Application of rosemary extract in prevention and treatment of Alzheimer's disease through intestine-brain axis

Abstract

The invention relates to the technical field of medicines, and particularly discloses application of a rosemary extract to prevention and treatment of Alzheimer's disease through an intestine-brain axis. The oral formulation comprises a rosemary extract, specific prebiotics, and a colon-targeted delivery system. The core of the preparation is that the preparation is designed to have colon-specific release capacity, and a sequential release mode of prebiotics prior to rosemary extract is realized at the part. This is achieved by constructing the two in a composite porous particle or an independent unit with a differential coating, with the assistance of a pH dependent layer and a time-lag layer coating. The prebiotics are preferentially released and regulate colonic flora and microenvironment, and then the rosemary extract is released and absorbed in the optimized environment, so that the intestinal-brain axis is synergistically regulated in a programmed manner. According to the invention, the targeting property and bioavailability of the active ingredients are improved, the prevention and treatment effect is enhanced through time sequence synergy, and the preparation has clear quality control parameters.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to the application of rosemary extract in the prevention and treatment of Alzheimer's disease through the gut-brain axis. Background Technology

[0002] Alzheimer's disease is an age-related neurodegenerative disease whose pathological process involves multiple mechanisms, including β-amyloid protein deposition, tau protein hyperphosphorylation, and chronic neuroinflammation. In recent years, the gut-brain axis theory has provided a new perspective for understanding the development of this disease. Studies have shown that gut microbiota and its metabolites can affect central nervous system function through immune, neural, and endocrine pathways. Therefore, regulating systemic inflammation and neuroimmune homeostasis by intervening in the gut microbiota has become a promising research direction for the prevention and treatment of Alzheimer's disease. Rosemary, a traditional medicinal and edible plant, has had its extracts proven to possess antioxidant, anti-inflammatory, and neuroprotective activities, while prebiotics can selectively promote the growth of beneficial gut microbiota; both have the potential to exert their effects through the gut-brain axis.

[0003] Existing technologies include studies and applications of using rosemary extract or prebiotics alone to support cognitive health. However, the conventional approach of simply combining the two has significant limitations. First, the polyphenols in rosemary extract are easily degraded or transformed by pH, digestive enzymes, and microorganisms in the stomach and small intestine, resulting in low oral bioavailability and a limited proportion of effective components that actually reach the colon and exert their effects. Second, conventional oral formulations cannot control the release site of active ingredients in the digestive tract. Prebiotics may be partially fermented in the precolon, while rosemary extract is dispersed throughout the gastrointestinal tract, making it difficult for the two to form an effective overlap and temporal synergy at the colon, a key site for gut-brain axis signal generation. Furthermore, the lack of precise design of the release kinetics of the two components prevents the "microbiome regulation" and "direct neuroprotection" mechanisms from being sequentially linked in time, resulting in a high degree of randomness in the synergistic effect, unstable efficacy, and difficulty in optimization.

[0004] Therefore, the shortcomings of existing technologies are mainly reflected in: insufficient oral bioavailability and targeting, and the lack of controllable temporal synergistic effects among mixed components. These problems restrict the transformation of compound intervention strategies based on the gut-brain axis theory into efficient, stable, and predictable products. Summary of the Invention

[0005] To overcome the aforementioned deficiencies of the prior art, embodiments of the present invention provide an application of rosemary extract in the prevention and treatment of Alzheimer's disease through the gut-brain axis, in order to solve the problems mentioned in the background art. Specifically, the problems are: firstly, after oral administration, it is easily degraded in the upper gastrointestinal tract, resulting in low bioavailability and a lack of ability to target key sites of the gut-brain axis; secondly, conventional methods of simply physically mixing it with prebiotics cannot control the release sequence and synergistic effects of the two in the complex intestinal environment.

[0006] To achieve the above objectives, the present invention provides an application of rosemary extract in the prevention and treatment of Alzheimer's disease through the gut-brain axis.

