Traditional Chinese medicine compound multi-layer coated microsphere preparation for treating pancreatic cancer and preparation method of traditional Chinese medicine compound multi-layer coated microsphere preparation

Abstract

The invention discloses a traditional Chinese medicine compound multi-layer coated microsphere preparation for treating pancreatic cancer and a preparation method thereof. The preparation is prepared from the following active components in parts by weight: 10-35 parts of astragalus extract, 8-25 parts of ganoderma lucidum spore powder, 5-18 parts of sculellaria barbata general flavone and the like. The preparation method comprises the following steps: a) directionally extracting active ingredients; b) removing toxic substances from the dried toad skin through molecular imprinting; c) constructing three layers of coated microspheres, wherein a core layer is a nanocrystal (indirubin / chelidonine / toad peptide), a middle layer is a phospholipid complex (flavone / polysaccharide), and an outer layer is a pH response polysaccharide microsphere; and d) pressing to obtain the three-layer sustained-release tablet. The preparation realizes colon-targeted drug release, the bioavailability is obviously improved, the tumor inhibition rate of animal experiments is improved, and the chemotherapy drug resistance can be reversed.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, specifically to a multi-layered coated microsphere preparation of traditional Chinese medicine compound for treating pancreatic cancer and its preparation method. Background Technology

[0002] Pancreatic cancer is one of the most malignant tumors, and the traditional chemotherapy drug gemcitabine has developed severe resistance. While traditional formulas from the Huangjia Medical Circle have some efficacy, they suffer from low bioavailability, toxicity risks, and unstable components. Current technologies cannot achieve targeted removal of toxic components using traditional decoction processes; single-layer nanoparticles have low drug loading capacity and cannot achieve synergistic delivery of multiple components; and some heavy metal-containing components do not meet modern drug safety requirements. Summary of the Invention

[0003] The purpose of this invention is to provide a multi-layered coated microsphere formulation of traditional Chinese medicine for the treatment of pancreatic cancer and its preparation method. The aim is to achieve colon-targeted drug release, significantly improve bioavailability, reduce toxicity, and reverse chemotherapy resistance in pancreatic cancer through a novel multi-layered coated microsphere formulation of traditional Chinese medicine.

[0004] According to the purpose of this invention, this invention provides a multi-layered coated microsphere preparation of traditional Chinese medicine compound for treating pancreatic cancer, which is composed of the following raw materials in parts by weight: Immunomodulatory components: Astragalus extract (verrucae flavonoids ≥5%) 10~35 parts, Ganoderma lucidum spore powder (triterpenoids ≥8%) 8~25 parts; Antitumor components: 5-18 parts of total flavonoids from Scutellaria barbata (baicalin ≥40%), and 3-15 parts of polysaccharides from Hedyotis diffusa (ASP-3 ≥60%). Drug resistance reversal components: Indigofera tinctoria (purity ≥98%) 0.3~5 parts, Shikonin (acetylshikonin ≥85%) 0.5~4 parts; Microenvironment regulation components: 2-10 parts of dried toad skin active peptide (Buforin II ≥ 50%), 1-6 parts of Angelica ferulic acid (≥ 90%); Auxiliary components: Chelidonium alkaloids (Clidonium red alkaloids ≥95%) 0.5~4 parts, Tanshinone acid (Tamshinone B ≥40%) 4~15 parts, Gynostemma pentaphyllum saponins (GP-LVI ≥80%) 3~12 parts, Curcuma zedoaria volatile oil (β-elemene ≥90%) 0.3~3 parts, Glycyrrhizic acid (≥98%) 1~6 parts.

