Formula of plaster for treating insomnia

Abstract

The invention discloses a formula and a preparation method of a plaster for treating insomnia, and belongs to the technical field of traditional Chinese medicine transdermal delivery. Based on the traditional Chinese medicine dialectical theory, spina date seed, tuber fleeceflower stem and the like are used as monarch drugs for tranquilizing mind by nourishing the heart, poria cocos, bighead atractylodes rhizome and the like are used as ministerial drugs for strengthening the spleen and harmonizing the stomach, nacre mother of pearl, magnetite and the like are used as adjuvant drugs for calming the mind by heavy weight, and liquorice is used for regulating and promoting permeation, so that a basic formula and dialectical addition and subtraction system is formed, and the traditional Chinese medicine is adaptive to symptoms such as heart-spleen deficiency, hyperactivity of heart-liver fire and the like. The key process comprises the steps of mineral medicine nanometer calcination (the particle size is smaller than or equal to 50 nm, and the Fe dissolution rate is increased by 65%), alcohol-water double extraction and effective component enrichment, and preparation of an intelligent controlled-release matrix containing a chitosan-beta-cyclodextrin inclusion compound, and the transdermal rate is increased by 60%. The plaster is applied to acupoints such as Shenque and Xinshu, the functions of the braingut axis are improved by adjusting GABA / 5-HT neurotransmitters, multi-target synergistic effect is achieved, the total effective rate is 92.5%, the recurrence rate is 15% after one week of drug withdrawal, safety and no dependence are achieved, and an efficient and accurate external scheme is provided for insomnia treatment.

Description

Technical Field

[0001] This invention belongs to the field of transdermal drug delivery technology of traditional Chinese medicine, specifically involving a formula and preparation method of a plaster for treating insomnia based on the TCM theory of "heart-spleen-brain-spirit axis", integrating nano-calcination technology, intelligent controlled-release matrix and alcohol-water dual extraction process, and especially involving an innovative TCM patch that achieves multi-target synergistic effects through specific monarch-minister-assistant-guide combination. Background Technology

[0002] Insomnia is a common sleep disorder in clinical practice, characterized by difficulty falling asleep, difficulty maintaining sleep, early awakening, or decreased sleep quality, seriously affecting patients' quality of life and mental and physical health. Its pathogenesis is complex; Traditional Chinese Medicine (TCM) considers the core pathogenesis to be "malnourishment of the heart and spirit, and failure of yang to enter yin," often accompanied by complex syndromes such as deficiency of both heart and spleen, and excessive heart and liver fire. According to the World Health Organization, approximately 30% of the global population suffers from insomnia, with an incidence rate of 38.2% in my country, and this rate is increasing year by year. Currently, the main drugs used to treat insomnia clinically are benzodiazepines and non-benzodiazepine sedative-hypnotics, but long-term use can easily lead to side effects such as drug dependence, drug tolerance, and cognitive impairment.

[0003] Traditional Chinese medicine (TCM) treatment for insomnia has the advantages of holistic regulation and fewer side effects. As a topical dosage form of TCM, plasters exert their effects through transdermal absorption, avoiding the first-pass effect of oral medications and gastrointestinal irritation. However, existing TCM insomnia plasters have the following technical shortcomings:

[0004] The prescriptions are too simple: they mainly use single sedative drugs (such as jujube seed and polygala), and lack systematic treatment for the complex pathogenesis of insomnia (such as deficiency of both heart and spleen, excessive fire of heart and liver, internal disturbance of phlegm and heat).

[0005] Insufficient release of active pharmaceutical ingredients: Mineral drugs (such as magnetite and dragon bone) use traditional calcination and pulverization processes, resulting in low dissolution rates of active ingredients and poor transdermal absorption efficiency;

[0006] Limitations of matrix properties: Commonly used matrices such as petroleum jelly have weak transdermal penetration enhancement capabilities, uncontrollable drug release rates, and difficulty in achieving long-term stable efficacy.

[0007] Therefore, there is an urgent need to develop a new type of insomnia treatment plaster with a scientifically formulated composition, advanced technology, and significant efficacy to meet clinical needs. Summary of the Invention

[0008] The purpose of this invention is to provide a medicated plaster and formula for treating insomnia based on the holistic view of traditional Chinese medicine and modern pharmaceutical technology, and to solve the problems of existing technologies through the following innovations:

[0009] Construct a precise "principal-minister-assistant-guide" formulation system to achieve synergistic regulation of the functions of the heart, brain, spirit, spleen, and stomach;

[0010] Develop a nano-calcination and alcohol-water dual extraction process to break through the bottleneck of release and absorption of effective components in mineral and plant drugs;

[0011] We designed a pH-responsive smart controlled-release matrix to achieve continuous and stable drug release, meeting the clinical need for long-term treatment.

[0012] To achieve the above objectives, the present invention is implemented through the following technical solution: a formula for a plaster for treating insomnia, made from the following raw materials and preparation process in parts by weight: 12-18 parts of Ziziphus jujuba seed, 16-19 parts of Polygonum multiflorum stem, 11-14 parts of Poria cocos, 9-11 parts of Atractylodes macrocephala, 16-19 parts of mother-of-pearl, 11-14 parts of dragon bone, 11-14 parts of magnetite, 11-14 parts of Albizia julibrissin bark, 8-12 parts of Platycladus orientalis seed, 9-11 parts of Angelica sinensis, 11-14 parts of Astragalus membranaceus, and 6-9 parts of licorice; wherein the mother-of-pearl, dragon bone, and magnetite are subjected to nano-calcination treatment to an average particle size ≤50nm, and the matrix contains 1.5%-2.5% of chitosan-β-cyclodextrin inclusion complex.

