A probiotic-coenzyme Q10 composite microcapsule for synergistic delivery in lowering blood pressure and blood lipids, and its preparation method.

Abstract

This invention discloses a probiotic-coenzyme Q10 composite microcapsule for synergistic delivery in lowering blood pressure and blood lipids, and its preparation method, belonging to the field of pharmaceutical formulation technology. The composite microcapsule has a multi-layered core-shell structure, comprising: an inner oleogel microcore composed of an oleogel matrix formed by a lipophilic oil-phase carrier and an oil-phase gelling agent; a middle probiotic hydrogel encapsulation layer covering the outer side of the inner oleogel microcore; and an outer enteric protective shell layer, a multi-layered polyelectrolyte composite membrane formed by the alternating deposition of chitosan and sodium alginate through layer-by-layer self-assembly. This invention is the first to construct a composite structure that encapsulates hydrophobic coenzyme Q10 and hydrophilic probiotics in the same microcapsule but distributed in different physical regions. This not only avoids the problem of lipid-soluble components migrating to the bacterial surface during storage, leading to bacterial inactivation, but also places the bacteria in a semi-closed microenzyme Q10-surrounded environment, facilitating synergistic effects between the two at the intestinal interface.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically referring to a probiotic-coenzyme Q10 composite microcapsule that assists in lowering blood pressure and blood lipids and its preparation method. Background Technology

[0002] In recent years, probiotics and coenzyme Q10 have been proven to have the potential to help lower blood pressure and lower blood lipids, respectively, and have received widespread attention in the field of cardiovascular health management.

[0003] In terms of lowering blood lipids, the mechanisms of action of probiotics mainly include bile salt hydrolase (BSH)-mediated bile acid deconjugation and excretion promotion, cholesterol assimilation and absorption disorders, and gut-hepatic axis regulation. Certain probiotic strains possess BSH activity, which can hydrolyze conjugated bile acids into free bile acids. The co-precipitation of free bile acids with cholesterol is enhanced, thereby reducing cholesterol reabsorption in the intestine and promoting cholesterol excretion in feces. Simultaneously, probiotics can assimilate cholesterol into their own cell membranes and inhibit intestinal cholesterol absorption and transport. Studies have shown that *Lactobacillus plantarum* with BSH activity can significantly reduce non-HDL-C and LDL-C levels. For example, *Lactobacillus plantarum* LP-LDL® has been shown in a double-blind, randomized, placebo-controlled clinical study to simultaneously reduce LDL cholesterol and blood pressure.

[0004] Coenzyme Q10 (CoQ10) is a key component of the mitochondrial electron transport chain and an important lipid-soluble endogenous antioxidant. Low levels of CoQ10 are closely associated with neurodegenerative, metabolic, muscular, and cardiovascular diseases. The mechanisms by which CoQ10 assists in lowering blood pressure and lipids include: as a lipid-soluble antioxidant, it scavenge reactive oxygen species in vascular endothelial cells, reducing the oxidative modification of low-density lipoprotein; it protects the biological activity of nitric oxide, promoting vasodilation; and by maintaining mitochondrial function and ATP supply, it improves the energy metabolism of endothelial cells, enhancing endothelial-dependent vasodilation. Furthermore, CoQ10 can prevent lipid peroxidation in membranes and cells. In recent years, novel delivery systems such as oleogels have been shown to effectively load CoQ10 and improve its bioavailability. A 1g CoQ10 / 5g oleogel formulation has comparable bioavailability to solid dosage forms and achieves higher plasma levels after repeated administration.

[0005] However, the combined delivery of probiotics and coenzyme Q10 faces three major technical challenges.

[0006] First, there is a conflicting requirement for maintaining activity. Probiotics need to reach the intestines in live form to colonize and exert their effects in lowering blood pressure and blood lipids. They are extremely sensitive to factors such as high temperatures, extreme pH, high shear forces during processing, and moisture and oxygen during storage. A decrease in survival rate will directly affect their function. On the other hand, coenzyme Q10 is a strongly hydrophobic substance with extremely poor water solubility. It is difficult to maintain stable dispersion in ordinary aqueous matrices, and its bioavailability in conventional oral formulations is only about 2-3%. There is a fundamental contradiction in the requirements of the formulation environment for both—an aqueous environment is conducive to maintaining the activity of probiotics, but it is not conducive to the dispersion and absorption of hydrophobic coenzyme Q10.

[0007] Second, there is a spatial mismatch in delivery targets. The primary target site for probiotics to lower blood pressure and lipids is the colon. They must overcome the harsh conditions of stomach acid and bile salts to reach the colon as live bacteria and colonize. The structural regulation of W / O / W dual emulsions can encapsulate probiotics within the inner aqueous phase, enhancing their resistance to adverse environments and thus enabling targeted delivery in the colon. In contrast, coenzyme Q10 is primarily absorbed in the upper small intestine and must be absorbed and utilized in a dissolved state. The two have different spatiotemporal requirements for release sites—probiotics need to be adequately protected in the stomach, released and colonized in the colon; coenzyme Q10 needs to be released and absorbed as early as possible in the small intestine. A single dosage form cannot simultaneously meet the dual requirements of live bacterial delivery in the colon and efficient absorption in the small intestine. Although three-layer tablet technology has attempted to achieve time-sequential release, the physical separation between its components is limited, and mutual interference still exists in the gastrointestinal environment.

[0008] Third, there is the issue of mutual interference between the two. Most existing products involve simple physical mixing (such as directly mixing and encapsulating probiotic freeze-dried powder and coenzyme Q10 powder) or simple compressed tablet layering. During storage, the fat-soluble coenzyme Q10 may migrate to the surface of the probiotics, forming a hydrophobic layer that blocks the probiotics from contacting water and restoring their metabolic activity, affecting their survival rate and colonization ability. Simultaneously, coenzyme Q10 lacks effective protection and is easily oxidized and degraded in the gastrointestinal environment. Even with layered tableting technology, there is still a risk of component migration between the layers, and the large contact area at the interlayer interfaces makes it difficult to completely avoid mutual interference. Summary of the Invention

[0009] To address the problems mentioned in the above technical background, the present invention provides a probiotic-coenzyme Q10 composite microcapsule that synergistically delivers blood pressure and blood lipids and its preparation method.

[0010] The technical solution of the present invention is as follows: In a first aspect, the present invention provides a probiotic-coenzyme Q10 composite microcapsule that synergistically assists in lowering blood pressure and blood lipids, wherein the composite microcapsule has a multi-layered core-shell structure, comprising: The inner oleogel micronucleus is composed of an oleogel matrix formed by an oil phase carrier and an oil phase gelling agent, in which coenzyme Q10 and antioxidants are uniformly loaded. The middle layer of probiotic hydrogel encapsulation layer covers the outer side of the inner layer of oleogel micronucleus and is composed of a hydrogel matrix containing probiotics, wherein the hydrogel matrix includes sodium alginate and gelatin. The outer enteric protective shell is a multilayer polyelectrolyte composite membrane composed of chitosan and sodium alginate deposited alternately through layer-by-layer self-assembly.

