Traditional Chinese medicine compound sustained-release patch for treating senile constipation and application thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine preparations, in particular to a traditional Chinese medicine compound sustained-release patch for treating senile constipation and application thereof.The patch is prepared from 10 parts of fructus evodiae, 10 parts of fresh ginger, 15 parts of codonopsis pilosula, 10 parts of water chestnuts, 10 parts of white pepper, 8 parts of clove, 15 parts of folium artemisiae argyi, 10 parts of dried ginger and 2 parts of borneol. According to the traditional Chinese medicine compound sustained-release patch for treating the senile constipation and the application of the traditional Chinese medicine compound sustained-release patch, targeted absorption of the medicine is enhanced by utilizing the characteristics of the Shenque acupoint, the medicine is continuously released within 12-24 hours, the clinical total effective rate is 95.0% and is obviously higher than 78.9% of a lactulose control group, and the traditional Chinese medicine compound sustained-release patch has the advantages that the traditional Chinese medicine compound sustained-release patch is suitable for being used for treating the senile constipation and the application of the traditional Chinese medicine compound sustained-release patch. The traditional Chinese medicine composition is free of systemic adverse reaction, only has 3.3% of transient skin erythema, can improve defecation frequency, consumed time and excrement characters, regulate intestinal flora and fill the medicine blank of over 80-year-old super-elderly patients, and is suitable for old patients with deficiency-cold type functional constipation.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, specifically a traditional Chinese medicine compound sustained-release patch for treating senile constipation and its application. Background Technology

[0002] Constipation in the elderly is a common digestive system disease, mainly manifested as difficulty in defecation, reduced defecation frequency (many patients defecate less than twice a week, and in severe cases, only once every 2 to 4 weeks), and dry stools. With age, the intestinal function of the elderly gradually declines, gastrointestinal motility slows down, and intestinal mucus secretion decreases, leading to prolonged retention of feces in the intestines and excessive water absorption, thus causing constipation. Furthermore, the elderly often have multiple chronic diseases and medication use, which may also exacerbate constipation. Long-term constipation further disrupts normal intestinal motility and secretion, aggravating gastrointestinal dysfunction, manifesting as symptoms such as abdominal distension, abdominal pain, and loss of appetite. Severe cases can lead to acute complications such as fecal impaction and intestinal obstruction, and fatal risks like cardiovascular and cerebrovascular accidents, seriously affecting the patient's quality of life and causing psychosocial collapse, creating a vicious cycle. Studies have shown that elderly patients with constipation have an average annual medical expenditure of $1840 (oral medication + enema treatment), and cardiovascular and cerebrovascular events induced by constipation account for 3.1% of accidental deaths in the elderly. Global epidemiological studies show that the prevalence of this disease increases exponentially with age: 24.3% in the 60-69 age group, jumping to 32.7% in the 70-79 age group, and as high as 41.5% in the elderly over 80 years old, with an average annual growth rate of 4.5%, significantly higher than other age groups. The risk of disease in women (34.6%) is significantly higher than that in men (27.9%). Constipation in the elderly is essentially a concentrated manifestation of systemic aging in the intestines. It is driven by a triple force of aging biological mechanisms (neurodegenesis, muscle fiber degeneration, and endocrine disorders), differences in environmental exposure, and comorbidity networks. For example, the number of neurons in the myenteric plexus decreases by 15%-20% every ten years, the strength of the pelvic floor muscles and abdominal wall muscles decreases by 1.5%-2.0% annually, serum motilin levels decrease by 40%, the expression of colonic aquaporin 3 is downregulated by 45% after menopause in women, and the risk of pelvic floor muscle relaxation increases by 2.3 times in multiparous women. The incidence of constipation in the elderly with neurodegenerative diseases exceeds 60%, diabetic autonomic neuropathy increases the risk of constipation by 3 times, and the incidence of constipation in the elderly taking ≥3 medications simultaneously soars to 78%.

[0003] Currently, the main drugs for treating constipation in the elderly have many shortcomings, falling into a "triple paradox": While secretagogues (such as lubiprostone and linaclotide) can activate chloride ion channels in intestinal epithelial cells and increase intestinal fluid secretion, linaclotide causes orthostatic hypotension in patients over 80 years old in as high as 12.3%; lubiprostone's monthly treatment cost is over $300, and its metabolism via CYP3A4 easily leads to abnormally high blood drug concentrations in elderly patients, increasing the risk of ALT elevation by 3 times; osmotic laxatives (such as polyethylene glycol and lactulose) create a hypertonic intestinal environment, promoting water retention, but easily causing electrolyte imbalance; lactulose increases the risk of hypermagnesemia by 6 times in patients with eGFR <45 mL / min; polyethylene glycol has an incidence of abdominal distension / pain >60%, and lactulose also interferes with digoxin absorption; stimulant laxatives (such as...) Bisaccharide and senna stimulate the enteric plexus to enhance peristalsis. Continuous use for 6 months leads to a decrease in the density of the myenteric plexus and irreversible melanosis coli (incidence rate 38.2%). Anthraquinone metabolites are genotoxic. Bulk-forming laxatives require 200mL of water to take, increasing the risk of aspiration by 5 times in elderly people with dementia. The rate of esophageal / intestinal obstruction in frail elderly people is as high as 9.3%. Probiotics (such as Bifidobacterium) have a colonization rate of <20% in elderly patients and an efficacy rate of only 15.7% for slow transit constipation. Prokinetic drugs (such as prucalopride) cause QTc interval prolongation >500ms in 4.1% of cases. Combined use with many commonly used drugs for the elderly can easily induce torsades de pointes. Furthermore, clinical trials of all the above drugs excluded the very elderly population over 80 years of age, resulting in almost no drugs available for this group.

[0004] Therefore, in view of the above situation, there is an urgent need to develop a traditional Chinese medicine compound sustained-release patch for treating constipation in the elderly and its application, so as to overcome the shortcomings in current practical applications. Summary of the Invention

[0005] The purpose of this invention is to provide a traditional Chinese medicine compound sustained-release patch for treating constipation in the elderly and its application, so as to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A traditional Chinese medicine compound sustained-release patch for treating constipation in the elderly is made from the following ingredients in parts by weight: 10 parts Evodia rutaecarpa, 10 parts fresh ginger, 15 parts Codonopsis pilosula, 10 parts water chestnut, 10 parts white pepper, 8 parts clove, 15 parts Artemisia argyi, 10 parts dried ginger, and 2 parts borneol.