[0013] As a further improvement to the technical solution of the present invention, the principal ingredient in the raw material composition is a combination of 12-18 parts of Ziziphus jujuba seed and 16-19 parts of Polygonum multiflorum stem; the assistant ingredient is a combination of 11-14 parts of Poria cocos and 9-11 parts of Atractylodes macrocephala; the adjuvant ingredient is a combination of 16-19 parts of pearl powder, 11-14 parts of dragon bone, and 11-14 parts of magnetite; and the guiding ingredient is a combination of 11-14 parts of Albizia julibrissin bark, 8-12 parts of Platycladus orientalis seed, 9-11 parts of Angelica sinensis, 11-14 parts of Astragalus membranaceus, and 6-9 parts of Glycyrrhiza uralensis.

[0014] As a further improvement to the technical solution of the present invention, the nano-calcination treatment is a three-stage gradient heating calcination: first calcination at 300℃ for 30 minutes, then heating to 600℃ for 30 minutes, and finally heating to 900℃ for 30 minutes. After calcination, the material is processed into nanoparticles with an average particle size ≤50nm by airflow pulverization technology.

[0015] As a further improvement to the technical solution of the present invention, the matrix is ​​made by mixing petrolatum and lanolin in a weight ratio of 2:1-3:1, and the weight ratio of chitosan to β-cyclodextrin in the chitosan-β-cyclodextrin inclusion complex is 1:2-1:3.

[0016] As a further improvement to the technical solution of this invention, the extraction of the herbal medicine adopts a dual extraction process of alcohol and water: the jujube seed and cypress seed are extracted by reflux with 75% ethanol, the extraction conditions are 10 times the weight of the medicinal materials by solvent, 2 extractions, 1.5 hours each time; the albizia bark, poria cocos, atractylodes macrocephala, astragalus membranaceus and angelica sinensis are extracted by decoction with water, the extraction conditions are 8 times the weight of the medicinal materials by solvent, 3 extractions, 1 hour each time, the alcohol extract and the water decoction are combined and concentrated into an extract.

[0017] As a further improvement to the technical solution of the present invention, the concentration conditions for the alcohol extract are: reduced pressure concentration to 60°C with a relative density of 1.25-1.30, and the concentration conditions for the water extract are: normal pressure concentration to 60°C with a relative density of 1.30-1.35.

[0018] As a further improvement to the technical solution of the present invention, the preparation process of the plaster includes an ultrasonic dispersion step: after mixing the nano-mineral powder, the herbal extract and the matrix, the mixture is ultrasonically dispersed for 20-40 minutes at a frequency of 40-50kHz and a power of 200-400W, so that the nanoparticles are uniformly dispersed in the matrix.

[0019] As a further improvement to the technical solution of the present invention, the plaster is coated on a non-woven fabric substrate to form a patch with a drug content of ≥1.5g / 10cm². The patch matrix also contains 0.5%-1.0% glycyrrhizic acid as a natural transdermal penetration enhancer.

[0020] As a further improvement to the technical solution of the present invention, the plaster achieves multi-target synergistic effects through transdermal absorption, including regulating GABA_A receptors to enhance central inhibition, regulating the gut-brain axis to improve gastrointestinal function, and stabilizing neuronal membrane potential through the microcurrent effect of nano-mineral drugs.

[0021] As a further improvement to the technical solution of the present invention, the method of using the plaster is to apply it to the Shenque acupoint, Xinshu acupoint, or Yongquan acupoint for 12-24 hours per day, and use it continuously for 7-14 days as a course of treatment.

[0022] This invention, through innovative formulation, optimized process, and improved matrix, forms a multi-dimensional and synergistic insomnia treatment plan, with the following specific beneficial effects:

[0023] 1. Multi-target compound formulation, overcoming the limitations of single-effect therapy.

[0024] The principal herbs, Ziziphus jujuba seed and Polygonum multiflorum stem, regulate GABA / 5-HT neurotransmitters to prolong deep sleep; the assistant herbs, Poria cocos and Atractylodes macrocephala, improve the intestinal-brain axis and relieve spleen deficiency symptoms; and the adjuvant herbs, nano-calcined mineral drugs, stabilize neuronal membrane potential. The three effects combined achieve a systematic regulation of the functions of the heart, brain, mind, spleen, and stomach. The total clinical effective rate reaches 92.5%, and it has significant effects on insomnia caused by deficiency of both heart and spleen and excessive fire of heart and liver.

[0025] 2. Nanotechnology and dual extraction processes enhance the utilization of active pharmaceutical ingredients.

[0026] Mineral drugs are subjected to gradient calcination and airflow milling to ≤50nm, Fe³⁺ + The dissolution rate is increased by 65%, and the transdermal absorption rate reaches 18.6 μg / cm² / 24h (2.3 times higher than the traditional process).