[0005] According to another objective of the present invention, the present invention provides a method for preparing the above-mentioned multilayer coated microsphere formulation of traditional Chinese medicine for treating pancreatic cancer, comprising the following steps: (1) Targeted extraction of active ingredients: The volatile oil of Curcuma zedoaria was extracted using supercritical CO2 extraction. Chelidonium alkaloids were purified by gradient elution using macroporous resin, HPD-826 resin, pH 9.0~10.0, ammonia-ethanol; Astragalus polysaccharides and Hedyotis diffusa polysaccharides were extracted by enzymatic hydrolysis in simulated intestinal fluid; (2) Removal of toxic components from dried toad skin: Detoxification was performed using molecularly imprinted polymers containing toad venom ligands. (3) Preparation of nanocrystals: Nano-suspensions were prepared from indigo carmine, celandine alkaloids, and active peptides from dried toad skin using an antisolvent precipitation method. (4) Formation of phospholipid complexes: The total flavonoids of Scutellaria barbata and polysaccharides of Hedyotis diffusa were reacted with soybean lecithin in supercritical CO2 at a molar ratio of 1:1.5~2.5. (5) Microfluidic encapsulation: Internal aqueous phase: PBS solution containing nanocrystals; Oil phase: 8-12% PLGA dichloromethane solution; External aqueous phase: 0.5-2% sodium alginate solution; The flow rate ratio (internal:oil:external) = 1:(4-6):(8-12), forming a W / O / W double emulsion; (6) Spray drying: Mix the compound emulsion with Astragalus polysaccharide-Ganoderma lucidum polysaccharide solution (1.5-2.5:1), and spray dry with air inlet at 100-120℃ and air outlet at 50-60℃; (7) Tableting and coating: After the microspheres and excipients are compressed into tablets, enteric coating is applied, resulting in a weight gain of 3-6%.

[0006] The beneficial effects of this invention are: This invention achieves colon-targeted drug release through an innovative three-layer coating structure (nanocrystalline core, phospholipid complex intermediate layer, and pH-responsive polysaccharide outer layer). This formulation effectively reverses chemotherapy resistance to gemcitabine in pancreatic cancer, and its manufacturing process is stable and reliable, meeting the requirements for industrial production. Attached Figure Description

[0007] Figure 1 This is a flowchart of the method according to an embodiment of the present invention; Detailed Implementation The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0008] Example 1 A multi-layered coated microsphere formulation of traditional Chinese medicine for treating pancreatic cancer, the specific technical solution of which is as follows: Formula composition It is composed of the following medicinal materials in parts by weight: 10 parts Astragalus extract, 8 parts Ganoderma lucidum spore powder, 5 parts total flavonoids of Scutellaria barbata, 3 parts Hedyotis diffusa polysaccharide, 2 parts active peptides of dried toad skin, 0.3 parts indigo carmine, 1 part ferulic acid of Angelica sinensis, 0.5 parts alkaloids of Chelidonium majus, 4 parts tanshinone, 3 parts Gynostemma pentaphyllum saponins, 0.3 parts volatile oil of Curcuma zedoaria, 0.5 parts shikonin, and 1 part glycyrrhizic acid.

[0009] Example 2 A multi-layered coated microsphere formulation of traditional Chinese medicine for treating pancreatic cancer, the specific technical solution of which is as follows: Formula composition It is composed of the following medicinal materials in parts by weight: 25 parts Astragalus extract, 20 parts Ganoderma lucidum spore powder, 10 parts total flavonoids of Scutellaria barbata, 10 parts polysaccharide of Hedyotis diffusa, 8 parts active peptides of dried toad skin, 3 parts indigo naturalis, 5 parts ferulic acid of Angelica sinensis, 2 parts alkaloids of Chelidonium majus, 10 parts tanshinone, 10 parts saponins of Gynostemma pentaphyllum, 2 parts volatile oil of Curcuma zedoaria, 2 parts shikonin, and 4 parts glycyrrhizic acid.

[0010] Example 3 A multi-layered coated microsphere formulation of traditional Chinese medicine for treating pancreatic cancer, the specific technical solution of which is as follows: Formula composition It is composed of the following medicinal materials in parts by weight: 35 parts Astragalus extract, 25 parts Ganoderma lucidum spore powder, 18 parts total flavonoids of Scutellaria barbata, 15 parts Hedyotis diffusa polysaccharide, 10 parts active peptides of dried toad skin, 5 parts indigo carmine, 6 parts ferulic acid of Angelica sinensis, 4 parts alkaloids of Chelidonium majus, 15 parts tanshinone, 12 parts saponins of Gynostemma pentaphyllum, 3 parts volatile oil of Curcuma zedoaria, 4 parts shikonin, and 6 parts glycyrrhizic acid.