[0011] Preferably, the probiotic is one or more lactic acid bacteria strains with ACE inhibitory activity and / or BSH activity.

[0012] Preferably, the oil phase carrier is a lipophilic oil phase carrier, and the lipophilic oil phase carrier is one or more of MCT oil, linseed oil and olive oil; The oil phase gelling agent is one or both of glyceryl monostearate and ethyl cellulose; The antioxidant is one or both of vitamin E and rosemary extract.

[0013] Preferably, the hydrogel matrix further includes prebiotics, which are one or both of fructooligosaccharides and inulin; The number of self-assembled layers of the outer enteric protective shell is 2-4 cycles, and the thickness of the composite membrane is 10-50 μm. The outermost part of the enteric protective shell also contains folic acid or biotin targeted modification.

[0014] In a second aspect, the present invention also provides a method for preparing the probiotic-coenzyme Q10 complex microcapsules that synergistically deliver blood pressure and blood lipids as described above, comprising the following steps: Step 1: Activate and amplify probiotic strains to obtain concentrated probiotic solution or freeze-dried probiotic powder; Step 2: Dissolve coenzyme Q10 in the oil phase carrier, add oil phase gelling agent and antioxidant, heat to dissolve and then cool to form an oleogel matrix. Mix the oleogel matrix with the aqueous phase containing emulsifier and homogenize to form an O / W primary emulsion. Step 3: Slowly add the O / W primary emulsion obtained in Step 2 to the aqueous phase containing the probiotic concentrated bacterial solution or probiotic lyophilized powder reconstituted solution obtained in Step 1 and the hydrogel matrix to form a W / O / W dual emulsion as the oil phase; Step 4: Add calcium chloride solution dropwise to the double emulsion obtained in Step 3 to perform ion cross-linking and solidification, forming calcium alginate hydrogel microspheres, which are then collected and washed. Step 5: The microspheres obtained in Step 4 are sequentially deposited in chitosan solution and sodium alginate solution, forming a multilayer polyelectrolyte composite membrane coating through layer-by-layer self-assembly; Step 6: Freeze-dry to obtain dried probiotic-coenzyme Q10 complex microcapsule powder.

[0015] Preferably, in step two, coenzyme Q10 is dissolved in an oil phase carrier, and the concentration of coenzyme Q10 is 5-15% (w / w). The amount of oil phase gelling agent used is 0.5-3% (w / w) of the mass of the oil phase carrier. The amount of antioxidant is 0.1-1% (w / w) of the oil phase carrier mass. In step three, the volume ratio of the concentrated probiotic solution or the reconstituted lyophilized probiotic powder to the oil phase is 1:2 to 1:4, and the volume ratio of the O / W primary emulsion to the aqueous phase containing probiotics and the hydrogel matrix is ​​1:3 to 1:5.

[0016] Preferably, in step four, the concentration of the calcium chloride solution is 1-3% (w / v), the dropping rate is 0.5-1 mL / min, the cross-linking time is 30-60 min, and the cross-linking temperature is 4-10℃.

[0017] Preferably, in step five, the concentration of the chitosan solution is 0.1-0.5% (w / v), the concentration of the sodium alginate solution is 0.1-0.5% (w / v), and the number of layer-by-layer self-assembly cycles is 2-4 cycles.

[0018] Preferably, in step six, the freeze-drying temperature is -40°C to -50°C, the vacuum degree is <20Pa, and the time is 24-48h.

[0019] Thirdly, the present invention also provides the application of the probiotic-coenzyme Q10 complex microcapsule, as described above, which synergistically delivers blood pressure and blood lipids, in the preparation of drugs, functional foods, or dietary supplements that assist in lowering blood pressure and blood lipids.

[0020] Beneficial effects: 1. This invention is the first to construct a composite structure that encapsulates hydrophobic coenzyme Q10 and hydrophilic probiotics in the same microcapsule but distributed in different physical regions. Coenzyme Q10 is located in the center of the microsphere in the form of an oleogel microcore, and the probiotics are surrounded by a hydrogel coating layer, with an oil-water interface separating them. This heterogeneous partitioning design not only avoids the problem of lipid-soluble components migrating to the surface of the bacteria during storage, leading to bacterial inactivation, but also places the bacteria in a semi-closed microenvironment surrounded by coenzyme Q10, which is conducive to the synergistic effect of the two at the intestinal interface.

[0021] 2. This invention addresses the core need for maintaining bacterial cell activity by constructing a three-tiered protection system: the first tier consists of cryoprotectants (skim milk powder + trehalose + monosodium glutamate) during the freeze-drying process, maintaining the activity of the bacteria in the dry state; the second tier utilizes coenzyme Q10 and vitamin E in the oleogel micronucleus as antioxidants to neutralize reactive oxygen species in the microenvironment; and the third tier consists of a multi-layered polyelectrolyte shell to block adverse external environmental factors. This progressive and synergistic protection system significantly improves the survival rate of probiotics stored in microcapsules and their survival rate after gastrointestinal delivery compared to conventional single-layer encapsulation systems.

[0022] 3. This invention constructs a multilayer polyelectrolyte composite membrane through LbL layer-by-layer deposition of chitosan and alginate. This allows for precise control of the number and thickness of the membrane layers, thereby achieving precise colon-targeted release behavior—maintaining integrity in the gastric and duodenal environments while undergoing controlled disintegration in the colonic microenvironment, and simultaneously degrading with the assistance of colonic microbiota enzymes (such as pectinase and cellulase). The outermost layer can be actively modified through covalent coupling with folic acid or biotin, further enhancing the adhesion and colonization efficiency of the colonic mucosa.

[0023] 4. The oleogel micronuclei constructed using glyceryl monostearate or ethyl cellulose as gelling agents in this invention possess higher mechanical strength and melting point than conventional oils. They maintain a stable spherical structure during processing and in vivo delivery, preventing the collapse or deformation of microspheres that occur during the thermal processing and storage of traditional oils. The formation of the oleogel also restricts the molecular migration of coenzyme Q10 within the microspheres, improving the chemical stability of coenzyme Q10 during storage. Detailed Implementation

[0024] The technical solutions in the embodiments will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection.

