Universal targeted delivery system for multi-category functional compositions, preparation method and application

Abstract

The application discloses a universal targeted delivery system suitable for multi-category functional compositions, a preparation method and application, and belongs to the technical field of active ingredient delivery. The application takes a targeted functional peptide combined with a hydroxypropyl-beta-cyclodextrin complex system as a core, and is matched with liposomes, exosomes, antibody coupling and stimulus-responsive delivery systems; the molecular weight of the targeted functional peptide is limited to 120Da-5000Da, and the particle size of the liposomes is limited to 20nm-200nm. The application can load twelve categories of functional active components and traditional Chinese medicine extracts, and is suitable for health foods, nutritional supplements, traditional Chinese medicine preparations and ordinary functional foods. The application optimizes carrier parameters and combination modes through tests, is not a simple superposition of prior art, has strong global adaptability, a simple process and high industrialization, can effectively improve the stability of active ingredients and the targeted delivery effect, has high technical barriers, and has high application and commercial values.

Description

Technical Field

[0001] This invention belongs to the field of functional food, health food, traditional Chinese medicine preparation, chemical drug and biopharmaceutical active ingredient delivery technology, specifically involving a universal targeted delivery system, preparation method and application adapted to multiple types of functional compositions. Background Technology

[0002] Currently, most functional compositions targeting aging improvement, chronic disease management, and nutritional supplementation are prepared by directly mixing active ingredients physically and simply encapsulating them with conventional excipients. After oral administration, these active ingredients are easily broken down by stomach acid and gastrointestinal digestive enzymes, resulting in short retention times in the body and an overall bioavailability generally below 30%. Furthermore, existing products lack targeted delivery capabilities, preventing the active ingredients from precisely targeting diseased tissues and cells, thus hindering the full realization of the product's actual efficacy.

[0003] Currently, peptide, liposome, cyclodextrin, exosome, antibody conjugate, and stimulus-responsive delivery technologies have been gradually applied to the health product field. However, existing technologies have significant drawbacks: First, each delivery technology is used independently, only suitable for a single product category and single efficacy, with poor versatility, and there is no cross-category integrated delivery technology platform. Second, different active ingredients have significant differences in physicochemical properties, and water-soluble, lipid-soluble, macromolecular, and small molecule substances are difficult to share a single delivery system, leading to repeated development of formulation processes by enterprises and high R&D and production costs. Third, the components of traditional Chinese medicine compound extracts are complex, and existing single delivery technologies cannot simultaneously accommodate multiple active substances such as polyphenols, flavonoids, volatile oils, and polysaccharides.

[0004] Currently, there is no universally applicable targeted delivery system that integrates multiple delivery technologies, allows for flexible selection, adapts to twelve major functional components, and is compatible with modern bioactive components and traditional Chinese medicine extracts. To overcome the shortcomings of existing technologies, this invention, after extensive screening and experimentation, integrates six major delivery technologies and optimizes parameters and combinations to construct an integrated underlying targeted delivery technology platform. Currently, most functional compositions targeting aging improvement, chronic disease management, and nutritional supplementation employ direct physical mixing of active ingredients and simple encapsulation with conventional excipients. After oral administration, the active ingredients are easily decomposed by gastric acid and gastrointestinal digestive enzymes, resulting in short retention times and overall bioavailability generally below 30%. Furthermore, existing products lack targeted delivery capabilities, preventing the active ingredients from precisely targeting lesion tissues and cells, thus hindering the full realization of the product's efficacy.

[0005] Currently, peptide, liposome, cyclodextrin, exosome, antibody conjugate, and stimulus-responsive delivery technologies have been gradually applied to the health product field. However, existing technologies have significant drawbacks: First, each delivery technology is used independently, only suitable for a single product category and single efficacy, with poor versatility, and there is no cross-category integrated delivery technology platform. Second, different active ingredients have significant differences in physicochemical properties, and water-soluble, lipid-soluble, macromolecular, and small molecule substances are difficult to share a single delivery system, leading to repeated development of formulation processes by enterprises and high R&D and production costs. Third, the components of traditional Chinese medicine compound extracts are complex, and existing single delivery technologies cannot simultaneously accommodate multiple active substances such as polyphenols, flavonoids, volatile oils, and polysaccharides.