[0007] 1. Standardization of system composition and core components

[0008] The oral formulation contains rosemary extract, at least one prebiotic, and a colon-targeted delivery system.

[0009] Rosemary extract: An extract prepared using a standardized process, characterized by a specific mass ratio of caryopsisic acid to rosmarinic acid. ( The ratio is between 1:2 and 2:1. This standardized ratio aims to balance its lipid-soluble and water-soluble active ingredients, optimizing its dual pharmacological activity spectrum of central nervous system protection and peripheral anti-inflammatory / barrier regulation.

[0010] Prebiotics: The prebiotics are oligosaccharides that can be metabolized by intestinal flora to produce short-chain fatty acids. Further, the oligosaccharides preferably contain... The fructose units are linked by (2,1) glycosidic bonds and have a degree of polymerization (DP) of 2 to 10. This specific structure ensures that they can be rapidly fermented by butyrate-producing bacteria in the colon, generating an effective butyrate signal within a predetermined time window.

[0011] 2. Definition and Implementation of Sequential Release Pattern

[0012] The "sequential release pattern" is the core feature of the formulation of this invention, which is objectively defined and verified through in vitro release kinetic parameters: the time required for the cumulative release of the prebiotic to reach 50% (denoted as...). (This refers to the time required for the cumulative release of rosemary extract to reach 50%) ).

[0013] Furthermore, the term "earlier than" can be quantified as Compare Please arrive at least 2 hours in advance.

[0014] This sequential release mode is achieved through one of the following two formulation design pathways:

[0015] Path 1: Structurally Coupled Sequential Release. Prebiotics are constructed to have a predetermined porosity. A porous framework was constructed, and rosemary extract was loaded into the pores of this framework to form composite particles.

[0016] Furthermore, the porosity The preferred concentration is 45% to 55%. In the colonic environment, the rapid dissolution of the prebiotic skeleton enables preferential release, followed by the diffusion release of rosemary extract through a porous network.

[0017] Pathway 2: Functionally Decoupled Sequential Release. Prebiotics and rosemary extracts are prepared as independent drug release units, and their colon-targeting coatings are designed differently to allow the prebiotic unit to be released before the rosemary extract unit.

[0018] One specific and controllable implementation method is to control the average thickness of the coating layer of the prebiotic drug release unit. Less than the average thickness of the coating layer of the rosemary extract drug delivery unit .

[0019] 3. Optimized design of colon-targeted delivery system

[0020] The colon-targeted delivery system is configured to selectively deliver the active ingredient to the colonic region for release. Its performance is validated through in vitro simulated gastrointestinal transport experiments, with a design goal of achieving a total cumulative release of less than 10% of the formulation in simulated gastric and small intestinal fluid stages.

[0021] Furthermore, the system preferably employs a dual guarantee mechanism of pH triggering and time delay: the inner layer is a pH-dependent coating layer that dissolves when the ambient pH reaches or exceeds 7.0; the outer layer is a time-delay layer (time-lag layer) composed of a hydrophilic material that dissolves at a near-constant rate in gastrointestinal fluid. The two layers work synergistically to ensure that the release event occurs with a high probability in the mid-to-rear colon.

[0022] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects:

[0023] Compared to existing technologies that involve simple physical mixing and oral administration, this invention designs an oral formulation incorporating a colon-targeted delivery system. Rosemary extract and prebiotics are co-encapsulated within a pH-sensitive and time-delayed coating. This system resists gastric acid and the small intestinal digestive environment, releasing its contents only upon reaching the colonic region and triggering at a specific pH and time. This design precisely confines the release space of the two active ingredients to the colon, reducing degradation losses of rosemary extract in the upper digestive tract and improving its bioavailability at the site of action. Simultaneously, it ensures the co-localization of prebiotics and rosemary extract at key sites of action along the gut-brain axis, creating prerequisites for their local synergistic effect and thus enhancing the targeting and efficiency of the intervention.