[0025] This invention overcomes the shortcomings of the prior art by providing a probiotic-coenzyme Q10 composite microcapsule that synergistically delivers blood pressure and lipid-lowering substances. The composite microcapsule has a multi-layered core-shell structure, comprising: (a) Inner layer oleogel micronucleus: The inner oleogel micronucleus is composed of an oleogel matrix formed by a lipophilic oil phase carrier and an oil phase gelling agent, wherein coenzyme Q10 and antioxidants are uniformly loaded.

[0026] The lipophilic oil phase carrier is selected from one or more of medium-chain triglyceride (MCT) oil, flaxseed oil, and olive oil, preferably a combination of MCT oil and flaxseed oil in a mass ratio of 2:1.

[0027] The oil phase gelling agent is selected from one or two of glyceryl monostearate and ethyl cellulose.

[0028] The antioxidant is selected from one or two of vitamin E and rosemary extract.

[0029] In the oleogel matrix, the concentration of coenzyme Q10 is 5-15% (w / w), the amount of oil phase gelling agent is 0.5-3% (w / w) of the oil phase carrier mass, and the amount of antioxidant is 0.1-1% (w / w) of the oil phase carrier mass.

[0030] (II) Middle layer probiotic hydrogel coating: The middle layer of probiotic hydrogel coating covers the outer side of the inner layer of oleogel micronucleus and is composed of a hydrogel matrix. The hydrogel matrix includes sodium alginate and gelatin, lyophilized probiotic powder or concentrated probiotic solution, and prebiotics.

[0031] The probiotics are selected from one or more lactic acid bacteria strains with ACE inhibitory activity and / or BSH activity. Preferably, the probiotics are selected from a combination of at least two of the following strains: *Lactobacillus plantarum* Lp-LDL (product number HYCC155946), *Lactobacillus plantarum* LZ010 (product number HYCC155677), *Lactobacillus casei* (product number HYCC151599), and *Lactobacillus helveticus* (product number HYCC154128). More preferably, the probiotics are a combination of *Lactobacillus plantarum* Lp-LDL and *Lactobacillus helveticus*, or a combination of *Lactobacillus plantarum* Lp-LDL and *Lactobacillus casei*.

[0032] The probiotic content in the compound microcapsules is ≥1×10⁻⁶ viable bacteria. 9 CFU / g capsules.

[0033] The prebiotics are selected from one or two of fructooligosaccharides and inulin.

[0034] In the hydrogel matrix, the mass fraction of sodium alginate is 1-5% (w / w), the mass fraction of gelatin is 0.5-2% (w / w), and the amount of prebiotics is 2-8% (w / w) of the total mass of the hydrogel matrix.

[0035] (iii) Outer enteric protective shell The outer enteric protective shell is a multilayer polyelectrolyte composite membrane composed of chitosan and sodium alginate through alternating layer-by-layer self-assembly (LbL).

[0036] The chitosan has a molecular weight of 50-150 kDa and a degree of deacetylation of ≥85%.

[0037] The number of alternating layers of chitosan and sodium alginate is 2-4 cycles (i.e., an alternating structure of chitosan-sodium alginate-chitosan-sodium alginate, totaling 4-8 monolayers), and the thickness of the composite film formed after coating is 10-50 μm.

[0038] The components of the composite microcapsules, by weight percentage, range as follows: Coenzyme Q10 1-10%, probiotic freeze-dried powder (or bacterial liquid concentrate) 5-25%, oil phase carrier 10-30%, oil phase gelling agent 0.5-3%, sodium alginate (middle layer matrix) 1-5%, gelatin (middle layer matrix) 0.5-2%, prebiotics 2-8%, chitosan (outer wall material) 0.5-3%, calcium chloride (crosslinking agent) 0.1-1%, antioxidant (VE and / or rosemary extract) 0.1-1%, and the balance being deionized water or buffer solution.

[0039] The average particle size of the composite microcapsules is 200-800 μm.

[0040] Preferably, the outermost part of the enteric protective shell can also be targeted modified, including but not limited to folic acid covalent coupling modification or biotin covalent coupling modification, to enhance the adhesion of the composite microcapsule to the colonic mucosa and the accuracy of targeted delivery.

[0041] The synergistic effect of this invention in lowering blood pressure and blood lipids is as follows: This invention encapsulates probiotics and coenzyme Q10 in the same microcapsule but distributes them in different physical compartments. The hydrophobic environment of the inner oil gel micronucleus stabilizes coenzyme Q10 and achieves sustained release. The aqueous environment of the middle hydrogel encapsulation layer maintains the activity of probiotics and promotes intestinal colonization. The outer enteric protective shell protects the composite microcapsule from the gastric acid environment and allows it to be released in the colon. Based on this, probiotics and coenzyme Q10 can produce multiple synergistic effects: First, coenzyme Q10 neutralizes the oxidative stress environment faced by probiotics during gastrointestinal transport, reducing the damage of reactive oxygen species to probiotic activity and indirectly increasing the number of viable bacteria reaching the colon and the colonization efficiency; Second, the short-chain fatty acids and extracellular polysaccharides produced by probiotic metabolism enhance the antioxidant defense capacity of intestinal epithelial cells, forming an exogenous + endogenous dual antioxidant barrier with coenzyme Q10; Third, probiotics reduce angiotensin II production through ACE inhibitory peptides, while coenzyme Q10 protects nitric oxide activity through antioxidant action. Both act on vasodilatory regulatory pathways, producing additive or even superadditive antihypertensive effects; Fourth, after colonization, probiotics enhance intestinal barrier function, reduce the entry of endotoxins, and lower systemic inflammation levels. The antioxidant effect of coenzyme Q10 further reduces oxidative stress damage to blood vessels.

[0042] To solve the above-mentioned technical problems, the second technical solution provided by the present invention is: a method for preparing a probiotic-coenzyme Q10 composite microcapsule that synergistically delivers blood pressure and blood lipids reduction, comprising the following steps: Step 1: Probiotic strain activation and amplification Probiotic strains exhibiting ACE inhibitory activity (ACE inhibition rate ≥60%) and BSH activity were selected. The strains were at least two of *Lactobacillus plantarum* Lp-LDL, *Lactobacillus casei*, and *Lactobacillus helveticus*. These strains were inoculated into MRS liquid medium and cultured anaerobically at 37°C for 24-48 hours until the end of the logarithmic growth phase. The bacterial cells were collected by centrifugation and resuspended in a protective solution containing 10-20% (w / v) skim milk powder, 5-10% (w / v) trehalose, and 1-3% (w / v) monosodium glutamate to obtain a concentrated probiotic solution (viable cell concentration ≥1×10⁻⁶). 10 (CFU / mL), or obtain probiotic freeze-dried powder through freeze drying for later use.

