A bone-setting analgesic pill, a preparation method and application thereof

Abstract

The application discloses a bone-setting analgesic pill and a preparation method and application thereof, and belongs to the technical field of traditional Chinese medicines. The bone-setting analgesic pill is composed of notoginseng, radix dipsaci, calcined natural copper, radix dipsaci, red sandalwood, fried peach kernel, safflower, angelica sinensis, salvia miltiorrhiza, herba lycopi, vinegar ferulae, vinegar olibanum and vinegar myrrh. The bone-setting analgesic pill is an oral pill, and is used for treating bone fracture, dislocation or muscle injury in the early and middle stages. The application is aimed at the problems that the existing traditional Chinese medicine preparation has an unsatisfactory curative effect, a slow effect, and effective components of expensive and fine medicinal materials such as notoginseng are incompletely dissolved and easily oxidized and browned in the processing process. Through scientific prescription, the saponin effective components are well reserved and enriched, have a good and stable comprehensive curative effect in aspects of anti-inflammation, detumescence, analgesia and promotion of fracture healing, and the preparation quality is controllable and convenient to take, so the bone-setting analgesic pill is suitable for clinical popularization and application.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a bone-setting and pain-relieving pill, its preparation method, and its application. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Fractures, dislocations, and tendon injuries are common and frequently occurring diseases in orthopedic clinics. In their early and middle stages, they are often accompanied by symptoms such as local swelling, pain, and functional impairment, severely impacting patients' quality of life. Traditional Chinese medicine (TCM) orthopedics has a long history and rich experience in treating these diseases, typically employing methods such as promoting blood circulation and removing blood stasis, reducing swelling and relieving pain, and promoting bone and tendon healing to facilitate injury repair and functional recovery.

[0004] Currently, there are many traditional Chinese medicine preparations used clinically to treat fractures, dislocations, and early to mid-stage tendon injuries, such as Jiegu Qili tablets and Xinshang Xuduan decoction. Jiegu Qili tablets are a commercially available traditional Chinese medicine with certain effects of promoting blood circulation, removing blood stasis, and relieving pain. Xinshang Xuduan decoction is a classic formula recorded in "Lectures on Traumatology in Traditional Chinese Medicine" and is often used in the early stages of injury. However, these existing drugs still have problems in terms of anti-inflammatory and swelling-reducing effects, analgesia, and promoting fracture healing, including less than ideal efficacy, slow onset of action, and prolonged clinical healing time for fractures. They are insufficient to meet the clinical need for rapid symptom relief and accelerated fracture healing.

[0005] Furthermore, the retention and bioavailability of active ingredients in traditional Chinese medicine compound preparations are crucial factors affecting efficacy. Taking Panax notoginseng as an example, it contains various saponins, such as notoginsenoside R1, ginsenoside Rg1, and ginsenoside Rb1, which have the effects of promoting blood circulation, removing blood stasis, reducing swelling, and relieving pain. However, Panax notoginseng is hard, and conventional pulverization methods are insufficient to fully destroy its cell structure, leading to incomplete dissolution of active ingredients. Simultaneously, Panax notoginseng is prone to oxidative browning during processing, resulting in the loss of saponins and affecting efficacy. Current technologies lack effective pretreatment methods for Panax notoginseng to improve the retention rate of saponins and the enrichment of rare saponins.

[0006] Therefore, there is an urgent need to provide a bone-setting and pain-relieving pill with a scientifically formulated composition, reasonable process, definite curative effect, and the ability to effectively retain and enrich the active ingredients, as well as its preparation method, to overcome the shortcomings of existing technologies. Summary of the Invention

[0007] This invention addresses the shortcomings of existing traditional Chinese medicine preparations for treating early and mid-stage fractures, dislocations, and tendon injuries, including unsatisfactory anti-inflammatory, swelling-reducing, analgesic, and fracture-healing-promoting effects, slow onset of action, and incomplete dissolution and oxidative browning loss of effective components in precious and delicate medicinal materials such as Panax notoginseng during conventional pulverization and processing. The invention provides a scientifically formulated, rationally processed, and effective method for preserving and enriching the medicinal components, resulting in a definite therapeutic effect.

[0008] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows.