[0008] As a further aspect of the present invention: the traditional Chinese medicine compound is formulated according to the principle of principal, assistant, adjuvant and guide, wherein the principal medicine is Evodia rutaecarpa and ginger, the assistant medicine is Codonopsis pilosula and water chestnut, the adjuvant medicine is white pepper, clove, mugwort and dried ginger, and the guide medicine is borneol.

[0009] As a further aspect of the present invention, the drug release rate of the patch is: less than 20% burst release rate at 8 hours and greater than 90% cumulative release rate at 24 hours.

[0010] A method for preparing a traditional Chinese medicine compound sustained-release patch as described above includes the following steps: raw material pretreatment and directional extraction; ointment synthesis and activity protection; sustained-release matrix preparation and drug loading; coating, drying and finished product processing.

[0011] As a further aspect of the present invention: the ointment synthesis and activity protection steps include: adding vitamin E to the mixed drug solution and adjusting the pH value to 6.0-6.5 using citric acid solution.

[0012] As a further aspect of the present invention: the coating, drying and finished product processing steps include: cutting the dried drug-loaded film into 4cm×4cm patches and sterilizing them by cobalt-60 irradiation.

[0013] The application of a traditional Chinese medicine compound sustained-release patch as described above in the preparation of a drug for treating senile constipation.

[0014] As a further aspect of the present invention, the patch is administered transdermally through the Shenque acupoint.

[0015] As a further aspect of the present invention: the elderly constipation patient is a patient aged 80 years or older.

[0016] As a further aspect of the present invention: the senile constipation is functional constipation of the deficiency-cold type.

[0017] Compared with the prior art, the beneficial effects of the present invention are:

[0018] The traditional Chinese medicine compound sustained-release patch of this invention uses transdermal sustained-release technology to replace oral medications (avoiding the first-pass effect and gastrointestinal irritation) and suppositories (solving the problem of inconvenience in use), significantly improving medication safety and patient compliance. No patients in the treatment group dropped off the patch, and the overall completion rate was high.

[0019] It utilizes the anatomical characteristics of the Shenque acupoint—thin skin, strong permeability, and direct connection to the intestines—to enhance targeted drug absorption. At the same time, it stimulates the acupoint to regulate intestinal function. Pharmacodynamic experiments show that it can improve intestinal propulsion rate and increase defecation frequency.

[0020] By using a sustained-release matrix to control the continuous release of the drug for 12-24 hours, fluctuations in blood drug concentration are avoided, and side effects such as diarrhea are reduced. Toxicity studies show that the drug is safe and has low skin irritation. Only 3.3% of patients experienced transient mild skin erythema, which subsided within 48 hours. There were no systemic adverse reactions, electrolyte disturbances, QTc interval prolongation, or abnormal liver and kidney function.

[0021] The overall effective rate in clinical application reached 95.0% (clinical cure 20.0% + marked effect 46.7% + effective 28.3%), significantly higher than the 78.9% in the lactulose control group. The difference in effective rate was even more significant in the ultra-elderly subgroup (>85 years old) (93.3% vs 64.3%). 50% of patients experienced spontaneous defecation within 3 days, twice as fast as the control group. After 14 days of treatment, the frequency of defecation increased from 1.21±0.17 times / week to 3.32±0.41 times / week (an increase of 174%), the time taken for defecation decreased from 9.8±2.4 minutes to 4.7±1.2 minutes (a decrease of 62%), and the Bristol score increased from 1.57±0.25 to 3.95±0.42 (an increase of 156%). The improvement was significantly better than that in the control group.

[0022] This patch can also effectively regulate the intestinal flora, increasing the number of Bifidobacteria and Lactobacillus by 24.9% and 27.2% respectively, and decreasing the number of Escherichia coli by 21.5%. The Bifidobacteria / Escherichia coli ratio is strongly correlated with the improvement of defecation frequency (r=0.68, P<0.001). It has a low recurrence rate and is easy to use, providing a breakthrough treatment option for constipation in the elderly. In particular, it fills the clinical gap of "no safe prokinetic drugs" for patients over 80 years old. It is suitable for elderly patients with functional constipation of the deficiency-cold type, especially those with multiple underlying diseases and intolerant to oral medications. Attached Figure Description

[0023] Figure 1 This is a bar chart illustrating the effects of the traditional Chinese medicine compound sustained-release patch on peripheral blood routine indicators in mice under hypoxic conditions, as described in this invention.

[0024] Among them, A is a bar chart showing the effect of the traditional Chinese medicine compound sustained-release patch on the total white blood cell count (WBC) in mice under hypoxic conditions; B is a bar chart showing the effect of the traditional Chinese medicine compound sustained-release patch on the percentage of lymphocytes (LYMPH%) in mice under hypoxic conditions; C is a bar chart showing the effect of the traditional Chinese medicine compound sustained-release patch on the red blood cell count (RBC) in mice under hypoxic conditions; and D is a bar chart showing the effect of the traditional Chinese medicine compound sustained-release patch on the percentage of neutrophils (NEUT%) in mice under hypoxic conditions.

[0025] Figure 2 This is a composite diagram showing the effects of traditional Chinese medicine compound sustained-release patch on organ coefficients and pathological structures of mouse immune organs (spleen and thymus) under hypoxic conditions in an embodiment of the present invention.

[0026] Among them, A is a bar chart showing the effect of the traditional Chinese medicine compound sustained-release patch on the spleen coefficient of mice under hypoxic conditions; B is a bar chart showing the effect of the traditional Chinese medicine compound sustained-release patch on the thymus coefficient of mice under hypoxic conditions; C is an optical microscope image (20×) showing the effect of the traditional Chinese medicine compound sustained-release patch on the pathological structure of the spleen of mice under hypoxic conditions (labeled groups: normal control group NC, model group MOD, patch treatment group WZYP-SP); D is an optical microscope image (20×) showing the effect of the traditional Chinese medicine compound sustained-release patch on the pathological structure of the thymus of mice under hypoxic conditions (labeled groups: normal control group NC, model group MOD, patch treatment group WZYP-SP). Detailed Implementation

[0027] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] The specific implementation of the present invention will be described in detail below with reference to specific embodiments.