[0043] Step 2: Preparation of Coenzyme Q10 Oil Gel Micronuclei Coenzyme Q10 is dissolved in an oil-phase carrier, which is selected from one or more of MCT oil, flaxseed oil, and olive oil, preferably a combination of MCT oil and flaxseed oil in a mass ratio of 2:1. The concentration of coenzyme Q10 is 5-15% (w / w). An oil-phase gelling agent, selected from glyceryl monostearate or ethyl cellulose, is added at 0.5-3% (w / w) of the oil-phase carrier mass. The mixture is heated and stirred in a water bath at 50-70°C until completely dissolved. A fat-soluble antioxidant, selected from one or two of vitamin E and rosemary extract, is added at 0.1-1% (w / w) of the oil-phase carrier mass. After stirring evenly, the mixture is cooled to room temperature to form an oil gel.

[0044] The above-mentioned oleogel is added to an aqueous phase containing 1-3% (w / v) emulsifier under stirring conditions (500-1000 rpm), wherein the emulsifier is selected from one or two of Tween 80 and soybean lecithin, and homogenized at 8000-15000 rpm for 2-5 min using a high-shear homogenizer to form an O / W primary emulsion as the oil phase.

[0045] Step 3: Construction of W / O / W dual emulsion: Slowly add the O / W colostrum obtained in step two to a solution containing the probiotic concentrate prepared in step one (or a reconstituted solution of lyophilized probiotic powder with a live bacteria concentration of 1×10⁻⁶). 10 -1×10 11The mixture was prepared in an aqueous phase containing 1-5% (w / v) sodium alginate, 0.5-2% (w / v) gelatin, and 2-8% (w / v) fructooligosaccharides (or inulin), dissolved in PBS buffer (pH 6.8-7.4). The mixture was gently stirred with a magnetic stirrer (300-500 rpm) to form a w / o / w dual emulsion.

[0046] During the preparation process, the volume ratio of the internal aqueous phase (bacterial solution) to the oil phase is controlled to be 1:2 to 1:4, and the volume ratio of the O / W primary emulsion to the external aqueous phase (aqueous phase containing probiotics and hydrogel matrix) is controlled to be 1:3 to 1:5.

[0047] Step 4: Ion crosslinking and curing: Slowly add 1-3% (w / v) calcium chloride solution dropwise to the double emulsion obtained in step three, controlling the dropwise addition rate at 0.5-1 mL / min, while stirring continuously, so that Ca²⁺... + Ionic cross-linking with sodium alginate forms a calcium alginate gel network, co-immobilizing probiotics and oleogel micronuclei within the gel microspheres. The cross-linking time is 30-60 min, and the cross-linking temperature is controlled at 4-10℃. After cross-linking, the microspheres are collected by static precipitation or by low-speed centrifugation at 500-1000 rpm for 3-5 min. The microspheres are then washed 2-3 times with sterile PBS buffer (pH 6.8-7.4) to remove uncross-linked sodium alginate and residual calcium ions.

[0048] Step 5: Layer-by-layer self-assembly coating The microspheres obtained in step four are suspended in a 0.1-0.5% (w / v) chitosan solution, which is prepared with 1% (v / v) acetic acid solution and the pH is adjusted to 5.0-5.5. The mixture is gently stirred for 10-20 min, allowing chitosan to electrostatically adsorb onto the negatively charged calcium alginate microspheres, forming the first cationic coating. The microspheres are collected by centrifugation at 500-1000 rpm for 3-5 min, washed with PBS buffer, and then suspended in a 0.1-0.5% (w / v) sodium alginate solution (dissolved in PBS buffer). The mixture is gently stirred for 10-20 min to form the second anionic coating. This alternating deposition process is repeated 2-4 times (i.e., an alternating structure of chitosan-sodium alginate-chitosan-sodium alginate, totaling 4-8 monolayers) to form a multilayer polyelectrolyte composite membrane.

[0049] Step Six: Freeze-drying After the coated microspheres were rapidly frozen with liquid nitrogen, they were transferred to a freeze dryer and freeze-dried at -40℃ to -50℃ and a vacuum degree of <20Pa for 24-48 hours to obtain dried probiotic-coenzyme Q10 composite microcapsule powder.

[0050] In the above preparation method, the crosslinking temperature in step four is preferably 4-8℃; the number of layer-by-layer self-assembly cycles in step five is preferably 3 cycles (a total of 6 monolayers); and the freeze-drying time in step six is ​​preferably 36-48h to obtain a low residual moisture content (≤5%).

[0051] The present invention also provides the application of the composite microcapsules in the preparation of drugs, functional foods or dietary supplements that help lower blood pressure and blood lipids.

[0052] Example 1 Group allocation ratio: Coenzyme Q10 6% (w / w), probiotic freeze-dried powder (Lactobacillus plantarum Lp-LDL + Lactobacillus helveticus, mass ratio 1:1) 15% (w / w), oil phase carrier (MCT oil: linseed oil = 2:1, w / w) 20% (w / w), glyceryl monostearate (oil phase gelling agent) 1.2% (w / w), sodium alginate (middle layer matrix) 3% (w / w), gelatin (middle layer matrix) 1% (w / w), fructooligosaccharides (prebiotics) 5% (w / w), chitosan (outer wall material) 1.5% (w / w), calcium chloride (crosslinking agent) 0.5% (w / w), vitamin E (antioxidant) 0.3% (w / w), balance deionized water.

[0053] Preparation method: In the probiotic strain activation and amplification steps, *Lactobacillus plantarum* Lp-LDL and *Lactobacillus helveticus* were inoculated into MRS liquid medium and anaerobically cultured at 37°C for 36 hours until the end of the logarithmic growth phase. The bacterial cells were collected by centrifugation and resuspended in a protective solution containing 15% (w / v) skim milk powder, 8% (w / v) trehalose, and 2% (w / v) monosodium glutamate to obtain a concentrated probiotic solution (live bacteria concentration approximately 1×10⁻⁶). 10 (CFU / mL), freeze-dried to obtain probiotic lyophilized powder. Add the probiotic lyophilized powder to sterile PBS buffer (pH 6.8–7.4), vortex for 4 min until completely dissolved, and adjust the viable bacteria concentration to 1×10¹. 0 –1×10¹¹ CFU / mL, to obtain a reconstituted solution containing probiotic lyophilized powder.

[0054] In the preparation of the coenzyme Q10 oleogel micronucleus, coenzyme Q10 is dissolved in a mixed oil phase carrier of MCT oil and flaxseed oil at a concentration of 10% (w / w). 1.2% (w / w) of glyceryl monostearate is added, and the mixture is heated and stirred in a water bath at 60°C until completely dissolved. 0.3% (w / w) of vitamin E is added, and the mixture is cooled to room temperature to form an oleogel. The oleogel is then added to an aqueous phase containing 2% (w / v) Tween 80 under stirring at 800 rpm, and homogenized at a high shear rate of 10,000 rpm for 3 min to form an O / W primary emulsion.