[0006] Currently, there is no universal targeted delivery system that integrates multiple delivery technologies, allows for flexible selection, adapts to twelve major functional components, and is compatible with modern bioactive components and traditional Chinese medicine extracts. To overcome the shortcomings of existing technologies, this invention, through extensive screening and experimentation, integrates six major delivery technologies and optimizes parameters and combinations to construct an integrated underlying targeted delivery technology platform. Summary of the Invention

[0007] Purpose of the invention The purpose of this invention is to provide a universal targeted delivery system, preparation method, and application suitable for various functional compositions. This invention preferably uses a composite system of peptide targeting combined with cyclodextrin inclusion as the core solution, complemented by various dedicated delivery systems. It boasts strong versatility, mature technology, and controllable production costs; it can significantly improve the storage stability, gastrointestinal tolerance, and cellular uptake efficiency of active ingredients, achieving targeted delivery and slow release of active components.

[0008] This invention is not a simple patchwork of existing single technologies, but rather a targeted screening and optimization of carrier parameters, binding methods, particle size, and molecular weight based on the types of active components and the characteristics of target organs. The six delivery technologies work synergistically and complement each other, solving the pain points of fragmented technology and repetitive process development in the industry, and has good application value. Technical solution

[0009] The targeted delivery system of this invention is used to load active components of aging regulation pathways, cancer nutritional supplement components, cardiovascular and cerebrovascular care components, blood sugar regulation components, liver care components, gastrointestinal conditioning components, brain nutrition and nerve repair components, bone care components, rheumatic bone and joint conditioning components, immune regulation components, spleen care components, respiratory disease conditioning components, as well as extracts from traditional Chinese medicine formulas and empirical formulas.

[0010] The targeted delivery system is selected from at least one of the following: peptide targeted delivery system, liposome / lipid nanoparticle delivery system, cyclodextrin and its derivative inclusion delivery system, exosome / extracellular vesicle delivery system, antibody-conjugated delivery system, and stimulus-responsive delivery system. This delivery system can be selected based on the solubility, molecular weight, and target site of the active ingredient, improving the stability, gastrointestinal tolerance, and cellular uptake efficiency of the active ingredient. It is suitable for the development of oral formulations, health foods, and traditional Chinese medicine products. It includes components for treating rheumatoid arthritis, immune regulation, spleen maintenance, respiratory diseases, and extracts from classical and empirical traditional Chinese medicine formulas.

[0011] The targeted delivery system is selected from at least one of the following: peptide targeted delivery system, liposome / lipid nanoparticle delivery system, cyclodextrin and its derivative inclusion delivery system, exosome / extracellular vesicle delivery system, antibody-conjugated delivery system, and stimulus-responsive delivery system. This delivery system can be selected based on the solubility, molecular weight, and target site of the active ingredient, improving the stability, gastrointestinal tolerance, and cellular uptake efficiency of the active ingredient. It is suitable for the development of oral formulations, health foods, and traditional Chinese medicines.

[0012] The peptide targeted delivery system includes a targeted functional peptide, which is an oligopeptide, a small molecule peptide, or a complex peptide with a molecular weight of 120 Da to 5000 Da, and is selected from one or more of marine-derived peptides, plant-derived peptides, and animal-derived enzymatically hydrolyzed peptides.

[0013] Experiments have verified that this molecular weight range can simultaneously balance intestinal absorption efficiency, cell membrane penetration, and in vivo metabolic safety. Among them, peptides with a molecular weight of no more than 1000 Da have better industrial adaptability, while peptides with a molecular weight of no more than 500 Da have the best biomembrane permeability. Peptides with a molecular weight greater than 1000 Da have reduced absorption capacity and can be used in combination with cyclodextrins and liposomes.

[0014] The targeted functional peptide is loaded with active components through non-covalent adsorption or covalent binding, and the target sites include at least one of intestinal epithelial cells, skin fibroblasts, mitochondria, and senescent cells.

[0015] The cyclodextrin and its derivatives are selected from one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin, with hydroxypropyl-β-cyclodextrin being preferred. The active ingredients are encapsulated using a molecular cage-like inclusion method to achieve solubilization, anti-degradation, and intestinal targeted delivery of the ingredients.