[0024] Furthermore, compared to the random release of active ingredients in existing technologies, this invention constructs a sequential release mechanism within the formulation, specifically manifested in the faster release kinetics of prebiotics than rosemary extract. This is achieved by designing the prebiotics as a rapidly dissolving porous framework to load the extract, or by setting differentiated coating thicknesses for both. This mechanism ensures that the prebiotics are preferentially released in the colon and rapidly fermented by the gut microbiota, locally increasing the concentration of short-chain fatty acids, optimizing the redox state, and creating an anti-inflammatory microenvironment. Subsequently, the rosemary extract begins to be released and absorbed in this pre-regulated microenvironment. This creates a temporal cascade and synergistic effect between the metabolic signals of the prebiotics and the pharmacological effects of the rosemary extract, amplifying the overall regulatory effect on the gut-brain axis pathway and enhancing the scientific validity and predictability of the intervention strategy.

[0025] Furthermore, addressing the issue of low standardization of raw materials and products in existing technologies, this invention precisely defines the active ingredients themselves and their structural state in the formulation. It specifies the specific ratio range of rosmarinic acid and salicylic acid in rosemary extract, as well as the specific glycosidic bond types and polymerization degree ranges of prebiotic oligosaccharides. Simultaneously, it quantifies the key formulation structural parameters for achieving sequential release (such as the porosity of the porous framework and the thickness of the differential coating layer) and in vitro release kinetic parameters (such as the time point corresponding to a specific cumulative release rate). This series of clearly defined characteristic parameters provides objective and measurable standards for product manufacturing quality control, batch-to-batch consistency assessment, and correlation prediction of in vitro and in vivo efficacy. Attached Figure Description

[0026] Figure 1 This is a flowchart illustrating the colon-targeted release process of the oral formulation of rosemary extract according to the present invention.

[0027] Figure 2 This is a schematic diagram of the colon-targeted delivery system of the present invention. Detailed Implementation

[0028] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] Example 1

[0030] As attached Figures 1 to 2The invention illustrates the application of rosemary extract in the prevention and treatment of Alzheimer's disease through the gut-brain axis. The following describes the application and the preparation and action process of its oral formulation. It should be noted that the process routes and specific parameters listed below are exemplary embodiments for achieving the technical solution described in this invention. Those skilled in the art, after understanding the core concept of this invention, can achieve the objectives of this invention by using different formulation technologies or adjusting relevant parameters.

[0031] S100: Preparation of standardized rosemary extract

[0032] This step involves the extraction and purification of rosemary raw materials to obtain an extract with a clearly defined proportion of active ingredients.

[0033] S101: Crush the dried rosemary leaves and pass them through a 20-mesh sieve.

[0034] Weigh 1.0 kg of powder, add 10 L of 70% (v / v) ethanol aqueous solution, and extract by reflux at 80°C for 2 hours. Repeat the extraction twice.

[0035] The extracts were combined and concentrated under reduced pressure at 60°C using a rotary evaporator until no alcohol odor remained, yielding a crude extract.

[0036] S102: Disperse the crude extract with water and separate it using a pH-zone purification countercurrent chromatograph.

[0037] The stationary phase is a hexane-ethyl acetate-methanol-water solvent system with a volume ratio of 1:5:1:5.

[0038] A pH gradient is created within the chromatographic column by adding trifluoroacetic acid and ammonia to the stationary and mobile phases, respectively.

[0039] The main unit rotation speed was set to 850 r / min, and the mobile phase flow rate was set to 2.0 mL / min. The target fraction was collected based on the real-time UV absorption spectrum.

[0040] In a preferred embodiment, by adjusting the injection volume and the fraction collection time window, the final combined active fraction, after drying, contains a specific mass ratio of oxalic acid to rosmarinic acid. ( The ratio is between 1:2 and 2:1.

[0041] This range was set based on previous efficacy screening experiments, within which the central permeability of rosmarinic acid and the peripheral anti-inflammatory properties of rosmarinic acid showed a good synergistic effect.

[0042] The total polyphenol content was determined by high performance liquid chromatography and was not less than 40%.