[0055] In the W / O / W dual emulsion construction step, the O / W primary emulsion is slowly added to a reconstitution solution containing lyophilized probiotic powder (live bacteria concentration 1×10⁻⁶). 10 In the aqueous phase of the hydrogel matrix (3% sodium alginate, 1% gelatin, and 5% fructooligosaccharide dissolved in PBS buffer), the ratio of inner aqueous phase to oil phase is 1:3 (v / v), and the ratio of primary emulsion to outer aqueous phase is 1:4 (v / v). The mixture is gently stirred at 400 rpm to form a W / O / W dual emulsion.

[0056] In the ion crosslinking curing step, 2% (w / v) calcium chloride solution was added dropwise at a rate of 0.8 mL / min for 45 min, and the temperature was 6 °C. The microspheres were then collected and washed twice with PBS.

[0057] In the layer-by-layer self-assembly coating step, the microspheres were alternately deposited in 0.3% (w / v) chitosan solution (prepared with 1% acetic acid, pH 5.3) and 0.3% (w / v) sodium alginate solution, with each cycle lasting 15 min, for a total of 3 cycles (chitosan-sodium alginate-chitosan-sodium alginate-chitosan-sodium alginate, for a total of 6 monolayers).

[0058] In the freeze-drying step, the composite microcapsule powder was obtained by freeze-drying at -45℃ and a vacuum degree of <20Pa for 36 hours, with an average particle size of 500μm.

[0059] Example 2 Group allocation ratio: Coenzyme Q10 4% (w / w), probiotic freeze-dried powder (Lactobacillus plantarum Lp-LDL + Lactobacillus casei, mass ratio 1:1) 18% (w / w), oil phase carrier (MCT oil: flaxseed oil = 2:1, w / w) 25% (w / w), glyceryl monostearate 1.5% (w / w), sodium alginate 2.5% (w / w), gelatin 1.2% (w / w), fructooligosaccharides 4% (w / w), chitosan 1.2% (w / w), calcium chloride 0.4% (w / w), vitamin E 0.2% (w / w), balance deionized water.

[0060] Preparation method: The results are basically the same as in Example 1, except that: the probiotics used are a combination of Lactobacillus plantarum Lp-LDL and Lactobacillus casei, the content of probiotic freeze-dried powder is 18%, the content of fructooligosaccharides is 4%, and the content of oil phase carrier is 25%; the ratio of internal aqueous phase to oil phase is 1:4 (v / v); the number of self-assembly layers is 2 cycles (a total of 4 monolayers); and the freeze-drying process is 48 hours.

[0061] Example 3 Group allocation ratio: Coenzyme Q10 8% (w / w), probiotic freeze-dried powder (Lactobacillus plantarum Lp-LDL + Lactobacillus helveticus + Lactobacillus casei, mass ratio 1:1:1) 12% (w / w), oil phase carrier (olive oil) 20% (w / w), ethyl cellulose (oil phase gelling agent) 2% (w / w), sodium alginate 3.5% (w / w), gelatin 0.8% (w / w), inulin (prebiotic) 6% (w / w), chitosan 2% (w / w), calcium chloride 0.6% (w / w), rosemary extract (antioxidant) 0.4% (w / w), balance deionized water.

[0062] Preparation method: The process was basically the same as in Example 1, except that: ethyl cellulose was used as the oil phase gelling agent, olive oil was used as the oil phase carrier, and rosemary extract was used as the antioxidant; the oil gel preparation temperature was 70°C; inulin was used instead of fructooligosaccharides as the prebiotic; a combination of three probiotic strains was used; the ratio of internal aqueous phase to oil phase was 1:2 (v / v); the layer-by-layer self-assembly was performed for 4 cycles (a total of 8 monolayers); and the process was freeze-drying for 48 hours.

[0063] Example 4 Group allocation ratio: Coenzyme Q10 3% (w / w), probiotic freeze-dried powder (Lactobacillus plantarum Lp-LDL + Lactobacillus helveticus, mass ratio 2:1) 22% (w / w), oil phase carrier (flaxseed oil) 15% (w / w), glyceryl monostearate 1% (w / w), sodium alginate 2% (w / w), gelatin 1.5% (w / w), fructooligosaccharides 7% (w / w), chitosan 1% (w / w), calcium chloride 0.3% (w / w), vitamin E 0.5% (w / w), balance deionized water.

[0064] Preparation method: The method is basically the same as in Example 1, except that: the oil phase carrier is a single flaxseed oil; the ratio of probiotic strains is Lp-LDL: Lactobacillus helveticus = 2:1; the ratio of internal aqueous phase to oil phase is 1:3.5 (v / v); the number of self-assembled layers is 3 cycles (a total of 6 monolayers); and the method is freeze-dried for 30 hours.

[0065] Example 5 Group allocation ratio: Coenzyme Q10 5% (w / w), freeze-dried probiotic powder (Lactobacillus casei + Lactobacillus helveticus, mass ratio 1:1) 16% (w / w), oil phase carrier (MCT oil: flaxseed oil: olive oil = 1:1:1, w / w / w) 22% (w / w), ethyl cellulose 1.8% (w / w), sodium alginate 2.8% (w / w), gelatin 1% (w / w), inulin 5% (w / w), chitosan 1.8% (w / w), calcium chloride 0.5% (w / w), vitamin E 0.3% (w / w), balance deionized water.

[0066] Preparation method: The results are basically the same as in Example 3, except that: the oil phase carrier is a ternary mixed oil phase with equal mass ratios of MCT oil, flaxseed oil and olive oil; the probiotics are a combination of Lactobacillus casei and Lactobacillus helveticus (without Lp-LDL); the content of probiotic freeze-dried powder is 16%; the ratio of internal aqueous phase to oil phase is 1:3 (v / v).

[0067] Example 6 Group allocation ratio: Coenzyme Q10 7% (w / w), probiotic freeze-dried powder (Lactobacillus plantarum Lp-LDL + Lactobacillus casei, mass ratio 2:1) 14% (w / w), oil phase carrier (MCT oil) 18% (w / w), glyceryl monostearate 2.5% (w / w), sodium alginate 4% (w / w), gelatin 0.5% (w / w), fructooligosaccharides 3% (w / w), chitosan 2.5% (w / w), calcium chloride 0.8% (w / w), vitamin E 0.8% (w / w), balance deionized water.

[0068] Preparation method: The method is basically the same as Example 2, except that: the oil phase carrier is a single MCT oil; the ratio of probiotic strains is Lp-LDL:Lactobacillus casei = 2:1; the high sodium alginate concentration (4%) makes the microsphere cross-linking more compact; the number of self-assembled layers is 3 cycles (a total of 6 monolayers); and the calcium chloride concentration is 0.8% to match the sodium alginate concentration.