[0029] Please see Figure 1 and Figure 2 The present invention provides a traditional Chinese medicine compound sustained-release patch for treating senile constipation and its application, including the following:

[0030] I. Composition of Traditional Chinese Medicine Compound Sustained-Release Patches;

[0031] The active ingredients of the traditional Chinese medicine compound sustained-release patch of this invention are composed of the following parts by weight of traditional Chinese medicine raw materials. The functions and active ingredients of each raw material are shown in the table below:

[0032]

[0033] II. The compatibility and scientific connotation of traditional Chinese medicine compound prescriptions;

[0034] 1. Compatibility relationships (ruler, minister, assistant, envoy);

[0035] The principal herbs are Evodia rutaecarpa and fresh ginger. Together, they activate the main effect of "warming the kidneys and promoting yang", targeting the core pathogenesis of "deficiency of the fire of the gate of life" in constipation in the elderly. Evodia rutaecarpa disperses cold stagnation in the lower jiao (targeting the deficiency of the fire of the gate of life in the elderly) and contains evodia alkaloids, which can promote transdermal absorption (proven by modern pharmacology). However, Evodia rutaecarpa is slightly toxic and needs to be restrained by the assistant herbs: fresh ginger and dried ginger work together to warm the middle jiao, which can restrain its toxicity, in line with the principle of "restraint prevents anger".

[0036] Assistant herbs: Codonopsis pilosula and water chestnut. Codonopsis pilosula tonifies the spleen and lung qi to help the principal herb warm and transport the intestines. Water chestnut "increases water to move the boat" to prevent the principal herb from being too warm and dry and damaging yin. At the same time, water chestnut is neutral in nature and can counteract the warm and dryness of the principal and assistant herbs (preventing yin damage in the elderly). In addition, its high potassium properties (containing 490mg / 100g of potassium) prevent osmotic diarrhea. The two constitute a dual-axis regulation of "attack and tonification".

[0037] Adjuvant herbs: white pepper, cloves, mugwort, and dried ginger (accounting for 75% of the total herbs). White pepper and cloves assist the principal and assistant herbs in enhancing their warming and invigorating effects. Mugwort and dried ginger specialize in "penetrating acupoints and unblocking meridians" to promote the penetration of the medicine through the Shenque acupoint, while also eliminating adverse reactions such as vomiting that may be caused by the principal herb (such as Evodia rutaecarpa). Among them, white pepper can inhibit the liver drug-metabolizing enzyme CYP3A4, extending the half-life of evodia rutaecarpa alkaloid from 4 hours to 8.5 hours, achieving a sustained-release effect. Dried ginger and white pepper form a "warming navel pair," initiating thermal convection to promote drug penetration. Codonopsis pilosula and mugwort form a "replenishing and penetrating pair," with codonopsis pilosula glycosides promoting nerve regeneration and mugwort volatile oil promoting absorption, forming a complementary effect.

[0038] The guiding drug, borneol, acts as the key to "guide and deliver" other drugs, enabling them to penetrate the Shenque acupoint and reach the celiac plexus. It also has analgesic effects (involving allosteric regulation of the GABA_A receptor β3 subunit, which increases the pain threshold by 150%), further improving patient tolerance. Its permeation-enhancing mechanism not only disrupts the lipid arrangement of the stratum corneum but also reversibly opens the tight junction channels formed by the epidermal Claudin-1 protein, making the permeability coefficient of the Shenque acupoint 3.4 times that of ordinary skin (J=9.7μg / cm² / h).

[0039] 2. Scientific connotations of compatibility;

[0040] Multi-target synergistic effect: Simultaneously regulates three major pathological aspects of constipation: Cajal interstitial cells (ICC), enteric neurons (VIP), and gut microbiota ecology (Bifidobacterium / Escherichia coli ratio, F / B ratio), achieving comprehensive regulation of intestinal function; Modern pharmacological studies show that, in addition to its known TRPV1 activation effect, evodiamine can also dose-dependently inhibit intestinal SERT transporters, increasing local 5-HT concentration by 3 times (EC50=2.1μM), which is particularly important for constipation in the elderly, as the reduction of chromaffin cells in the intestine leads to 5-HT deficiency; In terms of transdermal effects, evodiamine can downregulate P-gp expression in epidermal cells, increasing drug transdermal flux by 2.8 times; Piperine can covalently modify CYP3A4 heme The addition of a receptor sensitizing group reduced the metabolic clearance rate of evodiamine from 6.7 to 1.2 L / h / kg and increased the sensitivity of TRPV1 to evodiamine by 3 times. This "receptor sensitization" may be more important than enzyme inhibition in the compound. The enteric nerve regulation mechanism of acupoint stimulation is unique. Animal experiments showed that after electroacupuncture at Shenque acupoint, the secretion of GDNF by intestinal glial cells increased by 7 times and the density of enteric nerves increased by 80%. This effect is achieved by activating the dorsal nucleus of the vagus nerve-myocardial nerve plexus pathway. PET-CT showed that the glucose metabolic rate (SUVmax) of the mesenteric nerve plexus increased by 180%. When evodiamine and piperine were combined in a ratio of 10:8, the intestinal propulsion speed reached its peak (70% higher than when used alone), proving the scientific validity of the traditional monarch-minister-assistant-guide combination.

[0041] Dynamic and static balance: The weight ratio of warming and invigorating drugs (Evodia rutaecarpa, dried ginger) to moistening and descending drugs (water chestnut, borneol) is strictly controlled at 5:3 to ensure the efficacy of warming and invigorating the intestines while avoiding the risk of warming and drying and damaging yin.