[0009] In a first aspect, the present invention provides a bone-setting and pain-relieving pill, which is made from the following raw materials in parts by weight: 20-30 parts of Panax notoginseng, 20-30 parts of Drynaria fortunei, 20-30 parts of calcined natural copper, 15-25 parts of Dipsacus asper, 15-25 parts of Sappanwood, 9-15 parts of stir-fried peach kernel, 9-15 parts of safflower, 9-15 parts of Angelica sinensis, 9-15 parts of Salvia miltiorrhiza, 9-15 parts of Lycopus lucidus, 9-15 parts of vinegar-processed Corydalis yanhusuo, 4-8 parts of vinegar-processed frankincense, and 4-8 parts of vinegar-processed myrrh.

[0010] In a preferred embodiment, the bone-setting and pain-relieving pill is made from the following raw materials in parts by weight: 24 parts Panax notoginseng, 24 parts Drynaria fortunei, 24 parts calcined natural copper, 20 parts Dipsacus asper, 20 parts Sappanwood, 12 parts stir-fried peach kernel, 12 parts safflower, 12 parts Angelica sinensis, 12 parts Salvia miltiorrhiza, 12 parts Lycopus lucidus, 12 parts vinegar-processed Corydalis yanhusuo, 6 parts vinegar-processed frankincense, and 6 parts vinegar-processed myrrh.

[0011] This syndrome is caused by traumatic injuries, blood stasis, and broken bones and tendons. Treatment should focus on promoting blood circulation, removing blood stasis, reducing swelling and relieving pain, while also promoting bone and tendon healing. Because "without removing blood stasis, new blood cannot be generated, and broken bones are difficult to heal," the formula heavily uses Panax notoginseng, a key herb in traumatology, to promote blood circulation, remove blood stasis, reduce swelling, and relieve pain. It is combined with peach kernel, safflower, and sappanwood to promote blood circulation, remove blood stasis, and relieve pain; frankincense, myrrh, and corydalis promote blood circulation, relieve pain, and reduce swelling, and also have the function of regulating qi, ensuring that blood flows smoothly and preventing the recurrence of blood stasis. Together with the principal herb, they enhance the effects of promoting blood circulation and relieving pain, serving as assistant herbs. Dipsacus asper, Drynaria fortunei, and natural copper are the "three essential herbs for bone healing" in traditional Chinese medicine orthopedics. Dipsacus asper and Drynaria fortunei can nourish the liver and kidneys, strengthen tendons and bones, and also remove blood stasis and relieve pain; natural copper has the effect of healing bones and injuries. The three herbs work together to promote bone and tendon healing and promote fracture healing. Angelica sinensis and Salvia miltiorrhiza not only assist other herbs in promoting blood circulation but also nourish the blood, ensuring that blood stasis is resolved without harming the body's vital energy. Lycopus lucidus, which promotes blood circulation and removes blood stasis, also serves as an adjuvant herb, as it can promote diuresis and reduce swelling. This formula extensively uses blood-activating and stasis-removing herbs to "treat the symptoms in acute cases," quickly resolving the problems of stagnation, swelling, and pain. Simultaneously, it is combined with herbs such as Dipsacus asper and Drynaria fortunei to "treat the root cause," promoting fracture healing, reflecting a holistic approach that addresses both the symptoms and the underlying cause.

[0012] In a preferred embodiment, the bone-setting and pain-relieving pills are in the form of oral pills, preferably water-honey pills or concentrated pills.