[0043] S103: The collected active fractions were combined, concentrated under reduced pressure at 60°C, and then freeze-dried to obtain a standardized rosemary extract in the form of a light brown powder.

[0044] High-performance liquid chromatography was used to ensure that the ratio of arugula acid to rosmarinic acid was within the set range. The standardized extract was sealed and stored in a cool, dry place.

[0045] S200: Selection and Processing of Prebiotics

[0046] This step involves screening and preparing prebiotic ingredients for use in the composition.

[0047] S201: Select fructooligosaccharides as prebiotics, with a purity of not less than 95%.

[0048] Furthermore, the selected prebiotics are oligosaccharides that can be metabolized by colonic flora to produce short-chain fatty acids.

[0049] As a more specific implementation, the molecular structure of the oligofructose is based on The fructose units are mainly linked by glycosidic bonds (-(2,1)), and their degree of polymerization distribution is determined by ion chromatography. Among them, the components with a degree of polymerization (DP) in the range of 2 to 10 account for more than 90%.

[0050] The selection of this degree of polymerization range is based on in vitro fermentation kinetics studies. The components may be absorbed prematurely in the small intestine, while If the fermentation of any component starts too slowly, it will be detrimental to achieving the desired fermentation time within the preset time window. Sufficient butyric acid signal is generated internally.

[0051] S300: Constructing active ingredient units to achieve sequential release

[0052] This step constructs the active ingredient unit through one of two technical approaches, with the common design goal of achieving prebiotic release kinetic parameters. Greater than the release kinetic parameters of rosemary extract .

[0053] Path 1: Preparation of composite particles

[0054] S311: Weigh 500g of the fructooligosaccharides obtained in step S200 and place them in a fluidized bed granulator. Dissolve 50g of polyvinylpyrrolidone K30 in 200mL of purified water as a binder solution.

[0055] The adhesive solution is added in spray form at an inlet air temperature of 60°C for granulation.

[0056] After completion, the granules are dried at 50°C until the moisture content is below 3.0%.

[0057] As a preferred embodiment, 30g of microcrystalline cellulose is added to the granulation formulation as a pore-forming agent.

[0058] Furthermore, the drug-carrying framework formed by prebiotics was fabricated into a porous structure. The porosity of the resulting particles was determined by mercury porosimetry. Between 45% and 55%, the pore size is mainly distributed in the 5 pore size range. m to 30 Within the range of m.

[0059] The prebiotic porous framework prepared by the method shall have a bulk density (determined according to the pharmacopoeia general rules) between 0.4 g / mL and 0.6 g / mL.

[0060] In a dissolution experiment conducted in simulated colonic fluid (such as phosphate buffer at pH 7.4), the framework should lose more than 50% of its weight within 60 minutes to verify that it meets the requirements for rapid initiation release (high... Design requirements.

[0061] S312: Weigh 100g of the standardized rosemary extract obtained in step S100 and dissolve it in 200mL of 95% (v / v) ethanol.

[0062] The porous prebiotic particles obtained from S311 were placed in a fluidized bed coating machine, and the rosemary extract ethanol solution was uniformly loaded onto the particle surface and pores by spraying at an inlet air temperature of 50°C.

[0063] After drying, composite particles were obtained. The loading rate of rosemary extract in the composite particles was determined by high performance liquid chromatography to be no less than 95%.

[0064] At least 10 samples were randomly selected for content determination, and the relative standard deviation (RSD) of the rosemary extract content should not exceed 5.0%.

[0065] This process integrates prebiotics and rosemary extract into the same composite particle, in which the prebiotics form a porous drug-carrying framework and the rosemary extract is dispersed within the framework.

[0066] Pathway 2: Preparation of independent drug release units

[0067] S321: Sucrose microspheres with a particle size of 0.25 mm to 0.35 mm were used as the core. An aqueous solution containing 30% (w / w) fructooligosaccharides (for the prebiotic unit) and a 70% (v / v) ethanol aqueous solution containing 15% (w / w) standardized rosemary extract (for the extract unit) were prepared separately.