[0042] Optimized transdermal absorption: The proportion of penetration enhancers (borneol, piperine) in the total medicinal ingredients is ≤12%, and the irritation index is only 0.43 as verified by skin irritation test, which significantly reduces the risk of adverse skin reactions.

[0043] III. Preparation process of traditional Chinese medicine compound sustained-release patch;

[0044] The preparation process of the traditional Chinese medicine compound sustained-release patch of this invention includes four stages in sequence: raw material pretreatment and targeted extraction, ointment synthesis and activity protection, sustained-release matrix preparation and drug loading, coating and drying, and finished product processing. The specific operations of each stage are as follows:

[0045] 1. First stage: Raw material pretreatment and targeted extraction;

[0046] Preparation of fresh ginger juice: Take 10 parts by weight of fresh ginger, wash and peel it, and use a screw press to extract the juice. Filter the extracted juice through a 200-mesh filter cloth and collect the filtrate. Refrigerate the filtrate at 4°C for later use and use it within 2 hours after preparation to ensure that the active ingredients are not degraded.

[0047] Treatment of alcohol extract components: Take 10 parts by weight of Evodia rutaecarpa and 8 parts by weight of clove, crush them separately and mix them, and pass them through a 40-mesh sieve; add 8 times the amount (based on the weight of the mixed powder) of 60% ethanol solution to the mixed powder, place it in an extraction tank, and reflux extract at 80℃ for 1.5 hours; after extraction, filter it using a filtration device and collect the filtrate; place the filtrate in a vacuum concentration device and concentrate it under vacuum at 60℃ to a specific gravity of 1.15 (specific gravity measurement temperature is 60℃) to obtain the alcohol extract concentrate for later use.

[0048] Water extraction component processing: Take dried ginger (10 parts by weight), Codonopsis pilosula (15 parts by weight), and Artemisia argyi (15 parts by weight), mix them evenly, add 12 times the amount of purified water (based on the weight of the mixed medicinal materials), place them in a decoction pot and decoct twice, each time for 1 hour; combine the decoctions from the two decoctions, filter them using a filtration device to remove the dregs; place the filtrate in a vacuum concentration device, concentrate it under reduced pressure at 70℃ to a specific gravity of 1.25, and obtain the concentrated water extract for later use.

[0049] Auxiliary material pretreatment:

[0050] Take 10 parts by weight of water chestnuts, peel them and cut them into chunks. Add twice the amount of purified water (by weight of water chestnuts) to the chunks of water chestnuts and blend them in a high-speed blender at 20,000 rpm for 5 minutes to obtain a homogeneous water chestnut pulp. Set aside.

[0051] Take 10 parts by weight of white pepper, grind it into 300-mesh fine powder using an ultra-fine grinding equipment, and pass it through a 300-mesh sieve (sieving rate ≥95%) to obtain white pepper ultra-fine powder for later use.

[0052] 2. Second stage: Ointment synthesis and activity protection;

[0053] Preparation of mixed medicinal solution: The alcohol extract concentrate, water extract concentrate, fresh ginger juice, and homogenized water chestnut pulp obtained in the first stage are added to a 50°C constant temperature stirring tank and stirring is started; then white pepper ultrafine powder is added, the stirring speed is adjusted to 200 rpm, and stirring is continued for 30 minutes until the white pepper ultrafine powder is completely dispersed in the mixed solution to obtain the mixed medicinal solution.

[0054] Antioxidant treatment: Add 0.1% (w / w, based on the total weight of the mixed medicine) of vitamin E to the above mixed medicine solution and stir evenly; then adjust the pH value of the mixed medicine solution to 6.0-6.5 with 1% citric acid solution, and continue to stir at 200 rpm for 10 minutes to obtain the traditional Chinese medicine ointment; the addition of vitamin E can prevent the oxidative degradation of active ingredients (such as 6-gingerol and eugenol) in the ointment, and pH adjustment can ensure the stability of active ingredients.

[0055] 3. Third stage: Preparation of sustained-release matrix and drug loading;

[0056] Sustained-release matrix formulation:

[0057] Take sodium carboxymethyl cellulose (CMC-Na), add purified water at a ratio of 10% (w / w, based on the total weight of the matrix), stir and let it swell at room temperature for 30 minutes to obtain CMC-Na swelling solution;

[0058] Transfer the CMC-Na swelling solution to a 55°C water bath, add polyvinyl alcohol (PVA) (at a ratio of 15% (w / w, based on the total weight of the matrix)), start stirring, and continue stirring for 1 hour until the PVA is completely dissolved and a transparent colloid is formed.

[0059] Cool the transparent colloid to 40°C, add acrylic pressure-sensitive adhesive (at a ratio of 30% (w / w, based on the total weight of the matrix)), transfer it to an ice-water bath environment and continue stirring until the viscosity of the colloid reaches 4500±500 cP (measured using a Brookfield viscometer under the following conditions: rotor No. 4, rotation speed 30 rpm), thus obtaining the slow-release matrix.

[0060] Drug-loaded mixture:

[0061] The traditional Chinese medicine ointment and the sustained-release matrix were put into a vacuum homogenizer together at a weight ratio of 1:3.

[0062] Set the temperature of the vacuum homogenizer to 35℃, the rotation speed to 200rpm, and the vacuum degree to -0.08MPa. Turn on the stirring and continue stirring for 40 minutes to ensure that the ointment and the matrix are fully and evenly mixed.

[0063] After stirring, cool the mixture to ≤35℃, add borneol (2 parts by weight, pre-crushed into fine powder), and continue stirring for 10 minutes until the borneol is completely dissolved to obtain a drug-loaded colloid. Controlling the temperature to ≤35℃ can prevent the loss of borneol (boiling point 212℃, easily volatile) due to high temperature volatilization, thus ensuring the permeation-enhancing effect of borneol.

[0064] 4. Fourth stage: Coating drying and finished product processing;

[0065] Coating operation: Inject the drug-loaded colloid into the material trough of the coating machine, adjust the doctor blade gap of the coating machine to 0.45±0.03mm, and select elastic non-woven fabric as the backing material; set the coating speed to 0.8m / min, so that the backing material passes through the coating machine at a uniform speed, and the drug-loaded colloid is evenly coated on the surface of the backing material to form a drug-loaded film layer.

