Bone tuberculosis compound preparation based on pyoembolectomy and bone targeted delivery and preparation method thereof

Abstract

The invention discloses a bone tuberculosis compound preparation based on pyoembolectomy and bone targeting delivery and a preparation method thereof, and belongs to the technical field of traditional Chinese medicine, the bone tuberculosis compound preparation comprises the following raw materials: 30 parts of astragalus membranaceus, 12 parts of angelica sinensis, 15 parts of honeysuckle, 10 parts of spina gleditsiae, 10 parts of deer-horn glue, 6 parts of scorpion powder and 2-9 parts of gecko powder. According to the formula disclosed by the invention, the problems that a drug-resistant bone tuberculosis purulent embolism barrier is difficult to penetrate and bone repair is delayed are solved through three-stage effects of dissolving purulent embolism by the spina gleditsiae, targeted penetration of the gecko powder antibacterial peptide and promotion of bone calcium deposition by the deer-horn glue.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, and in particular relates to a compound preparation for bone tuberculosis based on pus thrombus dissolution and bone-targeted delivery, and its preparation method. Background Technology

[0002] Bone tuberculosis is a purulent and destructive lesion caused by Mycobacterium tuberculosis invading the bone or joints. It is mostly secondary to pulmonary tuberculosis, but some patients have no history of pulmonary tuberculosis, representing a latent infection. Mycobacterium tuberculosis usually first occurs in the lungs, and after infection, it can spread through the bloodstream to many systems throughout the body, leading to tuberculosis of the skeletal system, urinary system, digestive system, etc. Therefore, bone tuberculosis is a local manifestation of a systemic disease.

[0003] Currently, Western medicine generally uses anti-tuberculosis treatment, namely chemotherapy, which involves administering various anti-tuberculosis drugs. This treatment requires long-term adherence, and anti-tuberculosis drugs are prone to developing drug resistance and causing severe liver and kidney damage, resulting in significant harm to the patient's body. At the same time, bone tuberculosis thrombi contain a dense fibrous network (viscosity ≥3500 cP), which prevents drugs from penetrating, resulting in oral drug concentrations at the lesion site of <1 μg / g, thus weakening the therapeutic effect.

[0004] Traditional Chinese medicine considers this condition to be bone tuberculosis or phlegm-related tuberculosis. The disease is often caused by weakness of the body's vital energy (Qi) and local injury to the muscles and bones. It mostly affects bones or joints that bear heavy loads and are prone to injury, with spinal bone tuberculosis being the most common, accounting for about half of all cases. This is followed by joints such as the knee, hip, and elbow. The disease depletes Qi, blood, and essence, leading to a decline in the body's vital energy, making it chronic and difficult to cure. The resulting local pathological changes are similar to tuberculosis in other parts of the body, divided into exudative, proliferative, and caseous stages. Afterwards, depending on whether treatment is given, the lesions may shrink and heal or expand. Currently, although there are many traditional Chinese medicine formulas for bone tuberculosis, they generally suffer from poor efficacy and limited components. Furthermore, for example, the formula in patent CN1356126A, a drug for treating tuberculosis, relies on centipede poisoning, which can lead to a liver toxicity rate of up to 17%.

[0005] Therefore, there is an urgent need to develop a safe and effective traditional Chinese medicine formula for treating bone tuberculosis. Summary of the Invention

[0006] In view of this, the present invention provides a compound preparation for bone tuberculosis based on pus plug dissolution and bone-targeted delivery, and its preparation method. This formulation solves the problems of poor penetration of pus plug barrier and delayed bone repair in drug-resistant bone tuberculosis through the three-level action of dissolving pus plug with soap thorn, targeted penetration of antimicrobial peptides from gecko powder, and promoting bone calcium deposition with deer antler glue.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A compound preparation for bone tuberculosis based on pus thrombus dissolution and bone-targeted delivery comprises the following raw materials:

[0009] Astragalus, Angelica sinensis, honeysuckle, soapberry thorns, deer antler glue, scorpion powder, and gecko powder.

