A natural microcapsule time-release system with body temperature and pressure dual response and a preparation process thereof

Abstract

This invention discloses a time-controlled release system and preparation process of natural microcapsules with dual responses to body temperature and pressure, belonging to the fields of natural intelligent controlled-release materials and menstrual mucosal repair technology. This invention uses Hainan Li medicine compounded with mucosal repair liposomes as the core material and type A gelatin and gum arabic as natural shell materials, combined with transglutaminase site-directed biocrosslinking technology, to construct core-shell structured microcapsules with precise temperature and pressure dual responses, accurately locking the sustained-release range of 36.0–37.5℃ and the burst release threshold of 0.8N ± 0.1N pressure. This invention limits the average particle size of the microcapsules to 200–400 nm, the core material encapsulation rate to ≥82%, and the drug loading to ≥18%; under the extreme conditions of 38℃ simulating menstrual blood, the cumulative release rate remains stable at 75% ± 5% over 8 hours, preserving the liposome nanostructure and bioactivity throughout the process.

Description

Technical Field

[0001] This invention belongs to the technical fields of natural intelligent response controlled-release materials, female menstrual mucosal repair, and wearable hygiene product functional materials. Specifically, it relates to a temperature and pressure dual-response microcapsule system that is adapted to the dynamic physiological conditions of the human menstrual period, is all-natural and non-allergenic, and can achieve precise time-sequential drug release, as well as its low-temperature green preparation process. This invention addresses the technological gaps in that natural liposome repair materials cannot adapt to the dynamic usage conditions of wearable feminine care products and lack an intelligent on-demand drug release mechanism. It constructs an all-natural, highly stable, and quantitatively controllable time-series intelligent controlled release system, which can be applied to the industrialization of high-end feminine care products, the confirmation of high-value patents, and the PCT international layout. Background Technology

[0002] During menstruation, the vaginal mucosa of women is subjected to a complex and extreme environment of being flushed by menstrual blood, experiencing dynamic fluctuations in pH levels, friction from clothing, and the accumulation of localized high temperatures. This results in a fragile mucosal barrier and a high incidence of micro-injuries. Traditional static, uniform drug release repair methods cannot match the dynamic physiological state of the human body, which alternates between rest and activity, and therefore lack targeted and timely repair. The existing Hainan Li medicine compound liposome repair system relies on the compound active system of authentic Li medicines such as Malus halliana and Callicarpa nudiflora, combined with the flexible lipid membrane modification of virgin coconut oil and the dual natural polymer mucosal anchoring technology, to achieve high penetration, high retention and high physiological stability of active ingredients, providing a high-quality nano-active carrier for deep mucosal repair during menstruation. Conventional microcapsule controlled-release technology cannot meet the operational application requirements of this drug's liposome system, exhibiting several inherent technical defects: First, the response mechanism is singular, possessing only a single-dimensional response capability based on temperature or pressure, unable to recognize dynamic signals under dual operational conditions during menstruation, resulting in low matching degree between drug release timing and physiological repair needs; Second, the material system has poor compatibility, with existing dual-response microcapsules mostly employing synthetic polymers and chemical cross-linking agents, posing risks of mucosal sensitization and chemical residues, failing to meet natural medical-grade safety standards; Third, the preparation process is highly destructive, with conventional high-temperature processes and chemical cross-linking processes irreversibly damaging the liposome nanostructure and surface anchoring system, causing active ingredient failure and loss of repair function; Fourth, the drug release precision is uncontrollable, with traditional microcapsules lacking quantitative threshold locking capabilities, exhibiting poor batch stability and disordered drug release behavior, failing to achieve standardized, time-sequential, and precise repair. According to the search, the existing publicly available technology system cannot simultaneously meet the complete set of technical requirements for construction of all-natural materials, non-destructive encapsulation of liposomes in active state, precise temperature and pressure threshold response, time-series gradient drug release, and long-term stability under extreme physiological conditions, indicating that there is clear room for technical improvement. Summary of the Invention