[0066] Segmented drying:

[0067] First stage drying: The coated backing material is sent into a hot air circulating drying oven, the drying temperature is set to 40℃ and the wind speed is 2m / s, and it is dried for 15 minutes to remove some of the moisture in the drug-loaded film layer.

[0068] Second stage drying: Transfer the material after the first stage drying to a low-temperature drying oven, set the drying temperature to 35℃ and the relative humidity to ≤30%, and dry for 20 minutes to further remove moisture and avoid high temperature damage to active ingredients.

[0069] After drying, the moisture content of the drug-loaded film layer is controlled at 5%-8% (mass fraction) to ensure the adhesion and stability of the patch.

[0070] Cutting and Packaging: The dried drug-loaded film is cut into 4cm×4cm square patches using a laser cutting machine; each square patch is placed into an aluminum-plastic composite bag, sealed, and then sterilized.

[0071] Sterilization: Cobalt-60 irradiation sterilization was performed with an irradiation dose of 8 kGy and a dose uniformity controlled within ±10%. After sterilization, the aluminum-plastic composite bag was inspected for sealing to ensure no leakage, thus obtaining the finished product of the traditional Chinese medicine compound sustained-release patch.

[0072] IV. The advantages of the preparation process of this invention are as follows:

[0073] The dual-ginger synergistic system combines fresh ginger juice (which provides rapid-acting warming stimulation) with dried ginger extract (which provides sustained-release warming stimulation) to maintain the warming stimulation effect on the intestines for more than 12 hours and continuously promote intestinal peristalsis.

[0074] Borneol low-temperature protection process: During the drug loading, mixing and subsequent drying process, the temperature is controlled at ≤40℃ throughout. The borneol retention rate is >98%, which is significantly higher than that of the traditional process (borneol retention rate is only 60%).

[0075] Dynamic release regulation: Using acrylic pressure-sensitive adhesive-PVA composite matrix, the release rate test has verified that the drug burst release rate of the patch is <20% after 8 hours (which can effectively prevent diarrhea caused by drug burst release), and the cumulative drug release rate is >90% after 24 hours, achieving long-term and continuous drug release.

[0076] V. Quality control standards for traditional Chinese medicine compound sustained-release patches;

[0077] To ensure the quality stability and effectiveness of the traditional Chinese medicine compound sustained-release patch of this invention, the following quality control standards are established, and the test methods and qualification standards for each item are shown in the table below:

[0078]

[0079] VI. Pharmacodynamic verification experiment of traditional Chinese medicine compound sustained-release patch;

[0080] To verify the efficacy and safety of the traditional Chinese medicine compound sustained-release patch of this invention in treating senile constipation, animal experiments and clinical trials were conducted. The specific experimental protocols and results are as follows:

[0081] (a) Animal experiments;

[0082] Experimental background and objectives: In the early stage, the project team constructed a mouse model of immune damage at high altitude and used the preparation of this invention for intervention treatment. The team systematically explored the effect of this therapy on improving immune function damage in the high altitude environment and its potential mechanism of action. At the same time, it indirectly verified its protective effect on intestinal function (which is closely related to immune function).

[0083] Experimental ethics: This experiment has been approved for animal ethics review, with the ethics approval number IACUC-DWZX-2025-518, and the experimental procedures comply with animal ethics requirements; at the same time, it has been approved for ethics review of cohort studies of traditional Chinese medicine sustained-release preparations, with the approval number AF / SC-08 / 02.459.

[0084] Experimental model construction: A high-altitude immune injury mouse model was constructed. SPF-grade Kunming mice were placed in a hypoxic chamber (oxygen concentration 8%) for 7 days to establish a hypoxia-induced immune injury model (model group, MOD). At the same time, a normal control group (NC, conventional environment feeding) and a patch treatment group (WZYP-SP, hypoxia environment feeding + application of the traditional Chinese medicine compound sustained-release patch of this invention to the Shenque acupoint, once a day, 12 hours each time, for 7 days) were set up.

[0085] Test indicators and results:

[0086] Peripheral blood routine examination: The results showed that the intervention of the traditional Chinese medicine sustained-release patch had a significant regulatory effect on the changes in hematological parameters caused by hypoxia. Specifically, the patch could partially improve the hypoxia-induced decrease in total white blood cell count (WBC) and the decreasing trend of lymphocyte percentage (LYMPH%), although this improvement did not reach the level of statistical significance; at the same time, the red blood cell count (RBC) in the treatment group was significantly lower than that in the model group (P<0.05), indicating that the intervention may alleviate high-altitude polycythemia by regulating the erythropoiesis pathway; however, it is worth noting that the neutrophil percentage (NEUT%) in the treatment group was further increased compared with that in the model group. This phenomenon may be related to the activation of type I hypersensitivity reaction or Th2 immune response induced by the patch components. The specific mechanism still needs to be further elucidated through subsequent experiments (see Figure 1 ).

[0087] Spleen and thymus organ coefficients and pathological structures: As important immune organs, the spleen and thymus typically maintain a relatively constant organ coefficient (organ weight / body weight). However, under high-altitude hypoxia stress, significant splenomegaly and thymic atrophy were observed in the model group mice. After intervention with a sustained-release traditional Chinese medicine preparation, the spleen and thymus indices of the treatment group mice were significantly improved compared to the model group (P<0.05) (see...). Figure 2Histopathological analysis further revealed that the sustained-release formulation of traditional Chinese medicine significantly improved the structural disorder of spleen tissue caused by high-altitude hypoxia, including reconstructing a clear splenic trabecular structure, restoring the red and white medullary boundaries, increasing the number of small lymphocytes, and reducing inflammatory cell infiltration. Regarding thymus tissue, the integrity of the thymic cortex structure in the treatment group mice was significantly restored, with a clear boundary between the cortex and medulla, effectively alleviating hypoxia-induced thymic cell edema (pale cytoplasm) and inflammatory cell infiltration, among other pathological features (see...). Figure 2 Studies have shown that this sustained-release traditional Chinese medicine preparation has a significant regulatory effect on immune damage caused by hypoxia, and may exert its protective effect by maintaining the homeostasis of the immune organ microenvironment, thereby indirectly supporting the improvement of intestinal function. Animal experiments suggest that the mechanism of action of this sustained-release traditional Chinese medicine preparation in the treatment of senile constipation is likely closely related to its influence on immune regulation. Regulating the body's immune microenvironment promotes the restoration of overall health, and the protective effects of the spleen and thymus as core immune organs may indirectly enhance the stability of the enteric nervous system, improving intestinal motility through multi-target synergistic effects.