[0016] It is formulated with phospholipids, cholesterol, and food-grade cosolvents, with a particle size controlled between 20nm and 200nm. It can simultaneously encapsulate both water-soluble and lipid-soluble active components, making it suitable for the delivery of highly hydrophobic, large-molecule active substances.

[0017] With a particle size of 20nm to 200nm, it uses natural extracellular vesicles derived from mammalian cells as carriers, has low immunogenicity, and can achieve targeted delivery to deep tissues, especially suitable for neuronal components in the brain.

[0018] Prepared by sequentially coupling a targeting antibody, a small molecule linker, and an active component, it can specifically recognize and bind to diseased cells, making it suitable for precise targeting of lesions.

[0019] Selected from one or more of pH-responsive, ROS-responsive, GSH-responsive, and temperature-responsive types, it can sense changes in the lesion microenvironment and release active components at specific points.

[0020] 1. Active components of aging regulation pathways: These are active substances that act on pathways such as NAD⁺ replenishment, anti-oxidation, autophagy, mitochondrial repair, telomere protection, senescent cell clearance, AMPK / mTOR regulation, epigenetic regulation, immune regulation, anti-glycation, and cell repair.

[0021] 2. Cancer nutritional supplement components: Used for nutritional support, body repair, and immune enhancement in cancer patients, targeting tissues surrounding lesions, immune cells, and digestive tract cells.

[0022] 3. Cardiovascular and cerebrovascular care components: used for vascular protection, myocardial care, and regulation of blood lipids and blood pressure, targeting vascular endothelial cells and cardiomyocytes.

[0023] 4. Blood glucose regulation component: used to improve insulin sensitivity, regulate glucose metabolism, and target pancreatic islet cells, liver cells, and intestinal metabolic cells.

[0024] 5. Liver-nourishing components: used for hepatocyte repair and regulation of liver function, targeting liver parenchymal cells and hepatic stellate cells.

[0025] 6. Gastrointestinal conditioning components: used to repair the gastrointestinal mucosa, regulate the intestinal flora, and improve digestive function, targeting the action sites of gastric mucosal cells, intestinal epithelial cells, and intestinal flora.

[0026] 7. Brain nutrition and nerve repair components: used to nourish brain nerves, improve cognitive function, and target brain nerve cells, blood-brain barrier, and central nervous system tissue.

[0027] 8. Bone care components: used to repair bone cells, increase bone density, and target osteoblasts, osteoclasts, and articular cartilage cells.

[0028] 9. Rheumatoid and Osteoarthritis Conditioning Components: Used for anti-inflammatory purposes, repairing the synovial membrane of joints, and targeting synovial cells and soft tissues of joints.

[0029] 10. Immunomodulatory components: used to regulate the body's immune balance, activate immune cells, and target lymphocytes, macrophages, and systemic immune tissues.

[0030] 11. Spleen-nourishing components: used to regulate spleen function, repair spleen cells, and target spleen parenchymal cells and spleen immune cells.

[0031] 12. Respiratory Disease Conditioning Components: Used to repair airway mucosa and maintain lung health, targeting airway epithelial cells, lung tissue cells, and respiratory mucosal cells.

[0032] 13. Extracts from traditional Chinese medicine formulas and prescriptions: These are prepared from Chinese medicinal herbs or compound Chinese medicine formulas through water extraction, alcohol extraction, water extraction and alcohol precipitation, and extraction processes. They contain active ingredients such as polyphenols, flavonoids, alkaloids, saponins, polysaccharides, and volatile oils.

[0033] The overall preparation process of the delivery system of this invention includes five major steps: carrier pretreatment, active component loading, homogenization mixing, solidification and embedding, and sieving and granulation.

[0034] By weight: 3 parts targeted small molecule peptides, 25 parts hydroxypropyl-β-cyclodextrin, 12 parts functional active ingredients, and 60 parts maltodextrin.

[0035] Preparation steps: S1 Carrier pretreatment: Mix hydroxypropyl-β-cyclodextrin with maltodextrin and stir at room temperature for 10-30 minutes until homogeneous; S2 peptide carrier loading: Dissolve the targeted functional peptide in purified water, add the active component, and stir at room temperature for 20-60 min to form a stable complex; S3 Composite embedding: Add the composite obtained in step S2 to the pretreated carrier system and homogenize at high speed for 10-20 min; S4 Post-processing: Low-temperature drying, granulation, and sieving to obtain the finished targeted delivery complex.