[0027] The alcohol-water dual extraction process enriches fat-soluble sedative components and water-soluble spleen-strengthening components respectively. The content of jujube seed saponin A is 1.8 times higher than that of the traditional water decoction method, ensuring synergistic efficacy.

[0028] 3. Intelligent matrix enables long-lasting transdermal and acupoint targeting.

[0029] Glycyrrhizic acid, in synergy with chitosan-β-cyclodextrin inclusion complex, increases the transdermal penetration rate by 60%. Combined with acupoint application (Shenque, Xinshu, etc.), it forms a "drug-meridian" linkage effect. The relapse rate one week after drug withdrawal is only 15%, which is significantly lower than that of the control drug.

[0030] 4. Diagnostic adjustment and safety and convenience

[0031] The formulation of medicinal materials and matrix characteristics are adjusted according to different syndrome types (such as a low-irritant formula for children), which has strong adaptability; after verification by skin irritation and long-term toxicity tests, there are no allergic reactions or liver and kidney damage, and no drug dependence, which fills the safety gap of existing sedative drugs.

[0032] The above advantages have been quantitatively verified through experimental data, and a new insomnia treatment plan that is "efficient, safe and precise" has been constructed, which has outstanding clinical application value. Detailed Implementation

[0033] The present invention will be described in detail below with reference to specific embodiments. The illustrative embodiments and descriptions of the present invention are used to explain the present invention, but are not intended to limit the present invention.

[0034] A formula for a medicated plaster for treating insomnia, made from the following raw materials in parts by weight and prepared using the following process:

[0035] The ingredients are: 12-18 parts of Ziziphus jujuba seed, 16-19 parts of Polygonum multiflorum stem, 11-14 parts of Poria cocos, 9-11 parts of Atractylodes macrocephala, 16-19 parts of mother-of-pearl, 11-14 parts of dragon bone, 11-14 parts of magnetite, 11-14 parts of Albizia julibrissin bark, 8-12 parts of Platycladus orientalis seed, 9-11 parts of Angelica sinensis, 11-14 parts of Astragalus membranaceus, and 6-9 parts of licorice root; wherein the mother-of-pearl, dragon bone, and magnetite are subjected to nano-calcination treatment to an average particle size ≤50nm, and the matrix contains 1.5%-2.5% of chitosan-β-cyclodextrin inclusion complex.

[0036] Specifically, in this embodiment, the principal ingredient is a combination of 12-18 parts of Ziziphus jujuba seed and 16-19 parts of Polygonum multiflorum stem; the assistant ingredient is a combination of 11-14 parts of Poria cocos and 9-11 parts of Atractylodes macrocephala; the adjuvant ingredient is a combination of 16-19 parts of pearl powder, 11-14 parts of dragon bone, and 11-14 parts of magnetite; and the guiding ingredient is a combination of 11-14 parts of Albizia julibrissin bark, 8-12 parts of Platycladus orientalis seed, 9-11 parts of Angelica sinensis, 11-14 parts of Astragalus membranaceus, and 6-9 parts of Glycyrrhiza uralensis.

[0037] It should be noted that the principal herbs (for nourishing the heart and calming the mind): Ziziphus jujuba seed (12-18 parts) and Polygonum multiflorum stem (16-19 parts) are combined. Ziziphus jujuba seed saponins A / B stimulate GABA. a Receptors prolong slow-wave sleep stage II, while emodin in Polygonum multiflorum inhibits 5-HT reuptake and regulates circadian rhythms; the two work synergistically to enhance the central inhibitory effect.

[0038] The auxiliary medicine (strengthening the spleen and stomach): Poria cocos (11-14 parts) and Atractylodes macrocephala (9-11 parts) are combined. Poria cocos polysaccharides regulate the intestinal flora and improve the function of the brain-gut axis. Atractylodes macrocephala lactone I / III promote gastrointestinal motility and relieve symptoms of fullness, thus solving the common pathogenesis of spleen and stomach disorders in insomnia.

[0039] Adjuvant (sedative): Mother-of-pearl (16-19 parts), dragon bone (11-14 parts), and magnetite (11-14 parts) are calcined in nano to generate nano-sized metal oxides such as Fe3O4 and CaO, which stabilize neuronal membrane potential through the skin microcurrent effect and inhibit excessive central excitation.

[0040] The following ingredients are used to enhance transdermal penetration: Albizia bark (11-14 parts) inhibits the NF-κB inflammatory pathway and improves anxiety; Angelica sinensis (9-11 parts) contains ferulic acid to dilate cerebral blood vessels; Astragalus membranaceus (11-14 parts) enhances immune function; and Glycyrrhiza uralensis (6-9 parts) contains glycyrrhizic acid, which acts as a natural transdermal permeability enhancer and synergistically forms lipid delivery systems with lanolin-petrolatum matrix, increasing transdermal permeability by 30%-40%.

[0041] Specifically, in this embodiment, the nano-calcination treatment is a three-stage gradient heating calcination: first, calcination at 300℃ for 30 minutes, then heating to 600℃ for 30 minutes, and finally heating to 900℃ for 30 minutes. After calcination, the material is processed into nanoparticles with an average particle size ≤50nm using air jet milling technology. It should be noted that the nano-calcination technology employs a three-stage gradient calcination (300℃×30min→600℃×30min→900℃×30min), combined with air jet milling to produce ultrafine powder with an average particle size ≤50nm, thus reducing the Fe³⁺ content in the magnet. +The dissolution rate was increased from 35% in the traditional process to 65%, and the specific surface area of ​​the nanoparticles increased by 2.8 times, significantly enhancing the transdermal absorption capacity.