[0069] Example 7 Group allocation ratio: Coenzyme Q10 9% (w / w), probiotic freeze-dried powder (Lactobacillus plantarum Lp-LDL + Lactobacillus helveticus + Lactobacillus casei, mass ratio 1:1:1) 10% (w / w), oil phase carrier (MCT oil: linseed oil = 1:1, w / w) 28% (w / w), ethyl cellulose 0.8% (w / w), sodium alginate 1.5% (w / w), gelatin 1.8% (w / w), inulin 8% (w / w), chitosan 0.8% (w / w), calcium chloride 0.2% (w / w), rosemary extract 0.6% (w / w), balance deionized water.

[0070] Preparation method: The method is basically the same as Example 3, except that: the oil phase carrier is a mixture of MCT oil and flaxseed oil in equal mass ratio; the coenzyme Q10 content is 9%; the low sodium alginate concentration (1.5%) makes the microsphere cross-linking looser; and the layer-by-layer self-assembly is carried out in 2 cycles (a total of 4 monolayers) to promote the early release and absorption of coenzyme Q10 in the small intestine.

[0071] Example 8 Group allocation ratio: The composition ratio range of Example 1 was followed, but the middle hydrogel matrix did not contain prebiotics (fructooligosaccharides) to investigate the promoting effect of prebiotics on probiotic intestinal colonization. The specific components were: Coenzyme Q10 6%, probiotic freeze-dried powder (Lp-LDL + Lactobacillus helveticus) 15%, oil phase carrier (MCT oil: flaxseed oil = 2:1) 20%, glyceryl monostearate 1.2%, sodium alginate 3%, gelatin 1%, chitosan 1.5%, calcium chloride 0.5%, vitamin E 0.3%, and the balance being deionized water.

[0072] Preparation method: The process is basically the same as in Example 1, except that in the W / O / W dual emulsion construction in step three, no fructooligosaccharides are added to the external aqueous phase, which contains only 3% sodium alginate and 1% gelatin, and the remaining parameters are the same as in Example 1.

[0073] Example 9 Group allocation ratio: The composition ratio is the same as in Example 1, but folic acid covalently coupled and targeted modification is performed on the outermost side of the outer enteric protective shell. The specific components are the same as in Example 1: Coenzyme Q10 6%, probiotic lyophilized powder (Lp-LDL + Lactobacillus helveticus) 15%, oil phase carrier (MCT oil: flaxseed oil = 2:1) 20%, glyceryl monostearate 1.2%, sodium alginate 3%, gelatin 1%, fructooligosaccharides 5%, chitosan 1.5%, calcium chloride 0.5%, vitamin E 0.3%, and the balance is deionized water.

[0074] Preparation method: Similar to Example 1, but after completing all cycles (3 cycles, 6 layers) of layer-by-layer self-assembly in step five, a targeted modification step is added: the coated microspheres are suspended in a 0.2% (w / v) folic acid-chitosan conjugate solution (dissolved in PBS, pH 7.4) and gently stirred overnight at 4°C, allowing the folic acid ligands to be covalently coupled to the outermost surface of the microcapsules through the amino active sites of chitosan. After centrifugation, the collected microspheres are washed twice with PBS and then proceeded to step six for freeze-drying.

[0075] Example 10 Group allocation ratio: The composition ratio is the same as in Example 1, but a higher concentration of live bacteria (>5×10⁻⁶) is used in the middle layer hydrogel matrix. 10 The probiotic concentrate (CFU / mL) is added directly (without freeze-drying) to reduce the loss of bacterial activity during the freeze-drying-reconstitution process. Specific components are: Coenzyme Q10 6%, probiotic concentrate (Lp-LDL + Lactobacillus helveticus, viable cell concentration approximately 6 × 10⁻⁶ CFU / mL) 10The CFU / mL content is equivalent to approximately 15% (w / w) of bacterial solids by volume, 20% of the oil phase carrier (MCT oil: linseed oil = 2:1), 1.2% of glyceryl monostearate, 3% of sodium alginate, 1% of gelatin, 5% of fructooligosaccharides, 1.5% of chitosan, 0.5% of calcium chloride, 0.3% of vitamin E, and the balance being deionized water.

[0076] Preparation method: The results are basically the same as in Example 1, except that: after amplification and centrifugation, the probiotics from step one are not freeze-dried, but resuspended in a protective agent solution to directly obtain a viable bacterial concentration of approximately 6 × 10⁻⁶. 10 A concentrated bacterial culture of CFU / mL was used for the W / O / W dual emulsion construction in step three. All other parameters remained the same as in Example 1.

[0077] Comparative Example 1 Composition ratio and preparation method: A mixture of 15 parts (w / w) of *Lactobacillus plantarum* Lp-LDL and *Lactobacillus helveticus* lyophilized powder with the same composition and viable count as in Example 1, and 6 parts (w / w) of coenzyme Q10 were simply physically mixed under nitrogen protection and directly filled into ordinary capsule shells. The capsule shells were not subjected to any enteric or colon-targeting treatment. No microcapsules were prepared, no w / o / w double emulsion method was used, no oleogel was used, and no layer-by-layer self-assembly coating was performed.

[0078] Features: Comparative Example 1 represents the most basic probiotic + coenzyme Q10 combination product form on the market, in which the two active ingredients are directly mixed without any delivery carrier protection or spatiotemporal control design.

[0079] Comparative Example 2 Group allocation ratio: Same as in Example 1: Coenzyme Q10 6%, probiotic freeze-dried powder (Lp-LDL + Lactobacillus helveticus) 15%, oil phase carrier (MCT oil: flaxseed oil = 2:1) 20%, glyceryl monostearate 1.2%, sodium alginate 3%, gelatin 1%, fructooligosaccharides 5%, calcium chloride 0.5%, vitamin E 0.3%, and the balance being deionized water.

[0080] Preparation method: Only steps one through four of the preparation were performed, without step five, which involved layer-by-layer self-assembly coating. This resulted in a composite microcapsule structure consisting of an oleogel microcore and a probiotic hydrogel coating layer, without an LbL outer enteric protective shell. The freeze-drying parameters for step six were the same as in Example 1.

[0081] Features: Comparative Example 2 has a bilayer structure of oleogel microcore and middle hydrogel coating, but lacks LbL polyelectrolyte composite membrane. Its protective mechanism is improved compared with single-layer calcium alginate microcapsules, but it lacks the gastric acid blocking and colon-targeted release functions of LbL multilayer coating.

[0082] Comparative Example 3 Group allocation ratio: Same as Example 1.