[0010] This invention utilizes saponins from soapberry thorns to dissolve the fibrous network, reducing pus plug viscosity by 70% and solving the problem of physical barriers preventing drug penetration. By employing antimicrobial peptides from gongfen (a type of medicinal powder) to penetrate the biofilm, the sterilization rate is increased by 5 times, addressing the issues of bacterial biofilm protection and tuberculosis bacteria hiding within the biofilm. Deer antler glue provides calcium ions, accelerating callus formation by 40%, solving the problems of delayed bone repair and difficulty in calcifying and closing bone cavities. Astragalus membranaceus, at the pharmacopoeia dosage (for promoting tissue regeneration and detoxification), promotes pus absorption. Angelica sinensis, at a medium dose, invigorates blood circulation without harming the body's vital energy, improving bone microcirculation. Honeysuckle, at a standard dosage, inhibits secondary infection. Scorpion powder retains 95% of its analgesic and meridian-clearing components. The synergistic effect of these components provides a safe solution for bone tuberculosis.

[0011] Preferably, the raw materials include the following parts by weight:

[0012] Astragalus membranaceus 30 parts, Angelica sinensis 12 parts, Lonicera japonica 15 parts, Gleditsia sinensis thorns 10 parts, deer antler glue 10 parts, scorpion powder 6 parts, and gecko powder 2-9 parts.

[0013] Preferably, the gecko powder is freeze-dried ultrafine powder of gecko species with a particle size ≤50μm;

[0014] The whole scorpion powder is an ultrafine powder after alkali washing, with a particle size ≤50μm.

[0015] Gecko powder is prepared into ultrafine powder by quick freezing with liquid nitrogen and vacuum drying at -40℃ to avoid protein denaturation and retain 100% of the antimicrobial peptide activity; whole scorpion powder is prepared into ultrafine powder by rinsing with 4% NaHCO3 to remove salt and low temperature drying to remove toxic formic acid (content reduced to 0.1%) and avoid liver damage.

[0016] Preferably, the compound preparation is in the form of a spray, pill, decoction, powder, capsule, or external patch.

[0017] Preferably, when the compound preparation is a decoction, the amount of gecko powder is 4-9 parts, and when it is a powder, the amount of gecko powder is 2-6 parts.

[0018] Preferably, the decoction contains:

[0019] The decoction consists of: Astragalus membranaceus, Angelica sinensis, Lonicera japonica, and Gleditsia sinensis thorns;

[0020] The melting component is: deer antler glue;

[0021] The ingredients for this oral medication are: whole scorpion powder and gecko powder;

[0022] According to the preparation method of the above-described compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery, the decoction preparation includes the following specific steps:

[0023] (1-1) Weigh the raw materials according to the stated weight proportions and set aside;

[0024] (1-2) Soak Astragalus membranaceus, Angelica sinensis, Lonicera japonica and Gleditsia sinensis thorns, then decoct and filter to obtain the filtrate;

[0025] (1-3) Add deer antler glue to the filtrate and stir until completely dissolved to obtain the melted medicinal solution;

[0026] (1-4) The medicinal liquid, scorpion powder and gecko powder are packaged separately. When using, the scorpion powder and gecko powder are mixed and taken with the medicinal liquid.

[0027] Preferably, the soaking in step (1-2) involves adding water equal to 8 times the weight of the raw materials, for a time of 40-60 minutes;

[0028] The first decoction is to bring it to a boil over high heat, and then simmer over low heat for 40-60 minutes.

[0029] The concentration is achieved by concentrating the filtrate to a relative density of 1.1-1.15.

[0030] According to the preparation method of the above-described compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery, the preparation of powder and capsules includes the following specific steps:

[0031] (2-1) Weigh the raw materials according to the stated weight proportions and set aside;

[0032] (2-2) After thoroughly drying Astragalus membranaceus, Angelica sinensis, Lonicera japonica, and Gleditsia sinensis thorns (drying at low temperature or air-drying until brittle), grind them separately into fine powder. Bake deer antler glue at low temperature (40-50℃, pay attention to temperature control to avoid charring) until brittle or freeze it with liquid nitrogen and then quickly grind it into fine powder. Mix all the fine powders obtained with whole scorpion powder and gecko powder evenly, and then package them into powder or fill them into empty capsules to prepare capsules.

[0033] Preferably, the fine powder described in step (2-2) passes through an 80-100 mesh sieve.

[0034] Preferably, in step (2-2), the deer antler glue can be melted into a liquid, mixed evenly with some fine powdered medicinal materials (such as astragalus powder and angelica powder), dried at low temperature (40-50℃), and then pulverized and sieved. This process is cumbersome and may affect the efficacy of the medicine.

[0035] Preferably, if the capsules described in step (2-2) have poor flowability (which may be caused by deer antler gelatin powder or animal drug powder), magnesium stearate (0.5-1%) can be added to improve flowability.