[0068] Using a fluidized bed bottom spraying system, two solutions were sprayed onto two portions of sucrose microcapsules for drug deposition. The inlet air temperatures were set to 55°C (aqueous solution) and 45°C (ethanol solution), respectively.

[0069] After drug loading is completed, prebiotic-loaded microspheres and rosemary extract-loaded microspheres are obtained. The drug loading amount calculated based on the weight gain of the microspheres should be within the range of 90% to 110% of the theoretical drug loading amount calculated based on the feed amount.

[0070] S322: Preparation of colon-targeted coating solution. The coating material is an aqueous dispersion of acrylic resin with a solid content of 15% (w / w). The prebiotic-loaded microcapsules are coated first using the same fluidized bed top spraying equipment.

[0071] The colon-targeting coating layer of the prebiotic delivery unit is designed to be more easily broken down or dissolved in the colonic environment than the colon-targeting coating layer of the rosemary extract delivery unit. This design ensures that the prebiotic unit has a shorter trigger release time. .

[0072] One specific and easily controllable implementation method involves controlling the coating thickness of the two types of microcapsules. The prebiotic-loaded microcapsules are coated to a weight gain of 15% of the original microcapsule weight, and the rosemary extract-loaded microcapsules are coated to a weight gain of 25% of the original microcapsule weight.

[0073] The average thickness of the prebiotic microcapsule coating layer was monitored using a laser diffraction particle size analyzer. Approximately 30 m, average thickness of the coating layer of rosemary extract microspheres Approximately 50 m.

[0074] According to the thin film dissolution model, the rupture time is approximately proportional to the square of the thickness, i.e. Therefore, thickness variation can be reliably achieved. .

[0075] S323: The coated prebiotic microcapsules and rosemary extract microcapsules are physically mixed at a dry weight ratio of 2:1 to obtain a mixed microcapsule system.

[0076] This process enables the preparation of prebiotics and rosemary extracts into independent drug release units, and the release sequence is designed by controlling the difference in coating layer thickness.

[0077] S400: Assembled Colon-Targeted Delivery System

[0078] This step assembles the active ingredient unit obtained in step S300 with colon-targeting functionality, ensuring that the physical location of release is locked in the colon. The combined design of the pH-dependent layer and the time-delay layer allows the formulation to maintain a high probability of locking the initial large-volume drug release site in the colon even after undergoing individualized gastrointestinal transit.

[0079] S401: Place the particles or mixed microspheres obtained from path one or path two of S300 into a fluidized bed coating machine. Prepare a pH-dependent coating solution, use an acrylic resin aqueous dispersion for coating, control the inlet air temperature at 40°C, and increase the weight of the coating layer to 20% of the total weight of the active core.

[0080] Furthermore, the colon-targeted delivery system comprises a pH-dependent coating layer. This coating layer does not dissolve within 120 minutes in phosphate buffer at a pH below 7.0, and dissolves completely within 60 minutes in phosphate buffer at a pH of 7.4.

[0081] This design is based on the ionization equilibrium of the polymer's carboxyl groups and the degree of polymer ionization. Determined by the ambient pH level: When the environmental pH exceeds its (Approximately 7.0) The increase in hydrophilicity of the polymer chains leads to a dramatic increase in hydrophilicity, resulting in dissolution.

[0082] S402: After completing the pH-dependent coating, prepare the time-delay coating solution. The time-delay layer material is an aqueous solution of hydroxypropyl methylcellulose with a viscosity grade of 5 cP.

[0083] On the same equipment, coating was carried out at an air inlet temperature of 40°C, so that the weight of the time-delay layer increased to 15% of the total core weight.

[0084] In a preferred embodiment, the colon-targeted delivery system further includes a time-delay layer located outside the pH-dependent coating layer. This time-delay layer operates at an approximately constant rate in the aqueous environment of the gastrointestinal tract. Dissolution, for example, in simulated gastrointestinal fluids It is approximately 10 mg / (cm²·h).