[0083] Preparation method: Microcapsules were prepared using a conventional W / O / W double emulsion method, but without the partitioned design of the oleogel microcore. Coenzyme Q10 and lyophilized probiotic powder were co-dispersed in the same aqueous matrix, encapsulated with sodium alginate-gelatin as the wall material, and then cured by ionic cross-linking to form single drug-loaded hydrogel microspheres. That is, there is no clear partitioning between the inner oleogel microcore and the middle hydrogel encapsulation layer; both active ingredients coexist in the same hydrogel matrix. The layer-by-layer self-assembly coating step five was not performed.

[0084] Features: Comparative Example 3 represents a common W / O / W dual emulsion encapsulation scheme for probiotics and fat-soluble active substances in the prior art (no partitioning, no LbL), which poses a risk of fat-soluble components migrating to the surface of the bacteria.

[0085] Application methods and experimental data: 1. Application method: The products of Examples 1-10 and Comparative Examples 1-3 were administered orally to rats with a hypertension-hyperlipidemia complex model in the form of enteric-coated capsules (except for the folic acid-targeted modified microcapsules of Example 9, which were administered directly in powder form to enhance colonic adhesion through targeted modification). The dosage was 1 × 10⁻⁶ probiotic live bacteria count. 9 CFU / kg body weight / day, with Coenzyme Q10 administered according to the actual content (the Coenzyme Q10 content varies in each example, but all fall within the range of 1-10%). Each group had 12 animals (n=12), and the administration was continuous for 4 weeks, administered once daily by gavage.

[0086] Experimental animal model: Five-week-old male spontaneously hypertensive rats (SHR, SPF grade, weighing 160-180g) were selected and fed a high-fat diet (containing 20% ​​lard, 1.5% cholesterol, 0.5% sodium cholate, and the remainder of the basal diet) for 10 weeks, while simultaneously receiving intraperitoneal injections of N. 6A hypertension-hyperlipidemia composite model was established using nitro-L-arginine methyl ester (L-NAME, 10 mg / kg / day, for 2 weeks). After successful model establishment, rats with systolic blood pressure ≥160 mmHg and total cholesterol ≥2.5 mmol / L were selected for the drug administration experiment. The model control group was administered an equal volume of PBS buffer by gavage; the normal control group consisted of normotensive Kyoto rats (WKY) fed a standard diet without any intervention.

[0087] 2. Detection indicators: (1) Blood pressure measurement: On days 0 (before administration), 7, 14, 21 and 28 after administration, the systolic blood pressure (SBP) of rats in an awake state was measured using a non-invasive tail artery blood pressure measuring instrument. Before each measurement, the rats were placed in a constant temperature heating cylinder at 38℃ for 15-20 minutes to preheat. The measurement was taken after the rats were calm and the tail pulse fluctuations were stable. Five consecutive measurements were taken and the average value was taken.

[0088] (2) Blood lipid assay: Four weeks after administration, rats were fasted for 12 hours, and blood was collected from the abdominal aorta after ether anesthesia. The blood was allowed to stand at room temperature for 2 hours, and then centrifuged at 3000 rpm for 15 minutes at 4°C to separate the serum. The levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in the serum were detected using a fully automated biochemical analyzer. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also detected to assess the safety impact of the product on the liver.

[0089] (3) Evaluation of probiotic colonization: After 4 weeks of administration, rat colon contents were collected and cultured on MRS agar medium (containing vancomycin 4 μg / mL and gentamicin 80 μg / mL to selectively separate Lp-LDL and NK1) under anaerobic conditions at 37℃ for 48 h. Probiotic fecal viable counts were performed to evaluate the effect of microcapsules on the colonization efficiency of probiotics in the intestine under different formulations.

[0090] (4) Determination of Coenzyme Q10 plasma concentration: Blood samples were collected from the tail vein of rats at 0, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentration of coenzyme Q10 was determined by high performance liquid chromatography (HPLC), and pharmacokinetic parameters (Cmax, Tmax, AUC0-) were calculated. 24 h), to evaluate the effect of different formulations on the bioavailability of coenzyme Q10.

[0091] 3. Comparison of experimental results: The product performance results for each embodiment and comparative example are shown in Tables 1-3 below: Table 1

[0092] Table 2

[0093] Table 3

[0094] Note: The encapsulation efficiency of Coenzyme Q10 in Tables 1-3 is calculated as (actual encapsulation amount / feed amount) × 100%; the survival rate of probiotics refers to (number of live bacteria after freeze-drying / number of live bacteria before freeze-drying) × 100%; the survival rate of simulated gastric juice refers to (number of live bacteria / initial number of live bacteria) × 100% after sequential treatment with gastric juice (pH 1.2, 2h).

[0095] The results of comparing the in vitro simulated gastrointestinal fluid release behavior of Examples 1 and 3 with those of Comparative Examples 2 and 3 are shown in Table 4: Table 4

[0096] As shown in Table 4, the multi-layer coating of Examples 1 and 3 significantly delayed the release of probiotics in the gastric and initial intestinal fluid stages (release rates of only 5.2% and 3.8%, respectively), achieving colon-targeted release; while Comparative Examples 2 and 3 showed release rates as high as 28.5% and 42.3% in gastric fluid. Coenzyme Q10 was released more slowly in the examples, which is beneficial for sustained absorption.

[0097] Table 5 below shows the changes in blood pressure in a rat model of hypertension and hyperlipidemia after 4 weeks of drug administration. Table 5

[0098] *Note: The effective rate of blood pressure reduction is calculated as the percentage of animals in each group whose systolic blood pressure decreased by ≥10 mmHg and whose final systolic blood pressure was ≤150 mmHg. n=12. Data are expressed as mean ± SD.

[0099] As shown in Table 5, the systolic blood pressure decreased by 11.7-20.2 mmHg after 4 weeks of administration in each embodiment of the present invention, significantly better than the model control group (-1.8 mmHg). Among them, Example 3 (three-strain combination + ethyl cellulose oleogel + 4 cycles of LbL coating) and Example 9 (folic acid targeted modification) showed the most significant antihypertensive effects (approximately 20 mmHg decrease, effective rate 91.7%), indicating the complementary ACE inhibition effect of the three strains and the synergistic enhancement of colonic colonization by folic acid targeting on the antihypertensive effect. Example 5 showed a relatively weaker antihypertensive effect (13.7 mmHg decrease), indicating that Lp-LDL plays a key role in antihypertensive action. Example 8 (without prebiotics) showed a lower antihypertensive effect (13.5 mmHg) than Example 1 (18.6 mmHg), demonstrating that in-situ nutrient supply integrated with prebiotics significantly promotes probiotic colonization and antihypertensive effects.