[0003] Purpose of the invention This invention addresses the shortcomings of existing controlled-release technologies, such as low response precision, easy degradation of liposome activity, disordered drug release, poor adaptability to operating conditions, and insufficient safety levels. It provides a time-sequential controlled-release system and preparation process for natural microcapsules that respond to both body temperature and pressure. Through an all-natural material system, site-directed biocrosslinking technology, and low-temperature active preparation process, it achieves breakthroughs in preserving the integrity of liposome activity, quantifiable and controllable controlled-release parameters, precise adaptation to physiological conditions, and intelligent time-sequential drug release. This results in a mass-producible, verifiable, and highly stable natural intelligent repair controlled-release technology system. Core Original Technology Highlights 1. Natural system-specific adaptation, zero loss of liposome activity encapsulation: This invention is designed with the structural and activity characteristics of compound liposomes of Li medicine in mind, and a dedicated all-natural encapsulation and controlled-release system is matched and designed. The process is adapted to the nanostructure and surface anchoring characteristics of liposomes throughout, which solves the technical problems of traditional encapsulation processes that easily damage the structure of liposomes and lose the activity. 2. All-natural dual-threshold precise control, excellent batch consistency: Abandoning synthetic response materials and chemical cross-linking systems, it adopts a natural composite shell material of medical-grade type A gelatin and gum arabic, combined with transglutaminase site-directed biological cross-linking technology, to precisely lock the temperature-sensitive sustained-release range of 36.0~37.5℃ and the standardized pressure burst release threshold of 0.8N±0.1N suitable for the human private parts. The parameters are quantifiable and controllable, effectively solving the defects of traditional microcapsules such as wide response range, disordered triggering and large batch differences. 3. Unique time-sequential drug release logic with strong adaptability to dynamic working conditions: Breaking through the technical limitations of traditional uniform drug release and disordered burst release, it establishes a dual-mode time-sequential drug release mechanism of "body temperature slow release for stabilization and pressure trigger for enhanced repair", which accurately matches the dynamic alternation of working conditions during menstruation, such as rest and rest, and activity and friction, to achieve time-segmented and differentiated on-demand repair, filling the technical gap of time-sequential precise release control in wearable feminine care products. 4. Long-term stability under extreme working conditions and high industrial adaptability: The microcapsule system of this invention can work stably for 8 hours under the extreme and complex environment of simulated menstrual blood, preserving the liposome nanostructure, anchoring characteristics and bioactivity throughout the process, forming a synergistic effect of surface time-series stabilization and deep nano-penetration repair. The technical effect is repeatable, verifiable and can be mass-produced on a large scale. Core technology solutions A time-controlled release system of natural microcapsules that responds to both body temperature and pressure has an overall core-shell structure. It uses standardized Hainan Li medicine compound mucosal repair liposomes as the sole core material. Natural polymers are electrostatically combined and condensed with site-directed biological cross-linking to form a highly stable, dual-response dense capsule wall. It can accurately identify dual physiological signals of body temperature and mechanical pressure to achieve time-controlled and differentiated drug release. The core material, Li Yao liposome, uses the extracts of Tamanuum dasycarpus and Callicarpa nudiflora as the core active compound system. It constructs a flexible lipid membrane framework with virgin coconut oil, phospholipids, cholesterol, and phytosterol esters. The surface is modified with dual natural anchoring of low molecular weight chitosan and low molecular weight sodium hyaluronate, which gives it the characteristics of high permeability, high retention, and high physiological stability. The capsule wall is formed by specific electrostatic coagulation of type A gelatin and gum arabic, followed by site-directed cross-linking catalyzed by transglutaminase, forming a stable ε-(γ-glutamyl) lysine isopeptide bond network between the gelatin molecular chains. The formed capsule wall has precise dual-response characteristics: it can controllably swell and orderly expand its pores within the human body temperature range of 36.0~37.5℃, achieving stable diffusion and sustained release of liposomes; the capsule wall can controllably rupture under instantaneous mechanical pressure of 0.8N±0.1N, achieving rapid release of active liposomes, adapting to the dynamic physiological conditions of wearing during menstruation. The core quantitative parameters of this invention are as follows: the overall average particle size of the microcapsules is 200-400 nm, the encapsulation efficiency of the liposome core material is ≥82%, and the drug loading is ≥18%; under a standardized simulated menstrual blood environment (pH 7.0-7.4, containing 4.5 g / dL bovine serum albumin, 0.9 g / dL sodium chloride, and physiological electrolytes) at 38℃ for 8 hours, the cumulative release rate of the system is stable at 75%±5%, the release curve is smooth, and there is no sudden large-scale drug release phenomenon; throughout the 8-hour test, the polydispersity index (PDI) of the core material liposomes changes by ≤0.15, the particle aggregation rate is ≤5%, the nanostructure and dual anchoring function are completely preserved, and there is no activity decay. This invention features a unique time-release mechanism: Under resting conditions at 37°C, the capsule wall undergoes gentle swelling driven by body temperature for the first 4 hours, with the cumulative release rate stably controlled at 38%±2%, continuously maintaining the basic stability of the mucosal barrier; when the wearing pressure generates ≥0.8N above the threshold pressure, the release of active ingredients is rapidly increased within 0.5 hours, specifically repairing the micro-damage to the mucosa caused by friction during movement; after the pressure is released, the stable and sustained-release state is restored, fully covering the 8-hour complete repair cycle during menstruation. Optimal preparation process This process is a proprietary active encapsulation process for Li medicinal liposomes. It utilizes a low-temperature, all-aqueous system throughout, without high-temperature treatment, chemical cross-linking agents, or toxic additives. This maximizes the preservation of the nanostructure and bioactivity of the Li medicinal liposomes. The specific steps include: (1) Standardized core material shaping: Prepare a Hainan Li medicine compound mucosal repair liposome suspension with double natural anchoring modification, lock the core indicators of particle size, potential and encapsulation rate to ensure that the activity and stability of the core material meet the standards; (2) Precise electrostatic composite coagulation: Under constant temperature and homogeneity conditions of 40-45℃, type A gelatin aqueous solution and liposome suspension are uniformly mixed, the pH of the system is precisely controlled to 4.0-4.5, and gum arabic aqueous solution is slowly added. Relying on the charge-specific adsorption effect, a defect-free primordial capsule wall is uniformly formed on the surface of the liposome. (3) Low temperature gel solidification and shaping: rapidly cool down to 5-10℃ and solidify at a constant temperature for 1-2 hours to solidify the liquid condensation layer into a uniform and dense solid capsule wall, locking the microcapsule particle size distribution and water dispersion stability. (4) Site-directed enzyme cross-linking threshold locking: Adjust the pH of the system to 6.0-7.0, add 20-50 U / g gelatin transglutaminase, and perform gentle cross-linking at 20-30℃ for 2-4 hours. The cross-linking density of the capsule wall is precisely controlled through the enzymatic cross-linking reaction, and the temperature-sensitive swelling range and pressure triggering threshold are stably locked. (5) Aseptic purification and shaping: Low-speed centrifugation and repeated washing with sterile deionized water are used to remove impurities, so as to completely remove free macromolecules and residual enzyme solution and obtain high-purity, stable and active dual-response microcapsule products. Beneficial effects 1. Innovative construction of a natural intelligent time-sequential controlled release system: Combining the traditional Li medicine nanoliposome repair technology with all-natural dual-response time-sequential controlled release technology, it breaks through the technical limitations of traditional feminine care materials' static drug release and passive repair, forming a differentiated technical solution and filling the existing technological gap. 2. Medical-grade natural safety system, suitable for sensitive mucous membrane scenarios: The entire process uses natural and biodegradable materials, relying on green cross-linking molding with bio-enzymes. There are no synthetic allergens or chemical residues. The safety level is suitable for sensitive mucous membranes during menstruation and high-end private care scenarios for mothers and babies, meeting the compliance requirements for pure natural products. 3. Parameters are quantified and controllable, and the product batch stability is high: By using site-directed enzymatic cross-linking, dual parameters of temperature-sensitive range and pressure trigger threshold are quantitatively locked and controlled, which solves the industry pain points of traditional microcapsules, such as wide response range, disordered triggering and large batch performance differences, and provides standardized and high-precision functional substrates for intelligent repair products. 4. Liposome activity is fully preserved, and the repair effect is synergistically enhanced: The exclusive low-temperature aqueous phase process can fully preserve the liposome nanostructure, surface anchoring characteristics and bioactivity. After drug release, the liposomes still have the ability to penetrate deeply and target repair, achieving a dual synergistic effect of surface time-series stabilization and deep long-term repair. 5. Strong adaptability to extreme working conditions and high industrialization feasibility: It can achieve 8 hours of long-term stable operation under complex and extreme working conditions simulating menstrual blood, with no burst release, no particle aggregation, and no activity decay. The core performance parameters can be quantified, repeated, and standardized for production, and it meets the requirements of GMP large-scale mass production. 6. Dynamic time-series repair mode meets physiological needs: Based on the actual physiological conditions of the human body during menstruation, a dynamic on-demand drug release mode is constructed to match the differentiated repair needs during menstruation, whether at rest or during activity, effectively improving the accuracy of feminine care products and the user experience, with a wide range of applications. Detailed Implementation The following embodiments are the optimal industrialization scheme and boundary compliance scheme of the present invention. The parameters strictly fall within the protection scope of the present invention, and are repeatable and verifiable, and can be directly applied to industrial production. Example 1 (Optimal Industrialization Example) 1. Core material preparation: Prepare qualified liposome suspensions of Li Yao. The core indicators are average particle size of 175nm, PDI of 0.12, Zeta potential of +26.5mV, and total encapsulation efficiency of 86.1%. 