[0088] (ii) Clinical trials;

[0089] Experimental objective:

[0090] To verify the efficacy and safety of the traditional Chinese medicine compound sustained-release patch of this invention in treating functional constipation of the deficiency-cold type (meeting the Rome IV diagnostic criteria);

[0091] Compare the differences between the patch of this invention and traditional oral medication (lactulose oral solution) in terms of patient compliance and recurrence rate;

[0092] The extent to which the patch improves key symptoms of constipation in the elderly (cold abdominal pain, prolonged defecation time, and stool consistency) was evaluated.

[0093] Trial design: Randomized parallel controlled trial, the trial protocol has been approved for ethical review (ethics approval number: AF / SC-08 / 02.459).

[0094] Inclusion and exclusion criteria:

[0095] Inclusion criteria: Age 65-90 years; meeting the Rome IV diagnostic criteria for functional constipation; diagnosed with kidney yang deficiency syndrome according to traditional Chinese medicine (symptoms include aversion to cold, cold limbs, pale tongue with white coating, and deep and slow pulse); bowel frequency ≤ 2 times / week in the 4 weeks prior to enrollment; patients voluntarily participated and signed informed consent forms.

[0096] Exclusion criteria: coexisting organic intestinal diseases (such as intestinal obstruction, intestinal tumors) or malignant tumors; estimated glomerular filtration rate (eGFR) <45mL / min or left ventricular ejection fraction (LVEF) <40%; history of periumbilical skin injury, inflammation or allergy; use of other constipation treatment drugs within 2 weeks prior to enrollment.

[0097] Experimental subjects and groups:

[0098] A total of 120 elderly patients with constipation who met the diagnostic criteria (aged 60-89 years, with the final age range of patients included in the statistical analysis being 65-89 years) were recruited. All patients had to meet the diagnostic criteria for constipation and voluntarily participate in this study. They were randomly divided into a treatment group (60 cases) and a control group (60 cases) using a random number table.

[0099] Treatment group: The traditional Chinese medicine compound sustained-release patch of this invention was applied to the Shenque acupoint once a day for 12 hours each time, and the treatment continued for 2 weeks.

[0100] Control group: Oral lactulose solution, once daily, with dosage adjusted according to patient weight and constipation severity, for 2 weeks;

[0101] During the trial, 3 patients dropped out of the control group (2 withdrew due to severe diarrhea and 1 was lost to follow-up), while no patients dropped out of the treatment group. Ultimately, 60 patients in the treatment group and 57 patients in the control group completed the entire intervention, with a total completion rate of 97.5%, demonstrating good compliance.

[0102] Baseline characteristics: The baseline characteristics of the two groups of patients, such as age, duration of constipation, and baseline frequency of bowel movements, were equal between the groups (P>0.05), making them comparable. Specific data are shown in the table below (mean age of subjects 76.7±8.1 years, mean duration of constipation 9.8±3.3 years):

[0103]

[0104] Efficacy evaluation indicators and methods:

[0105] Defecation frequency: Record the number of spontaneous bowel movements per week during the 2 weeks of treatment and calculate the rate of change before and after treatment;

[0106] Stool characteristics: The Bristol Stool Scale (1-7 points, 1 point for hard, ball-shaped stool, 7 points for watery stool, and 4 points for well-formed soft stool) was used to assess stool characteristics and calculate the changes in scores before and after treatment.

[0107] Defecation time: Record the average time of a single defecation session and calculate the rate of change before and after treatment;

[0108] Gut microbiota analysis: Fecal samples were collected from patients before and after treatment. 16S rRNA gene sequencing technology was used to analyze the gut microbiota, focusing on changes in the levels of Bifidobacterium, Lactobacillus (beneficial bacteria), and Escherichia coli (harmful bacteria). The differences in gut microbiota structure and abundance between the two groups of patients before and after treatment were compared. Bioinformatics methods were used to analyze the results to explore the regulatory effect of traditional Chinese medicine poultices on gut microbiota.

[0109] Efficacy evaluation criteria: Clinically cured (defecation frequency returns to normal, Bristol score reaches 4 points, defecation time < 5 minutes, and symptoms completely disappear); Significantly effective (defecation frequency increases by ≥100% from baseline, Bristol score increases by ≥2 points, defecation time decreases by ≥50%, and symptoms are significantly improved); Effective (defecation frequency increases by 50%-99% from baseline, Bristol score increases by 1 point, defecation time decreases by 30%-49%, and symptoms are somewhat improved); Ineffective (does not meet the above effective criteria); Total effective rate = (number of clinically cured cases + number of significantly effective cases + number of effective cases) / total number of cases × 100%.

[0110] Statistical methods: SPSS software was used for statistical analysis. Quantitative data were expressed as mean ± standard deviation (x ± s), and t-tests or non-parametric tests were used for comparisons between groups. Categorical data were expressed as number of cases (percentage), and χ² tests were used for comparisons between groups. The significance level was set at P < 0.05. The results were presented in tables and graphs to facilitate comparison of the treatment effects and changes in gut microbiota between the two groups.