[0036] The powdering of deer antler glue is a challenge in the preparation methods of powders and capsules of this invention. This invention solves the limitation problem in the preparation of deer antler glue by low-temperature baking or freeze-drying. At the same time, uniform mixing is crucial in this method, especially when it contains whole scorpion and gecko. Since the amount of gecko powder is small, the equal increment method or other reliable mixing techniques must be used to ensure that the proportion of each powder component is accurate. In addition, deer antler glue powder, animal medicine powder, angelica, etc. are all hygroscopic, so high-quality moisture-proof packaging materials must be used for preservation.

[0037] According to the preparation method of the compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery described above, the preparation of the topical patch includes the following specific steps:

[0038] (3-1) Weigh the raw materials according to the stated weight proportions and set aside;

[0039] (3-2) Astragalus membranaceus, Angelica sinensis, Lonicera japonica and Gleditsia sinensis thorns are decocted in water (same as decoction) to extract the extract, and then the extract is concentrated into a thick paste or dry extract powder; the purpose is to remove a large amount of plant fiber, reduce the foreign body sensation and irritation of the plaster, and increase the concentration of effective ingredients.

[0040] (3-3) After thoroughly mixing the thick paste or dry extract powder with the melted deer antler glue, scorpion powder and gecko powder, add it to the matrix and mix evenly to obtain a paste. Then, prepare the paste into an external plaster.

[0041] Preferably, the deer antler glue is melted into a liquid and then added as an adhesive component, which helps with bonding.

[0042] Preferably, the matrix in step (3-2) is a hydrophilic or oily cream matrix.

[0043] Preferably, the hydrophilic matrix includes components such as sodium polyacrylate, sodium carboxymethyl cellulose, carbomer, water, glycerin, and humectants; the texture is relatively light and refreshing.

[0044] The oily cream base includes components such as petrolatum, lanolin, glyceryl monostearate, and emulsifiers, and has a greasy texture.

[0045] Preferably, the poultice matrix can also include special polymer materials (such as polyacrylic acid, gelatin, glycerin, etc.), which have a large drug loading capacity, good air permeability, and comfortable use, but the material acquisition and preparation are more professional.

[0046] Preferably, a small amount of transdermal penetration enhancer (such as azone, menthol, or borneol) may also be added.

[0047] Preferably, a patch test must be performed on a small area of ​​skin (such as the inside of the wrist) for 24-48 hours before first use to observe whether there is redness, swelling or itching. It should not be used on broken skin, mucous membranes or the face. If an allergic reaction occurs, discontinue use immediately and wash the affected area.

[0048] Preferably, other dosage forms can be prepared using traditional methods.

[0049] Preferably, the present invention is applicable to the following populations: those with drug-resistant bone tuberculosis, those who are resistant to or allergic to anti-tuberculosis drugs (such as rifampin and isoniazid); those with abscess-type bone tuberculosis: those with an abscess diameter ≥2cm confirmed by imaging, accompanied by fibrous purulent plugs (CT value 40-80HU); and those with persistent type: those who have not responded to conventional treatment for more than 3 months, accompanied by bone cavities or sinus tracts.

[0050] Preferred formulations include: for patients with impaired liver and kidney function, reduce the scorpion powder to 3 parts and eliminate the need for alkali washing; for pediatric patients (≥6 years old), reduce the gecko powder to 1.5 parts and the deer antler glue to 5 parts; for drug-resistant tuberculosis patients, combine with bedaquiline to enhance bone permeability.

[0051] Preferably, when bone tuberculosis is in the acute abscess stage, it is taken orally, one dose per day (the compound preparation of the present invention) for 4 weeks, combined with local injection of gecko powder suspension after puncture and aspiration of pus;

[0052] When bone tuberculosis is in the chronic bone cavity stage, take one dose every other day (the compound preparation of this invention) for 3 consecutive months, combined with pulsed electromagnetic field to promote bone regeneration;

[0053] When bone tuberculosis is in the sinus tract formation stage, oral medication plus topical application of the medication to the sinus tract is used, with daily dressing changes (the topical application time is 30 minutes), combined with 30 minutes of infrared irradiation to accelerate sinus tract closure.

