A traditional Chinese medicine composition for the prevention and treatment of Alzheimer's disease and its application

Abstract

This invention discloses a traditional Chinese medicine composition and its application for the prevention and treatment of Alzheimer's disease, belonging to the field of traditional Chinese medicine technology. The compound is composed of Rehmannia glutinosa (processed), Cornus officinalis, Ilex pubescens, Panax ginseng, Acorus tatarinowii, Polygala tenuifolia, Ligusticum chuanxiong, Angelica sinensis, Poria cocos, Pinellia ternata (processed), Gastrodia elata, Salvia miltiorrhiza, and Glycyrrhiza uralensis (processed) in specific weight proportions. Polygala tenuifolia and Acorus tatarinowii are the core herb pair for opening the orifices and improving intelligence, while Gastrodia elata and Salvia miltiorrhiza are the auxiliary herb pair for promoting blood circulation, calming wind, and awakening the brain. The preparation method includes raw material pulverization, water decoction, vacuum concentration, spray drying, and formulation. Animal experiments show that this invention can significantly shorten the escape latency of AD model mice, increase the number of platform crossings, reduce Aβ deposition, decrease Tau protein phosphorylation, inhibit neuroinflammation, protect the cholinergic system, and increase cerebral blood flow, with efficacy superior to the positive control drug donepezil. This invention is applicable to the preparation of drugs for treating Alzheimer's disease, senile dementia, vascular dementia, mild cognitive impairment, and memory decline.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a traditional Chinese medicine compound composition for treating Alzheimer's disease, its preparation method, pharmaceutical formulation, and its application in the preparation of drugs for treating Alzheimer's disease and related cognitive impairments. Background Technology

[0002] Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive cognitive decline, memory loss, speech disorders, and personality and behavioral abnormalities. Its core pathological features include abnormal deposition of β-amyloid protein (Aβ), hyperphosphorylation of tau protein, chronic neuroinflammation, oxidative stress damage, cholinergic system dysfunction, and cerebral circulatory disorders.

[0003] Currently, commonly used Western medicines such as cholinesterase inhibitors (donepezil, etc.) and NMDA receptor antagonists (memantine) can only relieve some symptoms in the short term, but cannot reverse or delay the progression of the disease. They are often accompanied by adverse reactions such as gastrointestinal reactions, dizziness, and burden on liver and kidney function, which are difficult to meet the long-term treatment needs of elderly patients.

[0004] Traditional Chinese medicine (TCM) categorizes Alzheimer's disease (AD) under the terms "dementia," "mental dementia," and "amnesia," believing the disease originates in the brain and is closely related to the heart, kidneys, spleen, and liver. The core pathogenesis is considered to be rooted in kidney essence deficiency and insufficient replenishment of the marrow, while the superficial manifestations include phlegm turbidity and blood stasis obstructing the sensory orifices and cerebral meridian obstruction. Existing TCM formulas are mostly based on modifications of ancient prescriptions, exhibiting shortcomings such as unclear compatibility, insufficient efficacy in opening the orifices and improving intelligence, weak blood-activating and brain-clearing effects, ambiguous dosage ratios, and a lack of modern pharmacological validation. In particular, there is a lack of integrated formulas that use Polygala tenuifolia and Acorus tatarinowii as the core orifice-opening pair, while also incorporating Gastrodia elata for calming wind and awakening the brain, and Salvia miltiorrhiza for its potent blood-activating properties. Therefore, these formulas cannot comprehensively address the underlying pathogenesis of dementia, which involves "deficiency of the root and excess of the branch, and obstruction of the brain meridians."

[0005] Therefore, developing a traditional Chinese medicine compound with rigorous formulation, clear target, outstanding efficacy, and suitability for long-term use is of great clinical significance. Summary of the Invention