[0011] Example 4 like Figure 1 As shown, a method for preparing a multi-layered coated microsphere formulation of traditional Chinese medicine for treating pancreatic cancer includes the following steps: (1) Targeted extraction of active ingredients: The volatile oil of Curcuma zedoaria was extracted using supercritical CO2 extraction. Chelidonium alkaloids were purified by gradient elution using macroporous resin, HPD-826 resin, pH 9.0~10.0, ammonia-ethanol; Astragalus polysaccharides and Hedyotis diffusa polysaccharides were extracted by enzymatic hydrolysis in simulated intestinal fluid; (2) Removal of toxic components from dried toad skin: Detoxification was performed using molecularly imprinted polymers containing toad venom ligands. (3) Preparation of nanocrystals: Nano-suspensions were prepared from indigo carmine, celandine alkaloids, and active peptides from dried toad skin using an antisolvent precipitation method. (4) Formation of phospholipid complexes: The total flavonoids of Scutellaria barbata and polysaccharides of Hedyotis diffusa were reacted with soybean lecithin in supercritical CO2 at a molar ratio of 1:1.5~2.5. (5) Microfluidic encapsulation: Internal aqueous phase: PBS solution containing nanocrystals; Oil phase: 8-12% PLGA dichloromethane solution; External aqueous phase: 0.5-2% sodium alginate solution; The flow rate ratio (internal:oil:external) = 1:(4-6):(8-12), forming a W / O / W double emulsion; (6) Spray drying: Mix the compound emulsion with Astragalus polysaccharide-Ganoderma lucidum polysaccharide solution (1.5-2.5:1), and spray dry with air inlet at 100-120℃ and air outlet at 50-60℃; (7) Tableting and coating: After the microspheres and excipients are compressed into tablets, enteric coating is applied, resulting in a weight gain of 3-6%.

[0012] Example 5 Preparation of active ingredients Curcuma zedoaria volatile oil: Take 500g of crude Curcuma zedoaria powder and extract by supercritical CO2 (45℃, 35 MPa) to obtain 12.8g of oil (GC detection showed β-elemene 92.3%). Detoxified dried toad peptides: 300g of dried toad skin was ultrasonically crushed, detoxified by molecular imprinting column (sample solution pH 6.0), separated by Sephadex G-25, and freeze-dried to obtain 15.6g of active peptides (HPLC detection showed that the residual amount of toad venom ligand was 42 ppm).

[0013] Example 6 Preparation of three-layer microspheres Nanocrystalline core: 100 mg of indigo red and 200 mg of celandine were dissolved in acetone, injected into 0.5% Poloxamer 188 aqueous solution, and stirred to obtain a suspension with a particle size of 89 nm. Phospholipid complex: 500mg Scutellaria barbata flavonoids, 300mg ASP-3 polysaccharide, 1.6g soybean lecithin, supercritical CO2 (45℃ / 15 MPa) reaction for 90 min; Microfluidic encapsulation: A double emulsion was formed by mixing the inner phase (nanocrystalline PBS) at 1 ml / min, the oil phase (10% PLGA) at 5 ml / min, and the outer phase (1% sodium alginate) at 10 ml / min. Spray drying: The re-emulsion was mixed with 2% Astragalus polysaccharide solution at a ratio of 1:2 and spray dried at 110℃ to obtain microspheres (average particle size 7.2μm, encapsulation efficiency 92.3%).

[0014] The multilayered coated microsphere formulation of traditional Chinese medicine compound of this invention exhibits significant beneficial effects, mainly in three aspects: enhanced efficacy, reduced toxicity, and reversal of drug resistance. This formulation achieves colon-targeted drug release through an innovative three-layer coating structure (nanocrystalline core, phospholipid complex intermediate layer, and pH-responsive polysaccharide outer layer). This formulation can effectively reverse chemotherapy resistance to gemcitabine in pancreatic cancer, and its production process is stable and reliable, meeting the requirements for industrial production.

[0015] Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A multi-layered coated microsphere formulation of traditional Chinese medicine for treating pancreatic cancer, characterized in that, It is composed of the following raw materials in parts by weight: 10-35 parts of Astragalus membranaceus extract, 8-25 parts of Ganoderma lucidum spore powder, 5-18 parts of total flavonoids from Scutellaria barbata, 3-15 parts of Hedyotis diffusa polysaccharide, 2-10 parts of active peptides from dried toad skin, 0.3-5 parts of indigo naturalis, 1-6 parts of ferulic acid from Angelica sinensis, 0.5-4 parts of chelidon alkaloids, 4-15 parts of tanshinone, 3-12 parts of Gynostemma pentaphyllum saponins, 0.3-3 parts of volatile oil from Curcuma zedoaria, 0.5-4 parts of shikonin, and 1-6 parts of glycyrrhizic acid.