2. Coagulation into a shell: Under the condition of uniform stirring at 42℃ and 400rpm, equal amounts of 2% (w / v) type A gelatin solution and liposome suspension were mixed. The pH of the system was adjusted to 4.2 with acetic acid. An equal amount of 2% (w / v) gum arabic solution was added dropwise. The mixture was kept warm and stirred for 45 minutes to complete the uniform coagulation into a shell on the surface of the liposomes. 3. Curing and shaping: Cool the system to 8℃ and cure at a low temperature for 1.5h to complete the homogeneous shaping of the capsule wall. 4. Enzyme cross-linking threshold locking: Adjust the pH of the system to 6.5, add 25 U / g gelatin transglutaminase, and cross-link at 25℃ for 3 hours to accurately lock the dual-response threshold parameters. 5. Purification of the finished product: Centrifuge at 3000 rpm for 15 min, wash twice with sterile deionized water, disperse in sterile aqueous medium to obtain the finished microcapsules. Finished product test results: average particle size 315nm, encapsulation rate 83.5%, drug loading 19.2%; burst pressure 0.82N (RSD=4.5%); cumulative release rate at 38℃ / 8h 77.2%, ΔPDI=0.02, aggregation rate 3.9%, all core indicators met the best standards. Example 2 (Parameter Upper Limit Boundary Example) In this embodiment, the transglutaminase dosage was adjusted to 50 U / g gelatin, the crosslinking temperature was 30℃, and the crosslinking time was 4h. All other process parameters and operating steps were completely consistent with Example 1. Finished product testing: bursting pressure 0.88N, upper limit of temperature-sensitive response 37.5℃, cumulative release rate over 8h 72.3%, PDI change 0.11, aggregation rate 3.2%. All parameters were within the protected range. Example 3 (Parameter Lower Boundary Example) In this embodiment, the transglutaminase dosage was adjusted to 20 U / g gelatin, the crosslinking temperature was 20℃, and the crosslinking time was 2h. All other process parameters and operating steps were completely consistent with Example 1. Finished product testing: burst pressure 0.78N, lower limit of temperature response 36.0℃, cumulative release rate 78.5% over 8 hours, PDI change 0.13, aggregation rate 4.1%, and both operational stability and time-sequential drug release effect met the standards. Control experiment Control Example 1 (Enzyme-free cross-linking control): The biological cross-linking process was omitted, and the capsule wall was formed solely through composite aggregation. The system lacked a stable cross-linked network structure. Test results showed that the burst release rate of the active ingredient exceeded 87% within 2 hours under high-temperature conditions, and the liposome nanostructure was completely broken, making stable sustained release and time-controlled release impossible. This demonstrates that site-specific cross-linking and threshold locking of transglutaminase are essential technical features for achieving dual-response time-controlled release in this invention. Comparative Example 2 (Chemical Crosslinking Substitute Control): Glutaraldehyde chemical crosslinking was used instead of bio-enzyme crosslinking, with the remaining processes consistent with Example 1. Test results showed that chemical crosslinking resulted in excessively rigid capsule walls and pore blockage, with a cumulative release rate of only 41.3% after 8 hours. The drug release efficiency could not meet the requirements for long-term repair, and the system posed a risk of chemical residue, failing to meet mucosal contact safety standards. This demonstrates the uniqueness and superiority of the bio-enzyme crosslinking system of this invention in balancing drug release performance and medical safety. Control Example 3 (Single Thermosensitive, No Pressure Response Control): Conventional single thermosensitive microcapsules were prepared, but the pressure-responsive structure was removed. This system can only achieve uniform temperature-controlled slow release, cannot recognize mechanical pressure signals from wearable devices, lacks a strengthening repair mechanism under motion conditions, has an incomplete time-series drug release logic, and cannot adapt to the differentiated repair needs under dynamic conditions during menstruation. Standardized testing basis All performance tests in this invention employ industry-standardized testing methods, ensuring data repeatability, verifiability, and benchmarking. The microcapsule pressure rupture threshold is determined using a TA.XT Plus texture analyzer, with a probe pressure rate of 0.5 mm / s, and the average of three parallel experiments is taken. Particle size and PDI are measured using a dynamic light scattering instrument to characterize particle dispersion stability. The particle size polydispersity coefficient (PDI) is a commonly used dimensionless stability evaluation parameter in the field of nano / microcapsule formulations, with an industry standard of PDI < 0.2. This invention strictly limits the PDI change to ≤ 0.15 under 8 hours of operation. The menstrual blood environment is simulated to replicate the physiological environment of the human body during menstruation. The solution is an aqueous solution with pH 7.0–7.4, containing 4.5 g / dL bovine serum albumin, 0.9 g / dL sodium chloride, and physiological electrolytes, accurately simulating real-world wearable usage conditions.