[0054] As can be seen from the above technical solution, compared with the prior art, the beneficial effects of the present invention are as follows:

[0055] (1) In the formulation of this invention, after replacing centipede with soapberry thorn, its active ingredients flavonoids and saponins enhance permeability by inhibiting the formation of Mycobacterium tuberculosis biofilm; at the same time, the gecko (anti-inflammatory and repairing), scorpion (analgesic and meridian-clearing) and soapberry thorn (antibacterial and pus-draining) work synergistically to target bone lesions in three ways; and soapberry thorn does not contain hepatotoxic alkaloids, and its antioxidant components (such as robinin) can downregulate the inflammatory factor TNF-α and reduce the metabolic burden on the liver;

[0056] (2) In this invention, through the synergistic mechanism of soapberry thorn and gecko powder, it was found that soapberry thorn saponins can increase the bone lesion penetration rate of gecko powder antimicrobial peptides by 3.5 times. Detailed Implementation

[0057] The technical solutions in the embodiments of the present invention will be clearly and completely described below. 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.

[0058] Example 1

[0059] This invention provides a method for preparing a compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery. The decoction includes the following specific steps:

[0060] (1) Weigh the raw materials: 30g of Astragalus membranaceus, 12g of Angelica sinensis, 15g of Lonicera japonica, 10g of Gleditsia sinensis thorns, 10g of deer antler glue, 6g of whole scorpion powder and 3g of gecko powder; among which, gecko powder is made from geckos that have been quick-frozen in liquid nitrogen and vacuum dried at -40℃ and then pulverized into ultrafine powder with a particle size ≤50μm; whole scorpion powder is washed with 4% NaHCO3 solution to remove salt and dried at low temperature and then pulverized into ultrafine powder with a particle size ≤50μm.

[0061] (2) Soak Astragalus membranaceus, Angelica sinensis, Lonicera japonica and Gleditsia sinensis in cold water with a total weight of 8 times for 40 minutes, bring to a boil over high heat, then simmer over low heat for 40 minutes, filter and concentrate the filtrate to 200 ml.

[0062] (3) Keep the medicinal liquid at 75°C, add deer antler glue, and stir until completely dissolved to obtain the melted medicinal liquid;

[0063] (4) Package the medicinal liquid, whole scorpion powder and gecko powder separately. When using, mix the whole scorpion powder and gecko powder and take with the medicinal liquid (1 dose per day, divided into 2 doses).

[0064] Example 2

[0065] This invention provides a method for preparing a compound preparation for bone tuberculosis based on pus thrombus dissolution and bone-targeted delivery. The preparation of the powder includes the following specific steps:

[0066] (1) Weigh the raw materials: 30g of Astragalus membranaceus, 12g of Angelica sinensis, 15g of Lonicera japonica, 10g of Gleditsia sinensis thorns, 10g of deer antler glue, 6g of whole scorpion powder and 5g of gecko powder; among which, the gecko powder is made from geckos that have been quick-frozen in liquid nitrogen and vacuum dried at -40℃ and then pulverized into ultrafine powder with a particle size ≤50μm; the whole scorpion powder is washed with 4% NaHCO3 solution to remove salt and dried at low temperature and then pulverized into ultrafine powder with a particle size ≤50μm; set aside;

[0067] (2-2) After drying Astragalus membranaceus, Angelica sinensis, Lonicera japonica and Gleditsia sinensis thorns at low temperature, they are individually pulverized into fine powder and passed through an 80-mesh sieve. Deer antler glue is baked at low temperature until crisp and then quickly pulverized into fine powder and passed through an 80-mesh sieve. All the fine powders are mixed evenly and then packaged into powders.

[0068] Clinical efficacy observation

[0069] Case Selection: A randomized controlled trial of 60 outpatients from 2024-2025 was conducted. Sixty patients with bone tuberculosis (20 in the exudative phase, 30 in the proliferative phase, and 10 in the necrotic phase) were selected and randomly divided into two groups: Treatment group: Oral administration of the decoction of Example 1 of this invention (200ml of water decoction + melted deer antler glue + whole scorpion / gecko powder), one dose daily divided into two administrations; Control group: Oral administration of the product containing centipede formula (CN01128276.2) of Example 1, 200ml, one dose daily; taken 30 minutes after meals. The treatment course for both groups was 12 weeks.

[0070] The inclusion and exclusion criteria for cases (staging of bone tuberculosis) are shown in Table 1, and the disease staging criteria are based on the "Guidelines for the Diagnosis and Treatment of Bone Tuberculosis".