[0042] Specifically, in this embodiment, the matrix is ​​prepared by mixing petrolatum and lanolin in a weight ratio of 2:1 to 3:1, and the weight ratio of chitosan to β-cyclodextrin in the chitosan-β-cyclodextrin inclusion complex is 1:2 to 1:3.

[0043] Specifically, in this embodiment, the extraction of the herbal medicine adopts a dual alcohol-water extraction process: jujube seed and cypress seed are extracted by reflux with 75% ethanol under the following conditions: solvent volume is 10 times the weight of the medicinal materials, extraction is performed twice, and each extraction lasts 1.5 hours; albizia bark, poria cocos, atractylodes macrocephala, astragalus membranaceus, and angelica sinensis are extracted by decoction with water under the following conditions: solvent volume is 8 times the weight of the medicinal materials, extraction is performed three times, and each extraction lasts 1 hour. The alcohol extract and the water decoction are combined and concentrated into an extract. It should be noted that the alcohol-water dual extraction process involves: jujube seed and cypress seed reflux extraction with 75% ethanol (10 times the volume, twice, 1.5 hours) to enrich fat-soluble calming components (such as jujube seed saponins and cypress seed oil); and albizia bark and poria cocos decoction with water (8 times the volume, three times, 1 hour) to retain water-soluble spleen-strengthening components (such as poria cocos polysaccharides and atractylodes lactone). The alcohol extract is concentrated under reduced pressure to a relative density of 1.25 (60℃), and the water decoction extract is concentrated under normal pressure to 1.35 (60℃), achieving differentiated extraction of effective components.

[0044] Specifically, in this embodiment, the concentration conditions for the alcohol extract are reduced pressure concentration to a relative density of 1.25-1.30 at 60°C, and the concentration conditions for the water extract are normal pressure concentration to a relative density of 1.30-1.35 at 60°C.

[0045] Specifically, in this embodiment, the preparation process of the plaster includes an ultrasonic dispersion step: after mixing the nano-mineral powder, herbal extract, and matrix, ultrasonic dispersion is performed at a frequency of 40-50kHz and a power of 200-400W for 20-40 minutes to ensure that the nanoparticles are uniformly dispersed in the matrix. It should be noted that the intelligent controlled-release matrix is: petrolatum and lanolin are mixed in a ratio of 2:1-3:1, and 1.5%-2.5% chitosan-β-cyclodextrin inclusion complex (chitosan:β-cyclodextrin = 1:2-1:3) is added to form a pH-responsive sustained-release system. This system slowly releases the drug in the weakly acidic environment of the skin surface. Combined with ultrasonic dispersion at 40-50kHz and 200-400W for 20-40 minutes, uniform dispersion of the nanoparticles is ensured, achieving continuous drug release for 12 hours.

[0046] Specifically, in this embodiment, the plaster is applied to a non-woven fabric substrate to form a patch with a drug content of ≥1.5g / 10cm². The patch matrix also contains 0.5%-1.0% glycyrrhizic acid as a natural transdermal penetration enhancer.

[0047] Specifically, in this embodiment, the plaster achieves multi-target synergistic effects through transdermal absorption, including regulating GABA_A receptors to enhance central inhibition, regulating the gut-brain axis to improve gastrointestinal function, and stabilizing neuronal membrane potential through the microcurrent effect of nanomineral drugs.

[0048] Specifically, in this embodiment, the plaster is applied to the Shenque (CV8), Xinshu (BL15), or Yongquan (KI1) acupoints for 12-24 hours daily, with a course of treatment lasting 7-14 days.

[0049] It should be noted that the formulation characteristics and usage methods are as follows:

[0050] The plaster contains a high drug content of ≥1.5g / 10cm², is coated on a non-woven fabric substrate, and 0.5%-1.0% glycyrrhizic acid is added to the matrix to form a dual transdermal permeability promotion system in conjunction with chitosan inclusion complex. According to Franz diffusion cell tests, the transdermal permeability rate is increased by 40% compared with the traditional matrix.

[0051] By applying patches to specific acupoints such as Shenque (Spleen and Stomach Meridian), Xinshu (Heart Meridian), and Yongquan (Kidney Meridian), the synergistic effect of "medicine-acupoint-meridian" is exerted. The patches are applied for 12-24 hours daily, with a course of treatment lasting 7-14 days, to meet the cyclical treatment needs of different types of insomnia.

[0052] Furthermore, it should be noted that the formulation principle of a certain insomnia treatment plaster is as follows:

[0053] The main herb combination: Ziziphus jujuba seed nourishes blood and calms the mind, while Polygonum multiflorum stem nourishes yin and unblocks the meridians. The combination of the two enhances the effects of nourishing the heart and calming the mind, regulates the GABAergic nervous system, and prolongs the deep sleep cycle.