Claims

1. A time-controlled release system of natural microcapsules that responds to both body temperature and pressure, characterized in that, The core material of the core-shell structure is a compound mucosal repair liposome composition of Hainan Li medicine, and the shell material of the core-shell structure is a dual-response composite capsule wall formed by electrostatic composite coagulation and transglutaminase biocrosslinking of type A gelatin and gum arabic. The Hainan Li medicine compound mucosal repair liposome composition uses Malus halliana extract and Callicarpa nudiflora extract as active cores, and constructs a lipid membrane framework with virgin coconut oil, phospholipids, cholesterol and phytosterol esters. The surface is modified by dual natural mucosal anchoring with low molecular weight chitosan and low molecular weight sodium hyaluronate. The composite capsule wall can swell controllably within the human genital temperature range of 36.0–37.5°C, achieving stable diffusion and sustained release of the core material liposomes; the mechanical rupture pressure threshold of the composite capsule wall is 0.8N ± 0.1N, and the capsule wall ruptures when subjected to instantaneous pressure greater than this threshold, achieving rapid release of the active liposomes.

2. The time-controlled release system of natural microcapsules with dual responses to body temperature and pressure according to claim 1, characterized in that, The transglutaminase catalyzes the formation of ε-(γ-glutamyl) lysine isopeptide bonds between gelatin molecular chains, and precisely regulates the cross-linking density of the capsule wall through site-directed biological cross-linking, locking the temperature-sensitive swelling range and the pressure trigger threshold.