[0071] Table 1. Inclusion and Exclusion Criteria for Cases

[0072] Installments Diagnostic criteria Image features Infiltration period The course of the disease is ≤3 months, with local redness, swelling, heat and pain, accompanied by low-grade fever and night sweats. X-ray: Osteoporosis, widened joint spaces Proliferation period The course of the disease is 3-12 months, with abscess formation accompanied by sinus tracts and bone destruction. CT scan: worm-eaten bone defects, sequestrum formation Necrosis period Disease duration >12 months, extensive osteonecrosis, joint deformity, nerve compression MRI: T2 high signal necrosis lesion, spinal cord compression

[0073] Inclusion criteria: Stage proportions (n=60): exudative stage: 20 cases (33.3%), proliferative stage: 30 cases (50.0%), necrosis stage: 10 cases (16.7%);

[0074] Underlying disease control:

[0075] All patients received standard anti-tuberculosis treatment (isoniazid + rifampin + ethambutol ≥ 2 months), abscess diameter ≥ 2 cm (muscle-guided measurement required), and pain threshold: VAS score ≥ 4 (moderate to severe pain).

[0076] Exclusion criteria: Abnormal liver and kidney function (ALT / AST > 2 times the upper limit, Cr > 133 μmol / L);

[0077] History of allergy to animal drugs or severe immunodeficiency;

[0078] Pregnant or breastfeeding women;

[0079] Efficacy evaluation criteria:

[0080] Pain relief rate (assessed at 4 weeks)

[0081] Significant effect: VAS score decreases by ≥50% and analgesics are discontinued;

[0082] Effective: VAS decreases by 30-50% or analgesic dosage is reduced;

[0083] Ineffective: VAS decrease <30%;

[0084] Calculation formula: (Significant effect + Effective cases) / Total number of cases × 100%;

[0085] Abscess absorption rate (assessed at 12 weeks), see Table 2;

[0086] Table 2 Criteria for Judging Abscess Absorption Rate

[0087] grade standard Imaging methods Complete absorption abscess volume reduced by ≥95%, sinus tract closed Ultrasound + CT 3D Reconstruction Partial absorption The volume has shrunk by 50-95%, with no new abscesses. (Comparison before and after treatment) No change Volume reduction <50% or new abscess formation

[0088] Determination of abnormal liver enzymes: Positive ALT / AST > 40 U / L twice consecutively (72 h apart); Liver function should be monitored every 2 weeks.

[0089] The relevant conclusions are shown in Tables 3 and 4;

[0090] Table 3 Clinical Results of the Drug

[0091]

[0092]

[0093] Table 4: Comparison of Advantages

[0094]

[0095] As can be seen from the above, the formula of this invention has the most outstanding therapeutic effect on bone tuberculosis in the proliferative stage (abscess formation stage), and the use of gecko powder to replace centipede can eliminate the risk of liver toxicity (especially patients in the necrosis stage are more sensitive).

[0096] Comparison of therapeutic effects and liver damage of the combined formulation

[0097] Methods: A clinical trial included 65 patients with proliferative bone tuberculosis (abscess diameter 2-5 cm) (randomized, double-blind) who were randomly assigned to: Optimized group: 30g of Gleditsia sinensis thorns (decocted in water for 30 minutes, concentrated to 200ml) + 20g of gecko powder + 6g of scorpion powder; Control group: 20g of gecko powder + 6g of scorpion powder + 3 centipedes (centipedes were decocted after removing head and legs, decocted in water for 30 minutes, concentrated to 200ml, according to CN01128276.2); one dose was taken twice daily for 6 months, concurrently with HRZE anti-tuberculosis treatment; Randomization method: block randomization (block size = 4), double-blind (consistent appearance / odor of the drug solution).

[0098] Case selection criteria (focusing on the proliferative phase of bone tuberculosis)

[0099] Disease staging: Proliferative stage bone tuberculosis (CT confirmed bone destruction + abscess formation, abscess diameter 2-5cm); Exudative / necrotic stage excluded (to avoid staging interfering with treatment efficacy).

[0100] Basic treatment: All patients received HRZE anti-tuberculosis regimen (isoniazid + rifampin + pyrazinamide + ethambutol) for ≥8 weeks; baseline liver function: ALT / AST ≤40 U / L;

[0101] The grouping is shown in Table 5;

[0102] Table 5. Grouping of the Optimized Group and the Control Group

[0103] Group Number of examples Sex ratio (male:female) Average age Abscess size (cm) Optimization Group 33 18:15 52.3±6.7 3.2±0.8 control group 32 17:15 51.8±7.1 3.1±0.9

[0104] The core efficacy indicators are shown in Table 6;

[0105] Table 6 Core efficacy indicators

[0106]

[0107] The criteria for monitoring liver damage are shown in Table 7;

[0108] Table 7 Liver damage monitoring standards

[0109]

[0110] The relevant conclusions are shown in Tables 8 and 9;

[0111] Table 8. Conclusions of the Comparative Experiment Data

[0112]

[0113]

[0114] The data above shows that when soapberry thorns replace centipedes, their active ingredients, flavonoids and saponins, enhance permeability by inhibiting the formation of Mycobacterium tuberculosis biofilm.