[0054] The combination of herbs: Poria cocos strengthens the spleen and eliminates dampness, Atractylodes macrocephala invigorates qi and dries dampness, and Astragalus membranaceus tonifies the middle jiao and invigorates qi. The three herbs work together to improve insomnia, excessive dreaming, fatigue and weakness caused by spleen deficiency and impaired function.

[0055] The adjuvant combination consists of mother-of-pearl to calm the liver and suppress yang, dragon bone to calm the nerves and relieve anxiety, and magnetite to improve hearing and vision. After calcination, the three drugs generate nano-sized metal oxides, which stabilize the neuronal membrane potential through the skin microcurrent effect.

[0056] The combination of herbs includes: Albizia bark for relieving depression and calming the mind, Angelica sinensis for promoting blood circulation and nourishing blood, and Glycyrrhiza uralensis for harmonizing the effects of the herbs and acting as a natural transdermal absorption enhancer, which in turn enhances the transdermal absorption of the drugs in synergy with the matrix.

[0057] Preparation method

[0058] Mineral drug processing: Mother-of-pearl, dragon bone, and magnetite are calcined at 900℃ for 2 hours, cooled, and then pulverized to 100-200 mesh. They are then processed into ultrafine powder with an average particle size of ≤50μm using airflow pulverization technology to improve the dissolution rate of active ingredients.

[0059] Herbal medicine processing: Ziziphus jujuba seed and Platycladus orientalis seed were extracted twice by reflux with 75% ethanol (10 times the amount of solvent each time, 1.5 hours each time), and the filtrates were combined and concentrated under reduced pressure to a relative density of 1.25 (60℃); Poria cocos, Astragalus membranaceus, Atractylodes macrocephala, Albizia julibrissin bark and Angelica sinensis were decocted three times with water (8 times the amount of water each time, boiled for 1 hour each time), and the filtrates were combined and concentrated to a relative density of 1.30 (60℃); the ethanol extract and the water extract were combined and spray-dried to prepare an extract powder.

[0060] Matrix preparation: Take 60 parts of petrolatum and 40 parts of lanolin, heat and melt them, add 10 parts of liquid paraffin to adjust the viscosity, and when cooled to 40℃, add 5% glycyrrhizic acid (transdermal penetration promoter) and 1% chitosan (thickener), and stir evenly.

[0061] Formulation: Mix the mineral drug ultrafine powder and the plant drug extract powder in a 1:1 ratio, add them to the matrix to make a paste with a drug content of 20%, coat it evenly on a non-woven fabric substrate (size 10cm×10cm), and cover it with silicone paper to obtain the final product.

[0062] Creative advantages

[0063] Innovative formulation: It is the first to propose the "heart-spleen-brain-nerve axis" regulation theory, which achieves three-dimensional synergy of central inhibition (principal drug), gastrointestinal regulation (assistant drug), and nerve stabilization (adjuvant drug) through the combination of principal, assistant, adjuvant and guide drugs. ELISA test confirmed that it can simultaneously regulate GABA / 5-HT neurotransmitters, intestinal flora and inflammatory factors (IL-6 decreased by 23.4%), which is different from the existing single sedative technology.

[0064] Technological breakthrough: Nano-calcination and ultrasonic dispersion technology increase the transdermal absorption of active ingredients in mineral drugs by 2.3 times (Fe³⁺). + The alcohol-water dual extraction process retains components with different polarities (reaching 18.6 μg / cm² / 24h). HPLC analysis showed that the content of jujube seed saponin A was 1.8 times higher than that of the traditional water decoction method.

[0065] Improved efficacy: Animal experiments showed that the proportion of delta waves (deep sleep waves) increased by 28.7%, the total effective rate in clinical pre-trial trials was 92.3%, and the time to fall asleep for insomnia due to deficiency of both heart and spleen was shortened by 35 minutes, which is significantly better than commercially available products (shortened by 18 minutes).

[0066] Example:

[0067] Example 1: Preparation of Basic Formula

[0068] Raw material composition (parts by weight): 10 parts Ziziphus jujuba seed, 10 parts Poria cocos, 8 parts Polygala tenuifolia root, 8 parts Platycladus orientalis seed, 10 parts Albizia julibrissin bark, 15 parts Polygonum multiflorum stem, 15 parts Pearl powder, 10 parts Dragon bone, 10 parts Magnetite, 8 parts Angelica sinensis root, 10 parts Astragalus membranaceus root, 8 parts Atractylodes macrocephala root, 5 parts Licorice root. Preparation method:

[0069] Mineral drugs are calcined and then pulverized through a 100-mesh sieve; plant drugs are extracted with alcohol and water to obtain extract powder.

[0070] Vaseline and lanolin are mixed in a 3:2 ratio, and then extract powder and mineral powder are added to make a plaster with a 15% drug content.

[0071] Example 2: Preparation of the preferred formulation

[0072] Raw material composition (parts by weight): 15 parts Ziziphus jujuba seed, 12 parts Poria cocos, 10 parts Polygala tenuifolia root, 10 parts Platycladus orientalis seed, 12 parts Albizia julibrissin bark, 18 parts Polygonum multiflorum stem, 18 parts Mother-of-Pearl, 12 parts Dragon bone, 12 parts Magnetite, 10 parts Angelica sinensis root, 12 parts Astragalus membranaceus root, 10 parts Atractylodes macrocephala root, 8 parts Licorice root. Preparation method:

[0073] Mineral drugs are pulverized by air jet milling to below 50μm, and plant extract powder is passed through a 200-mesh sieve;

[0074] Add 5% glycyrrhizic acid to the base to make a plaster with a drug content of 20% and apply it to an area of ​​10cm×10cm.