3. The time-controlled release system of natural microcapsules with dual responses to body temperature and pressure according to claim 2, characterized in that, The transglutaminase dosage is 20–50 U / g gelatin, and the enzymatic cross-linking reaction conditions are pH 6.0–7.0, temperature 20–30℃, and reaction time 2–4 h.

4. The time-controlled release system of natural microcapsules with dual response to body temperature and pressure according to claim 1, characterized in that, The microcapsules have an overall average particle size of 200–400 nm, an encapsulation efficiency of ≥82% for the liposome core material, and a drug loading of ≥18% based on the total weight of the liposomes.

5. The time-controlled release system of natural microcapsules with dual response to body temperature and pressure according to claim 1, characterized in that, In a standardized simulated menstrual blood environment with pH 7.0–7.4, containing bovine serum albumin 4.5 g / dL, sodium chloride 0.9 g / dL, and physiological electrolytes, under constant temperature and no external pressure at 38°C for 8 hours, the cumulative release rate of the system was 75% ± 5%, and the release curve was stable without sudden release.

6. The time-controlled release system of natural microcapsules with dual responses to body temperature and pressure according to claim 5, characterized in that, During the 8-hour continuous operating condition test, the polydispersity index (PDI) of the core material liposomes changed by ≤0.15, the particle aggregation rate was ≤5%, and the liposome nanostructure and dual anchoring structure remained intact with no activity decay.

7. The time-controlled release system of natural microcapsules with dual response to body temperature and pressure according to claim 1, characterized in that, The system has time-differentiated drug release characteristics: under resting conditions at 37℃, it relies on body temperature swelling for stable and slow release in the first 4 hours, with a cumulative release rate of 38%±2%, completing basic mucosal repair; after being triggered by pressure of ≥0.8N at the 4-hour mark, the release amount rapidly increases within 0.5 hours, achieving enhanced repair during the high-incidence period of menstrual activity damage, forming a time-series closed-loop repair mode of "long-acting slow release as the base and pressure-induced sudden release for enhancement".

8. A method for preparing a time-controlled release system of natural microcapsules with dual body temperature and pressure response as described in any one of claims 1 to 7, characterized in that, Includes the following steps: (1) Core material preparation: A double natural anchoring modified Hainan Li medicine compound mucosal repair liposome suspension was prepared according to the standardized process; (2) Constant temperature composite coagulation: Under constant temperature stirring at 40-45℃, type A gelatin aqueous solution and liposome suspension are mixed evenly, pH is adjusted to 4.0-4.5, gum arabic aqueous solution is slowly added, and the mixture is kept warm and stirred for 30-60 minutes to form a uniform composite coagulation prototype capsule wall on the surface of liposomes. (3) Low temperature curing and shaping: Cool the system to 5-10℃ and keep it at a constant temperature for 1-2 hours to complete the homogeneous shaping of the gel capsule wall; (4) Enzyme cross-linking threshold locking: Adjust the pH of the system to 6.0-7.0, add transglutaminase, and perform gentle cross-linking at 20-30℃ for 2-4 hours to precisely lock the dual response threshold and the stable structure of the capsule wall; (5) Purification of the finished product: Centrifugation and sterile water washing are used to remove impurities. The product is then dispersed in a sterile medium to obtain the target microcapsule system.

9. The preparation method according to claim 8, characterized in that, The amount of transglutaminase used in step (4) is 20-50 U / g gelatin.

10. The application of the temperature- and pressure-responsive natural microcapsule time-controlled release system according to any one of claims 1 to 7 in the preparation of menstrual vaginal mucosal repair products, characterized in that, The repair products are menstrual sanitary napkins, panty liners, or vaginal mucosal repair dressings; the microcapsule system is applied to the surface or core layer of the product, and through the dual signal triggering of human body temperature and dynamic squeezing pressure, it achieves intelligent repair throughout the entire 8-hour menstrual cycle.