2. A multi-layered coated microsphere preparation of traditional Chinese medicine compound for treating pancreatic cancer, characterized in that, It is composed of the following raw materials in parts by weight: 25 parts Astragalus extract, 20 parts Ganoderma lucidum spore powder, 10 parts total flavonoids of Scutellaria barbata, 10 parts polysaccharide of Hedyotis diffusa, 8 parts active peptides of dried toad skin, 3 parts indigo carmine, 5 parts ferulic acid of Angelica sinensis, 2 parts alkaloids of Chelidonium majus, 10 parts tanshinone, 10 parts saponins of Gynostemma pentaphyllum, 2 parts volatile oil of Curcuma zedoaria, 2 parts shikonin, and 4 parts glycyrrhizic acid.

3. The multi-layered coated microsphere preparation of traditional Chinese medicine compound for treating pancreatic cancer according to claim 1, characterized in that: The active peptides from dried toad skin were detoxified using molecular imprinting technology, with a residual amount of <50 ppm; the mass ratio of baicalin to apigenin in the total flavonoids of Scutellaria barbata was (2.5–3.5):1; and the molecular weight of the polysaccharide from Hedyotis diffusa was 8–60 kDa.

4. The multi-layered coated microsphere formulation of traditional Chinese medicine compound for treating pancreatic cancer according to claim 1, characterized in that... It has a three-layer encapsulation structure: Core layer: Nanocrystals of indigo, celandine alkaloids, and active peptides from dried toad skin, with a particle size of 40~120 nm, encapsulated in a mesoporous silica carrier; Middle layer: Phospholipid complex formed by total flavonoids of Scutellaria barbata and polysaccharides of Hedyotis diffusa, with a particle size of 150~250 nm; Outer layer: Sodium alginate-chitosan copolymer microsphere coating, particle size 4~10μm, dissolves in an environment with pH≥7.

0.

5. A method for preparing a multi-layered coated microsphere formulation of traditional Chinese medicine compound for treating pancreatic cancer as described in any one of claims 1 to 4, characterized in that, Includes the following steps: (1) Targeted extraction of active ingredients: The volatile oil of Curcuma zedoaria was extracted using supercritical CO2 extraction. Chelidonium alkaloids were purified by gradient elution using macroporous resin, HPD-826 resin, pH 9.0~10.0, ammonia-ethanol; Astragalus polysaccharides and Hedyotis diffusa polysaccharides were extracted by enzymatic hydrolysis in simulated intestinal fluid; (2) Removal of toxic components from dried toad skin: Detoxification was performed using molecularly imprinted polymers containing toad venom ligands. (3) Preparation of nanocrystals: Nano-suspensions were prepared from indigo carmine, celandine alkaloids, and active peptides from dried toad skin using an antisolvent precipitation method. (4) Formation of phospholipid complexes: The total flavonoids of Scutellaria barbata and polysaccharides of Hedyotis diffusa were reacted with soybean lecithin in supercritical CO2 at a molar ratio of 1:1.5~2.

5. (5) Microfluidic encapsulation: Internal aqueous phase: PBS solution containing nanocrystals; Oil phase: 8-12% PLGA dichloromethane solution; External aqueous phase: 0.5-2% sodium alginate solution; The flow rate ratio (internal:oil:external) = 1:(4-6):(8-12), forming a W / O / W double emulsion; (6) Spray drying: Mix the compound emulsion with Astragalus polysaccharide-Ganoderma lucidum polysaccharide solution (1.5-2.5:1), and spray dry with air inlet at 100-120℃ and air outlet at 50-60℃; (7) Tableting and coating: After the microspheres and excipients are compressed into tablets, enteric coating is applied, resulting in a weight gain of 3-6%.

6. The method according to claim 5, characterized in that: In step (6), the atomization pressure of spray drying is 0.2~0.4 MPa.

7. The use of the formulation according to any one of claims 1-4 in the preparation of a drug for treating pancreatic cancer, characterized in that... Used in combination with gemcitabine.

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