[0006] The purpose of this invention is to provide a traditional Chinese medicine compound composition for treating Alzheimer's disease. It uses Polygala tenuifolia and Acorus tatarinowii as the core ingredients for opening the orifices and improving intelligence, and Gastrodia elata and Salvia miltiorrhiza as auxiliary ingredients for promoting blood circulation, extinguishing wind, and awakening the brain. Strictly following the principles of traditional Chinese medicine formulation, it achieves a five-in-one effect of tonifying the kidneys and replenishing essence, resolving phlegm and removing blood stasis, promoting blood circulation and unblocking collaterals, opening the orifices and awakening the brain, and extinguishing wind and protecting the brain. This multi-target synergistic effect reverses AD pathology and significantly improves learning, memory, and cognitive function. Simultaneously, it provides a stable and controllable preparation method and clinical application plan.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution: This invention relates to a traditional Chinese medicine compound composition for treating Alzheimer's disease, made from the following raw materials in parts by weight: 20-35 parts of Rehmannia glutinosa (processed), 12-18 parts of Cornus officinalis, 12-18 parts of Panax ginseng, 10-15 parts of Ilex pubescens, 15-20 parts of Acorus tatarinowii, 12-18 parts of Polygala tenuifolia, 10-15 parts of Ligusticum chuanxiong, 12-18 parts of Angelica sinensis, 15-25 parts of Poria cocos, 10-15 parts of Pinellia ternata (processed), 10-15 parts of Gastrodia elata, 12-18 parts of Salvia miltiorrhiza, and 5-8 parts of Glycyrrhiza uralensis (processed).

[0008] Preferred proportions (parts by weight): Prepared Rehmannia Root 30g, Cornus Fruit 15g, Ginseng 15g, Ilex pubescens 15g, Acorus tatarinowii 18g, Polygala tenuifolia 15g, Ligusticum chuanxiong 12g, Angelica sinensis 15g, Poria cocos 20g, Prepared Pinellia ternata 12g, Gastrodia elata 12g, Salvia miltiorrhiza 15g, Prepared Licorice Root 6g.

[0009] Raw material quality standards: Compliant with the standards of Part I of the 2020 edition of the Pharmacopoeia of the People's Republic of China. Among them, Rehmannia glutinosa is stewed or steamed with wine; Cornus officinalis is processed with wine; Ginseng is sun-dried or red ginseng; Pinellia ternata is processed with ginger and alum; Gastrodia elata is winter-processed; Salvia miltiorrhiza is purple Salvia miltiorrhiza; and Glycyrrhiza uralensis is honey-processed.

[0010] The pairing of ruler, minister, assistant, and envoy: The principal herbs are Rehmannia glutinosa and Cornus officinalis – which nourish yin and blood, replenish essence and marrow, and target the root cause of AD, namely “kidney deficiency and marrow depletion”.

[0011] The accompanying herbs are: Acorus tatarinowii, Polygala tenuifolia, Ginseng, and Ilex pubescens. Acorus tatarinowii and Polygala tenuifolia are the core herb pair for opening the orifices and improving intelligence, resolving phlegm, opening the orifices, refreshing the mind and enhancing intelligence; Ginseng greatly replenishes vital energy, calms the mind and enhances intelligence.

[0012] The adjuvant herbs are: Ligusticum chuanxiong, Angelica sinensis, Poria cocos, Pinellia ternata, Gastrodia elata, and Salvia miltiorrhiza. Among them, Gastrodia elata and Salvia miltiorrhiza are the auxiliary herbs for promoting blood circulation, extinguishing wind, and awakening the brain. Together, they promote blood circulation, remove blood stasis, strengthen the spleen, resolve phlegm, extinguish wind, unblock the meridians, and open the brain orifices.

[0013] The guiding herb is roasted licorice root; it invigorates qi, strengthens the middle jiao, and harmonizes the effects of other herbs.

[0014] A method for preparing a traditional Chinese medicine compound composition, characterized by comprising the following steps: S1, Weighing Weigh each raw material according to the weight proportions, clean and pulverize it, pass it through a 40-60 mesh sieve, and mix it evenly. S2, Soaking Add 8–10 times the total weight of the raw material in purified water and soak at room temperature for 30–60 minutes; S3, frying First decoction: After bringing to a boil over high heat, reduce to a simmer and cook for 60 minutes. Collect the decoction. Second decoction: Add 8 to 10 times the amount of purified water to the dregs and simmer over low heat for 45 minutes; Combine the two decoctions and filter through a 200-mesh sieve; S4, Reduced Pressure Concentration Concentrate under reduced pressure at 60–70°C and a vacuum of –0.08 to –0.09 MPa to obtain a clear extract with a relative density of 1.15–1.20 (60°C); S5, Spray drying Set the inlet air temperature to 160–180℃ and the outlet air temperature to 80–90℃, and spray-dry the extract to obtain dry extract powder. Quality indicators: Active ingredient transfer rate ≥85%, batch-to-batch RSD <5%.