[0075] Experimental example: Pharmacodynamic study

[0076] 1. Effects on sleep latency in mice

[0077] Model preparation: A mouse insomnia model was induced using p-chlorophenylalanine (PCPA). Grouping and treatment:

[0078] Control group: administered normal saline via gavage;

[0079] Control group: Estazolam tablets (0.5 mg / kg);

[0080] Example 2 Group: Plaster applied to the back skin (medication content 0.5g / kg). Results: The sleep latency of Example 2 group (12.5±2.3min) was significantly shorter than that of the blank group (35.2±4.1min), but there was no statistically significant difference with the control group (10.2±1.8min) (P>0.05).

[0081] 2. Effects on slow-wave sleep in rats

[0082] Monitoring via electroencephalography (EEG) recording:

[0083] In Example 2, the duration of slow-wave sleep (SWS) in the group (182.5±15.3 min / 24h) increased by 58.4% compared with that in the model group (115.2±12.8 min / 24h).

[0084] No significant change was observed in the duration of rapid eye movement (REM) sleep, indicating that the plaster can specifically prolong the deep sleep cycle.

[0085] 3. Safety Evaluation

[0086] Skin irritation experiments on rabbits showed that after 7 days of continuous application, there were no allergic reactions such as redness, swelling, or exudation on the local skin. Long-term toxicity experiments on rats (dose 10g / kg / d) showed no abnormalities in liver and kidney function, proving that the ointment is safe.

[0087] Example 3: Special formula for insomnia caused by deficiency of both heart and spleen

[0088] Raw material composition (parts by weight): 18 parts of Ziziphus jujuba seed (strengthening the principal ingredient), 16 parts of Polygonum multiflorum stem, 14 parts of Poria cocos (strengthening the assistant ingredient), 11 parts of Atractylodes macrocephala, 14 parts of Astragalus membranaceus, 17 parts of pearl powder, 13 parts of dragon bone, 13 parts of magnetite, 13 parts of Albizia julibrissin bark, 12 parts of Platycladus orientalis seed, 11 parts of Angelica sinensis, and 9 parts of licorice root (increasing the dosage of other ingredients). Preparation characteristics: The proportion of lanolin in the matrix is ​​increased to 45% (Vaseline:lanolin = 55:45), enhancing the transdermal absorption of fat-soluble components. It is suitable for insomnia patients with spleen deficiency, loose stools, palpitations, and shortness of breath.

[0089] Example 4: Formula for Adjusting Insomnia Due to Excessive Heart and Liver Fire

[0090] Raw material composition (parts by weight): 12 parts Ziziphus jujuba seed, 20 parts Polygonum multiflorum stem, 19 parts mother-of-pearl (for enhanced adjuvant effect), 14 parts magnetite, 15 parts Albizia julibrissin bark (for enhanced guiding effect), 11 parts Poria cocos, 9 parts Atractylodes macrocephala, 10 parts Astragalus membranaceus, 8 parts Platycladus orientalis seed, 9 parts Angelica sinensis, and 6 parts Glycyrrhiza uralensis. Preparation characteristics: The calcination temperature of the mineral drugs is adjusted to 1000℃, and the calcination time is shortened to 90 minutes to enhance the sedative and tranquilizing effects. 1% menthol is added to the matrix to improve skin permeability, making it suitable for insomnia patients with irritability, red eyes, and bitter taste in the mouth.

[0091] Example 5: Low-irritant formula for children

[0092] Raw material composition (parts by weight): 14 parts Ziziphus jujuba seed, 17 parts Polygonum multiflorum stem, 13 parts Poria cocos, 10 parts Atractylodes macrocephala, 16 parts Mother-of-pearl, 12 parts Dragon bone, 11 parts Magnetite, 12 parts Albizia julibrissin bark, 10 parts Platycladus orientalis seed, 10 parts Angelica sinensis, 12 parts Astragalus membranaceus, 7 parts Glycyrrhiza uralensis. Preparation characteristics: Mineral drugs are pulverized to a particle size ≤30μm. The matrix contains petrolatum:lanolin = 7:3. 2% carbomer is added as a thickener to reduce adhesion. The application area is adjusted to 5cm × 5cm, suitable for children aged 3-12 years.

[0093] Experiment Example 1: Therapeutic Effect Experiment of Chronic Stress Insomnia Model

[0094] Model preparation: A rat model of chronic insomnia was established using a 7-day restraint stress method. Anxiety behaviors (total movement distance and time spent in the central area) were assessed using the open field test. Grouping and treatment:

[0095] Model group: Saline dressing;

[0096] Example 2: The preferred formula plaster was applied to the Xinshu acupoint;

[0097] Control group: A commercially available calming patch (CNXXXXXXX) was applied to the same acupoints. Test indicators:

[0098] Sleep latency (the time of first falling asleep after lights out is recorded via infrared monitoring).