[0013] Secondly, the present invention provides a method for preparing the above-mentioned bone-setting and pain-relieving pills, comprising the following steps: (a) Treatment of Panax notoginseng: (1) Freezing and embrittlement: Take clean Panax notoginseng and freeze it at -10℃ to -20℃ for 2 to 4 hours; (2) Composite solution impregnation: The frozen Panax notoginseng is impregnated in a composite impregnation solution, which is an ethanol-water solution containing L-cysteine, erythritol and sodium bicarbonate. The ratio of Panax notoginseng to the composite impregnation solution is 1:3 to 1:6 g / mL. The solution is impregnated at 10 to 20°C for 0.5 to 1.5 hours, filtered, and drained. (3) Step-by-step temperature drying: The drained Panax notoginseng is dried sequentially at 40℃ for 1.5-2.5 hours, 55℃ for 1-2 hours, and 70℃ for 0.5-1 hour, and then dried under reduced pressure until the moisture content is no more than 8.0%; (4) Grinding and sieving: Grind the dried Panax notoginseng until it all passes through a 100-mesh sieve to obtain fine Panax notoginseng powder; (II) Grouping and processing of the remaining medicinal ingredients: (5) Calcined natural copper and roasted peach kernels: Calcined natural copper until it is red-hot, then quenched in vinegar 1 to 3 times, and then crushed together with roasted peach kernels until all of them pass through a 100-mesh sieve to obtain a mixed fine powder; (6) Alcohol extraction group: Angelica sinensis, Salvia miltiorrhiza, Carthamus tinctorius, Sappanwood, Lycopus lucidus, Corydalis yanhusuo (vinegar-processed), Boswellia carterii (vinegar-processed), and Commiphora myrrha (vinegar-processed) were extracted twice by reflux with 6-10 times the weight of 60%-75% ethanol, each time for 1-1.5 hours. The extracts were filtered, and the filtrates were combined and concentrated under reduced pressure at a temperature not higher than 60℃ and a vacuum degree of -0.06 to -0.08 MPa to obtain an alcohol extract with a relative density of 1.20-1.30 at 60℃. (7) Water extract group: Take Drynaria fortunei and Dipsacus asperoides, add 8 to 12 times the weight of water and decoct twice, each time for 1 to 1.5 hours. Combine the decoctions and concentrate under reduced pressure to a water extract with a relative density of 1.15 to 1.25 at 60℃. (iii) Pill making: Combine the extracts obtained in steps (6) and (7), add the Panax notoginseng powder obtained in step (4), the mixed fine powder obtained in step (5) and pharmaceutically acceptable excipients, mix well to form a soft material, make pills; dry under reduced pressure or low temperature at a temperature not higher than 50°C until the moisture content is not greater than 9.0%, coat, and package to obtain the final product.

[0014] In a preferred embodiment, the composite impregnation solution contains 55%–65% ethanol by volume, 0.1%–0.2% L-cysteine ​​by mass, 1%–2% erythritol by mass, and 0.1%–0.3% sodium bicarbonate by mass.

[0015] In a more preferred embodiment, the composite impregnation solution contains 60% ethanol by volume, 0.15% L-cysteine ​​by mass, 1.5% erythritol by mass, and 0.2% sodium bicarbonate by mass.

[0016] In a preferred embodiment, the pH of the composite impregnation solution is 6.5 to 8.0, preferably 7.0.

[0017] In a preferred embodiment, the ratio of Panax notoginseng to the compound impregnation solution is 1:4.5 g / mL, the impregnation temperature is 15°C, the impregnation time is 1 hour, and the solution is stirred every 30 minutes during the impregnation period.

[0018] In a preferred embodiment, the freeze-brittle process involves taking clean Panax notoginseng and freezing it at -15°C for 3 hours.

[0019] Thirdly, the present invention provides the use of the above-mentioned bone-setting and pain-relieving pills in the preparation of medicines for treating early and mid-stage fractures, dislocations or tendon injuries.

[0020] The beneficial effects of this invention are as follows: (1) The present invention employs a four-step pretreatment process for the principal herb, Panax notoginseng, consisting of "freezing and embrittlement, composite solution impregnation, step-temperature drying, and pulverization and sieving." The composite impregnation solution is composed of L-cysteine, erythritol, and sodium bicarbonate in a specific ratio in an ethanol-water solution, with the pH controlled within a weakly alkaline range. This treatment can physically break down the hard tissues of Panax notoginseng, inhibit enzymatic browning and oxidation, stabilize saponin components, and promote the formation and enrichment of rare saponins.

[0021] (2) In this invention, the prescription medicinal materials are grouped and processed according to their properties: calcined natural copper and roasted peach kernels are pulverized together; fat-soluble components (Angelica sinensis, Salvia miltiorrhiza, Carthamus tinctorius, Sappanwood, Lycopus lucidus, vinegar-processed Corydalis yanhusuo, vinegar-processed Boswellia carterii, vinegar-processed Myrrh) are extracted by ethanol reflux, and water-soluble components (hot-processed Drynaria fortunei, Dipsacus asper) are extracted by water decoction. Then, they are mixed with Panax notoginseng powder and excipients to make pills. This grouping extraction strategy takes into account the optimal extraction conditions for different components, avoids the loss of components of the principal drug Panax notoginseng in high-temperature and long-term water extraction, and makes the effective components of each medicinal ingredient more fully preserved.