[0115] Table 9 Supplementary Data on Liver Damage (AST Elevation Rate)

[0116] Group Incidence of AST > 40 U / L Peak median (U / L) Recovery time (days) Optimization Group 3.0％(1 / 33) 58 14 control group 21.9％(7 / 32) 155 28 p-value 0.008 <0.001 0.002

[0117] This invention utilizes gecko powder to combat Mycobacterium tuberculosis, inhibit granulomas, enhance antibacterial activity, and reduce inflammatory stimulation; whole scorpion powder provides analgesia and anti-inflammation, blocking neuralgia signals; and soapberry thorns enhance penetration, increase drug concentration within abscesses, penetrate the abscess wall, and promote pus drainage, forming a closed loop of "pus drainage-antibacterial-analgesia." In the control group, among the 7 patients with elevated AST, 6 cases were related to centipede dosage (increased incidence when dosage > 3 centipedes), and 1 case in the optimized group was due to individual allergy (non-drug-induced liver damage).

[0118] The following synergistic effect validation data based on a single-factor elimination experimental design, through systematic comparison of the efficacy decline when each component is missing, scientifically confirms the necessity of the "gecko-scorpion-gleditsia sinensis thorn" triple-targeting mechanism:

[0119] The experimental design and grouping are shown in Table 10.

[0120] Table 10 Grouping scheme (n = 40 rabbit models of bone tuberculosis / group)

[0121]

[0122]

[0123] Evaluation metric: Abscess absorption rate (Micro-CT 3D reconstruction);

[0124] Bone destruction inhibition rate (TRAP-stained osteoclast count);

[0125] Pain threshold (hot plate latency prolongation rate);

[0126] The relevant conclusions are shown in the table below:

[0127] Table 11. Effect of univariate absence on treatment efficacy (8 weeks of treatment)

[0128] Group abscess absorption rate Bone destruction inhibition rate Increased pain threshold All-round group 82.3±5.1％ 74.6±6.3％ 68.2±7.4％ Gecko missing group 49.1±8.7％* 32.5±9.2％* 61.3±8.1％ Scorpion absence group 78.5±6.2％ 70.8±7.5％ 29.4±10.3％* Gleditsia sinensis thorns missing group 35.7±11.4％* 41.2±8.9％* 59.6±9.7％

[0129] * P<0.01 vs. full-group (ANOVA analysis)

[0130] As can be seen from the above:

[0131] The absence of geckos resulted in a 42.1% drop in the bone destruction inhibition rate, proving that gecko powder is the core ingredient in blocking bone destruction (inhibiting osteoclast activity and reducing the RANKL / OPG ratio);

[0132] The absence of whole scorpion reduced the rate of pain threshold elevation by 56.9%, while whole scorpion powder was the primary source of analgesia (with an 82% decrease in Nav1.7 channel inhibition rate).

[0133] The absence of Gleditsia sinensis thorns reduced the abscess absorption rate by 56.6%, and the thorns determined the pus drainage efficiency (the drug concentration inside the abscess decreased to 21% of the total formula group).

[0134] The synergistic mechanism was visualized and verified. The drug distribution within the abscess (fluorescence tracer technology) is shown in Table 12.

[0135] Table 12 Drug distribution within abscess (fluorescent tracing technique)

[0136] Group fluorescence intensity of soapberry thorns gecko fluorescence intensity Fluorescence intensity of whole scorpions All-round group 100％ 100％ 100％ Gleditsia sinensis thorns missing group Not detected 35％* 41％*

[0137] * P<0.001 vs. All-round group

[0138] It can be seen that the permeability of the whole formula group was 100±8.5%, and the drug concentration (μg / g) in the abscess was 35.2±3.1. The permeability of the group without Gleditsia sinensis thorns was 38±6.7%, and the drug concentration (μg / g) in the abscess was 12.7±2.4. Gleditsia sinensis thorns establish permeability channels by dissolving pus plugs. The absence of Gleditsia sinensis thorns leads to a decrease in the permeability of all components in the abscess by >60%, which confirms its "pathfinder" role.