[0100] Table 6 below shows the changes in blood lipid levels in a rat model of hypertension-hyperlipidemia after 4 weeks of drug administration. Table 6

[0101] Note: The values ​​in parentheses are percentage changes relative to the model control group (TC, TG, and LDL-C are percentage decreases, HDL-C is percentage increase). Data are expressed as mean ± SD, n=12.

[0102] As shown in Table 6, the lipid-improving effects of each embodiment of the present invention are significantly better than those of the comparative group. The best effect in lowering TC was observed in Example 3 (-36.6%), followed by Example 9 (-35.4%), Example 2 (-33.5%), and Example 10 (-33.2%). The best effect in lowering TG was observed in Example 3 (-46.0%), followed by Example 9 (-44.3%), Example 2 (-41.4%), and Example 10 (-39.7%). The best effect in lowering LDL-C was observed in Example 3 (-49.3%), followed by Example 9 (-47.1%), Example 2 (-44.9%), and Example 10 (-44.1%). The best effect in increasing HDL-C was observed in Example 3 (+66.7%), followed by Example 9 (+62.7%), Example 2 (+56.9%), and Example 10 (+54.9%).

[0103] Example 5 showed the weakest lipid-lowering effect, indicating that the BSH activity of Lp-LDL plays a key role in lipid-lowering. Example 8 (without prebiotics) showed a lower lipid-lowering effect (-30.2%) than Example 1 (-32.6%), similarly demonstrating the promoting effect of prebiotic integration on blood lipid improvement.

[0104] In summary, Examples 3 (three-strain combination + ethyl cellulose oleogel + 4 cycles of LbL coating) and Example 9 (folic acid targeted modification) showed the most outstanding effects in lowering blood pressure and lipids, while Example 1 achieved a good balance between process feasibility and overall product performance. In contrast, Comparative Examples 1-3 were significantly inferior to the Example groups in all evaluation indicators.

[0105] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A probiotic-coenzyme Q10 composite microcapsule that synergistically delivers blood pressure and lipid-lowering agents, characterized in that, The composite microcapsule has a multi-layered core-shell structure, comprising: The inner oleogel micronucleus is composed of an oleogel matrix formed by an oil phase carrier and an oil phase gelling agent, in which coenzyme Q10 and antioxidants are uniformly loaded. The middle layer of probiotic hydrogel encapsulation layer covers the outer side of the inner layer of oleogel micronucleus and is composed of a hydrogel matrix containing probiotics, wherein the hydrogel matrix includes sodium alginate and gelatin. The outer enteric protective shell is a multilayer polyelectrolyte composite membrane composed of chitosan and sodium alginate deposited alternately through layer-by-layer self-assembly.

2. The probiotic-coenzyme Q10 composite microcapsule for synergistic delivery of blood pressure and lipid-lowering agents according to claim 1, characterized in that, The probiotics are one or more lactic acid bacteria strains with ACE inhibitory activity and / or BSH activity.

3. The probiotic-coenzyme Q10 composite microcapsule for synergistic delivery of blood pressure and lipid-lowering agents according to claim 1, characterized in that, The oil phase carrier is a lipophilic oil phase carrier, and the lipophilic oil phase carrier is one or more of MCT oil, linseed oil and olive oil; The oil phase gelling agent is one or both of glyceryl monostearate and ethyl cellulose; The antioxidant is one or both of vitamin E and rosemary extract.

4. The probiotic-coenzyme Q10 composite microcapsule for synergistic delivery of blood pressure and lipid-lowering agents according to claim 1, characterized in that, The hydrogel matrix also includes prebiotics, which are one or two of fructooligosaccharides and inulin; The number of self-assembled layers of the outer enteric protective shell is 2-4 cycles, and the thickness of the composite membrane is 10-50 μm. The outermost part of the enteric protective shell also contains folic acid or biotin targeted modification.

5. A method for preparing a probiotic-coenzyme Q10 composite microcapsule for synergistic delivery of blood pressure and lipid-lowering agents as described in any one of claims 1-4, characterized in that, Includes the following steps: Step 1: Activate and amplify probiotic strains to obtain concentrated probiotic solution or freeze-dried probiotic powder; Step 2: Dissolve coenzyme Q10 in the oil phase carrier, add oil phase gelling agent and antioxidant, heat to dissolve and then cool to form an oleogel matrix. Mix the oleogel matrix with the aqueous phase containing emulsifier and homogenize to form an O / W primary emulsion. Step 3: Slowly add the O / W pre-emulsion obtained in Step 2 to the aqueous phase containing the probiotic concentrated bacterial solution or probiotic lyophilized powder reconstituted solution obtained in Step 1, and the hydrogel matrix to form a W / O / W dual emulsion as the oil phase. Step 4: Add calcium chloride solution dropwise to the double emulsion obtained in Step 3 to perform ion cross-linking and solidification, forming calcium alginate hydrogel microspheres, which are then collected and washed. Step 5: The microspheres obtained in Step 4 are sequentially deposited in chitosan solution and sodium alginate solution, forming a multilayer polyelectrolyte composite membrane coating through layer-by-layer self-assembly; Step 6: Freeze-dry to obtain dried probiotic-coenzyme Q10 complex microcapsule powder.

6. The preparation method according to claim 5, characterized in that, In step two, coenzyme Q10 is dissolved in an oil phase carrier, and the concentration of coenzyme Q10 is 5-15% (w / w). The amount of oil phase gelling agent used is 0.5-3% (w / w) of the mass of the oil phase carrier. The amount of antioxidant is 0.1-1% (w / w) of the oil phase carrier mass. In step three, the volume ratio of the concentrated probiotic solution or the reconstituted lyophilized probiotic powder to the oil phase is 1:2 to 1:4, and the volume ratio of the O / W primary emulsion to the aqueous phase containing probiotics and the hydrogel matrix is ​​1:3 to 1:

5.

7. The preparation method according to claim 5, characterized in that, In step four, the concentration of the calcium chloride solution is 1-3% (w / v), the dropping rate is 0.5-1 mL / min, the cross-linking time is 30-60 min, and the cross-linking temperature is 4-10℃.

8. The preparation method according to claim 5, characterized in that, In step five, the concentration of the chitosan solution is 0.1-0.5% (w / v), the concentration of the sodium alginate solution is 0.1-0.5% (w / v), and the number of layer-by-layer self-assembly cycles is 2-4 cycles.

9. The preparation method according to claim 5, characterized in that, In step six, the freeze-drying temperature is -40℃ to -50℃, the vacuum degree is <20Pa, and the time is 24-48h.

10. The application of a probiotic-coenzyme Q10 composite microcapsule as described in any one of claims 1-4, characterized in that, The composite microcapsules are used in the preparation of drugs, functional foods, or dietary supplements that help lower blood pressure and blood lipids.

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