[0111] Experimental results:

[0112] Overall efficacy: The total effective rate in the treatment group was 95.0% (12 cases of clinical cure, 20.0%; 28 cases of marked improvement, 46.7%; 17 cases of improvement, 28.3%; 3 cases of ineffectiveness, 5.0%), significantly higher than that in the control group (78.9% (5 cases of clinical cure, 8.8%; 18 cases of marked improvement, 31.6%; 22 cases of improvement, 38.6%; 12 cases of ineffectiveness, 21.1%). The difference between the groups was statistically significant (χ²=8.63, P=0.003, difference in total effective rate 16.1%, 95% confidence interval CI: 8.3%-23.9%). Particularly noteworthy is the more significant difference in efficacy rate in the very elderly subgroup (>85 years, n=23) (treatment group 93.3% vs. control group 64.3%). Regarding the onset time, 50% of patients in the treatment group experienced spontaneous bowel movements within 3 days, twice as fast as the control group (7 days). Specific data are shown in the table below.

[0113]

[0114] Improvement of key symptoms (after 14 days of treatment): After 14 days of treatment, the treatment group showed triple improvement in bowel movements, and the extent of improvement was significantly better than that in the control group (P<0.001), as detailed below:

[0115] Bowel movement frequency increased from 1.21±0.17 times / week to 3.32±0.41 times / week (↑174%), which was significantly higher than that of the control group (↑114%).

[0116] Defecation efficiency: The time taken for a single defecation session was reduced from 9.8±2.4 minutes to 4.7±1.2 minutes (↓62%), which was significantly lower than that of the control group (↓43%) (between groups -2.4 minutes, 95% CI -2.9 to -1.9).

[0117] Stool quality: Bristol score increased from 1.57±0.25 to 3.95±0.42 (↑156%), reaching the ideal formed soft stool standard (Type 4), while the control group only reached Type 2-3 (↑81%).

[0118] The specific data is shown in the table below:

[0119]

[0120] Intestinal flora regulation effect: After treatment, the number of beneficial bacteria (Bifidobacteria and Lactobacilli) and the number of harmful bacteria (Escherichia coli) in the intestines of both groups increased, but the change in the treatment group was significantly greater than that in the control group (P<0.001). Specifically, the Bifidobacteria / Escherichia coli ratio (F / B ratio) in the treatment group increased from 0.79 before treatment to 1.26 after treatment, and this change was strongly positively correlated with the improvement in bowel movement frequency (r=0.68, P<0.001). Specific data are shown in the table below.

[0121]

[0122] Safety analysis: The treatment group experienced zero systemic adverse reactions, with the main risk being only transient mild skin erythema (3.3%, resolving within 48 hours). In contrast, the control group had a diarrhea rate of 15.0% (9 / 60), with 2 patients withdrawing due to severe electrolyte disturbances, and an abdominal pain rate of 6.7% (4 / 60). The treatment group demonstrated an absolute advantage in key safety indicators for the elderly: no electrolyte disturbances (serum potassium / magnesium fluctuations <5%), no QTc interval prolongation (ΔQTc <10ms), and no abnormal liver or kidney function (ALT / Cr change rate <8%). Specific data are shown in the table below.

[0123]

[0124] Clinical trial conclusions:

[0125] The Shenque acupoint sustained-release herbal patch, through multi-target regulation (neural activation + flora remodeling), achieves a dual breakthrough in the treatment of constipation in the elderly, surpassing both efficacy (95.0% vs 78.9%) and safety (0% systemic toxicity vs 15% diarrhea rate). Its unique "acupoint-drug" synergistic mechanism provides a solution that conforms to physiological regulatory principles for the declining intestinal function of the elderly and frail, filling the current clinical gap of "no safe prokinetic drugs."

[0126] Meanwhile, combined with the results of animal experiments and clinical trials, it is known that the traditional Chinese medicine compound sustained-release patch of this invention, while improving immune damage under high-altitude hypoxia environment, may also enhance the intestinal barrier function of the elderly through a similar mechanism. The repair of spleen structure helps to improve the systemic inflammatory regulation capacity, and the restoration of thymus function may promote T cell-mediated local immune balance. This systemic regulation can reduce chronic intestinal inflammation caused by aging, thereby optimizing the composition and metabolic activity of intestinal flora. Moreover, the synergistic effect of multiple components in the traditional Chinese medicine compound provides dual protection for improving senile constipation: on the one hand, warming and invigorating drugs such as Evodia rutaecarpa and dried ginger can promote intestinal peristalsis by activating the TRPV1 channel; on the other hand, moistening and descending drugs such as water chestnut and borneol can prevent excessive stimulation by maintaining the moisture and integrity of the intestinal mucosa. This "attack and tonify" design can relieve constipation symptoms while avoiding the common adverse reactions of traditional prokinetic drugs, reflecting the organic combination of the holistic concept of traditional Chinese medicine and the precision treatment of modern medicine.

[0127] In addition, the choice of sustained-release administration method for traditional Chinese medicine is of great significance for the long-term compliance of elderly patients. Compared with oral drugs, transdermal administration can not only avoid the first-pass effect of the gastrointestinal tract, but also significantly reduce the risk of systemic toxicity. Especially in the elderly population, this method effectively reduces the safety risks caused by the decline in drug metabolism capacity, laying the foundation for achieving a mild and lasting therapeutic effect.

[0128] VII. Advantages and applications of the invention;

[0129] (a) Core advantages;

[0130] High safety: Transdermal drug delivery via Shenque acupoint avoids the first-pass effect and gastrointestinal irritation of oral drugs, with no systemic adverse reactions (diarrhea rate = 0), only a low probability (3.3%) of transient skin erythema, and has no effect on key safety indicators (electrolytes, QTc interval, liver and kidney function) in elderly patients. It is suitable for very elderly patients (>85 years old) and elderly patients with multiple underlying diseases.

[0131] High efficacy: The overall effective rate reaches 95.0%, significantly higher than traditional oral medications (78.9%). It can take effect quickly (50% of patients have a bowel movement within 3 days) and can simultaneously improve bowel movement frequency, time, and stool characteristics. It can also regulate the balance of intestinal flora (increase the F / B ratio), achieving the dual effect of "symptom improvement + etiological regulation". Pharmacodynamic experiments show increased intestinal propulsion rate and increased bowel movement frequency. Toxicity studies show safety and low skin irritation.

[0132] Good compliance: The patch is easy to use (applied to the Shenque acupoint, once a day), does not require drinking water to take it (avoiding the risk of aspiration in elderly people with dementia), has no irritating taste (avoiding the vomiting reflex caused by lactulose), and the patient completion rate is 100% (no dropout in the treatment group).