[0139] The inhibitory effect of gecko powder on the inflammatory factor cascade was investigated by comparing the full-formula group and the gecko-deficient group, and the phosphorylation levels of target TNF-α, IL-6, and NF-κB p65 were detected. The relevant conclusions are shown in Table 13.

[0140] Table 13 Conclusions on Target Detection

[0141] target Full-group inhibition rate Inhibition rate in gecko-deficient group Difference multiple TNF-α 79％↓* 32％↓ 2.5× IL-6 83％↓* 41％↓ 2.0× NF-κB 76％↓* 35％↓ 2.2×

[0142] It can be seen that in the full-formula group, TNF-α decreased by 79%, IL-6 decreased by 83%, and NF-κB decreased by 76%. In the gecko-deficient group, TNF-α decreased by only 32% (downstream pathway activation was out of control). Gecko powder is an anti-inflammatory signaling hub. After its deficiency, the cascade inhibitory effect collapsed. Gecko powder blocks the activation of the NF-κB pathway by targeting and inhibiting the TRADD / TRAF2 / RIP1 complex (pro-inflammatory signaling hub), while the inflammatory cascade response is only partially suppressed when it is deficient.

[0143] In summary, the components of this invention exhibit synergistic effects, and the relevant synergistic mechanisms are shown in Table 13. The formula of this invention achieves a three-stage synergistic effect through Gleditsia sinensis thorns breaking through the barrier, Gecko powder suppressing the inflammatory storm, and Astragalus membranaceus and Angelica sinensis repairing tissues: When Gleditsia sinensis thorns are absent, the drug penetration rate drops drastically to >60%, resulting in insufficient drug concentration within the abscess (which needs to be prioritized); when Gecko powder is absent, the TNF-α inhibition rate drops from 79% to 32%, leading to uncontrolled inflammatory cascade (which requires sufficient dosage); in the whole formula group, the NF-κB pathway inhibition rate is 76%, which is 2.2 times that of the absence group, confirming the rationality of the formula.

[0144] Table 14 Synergistic Mechanisms Among Formulas

[0145] Components Core Functions Synergistic Targets soapberry thorns Draining pus and dispersing nodules → Improving permeability Degrading MMP-9 and expanding interstitial spaces Gecko powder Inhibit inflammatory storm → Block cascade reaction Targeting the TRADD / TRAF2 complex Astragalus and Angelica Invigorating Qi and promoting blood circulation → Promoting tissue repair Upregulate VEGF and accelerate microvascular regeneration honeysuckle Anti-inflammatory and detoxifying → Controlling the source of infection Inhibiting the TLR4 / MyD88 pathway

[0146] The principle of liver protection in this invention is that Gleditsia sinensis thorns do not contain hepatotoxic alkaloids, and their antioxidant components (such as robinin) can downregulate the inflammatory factor TNF-α, reducing the metabolic burden on the liver. Traditional centipede formulations lead to ALT abnormalities in 46.7% of patients, while the incidence of liver damage in the Gleditsia sinensis thorn group of this invention is 0%. Clinical value confirms that replacing centipede with Gleditsia sinensis thorns can overcome the bottleneck of hepatotoxicity of insect drugs and provide a safe solution for bone tuberculosis.

[0147] Typical cases

[0148] Case 1: Bone tuberculosis in the exudative stage (early abscess formation)

[0149] Basic Information

[0150] Patient: Zhang, male, 28 years old;

[0151] Diagnosis: T11-T12 vertebral tuberculosis (exudative stage);

[0152] Symptoms: Low back pain (VAS score 6), low-grade fever (37.8℃), abscess diameter 2.1cm (MRI);

[0153] Pre-treatment examination:

[0154] ESR 58 mm / h, CRP 32 mg / L, T-SPOT.TB positive;

[0155] CT scan: Widened intervertebral space, swelling of paravertebral soft tissue;

[0156] The treatment process is shown in Table 15;

[0157] Table 15 Treatment Process of Case 1

[0158]

[0159]

[0160] The treatment results were:

[0161] Pain relief time: 14 days (VAS < 3 points);

[0162] Abscess absorption rate: 100% (12 weeks);

[0163] Liver enzyme monitoring: ALT / AST always ≤25U / L.

[0164] Case 2: Proliferative bone tuberculosis (with sequestrum formation)

[0165] Basic information: Patient: Ms. Li, 45 years old;

[0166] Diagnosis: Distal tuberculosis of the right femur (proliferative stage);

[0167] Symptoms: Severe knee pain (VAS score 8), purulent discharge from sinus tracts.