[0015] S6, Preparations Dry extract powder is formulated into the following dosage forms by adding pharmaceutically acceptable excipients: Granules: Add dextrin and stevia, granulate, dry, and sizing, then package into 10g / bags; Capsule formulation: Microcrystalline cellulose and magnesium stearate are added and filled into size 0 capsules; Tablets: Add starch and magnesium stearate, then compress into tablets; Oral liquid: Add purified water and flavoring agent, then fill and seal.

[0016] Mechanism of action of this invention (multi-target synergy): Inhibit Aβ deposition: Reduce Aβ1-42 generation and aggregation by regulating the APP processing pathway; Reduce Tau protein hyperphosphorylation: Inhibit GSK-3β and CDK5 activity, and downregulate p-Tau (Ser396, Thr231). Anti-neuroinflammatory: Reduces IL-1β, TNF-α, and IL-6 levels, and inhibits excessive activation of microglia; Antioxidant stress: Increases SOD and GSH-Px activity, and reduces MDA content; Protects the cholinergic system: increases ChAT activity, inhibits AChE, and increases acetylcholine levels; Improve synaptic plasticity: Upregulate synaptophysin and PSD-95 expression to promote synaptic regeneration; Increase cerebral blood flow: dilate cerebral blood vessels, improve cerebral perfusion, and protect the blood-brain barrier.

[0017] The present invention has the following beneficial effects: 1. Rigorous formulation and comprehensive coverage of pathogenesis: Based on the TCM pathogenesis of "deficiency of the root and excess of the branch, and obstruction of the brain collaterals", this invention uses Rehmannia glutinosa and Cornus officinalis as the principal herbs to tonify the kidney and replenish essence, Acorus tatarinowii, Polygala tenuifolia, and Ginseng as the assistant herbs to open the orifices and improve intelligence, Gastrodia elata, Salvia miltiorrhiza and other herbs as adjuvant herbs to invigorate blood, extinguish wind, resolve phlegm and unblock collaterals, and Glycyrrhiza uralensis as the guiding herb to harmonize the herbs, so as to achieve a five-in-one synergistic treatment and overcome the defects of existing compound prescriptions with unclear formulation structure and insufficient opening of orifices and invigoration of blood.

[0018] 2. Synergistic effect of multiple targets and significant efficacy: Validated by APP / PS1 double transgenic AD mouse model, the high-dose group of this invention can shorten the escape latency by 51.7% and increase the number of platform crossings by 3.2 times; at the same time, it can significantly reduce Aβ deposition, downregulate p-Tau, inhibit inflammatory factors IL-1β and TNF-α, enhance ChAT activity, reduce AChE, and increase cerebral blood flow. The efficacy is better than that of the positive control drug donepezil, showing a clear dose-response relationship.

[0019] 3. Stable process, suitable for industrial production: Adopting standardized water decoction, vacuum concentration and spray drying processes, the effective ingredient transfer rate is ≥85%, and the batch-to-batch RSD is <5%. It can be made into various dosage forms such as granules and capsules, which are convenient for patients to take for a long time.

[0020] 4. Good safety profile, suitable for elderly patients: All raw materials are pharmacopoeia standards, with no toxic components. No adverse reactions have been observed with long-term administration, meeting the long-term medication needs of Alzheimer's patients.

[0021] Of course, any product implementing this invention does not necessarily need to achieve all of the advantages described above at the same time. Attached Figure Description

[0022] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 The process flow diagram for preparing the traditional Chinese medicine compound composition of this invention. Detailed Implementation

[0024] 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 of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0025] In the description of this invention, it should be understood that the terms "upper," "middle," "outer," "inner," etc., which indicate orientation or positional relationship, are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the components or elements referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as limiting this invention.

[0026] In the description of this invention, it should be noted that, unless otherwise explicitly specified and limited, the terms "installed," "equipped with," "connected," etc., should be interpreted broadly. For example, "connection" can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium; it can be a connection within two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0027] Example 1: Preparation of granules with the optimal formulation A traditional Chinese medicine composition for the prevention and treatment of Alzheimer's disease and its application, made from the following raw materials in parts by weight: Weigh out: 300g of Rehmannia glutinosa (processed), 150g of Cornus officinalis, 150g of Panax ginseng, 15g of Ilex pubescens, 180g of Acorus tatarinowii, 150g of Polygala tenuifolia, 120g of Ligusticum chuanxiong, 150g of Angelica sinensis, 200g of Poria cocos, 120g of Pinellia ternata (processed), 120g of Gastrodia elata, 150g of Salvia miltiorrhiza, and 60g of Glycyrrhiza uralensis (processed).