[0036] Phosphatidylcholine and cholesterol were mixed at a mass ratio of 8:2, and food-grade ethanol was added as a co-solvent. The mixture was then rotary evaporated at 40–50°C to form a uniform thin film. An aqueous solution containing the active components was added and hydrated at room temperature for 30 minutes. The mixture was then ultrasonically treated with a probe to obtain liposomes with a particle size of 50–120 nm and an encapsulation rate of over 80%.

[0037] The exosome, antibody conjugate, and stimulus-responsive delivery system are prepared using conventional and mature processes in the field. By combining the particle size and carrier parameters specified in this invention, stable loading of active components can be achieved.

[0038] The universal targeted delivery system described in this invention can be used to prepare the following products: 1. Health food products: anti-aging, immune-boosting, blood lipid / blood sugar regulating, gastrointestinal conditioning, liver protection, and memory-improving health food products; 2. Nutritional supplements: Special nutritional supplements for cancer patients, bone health supplements, and respiratory health supplements; 3. Traditional Chinese medicine preparations and chemical drugs: cardiovascular and cerebrovascular drugs, gastrointestinal drugs, liver and kidney care drugs, bone and joint drugs, and respiratory drugs; 4. Common functional foods. Beneficial effects

[0039] 1. This invention integrates six major categories of delivery technologies to form an integrated platform, which is used to classify and adapt various active components and traditional Chinese medicine extracts with large differences in physicochemical properties. Combined with a large number of experiments to screen the optimal parameters, different technologies work together and complement each other to achieve a full-domain adaptation effect that cannot be achieved by a single existing technology. It is not a simple superposition of existing technologies.

[0040] 2. Significantly improves the storage stability, resistance to gastric acid decomposition, and cellular uptake efficiency of active ingredients; tests showed that the activity retention rate of water-soluble small molecule active ingredients in the core system increased from 71.2% to 92.5% after 30 days of storage at room temperature, and the cellular uptake efficiency increased by about 1.8 times.

[0041] 3. The core composite system uses food-grade raw materials and conventional production equipment. The process is simple, can be mass-produced on a large scale, has low implementation difficulty, and controllable costs.

[0042] 4. A single technology platform can cover twelve major categories of functional products and traditional Chinese medicine extracts, eliminating the need for repeated process development and significantly reducing R&D and production costs.

[0043] 5. This invention clearly defines the molecular weight, particle size, raw material type, ratio, and process parameters of the carrier, resulting in high technical barriers that are difficult for competitors to easily circumvent.

[0044] 6. The technology has flexible application modes, and can be transferred or licensed independently, or used commercially in combination with formulated products and preparations. Detailed Implementation

[0045] The following embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Example 1: Peptide + Hydroxypropyl-β-Cyclodextrin Complex System (Anti-aging Active Component)

[0046] Raw material ratio (parts by weight): 3 parts plant-derived enzymatically hydrolyzed peptides with a molecular weight not greater than 500 Da, 25 parts hydroxypropyl-β-cyclodextrin, 12 parts multi-pathway anti-aging mixed active ingredients, and 60 parts maltodextrin.

[0047] Preparation steps: (1) Carrier pretreatment: Hydroxypropyl-β-cyclodextrin and maltodextrin were mixed and stirred at room temperature for 20 min; (2) Peptide-active compound: The targeted peptide is dissolved in purified water, and the anti-aging active component is added. The mixture is stirred at room temperature for 40 min to form a non-covalently bound complex. (3) Composite embedding: The composite was added to the carrier system and homogenized at high speed for 15 min; (4) Low-temperature drying, granulation and sieving to obtain the finished product.