[0099] Serum cortisol (stress hormone levels detected by ELISA);

[0100] Brain 5-HT and GABA levels (detection of neurotransmitters by high-performance liquid chromatography). Experimental results:

[0101] Testing items Model group Example 2 Group control group Sleep latency (min) 42.3±5.1 18.5±3.2* 28.7±4.5* Serum cortisol (ng / mL) 125.6±12.3 89.7±9.1* 105.2±10.8 Brain 5-HT (pg / mL) 158.2±15.7 122.3±11.5* 140.5±13.2 Brain GABA (pg / mL) 85.3±8.2 112.6±10.3* 95.8±9.7 Note: * indicates that compared with the model group (P<0.05), the plaster of the present invention significantly improves stress-induced insomnia and neurotransmitter imbalance.

[0102] Experimental Example 2: Comparative Experiment of Transdermal Absorption Kinetics

[0103] Methods: Using a modified Franz diffusion cell and pigskin as a transdermal model, the transdermal permeation rate (μg / cm² / h) of jujube seed saponin A in the plaster of Example 2 was determined, comparing it with a traditional matrix (petrolatum: lanolin = 1:1, without glycyrrhizic acid) and a commercially available matrix (containing azone penetration enhancer). Results:

[0104] The matrix of this invention: 5.2 ± 0.6 (glycyrrhizic acid synergistically promotes chitosan penetration).

[0105] Traditional matrix: 3.1±0.4 (without penetration enhancer)

[0106] Commercially available matrix: 4.0±0.5 (containing 1% azone) Conclusion: The transdermal penetration rate of the matrix of this invention is 67.7% higher than that of traditional matrix and 30% higher than that of commercially available matrix, proving that the synergistic penetration-enhancing effect of glycyrrhizic acid and chitosan is significant.

[0107] Experimental Example 3: Clinical Multicenter Controlled Trial (Preliminary Trial Data)

[0108] Case selection: 120 patients with insomnia were included (60 cases of deficiency of both heart and spleen according to traditional Chinese medicine diagnosis, and 60 cases of excess of heart and liver fire), and were randomly divided into a treatment group (the plaster of this invention), control group 1 (oral administration of Gui Pi Wan), and control group 2 (estazolam tablets), with 40 patients in each group. Treatment methods:

[0109] Treatment group: Apply plasters to Shenque (CV8) and Xinshu (BL15) acupoints for 12 hours daily for 2 consecutive weeks;

[0110] Control group 1: Gui Pi Wan 6g / time, 3 times a day;

[0111] Control group 2: Estazolam 1mg / night, orally before bedtime. Efficacy evaluation (referring to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines"):

[0112] therapeutic indicators Treatment group Control Group 1 (Gui Pi Wan) Control group 2 (estazolam) Overall efficiency 92.5% 75.0% 85.0% Sleep onset time shortened (min) 38.2±10.5 22.3±8.7 30.5±9.2 Improved sleep quality score 6.8±1.2 4.5±1.0 5.3±1.1 Relapse rate 1 week after discontinuation of medication 15.0% 35.0% 27.5% Conclusion: The treatment group was superior to the control group in terms of overall effective rate, sleep quality and long-term efficacy, and there was no risk of drug dependence.

[0113] In summary, this invention, through innovative formulation, optimized process, and improved matrix, forms a multi-dimensional synergistic treatment plan for insomnia, with the following specific beneficial effects:

[0114] 1. Multi-target compound formulation, overcoming the limitations of single-effect therapy.

[0115] The principal herbs, Ziziphus jujuba seed and Polygonum multiflorum stem, regulate GABA / 5-HT neurotransmitters to prolong deep sleep; the assistant herbs, Poria cocos and Atractylodes macrocephala, improve the intestinal-brain axis and relieve spleen deficiency symptoms; and the adjuvant herbs, nano-calcined mineral drugs, stabilize neuronal membrane potential. The three effects combined achieve a systematic regulation of the functions of the heart, brain, mind, spleen, and stomach. The total clinical effective rate reaches 92.5%, and it has significant effects on insomnia caused by deficiency of both heart and spleen and excessive fire of heart and liver.

[0116] 2. Nanotechnology and dual extraction processes enhance the utilization of active pharmaceutical ingredients.

[0117] Mineral drugs are subjected to gradient calcination and airflow milling to ≤50nm, Fe³⁺ + The dissolution rate is increased by 65%, and the transdermal absorption rate reaches 18.6 μg / cm² / 24h (2.3 times higher than the traditional process).

[0118] The alcohol-water dual extraction process enriches fat-soluble sedative components and water-soluble spleen-strengthening components respectively. The content of jujube seed saponin A is 1.8 times higher than that of the traditional water decoction method, ensuring synergistic efficacy.

[0119] 3. Intelligent matrix enables long-lasting transdermal and acupoint targeting.

[0120] Glycyrrhizic acid, in synergy with chitosan-β-cyclodextrin inclusion complex, increases the transdermal penetration rate by 60%. Combined with acupoint application (Shenque, Xinshu, etc.), it forms a "drug-meridian" linkage effect. The relapse rate one week after drug withdrawal is only 15%, which is significantly lower than that of the control drug.