[0028] The dry extract powder was prepared according to the above preparation method (steps S1-S6), dextrin and stevioside were added, and the mixture was granulated, dried, and sized, then packaged into 10g / bag granules. Dosage: 1 bag / time, twice daily, taken with warm water.

[0029] Example 2: Preparation of Capsules Prepare 100g of dry extract powder according to the method in Example 1, add 30g of microcrystalline cellulose and 1g of magnesium stearate, mix well, fill into No. 0 capsules, and make 1000 capsules. Usage: 2-3 capsules / time, twice a day.

[0030] Example 3: Pharmacological Experiment Validation (APP / PS1 Double Transgenic AD Mice) 1. Experimental grouping and dosing regimen Normal control group: equal volume of physiological saline, administered by gavage for 8 weeks; Model group: Equal volume of physiological saline, administered by gavage for 8 weeks; Donepezil group: Clinically equivalent dose of donepezil administered by gavage for 8 weeks; The low-dose group of this invention: 0.75 g / kg·d compound dry extract powder, administered by gavage for 8 weeks; The medium-dose group in this invention: 1.50 g / kg·d compound dry extract powder, administered by gavage for 8 weeks; The high-dose group of this invention: 3.00 g / kg·d compound dry extract powder, administered by gavage for 8 weeks; Ten APP / PS1 double transgenic AD mice were used in each group, and the administration frequency was once daily. The dosage was converted to the clinical equivalent dose for mice (1.5 g / kg·d) according to the optimal ratio of the patent, which is the medium dose. The low and high doses are 1 / 2 and 2 times the medium dose, respectively, which is consistent with the classic 1:2:4 dosage gradient in traditional Chinese medicine pharmacology experiments.

[0031] 2. Morris water maze experiment Adaptation phase: One day before the experiment, mice were placed in a platformless water maze and swam freely for 2 minutes.

[0032] Orientation and navigation experiment: 5 consecutive days of training, 4 times a day, record the time it takes for mice to find the hidden platform within 60 seconds (escape latency); if they do not find it within 60 seconds, guide them to the platform and stay for 10 seconds, the latency is recorded as 60 seconds.

[0033] Space exploration experiment: On day 6, the platform was removed, and the number of times the mice crossed the original platform position within 60 seconds was recorded.

[0034] Results: The high-dose group of this invention shortened the escape latency by 51.7% (P<0.01) and increased the number of platform crossings by 3.2 times (P<0.01).

[0035] 3. Pathological and biochemical tests Aβ 1-42 Deposition decreased by 65.4%; p-Tau (Ser396) decreased by 61.2%; IL-1β and TNF-α decreased by 53.8% and 57.3%, respectively; ChAT activity increased by 47.5%, while AChE activity decreased by 42.1%. Synaptophysin expression was significantly increased; Cerebral blood flow increased by 36.8%.

[0036] Conclusion: The compound preparation of this invention is significantly more effective than donepezil, a positive control drug, showing a clear dose-response relationship, and has no adverse reactions.

[0037] Comparative Example 1 (original basic formula, without Gastrodia elata and Salvia miltiorrhiza, and with lower dosages of Acorus tatarinowii and Polygala tenuifolia) Formula: 25 parts Rehmannia glutinosa, 15 parts Cornus officinalis, 12 parts Ginseng, 12 parts Acorus tatarinowii, 10 parts Polygala tenuifolia, 10 parts Ligusticum chuanxiong, 12 parts Angelica sinensis, 15 parts Poria cocos, 10 parts Pinellia ternata, and 5 parts Glycyrrhiza uralensis (without Gastrodia elata and Salvia miltiorrhiza, and the dosage of Acorus tatarinowii and Polygala tenuifolia is lower than the scope of this invention).

[0038] The dry extract powder was prepared using the same preparation process as in Example 1. The animal experiment grouping, dosage, dosing cycle, and detection methods were completely consistent with those in Example 3.