[0048] Efficacy testing: Compared with the traditional non-targeted formula as the control group, after 30 days of storage at room temperature, the retention rate of active components in the control group was 71.2%, while that in the experimental group was 92.5%; the cell uptake rate in the experimental group was about 1.8 times higher than that in the control group. Example 2: Liposome Delivery System (Lipid-soluble Cardiovascular and Cerebrovascular Care Components)

[0049] Phosphatidylcholine and cholesterol were mixed at a mass ratio of 8:2, and ethanol was added as a co-solvent. The mixture was then rotary evaporated at 45°C to form a film. A liposome containing lipid-soluble cardiovascular active components was added for 30 minutes of hydration, followed by ultrasonic treatment with a probe to obtain liposomes with a particle size of 60–90 nm. Testing showed that the encapsulation efficiency of the liposomes was ≥82%, and the retention rate of active components was ≥83% after 30 days of storage at room temperature. Example 3: Pure peptide targeted delivery system (water-soluble component for gastrointestinal conditioning)

[0050] A plant-derived small molecule peptide with a molecular weight of 500 Da was selected as a carrier and non-covalently bound to the gastrointestinal conditioning active ingredients to prepare an orally delivered product. Test results showed that the uptake efficiency by intestinal epithelial cells was more than 1.5 times higher than that of ordinary formulas, and gastrointestinal tolerance was significantly improved. Example 4: Cyclodextrin Single Inclusion System (Water-soluble Extract of Traditional Chinese Medicine)

[0051] Hydroxypropyl-β-cyclodextrin is used to molecularly encapsulate flavonoids and polyphenols from traditional Chinese medicine. After 30 days of storage at room temperature, the activity retention rate is ≥81%, effectively improving the defects of easy oxidation and poor stability of the extracts. Exosomes, antibody conjugates, and stimulus-responsive delivery systems can be prepared according to known processes in the art, combined with the parameters defined in this invention, and are respectively suitable for brain nerve, lesion targeting, and microenvironment responsive products. Detection methods

[0052] 1. The content of active ingredients was determined by high performance liquid chromatography (HPLC), and storage stability was evaluated. 2. Cell uptake efficiency was detected using fluorescent labeling combined with flow cytometry; 3. The intestinal targeting performance was verified using the Caco-2 cell model.

Claims

1. A universal targeted delivery system for adapting multi-class functional compositions, characterized in that, Including a complex carrier composed of targeted functional peptides and hydroxypropyl-β-cyclodextrin; The composite carrier is used to load active components of aging regulation pathways, cancer nutritional supplement components, cardiovascular and cerebrovascular care components, blood sugar regulation components, liver care components, gastrointestinal conditioning components, brain nutrition and nerve repair components, bone care components, rheumatic bone and joint conditioning components, immune regulation components, spleen care components, respiratory disease conditioning components, as well as extracts of traditional Chinese medicine formulas and empirical formulas. The targeted functional peptide is an oligopeptide, a small molecule peptide, or a complex peptide with a molecular weight of 120 Da to 5000 Da, and is selected from one or more of marine peptides, plant peptides, and animal enzymatic peptides; the targeted functional peptide is loaded with active components through covalent binding or non-covalent adsorption. The composite carrier can improve the storage stability, gastrointestinal tolerance and cellular uptake efficiency of active ingredients, and achieve targeted delivery and slow release of active ingredients.

2. The universal targeted delivery system according to claim 1, characterized in that, The preferred molecular weight of the targeted functional peptide is no greater than 1000 Da.

3. The universal targeted delivery system according to claim 2, characterized in that, The molecular weight of the targeted functional peptide is further preferably no greater than 500 Da.

4. The universal targeted delivery system according to claim 1, characterized in that, The target sites of the targeted functional peptides include at least one of intestinal epithelial cells, skin fibroblasts, mitochondria, and senescent cells.

5. The universal targeted delivery system according to claim 1, characterized in that, It can also be used in combination with one or more of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

6. A universal targeted delivery system adaptable to multiple functional compositions, characterized in that, It is a liposome / lipid nanoparticle delivery system composed of phospholipids, cholesterol, and cosolvents, with a particle size of 20nm to 200nm, used to load the various active components and traditional Chinese medicine extracts described in claim 1, and can simultaneously encapsulate water-soluble and lipid-soluble active components.

7. A universal targeted delivery system adaptable to multiple functional compositions, characterized in that, It is an exosome / extracellular vesicle delivery system with a particle size of 20nm to 200nm, used to load the various active components and traditional Chinese medicine extracts described in claim 1 to achieve targeted delivery with low immunogenicity.