[0133] Long-lasting and gentle: The sustained-release matrix enables continuous drug release for 12-24 hours, avoiding fluctuations in blood drug concentration and eliminating the risk of diarrhea caused by sudden drug release. It is suitable for long-term management of chronic constipation in the elderly and has a low recurrence rate.

[0134] (ii) Application Scenarios;

[0135] This invention's traditional Chinese medicine compound sustained-release patch is mainly used for the treatment of constipation in the elderly, and is especially suitable for:

[0136] Patients with functional constipation of the deficiency-cold type who meet the Rome IV diagnostic criteria;

[0137] Elderly patients with constipation diagnosed by traditional Chinese medicine as having kidney yang deficiency syndrome (aversion to cold, cold limbs, pale tongue with white coating, and deep and slow pulse);

[0138] Constipation patients aged 80 and above (filling the gap in safe medication for this group);

[0139] Elderly patients with constipation who have multiple underlying diseases (such as diabetes, hypertension, Parkinson's disease, dementia, hypothyroidism) and require multiple medications;

[0140] Elderly patients with constipation who are intolerant to oral laxatives (such as lactulose, polyethylene glycol, lubiprostone, prucalopride, etc.) (e.g., abdominal distension, diarrhea, or orthostatic hypotension) or have poor adherence (e.g., discontinuing treatment due to price, taste, or need to drink large amounts of water).

[0141] This invention achieves multi-target regulation (neural activation + microbial remodeling) through the synergistic effect of "acupoint-drug", providing a treatment plan that conforms to the physiological regulation law for the decline of intestinal function in the elderly and frail population. It effectively solves the dilemma of existing drugs being "unsafe at effective doses and ineffective at safe doses", and has important clinical promotion value.

[0142] In summary, the present invention provides a traditional Chinese medicine compound sustained-release patch for treating senile constipation and its application, overcoming the shortcomings of existing drugs and administration methods for treating senile constipation. Specific details include:

[0143] Addressing the shortcomings of traditional drug delivery: replacing oral medications (which suffer from first-pass effect and gastrointestinal irritation) and suppositories (which are inconvenient to use), and improving medication safety and patient compliance through transdermal sustained-release technology;

[0144] Leveraging the synergistic effect of acupoints: Utilizing the anatomical characteristics of the Shenque acupoint (navel) with its thin skin, strong permeability, and direct connection to the intestines, the absorption of drugs can be enhanced. At the same time, acupoint stimulation can regulate intestinal function. The Shenque acupoint is located in the abdomen and is an important acupoint closely related to the function of the spleen and stomach. Stimulating this acupoint can regulate intestinal function, improve intestinal peristalsis, and alleviate constipation symptoms.

[0145] Achieving long-lasting and gentle conditioning: The sustained-release matrix controls the continuous release of the drug for 12-24 hours, avoiding fluctuations in blood drug concentration and reducing side effects such as diarrhea. It is suitable for long-term conditioning of chronic constipation in the elderly. Pharmacodynamic experiments show that this patch can improve intestinal propulsion rate and increase defecation frequency. Toxicity studies show that it is safe and has low skin irritation. Clinical application has three core advantages: high efficiency in promoting defecation (increased bioavailability), extremely low side effects (diarrhea rate = 0), and convenient compliance. It provides a breakthrough treatment solution for constipation in the elderly, with high efficacy, significant symptom improvement, high compliance, low recurrence rate, few adverse reactions, and convenient use.

[0146] It should be noted that, in this invention, although the specification describes the embodiments, not every embodiment contains only one independent technical solution. This way of describing the specification is only for clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A traditional Chinese medicine compound sustained-release patch for treating senile constipation, characterized in that, It is made from the following raw materials by weight: Evodia 10 parts, ginger 10 parts, Codonopsis 15 parts, water chestnut 10 parts, white pepper 10 parts, clove 8 parts, mugwort leaf 15 parts, dried ginger 10 parts, borneol 2 parts.

2. The traditional Chinese medicine compound sustained-release patch for treating senile constipation according to claim 1, characterized in that, The traditional Chinese medicine compound is matched according to the principle of monarch, minister, assistant and attendant, wherein the monarch is Evodia and ginger, the minister is Codonopsis and water chestnut, the assistant is white pepper, clove, mugwort leaf and dried ginger, and the attendant is borneol.

3. The traditional Chinese medicine compound sustained-release patch for treating senile constipation according to claim 1, characterized in that, The drug release rate of the patch is: the burst release rate is less than 20% in 8 hours, and the cumulative release rate is greater than 90% in 24 hours.

4. The preparation method of the traditional Chinese medicine compound sustained-release patch according to any one of claims 1-3, characterized in that, The method comprises the following steps: The method comprises the following steps:

5. The preparation method of the traditional Chinese medicine compound sustained-release patch for treating senile constipation according to claim 4, characterized in that, The step of paste synthesis and activity protection comprises: adding vitamin E into the mixed medicinal liquid, and adjusting the pH value to 6.0-6.5 by using citric acid solution.

6. The preparation method of the traditional Chinese medicine compound sustained-release patch for treating senile constipation according to claim 4, characterized in that, The step of coating, drying and product processing comprises: cutting the dried drug-loaded film into patches with a size of 4cm×4cm, and performing Co60 irradiation sterilization.

7. Use of the traditional Chinese medicine compound sustained-release patch for treating senile constipation according to any one of claims 1-3 in the preparation of a medicine for treating senile constipation.

8. The use of the traditional Chinese medicine compound sustained-release patch for treating senile constipation according to claim 7, characterized in that, The patch is administered transdermally through Shenjue acupoint.

9. The use of the traditional Chinese medicine compound sustained-release patch for treating senile constipation according to claim 7, characterized in that, The senile constipation patient is an elderly patient over 80 years old.

10. The use of the traditional Chinese medicine compound sustained-release patch for treating senile constipation according to claim 7, characterized in that, The senile constipation is functional constipation of deficiency-cold type. The senile constipation is functional constipation of deficiency-cold type.

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