[0039] Results: The escape latency period was shortened by only 29.4%, Aβ deposition was reduced by 38.6%, and p-Tau was downregulated by 31.2%, with efficacy significantly lower than the optimal ratio of this invention (P<0.01). This confirms that the addition of Gastrodia elata, Salvia miltiorrhiza, and the enhanced dosage of Acorus tatarinowii and Polygala tenuifolia have a synergistic effect, producing unexpected technical results.

[0040] In the description of this specification, references to terms such as "an embodiment," "example," and "specific example" indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0041] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A traditional Chinese medicine composition for the prevention and treatment of Alzheimer's disease and its application, characterized in that, It is made from the following raw materials in parts by weight: 20-35 parts Rehmannia glutinosa, 12-18 parts Cornus officinalis, 12-18 parts Panax ginseng, 10-15 parts Ilex pubescens, 15-20 parts Acorus tatarinowii, 12-18 parts Polygala tenuifolia, 10-15 parts Ligusticum chuanxiong, 12-18 parts Angelica sinensis, 15-25 parts Poria cocos, 10-15 parts Pinellia ternata, 10-15 parts Gastrodia elata, 12-18 parts Salvia miltiorrhiza, and 5-8 parts Glycyrrhiza uralensis.

2. The traditional Chinese medicine compound composition for treating Alzheimer's disease according to claim 1, characterized in that, The raw materials are composed of the following parts by weight: 30 parts Rehmannia glutinosa, 15 parts Cornus officinalis, 15 parts Panax ginseng, 15 parts Ilex pubescens, 18 parts Acorus tatarinowii, 15 parts Polygala tenuifolia, 12 parts Ligusticum chuanxiong, 15 parts Angelica sinensis, 20 parts Poria cocos, 12 parts Pinellia ternata, 12 parts Gastrodia elata, 15 parts Salvia miltiorrhiza, and 6 parts Glycyrrhiza uralensis.

3. The traditional Chinese medicine compound composition for treating Alzheimer's disease according to claim 1, characterized in that, The prepared Rehmannia root is a wine-stewed or wine-steamed product; the Cornus officinalis is a wine-processed product; the ginseng is a sun-dried ginseng or red ginseng; the prepared Pinellia ternata is a ginger-alum processed product; the Gastrodia elata is a winter-grown Gastrodia elata; the Salvia miltiorrhiza is a purple Salvia miltiorrhiza; and the prepared licorice root is a honey-processed product.

4. A traditional Chinese medicine compound for treating Alzheimer's disease according to claim 1, characterized in that, The Acorus tatarinowii and Polygala tenuifolia are the core medicinal pair for opening the orifices and improving intelligence, while the Gastrodia elata and Salvia miltiorrhiza are the auxiliary medicinal pair for promoting blood circulation, extinguishing wind, and awakening the brain.

5. A method for preparing a traditional Chinese medicine compound composition as described in any one of claims 1-4, characterized in that, Includes the following steps: S1. Weigh the raw materials according to the weight parts, clean and pulverize them, pass them through a 40-60 mesh sieve, and mix them evenly. S2. Add 8-10 times the total weight of the raw materials in purified water and soak for 30-60 minutes; S3. Bring to a boil over high heat, then simmer over low heat twice, the first time for 60 minutes and the second time for 45 minutes. Combine the decoctions and strain through a 200-mesh sieve. S4. Concentrate under reduced pressure at 60-70℃ and a vacuum degree of -0.08~-0.09MPa to obtain a clear paste with a relative density of 1.15-1.20 at 60℃. S5. Spray drying, with an inlet air temperature of 160-180℃ and an outlet air temperature of 80-90℃, to obtain dry extract powder; S6. Add pharmaceutically acceptable excipients to prepare granules, capsules, tablets or oral liquids.

6. The preparation method according to claim 5, characterized in that: The excipients mentioned in step S6 include dextrin, stevioside, microcrystalline cellulose, or magnesium stearate.

7. The use of the traditional Chinese medicine compound composition as described in any one of claims 1-4 in the preparation of a drug for treating or improving Alzheimer's disease, senile dementia, vascular dementia, mild cognitive impairment, or memory decline.

8. The application according to claim 7, characterized in that, The drug is used to inhibit Aβ protein deposition, reduce Tau protein hyperphosphorylation, inhibit central nervous system inflammation, resist oxidative stress damage, protect the cholinergic nervous system, improve synaptic plasticity, increase cerebral blood flow, and protect the blood-brain barrier.

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