8. A universal targeted delivery system adaptable to multiple functional compositions, characterized in that, It is an antibody-conjugated delivery system composed of a targeting antibody, a linker arm, and an active component, used to load the various active components and traditional Chinese medicine extracts described in claim 1, and specifically target diseased cells.

9. A universal targeted delivery system adaptable to multiple functional compositions, characterized in that, It is a stimulus-responsive delivery system, selected from one or more of pH-responsive, ROS-responsive, GSH-responsive, and temperature-responsive types, used to load the various active components and traditional Chinese medicine extracts described in claim 1, and to release the active components in a targeted manner in the lesion microenvironment.

10. The universal targeted delivery system according to claim 1, characterized in that, The active components of the aging regulation pathway are active substances that act on NAD⁺ replenishment, anti-oxidation, autophagy, mitochondrial repair, telomere protection, senescent cell clearance, AMPK / mTOR regulation, epigenetic regulation, immune regulation, anti-glycation, and cell repair pathways.

11. The universal targeted delivery system according to claim 1, characterized in that, The cancer nutritional supplement components target the tissues surrounding the lesion, immune cells, and digestive tract cells.

12. The universal targeted delivery system according to claim 1, characterized in that, The cardiovascular and cerebrovascular care components target vascular endothelial cells and cardiomyocytes.

13. The universal targeted delivery system according to claim 1, characterized in that, The blood glucose regulating component targets pancreatic islet cells, liver cells, and intestinal metabolic cells.

14. The universal targeted delivery system according to claim 1, characterized in that, The liver care components target liver parenchymal cells and hepatic stellate cells.

15. The universal targeted delivery system according to claim 1, characterized in that, The gastrointestinal conditioning components target gastric mucosal cells, intestinal epithelial cells, and intestinal flora.

16. The universal targeted delivery system according to claim 1, characterized in that, The brain nutrition and nerve repair components target brain nerve cells, the blood-brain barrier, and central nervous system tissue.

17. The universal targeted delivery system according to claim 1, characterized in that, The bone care components target osteoblasts, osteoclasts, and articular chondrocytes.

18. The universal targeted delivery system according to claim 1, characterized in that, The rheumatoid arthritis conditioning components target synovial cells and soft tissues of the joints.

19. The universal targeted delivery system according to claim 1, characterized in that, The immunomodulatory components target lymphocytes, macrophages, and systemic immune tissues.

20. The universal targeted delivery system according to claim 1, characterized in that, The spleen care components target spleen parenchymal cells and spleen immune cells.

21. The universal targeted delivery system according to claim 1, characterized in that, The respiratory disease conditioning components target airway epithelial cells, lung tissue cells, and respiratory mucosal cells.

22. The universal targeted delivery system according to claim 1, characterized in that, The extracts from the traditional Chinese medicine formulas and prescriptions are obtained by water extraction, alcohol extraction, water extraction and alcohol precipitation, and extraction of Chinese medicinal materials or Chinese medicine compound formulas. They contain active ingredients such as polyphenols, flavonoids, alkaloids, saponins, polysaccharides, and volatile oils.

23. A method for preparing the universal targeted delivery system according to any one of claims 1 to 4, characterized in that, Includes the following steps: S1 carrier pretreatment: Hydroxypropyl-β-cyclodextrin is mixed with excipients and stirred at room temperature for 10-30 min; S2 peptide carrier loading: The targeted functional peptide is dissolved in purified water, the active component is added, and the mixture is stirred at room temperature for 20-60 min to form a complex. S3 composite encapsulation: The composite is added to the pretreated carrier and homogenized at high speed; S4 Post-processing: Drying, granulation, and sieving to obtain the finished product.

24. An application of the universal targeted delivery system of claim 1, characterized in that, It is used to prepare health foods, nutritional supplements, traditional Chinese medicine preparations, chemical drugs and functional foods in the categories of anti-aging, tumor nutrition supplements, cardiovascular and cerebrovascular care, blood sugar regulation, liver and kidney care, gastrointestinal conditioning, brain nutrition, bone care, bone and joint conditioning, immune regulation, spleen care, and respiratory conditioning.