapsule suspension according to claim 1, characterized in that, The wall material of the phase change microcapsules is a gelatin-gum arabic system or a polylactic acid-glycolic acid copolymer prepared by solvent evaporation or emulsification-solvent evaporation.

7. The infusion device for a body cavity hyperthermic perfusion therapeutic agent based on phase change microcapsule suspension according to any one of claims 1 to 6, characterized in that, The device includes a liquid storage and heating unit, a circulation drive unit, and a separation and recovery module. The liquid storage and heating unit is connected to the body cavity infusion port of the body cavity treatment area via a pipeline. The circulation drive unit is located on the pipeline between the liquid storage and heating unit and the body cavity treatment area. The body cavity treatment area is connected to the separation and recovery module via a pipeline. The separation and recovery module is connected to the liquid storage and heating unit, thereby forming a closed circulation loop.

8. The injection device according to claim 7, characterized in that, The liquid storage heating unit includes a heater, and the circulation drive unit includes a peristaltic pump or a centrifugal pump.

9. A control method for an infusion device of a body cavity hyperthermic perfusion therapy preparation based on phase change microcapsule suspension as described in claim 7, characterized in that, Includes the following steps: S1. Preheat the preparation in the liquid storage heating unit to 43°C and add chemotherapy drugs; S2. Start the peristaltic pump or centrifugal pump of the circulation drive unit to infuse the preparation into the body cavity treatment area; in the body cavity treatment area, the phase change microcapsule suspension circulates and autonomously controls the temperature to maintain the temperature at 43℃±0.5℃; S3. The fluid in the body cavity treatment area is drained and collected through a porous drainage tube to the separation and recovery module, where the microcapsules are recovered and returned to the liquid storage and heating unit to form a closed loop.

Images