[0085] The design of the time delay layer provides a time delay independent of individual differences in gastrointestinal transit. ( (This, in conjunction with the pH-triggered mechanism, more reliably confines the release event to the mid-to-late colon.)

[0086] S500: Formulation into the final oral formulation

[0087] The granules or mixed microcapsules coated in step S400 are filled into No. 0 hydroxypropyl methylcellulose hard capsule shells using a capsule filling machine. Each capsule contains 500 mg of contents, thus producing colon-targeted capsules.

[0088] The capsule contents contain 60% prebiotics by weight and 12% standardized rosemary extract by weight.

[0089] S600: Programmed Action Flow of Oral Medications in the Body

[0090] To objectively illustrate the characteristics of the sequential release design, the formulation prepared in this embodiment can be compared with two control samples in terms of release behavior:

[0091] Compared with control sample B, which was a simple physical mixture of prebiotics and rosemary extract, the same colon-targeting coating was used.

[0092] Compared to control sample C, its prebiotics and rosemary extract were encapsulated under the same colon-targeting coating layer.

[0093] S601: After oral administration, the outer time-delay layer of the formulation begins to dissolve in the water-containing environment of the stomach and small intestine. Complete dissolution of the time-delay layer takes approximately 4 to 5 hours.

[0094] At this point, the formulation has typically passed through the small intestine. When the formulation reaches the colon, and the ambient pH rises above 7.0, the internal pH-dependent coating layer comes into contact with the colonic fluid and dissolves. At this point, the active ingredient unit is precisely targeted and released into the colonic region.

[0095] S602: After the pH-dependent layer dissolves, the active ingredient unit is exposed to the colonic environment.

[0096] S602a: Preferential release of prebiotics and regulation of the microenvironment. For composite particles, the fructooligosaccharide backbone begins to dissolve from the outside in; for mixed microspheres, prebiotic microspheres with thinner coatings rupture first.

[0097] Fructooligosaccharides diffuse rapidly and become a fermentation substrate for the colonic flora.

[0098] In the subsequent time period Inside( ,in and (Time to peak concentrations of prebiotics and rosemary extracts in the colon, respectively) and local concentrations of short-chain fatty acids in the colon. The pH level will rise, possibly accompanied by a slight decrease.

[0099] S602b: Subsequent release and synergistic intervention of rosemary extract. Rosemary extract begins to be released after prebiotic-initiated fermentation and changes in the local microenvironment.

[0100] For composite particles, the release is achieved through diffusion via a porous framework, and the cumulative release amount... With time The relationship can be approximated as: ;

[0101] For mixed microcapsules, the extract microcapsules with thicker coating layers rupture at this point.

[0102] Rosemary extract is released and absorbed in an altered microenvironment, where the increased concentration of butyrate may enhance intestinal barrier function and create favorable conditions for the absorption and utilization of phenolic acids.

[0103] S603: Through the above process, the formulation completes a sequential procedure from colon localization, pre-release of prebiotics to regulate the flora and microenvironment, to post-release of rosemary extract to exert its pharmacological effects.

[0104] In vitro release assays showed that the formulation of this embodiment met the following objective criteria for sequential release: the time required for the cumulative release of the prebiotic to reach 50% ( ), compared to rosemary extract Please arrive at least 2 hours in advance.

[0105] Compared to control samples B and C and The difference was less than 0.5 hours, indicating that their release behavior tended to be synchronous and did not have sequential characteristics.

[0106] This comparison demonstrates that the "sequential release mode" depends on the specific design defined by this scheme.

[0107] The porosity was measured in steps S300 and S400. Coating layer thickness / and The system design ultimately achieved controllable release delay in vivo. And optimized short-chain fatty acid concentration profile .