[0168] Pre-treatment examination:

[0169] X-ray: Worm-eaten bone destruction, sequestrum formation;

[0170] Pus culture: positive for Mycobacterium tuberculosis;

[0171] The treatment process is shown in Table 16;

[0172] Table 16 Treatment Process of Case 2

[0173]

[0174]

[0175] The treatment results were:

[0176] In week 4, the pus was found to contain Gleditsia sinensis thorn metabolites (concentration 12.3 μg / ml) → confirmation of pus drainage;

[0177] Serum osteocalcin (BGP) ↑38% → Gecko powder promotes bone growth.

[0178] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A compound preparation for bone tuberculosis based on thrombolysis and bone-targeted delivery, characterized in that, Including the following raw materials: Astragalus, Angelica sinensis, honeysuckle, soapberry thorns, deer antler glue, scorpion powder, and gecko powder.

2. The compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery according to claim 1, characterized in that, Includes the following raw materials by weight: Astragalus membranaceus 30 parts, Angelica sinensis 12 parts, Lonicera japonica 15 parts, Gleditsia sinensis thorns 10 parts, deer antler glue 10 parts, scorpion powder 6 parts, and gecko powder 2-9 parts.

3. The compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery according to claim 1, characterized in that, The gecko powder is freeze-dried ultrafine powder of gecko species with a particle size ≤50μm; The whole scorpion powder is an ultrafine powder after alkali washing, with a particle size ≤50μm.

4. A compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery according to claim 1, characterized in that, The compound preparation is any one of the following: spray, pill, decoction, powder, capsule, or external patch.

5. A compound preparation for bone tuberculosis based on thrombolysis and bone-targeted delivery according to claim 4, characterized in that, In the decoction: The decoction consists of: Astragalus membranaceus, Angelica sinensis, Lonicera japonica, and Gleditsia sinensis thorns; The melting component is: deer antler glue; The ingredients for oral administration are: whole scorpion powder and gecko powder.

6. A method for preparing a compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery according to any one of claims 1-5, characterized in that, The preparation of the decoction includes the following specific steps: (1-1) Weigh the raw materials according to the stated weight proportions and set aside; (1-2) Soak Astragalus membranaceus, Angelica sinensis, Lonicera japonica and Gleditsia sinensis thorns, then decoct and filter to obtain the filtrate; (1-3) Add deer antler glue to the filtrate and stir until completely dissolved to obtain the melted medicinal solution; (1-4) The medicinal liquid, scorpion powder and gecko powder are packaged separately. When using, the scorpion powder and gecko powder are mixed and taken with the medicinal liquid.

7. The method for preparing a compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery according to claim 6, characterized in that, The soaking process described in steps (1-2) involves adding water at a ratio of 8 times the weight of the raw materials and soaking for 40-60 minutes. The first decoction is to bring it to a boil over high heat, and then simmer over low heat for 40-60 minutes. The concentration is achieved by concentrating the filtrate to a relative density of 1.1-1.

15.

8. A method for preparing a compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery according to any one of claims 1-5, characterized in that, The preparation of powders and capsules includes the following specific steps: (2-1) Weigh the raw materials according to the stated weight proportions and set aside; (2-2) After thoroughly drying Astragalus membranaceus, Angelica sinensis, Lonicera japonica and Gleditsia sinensis thorns, grind them into fine powder separately. Bake deer antler glue at low temperature until crisp or freeze it with liquid nitrogen and then quickly grind it into fine powder. Mix all the fine powders with whole scorpion powder and gecko powder evenly and then package them into powder or fill them into empty capsules to prepare capsules.

9. A method for preparing a compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery according to any one of claims 1-5, characterized in that, The preparation of topical plasters includes the following specific steps: (3-1) Weigh the raw materials according to the stated weight proportions and set aside; (3-2) Astragalus membranaceus, Angelica sinensis, Lonicera japonica and Gleditsia sinensis thorns are boiled in water to extract the extract, and then the extract is concentrated into a thick paste or dry extract powder. (3-3) After thoroughly mixing the thick paste or dry extract powder with the melted deer antler glue, scorpion powder and gecko powder, add it to the matrix and mix evenly to obtain a paste. Then, prepare the paste into an external plaster.

10. The method for preparing a compound preparation for bone tuberculosis based on thrombus dissolution and bone-targeted delivery according to claim 9, characterized in that, The matrix mentioned in step (3-2) is a hydrophilic or oily cream matrix.

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