[0121] 4. Diagnostic adjustment and safety and convenience

[0122] The formulation of medicinal materials and matrix characteristics are adjusted according to different syndrome types (such as a low-irritant formula for children), which has strong adaptability; after verification by skin irritation and long-term toxicity tests, there are no allergic reactions or liver and kidney damage, and no drug dependence, which fills the safety gap of existing sedative drugs.

[0123] The above advantages have been quantitatively verified through experimental data, and a new insomnia treatment plan that is "efficient, safe and precise" has been constructed, which has outstanding clinical application value.

[0124] The technical solutions provided by the embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the embodiments of the present invention. The descriptions of the embodiments above are only for helping to understand the principles of the embodiments of the present invention. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the embodiments of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A formula for a medicated plaster for treating insomnia, characterized in that, It is made from the following raw materials and preparation process in parts by weight: 12-18 parts of Ziziphus jujuba seed, 16-19 parts of Polygonum multiflorum stem, 11-14 parts of Poria cocos, 9-11 parts of Atractylodes macrocephala, 16-19 parts of mother-of-pearl, 11-14 parts of dragon bone, 11-14 parts of magnetite, 11-14 parts of Albizia julibrissin bark, 8-12 parts of Platycladus orientalis seed, 9-11 parts of Angelica sinensis, 11-14 parts of Astragalus membranaceus, and 6-9 parts of licorice; wherein the mother-of-pearl, dragon bone, and magnetite are subjected to nano-calcination treatment to an average particle size ≤50nm, and the matrix contains 1.5%-2.5% of chitosan-β-cyclodextrin inclusion complex.

2. The formula for a medicated plaster for treating insomnia according to claim 1, characterized in that: The principal ingredient is a combination of 12-18 parts of Ziziphus jujuba seed and 16-19 parts of Polygonum multiflorum stem; the assistant ingredient is a combination of 11-14 parts of Poria cocos and 9-11 parts of Atractylodes macrocephala; the adjuvant ingredient is a combination of 16-19 parts of pearl powder, 11-14 parts of dragon bone, and 11-14 parts of magnetite; and the guiding ingredient is a combination of 11-14 parts of Albizia julibrissin bark, 8-12 parts of Platycladus orientalis seed, 9-11 parts of Angelica sinensis, 11-14 parts of Astragalus membranaceus, and 6-9 parts of Glycyrrhiza uralensis.

3. The formula for a medicated plaster for treating insomnia according to claim 1, characterized in that: The nano-calcination process is a three-stage gradient heating calcination: first, calcination at 300℃ for 30 minutes, then heating to 600℃ for 30 minutes, and finally heating to 900℃ for 30 minutes. After calcination, the material is processed into nanoparticles with an average particle size of ≤50nm by airflow pulverization technology.

4. The formula for a medicated plaster for treating insomnia according to claim 1, characterized in that: The matrix is ​​prepared by mixing petrolatum and lanolin in a weight ratio of 2:1 to 3:1, and the weight ratio of chitosan to β-cyclodextrin in the chitosan-β-cyclodextrin inclusion complex is 1:2 to 1:

3.

5. The formula for a medicated plaster for treating insomnia according to claim 1, characterized in that: The extraction of herbal medicines adopts a dual alcohol-water extraction process: Ziziphus jujuba seed and Platycladus orientalis seed are extracted by reflux with 75% ethanol. The extraction conditions are: solvent volume 10 times the weight of the medicinal materials, extraction twice, 1.5 hours each time; Albizia julibrissin bark, Poria cocos, Atractylodes macrocephala, Astragalus membranaceus, and Angelica sinensis are extracted by decoction with water. The extraction conditions are: solvent volume 8 times the weight of the medicinal materials, extraction three times, 1 hour each time. The alcohol extract and the water decoction are combined and concentrated into an extract.

6. The formula for a medicated plaster for treating insomnia according to claim 5, characterized in that: The concentration conditions for the alcohol extract were vacuum concentration to a relative density of 1.25-1.30 at 60℃, and the concentration conditions for the water extract were atmospheric concentration to a relative density of 1.30-1.35 at 60℃.

7. The formula for a medicated plaster for treating insomnia according to claim 1, characterized in that: The preparation process of the plaster includes an ultrasonic dispersion step: after mixing the nano-mineral powder, herbal extract and matrix, it is ultrasonically dispersed at a frequency of 40-50kHz and a power of 200-400W for 20-40 minutes to make the nanoparticles uniformly dispersed in the matrix.

8. The formula for a medicated plaster for treating insomnia according to claim 1, characterized in that: The plaster is applied to a non-woven fabric substrate to form a patch with a drug content of ≥1.5g / 10cm². The patch matrix also contains 0.5%-1.0% glycyrrhizic acid as a natural transdermal penetration enhancer.

9. The formula for a medicated plaster for treating insomnia according to any one of claims 1-8, characterized in that: The plaster achieves multi-target synergistic effects through transdermal absorption, including regulating GABA_A receptors to enhance central inhibition, regulating the gut-brain axis to improve gastrointestinal function, and stabilizing neuronal membrane potential through the microcurrent effect of nanomineral drugs.

10. The formula for a medicated plaster for treating insomnia according to any one of claims 1-8, characterized in that, The plaster is applied to the Shenque (CV8), Xinshu (BL15), or Yongquan (KI1) acupoints for 12-24 hours daily, with a course of treatment lasting 7-14 days.