[0108] Finally, the following points should be noted: First, in the description of this application, it should be noted that, unless otherwise specified and limited, the terms "installation", "connection", and "linkage" should be interpreted broadly, and can be mechanical or electrical connections, or internal connections between two components, or direct connections. "Up", "down", "left", "right", etc. are only used to indicate relative positional relationships. When the absolute position of the described object changes, the relative positional relationship may change.

[0109] Secondly: The accompanying drawings of the embodiments disclosed in this invention only involve the structures involved in the embodiments disclosed in this invention. Other structures can refer to the general design. In the absence of conflict, the same embodiment and different embodiments of this invention can be combined with each other.

[0110] In conclusion, the above description is only a preferred embodiment of the present invention and is 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. Use of rosemary extract for the prevention and treatment of Alzheimer's disease through the gut-brain axis, characterized in that, The oral formulation comprises rosemary extract, at least one prebiotic and a colon-targeted delivery system; The prebiotic is an oligosaccharide that can be metabolized by the colonic flora to produce short-chain fatty acids; The colon-targeted delivery system ensures release of the active ingredients in the colon area; The release of the prebiotic and the rosemary extract are configured to form a sequential release pattern in the colon, wherein the time required for the cumulative release of the prebiotic to reach 50% ( ) is earlier than the time required for the cumulative release of the rosemary extract to reach 50% ( ).

2. The rosemary extract for use according to claim 1, characterized in that, The sequential release pattern satisfies: than at least 2 hours in advance.

3. The rosemary extract for use according to claim 1, characterized in that, The prebiotic comprises fructose chains linked by -(2,1) glycosidic bonds, and a degree of polymerization (DP) of 2 to 10.

4. The rosemary extract for use according to claim 1, for preventing and treating Alzheimer's disease through the gut-brain axis, characterized in that, The mass ratio of carrageenan to rosmarinic acid in the rosemary extract ( The ratio is 1:2 to 2:

1.

5. The rosemary extract for use according to claim 1, characterized in that, The sequential release profile is achieved by integrating the prebiotic and rosemary extract in the same composite granule, wherein the prebiotic forms the drug-loaded skeleton and the rosemary extract is dispersed within the skeleton.

6. The rosemary extract for use according to claim 5, characterized in that, The drug-loaded matrix formed by the prebiotic is a porous structure, and the porosity of the porous structure is 45% to 55%. 45% to 55%.

7. The rosemary extract for use according to claim 1, characterized in that, The sequential release pattern is achieved by preparing the prebiotic and rosemary extract as separate drug release units, wherein the average thickness of the colon-targeted coating layer of the prebiotic drug release unit is less than the average thickness of the colon-targeted coating layer of the rosemary extract drug release unit. The sequential release pattern is achieved by preparing the prebiotic and rosemary extract as separate drug release units, wherein the average thickness of the colon-targeted coating layer of the prebiotic drug release unit is less than the average thickness of the colon-targeted coating layer of the rosemary extract drug release unit. The sequential release pattern is achieved by preparing the prebiotic and rosemary extract as separate drug release units, wherein the average thickness of the colon-targeted coating layer of the prebiotic drug release unit is less than the average thickness of the colon-targeted coating layer 8. The rosemary extract for use according to claim 1, for preventing and treating Alzheimer's disease through the gut-brain axis, characterized in that, The colon-targeted delivery system comprises a pH-dependent coating layer and a time-lag layer outside it; the pH-dependent coating layer dissolves when the pH value reaches or exceeds 7.0; the time-lag layer is composed of a material that uniformly dissolves and erodes in the gastrointestinal fluid.

9. The rosemary extract for use according to claim 1, for preventing and treating Alzheimer's disease through the gut-brain axis, characterized in that, The oral formulation has a cumulative release degree of less than 10% in the gastric and small intestinal fluid stages in an in-vitro test of continuous transport in simulated gastrointestinal fluid.

10. The rosemary extract for use according to claim 1, characterized in that, The use is for preparing a medicine or health food for regulating the intestinal flora, increasing the concentration of short-chain fatty acids in the colon cavity and inhibiting neuroinflammation in the brain.

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