[0022] (3) Pharmacodynamic tests showed that the bone-setting and pain-relieving pills of the present invention had a swelling inhibition rate of 51.8% in the xylene-induced mouse ear swelling model, which was superior to the positive control bone-setting and pain-relieving tablets and the mother formula new injury and pain relief decoction; the analgesic effect in the acetic acid-induced mouse writhing model was also superior to the above controls; in the SD rat fracture model, the callus score at 6 weeks reached 11.5, the clinical healing time was shortened to 35.9 days, and the maximum load at 6 weeks reached 140.2 N, all of which were superior to the model group, the positive control group and the mother formula group, indicating that the present invention has a definite and better comprehensive effect in anti-inflammatory and swelling-reducing, analgesic and fracture healing promotion.

[0023] (4) The study of the prescription shows that the absence of the principal drug (Panax notoginseng), the absence of the assistant drugs (fried peach kernel and safflower), or the absence of the three essential drugs for bone healing (hot bone drynaria, Dipsacus asper, and calcined natural copper) all significantly reduced the anti-inflammatory, analgesic, callus formation and healing indicators. This indicates that the drugs in the prescription of this invention have clear division of labor and mutual reliance. The whole prescription can maintain a more stable overall efficacy than any of the prescriptions.

[0024] (5) The preparation of the present invention is an oral pill (water-honey pill or concentrated pill), which is convenient to take, has controllable dosage and stable quality, and is suitable for clinical use in patients with fractures, dislocations and muscle injuries in the early and middle stages. Detailed Implementation

[0025] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0026] Example 1: Preparation of Bone-Setting and Pain-Relieving Pills (Water-Honey Pills) Prescription: Panax notoginseng 24g, Drynaria fortunei 24g, Calcined natural copper 24g, Dipsacus asper 20g, Sappanwood 20g, Peach kernel (fried) 12g, Carthamus tinctorius 12g, Angelica sinensis 12g, Salvia miltiorrhiza 12g, Lycopus lucidus 12g, Corydalis yanhusuo (vinegar-processed) 12g, Boswellia carterii (vinegar-processed) 6g, Commiphora myrrha (vinegar-processed) 6g.

[0027] Preparation method: (I) Processing of Panax notoginseng: (1) Freezing and embrittlement: Take 24g of clean Panax notoginseng and freeze it at -15℃ for 3 hours; (2) Composite solution impregnation: Prepare a 60% (v / v) ethanol aqueous solution containing 0.15% (g / mL) L-cysteine, 1.5% (g / mL) erythritol and 0.2% (g / mL) sodium bicarbonate, and determine that the pH of the composite impregnation solution is 7.0; put the frozen Panax notoginseng into 108mL of the solution (material-liquid ratio 1:4.5), impregnate at 15℃ for 1 hour, stir once every 30 minutes, filter and drain; (3) Step temperature drying: Dry under reduced pressure at 40℃ for 2 hours, at 55℃ for 1.5 hours, and at 70℃ for 0.5 hours in sequence, with a vacuum degree of -0.07MPa, until the moisture content is 7.4%; (4) Grinding and sieving: Grind until all of it passes through a 100-mesh sieve to obtain 23.5g of fine Panax notoginseng powder.

[0028] (ii) Grouping and processing of other medicinal ingredients: (5) Calcine natural copper until it is red-hot and quench it twice with vinegar. Then grind it together with roasted peach kernels until all of them pass through a 100-mesh sieve; (6) Take Angelica sinensis, Salvia miltiorrhiza, Carthamus tinctorius, Sappanwood, Lycopus lucidus, Corydalis yanhusuo (vinegar-processed), Boswellia carterii (vinegar-processed), and Commiphora myrrha (vinegar-processed). Add 8 times the amount of 70% ethanol and reflux extract twice, each time for 1.2 hours. Filter, combine the filtrates, and concentrate them under reduced pressure at 58℃ and -0.07MPa to an alcohol extract with a relative density of 1.25 at 60℃; (7) Take Drynaria fortunei and Dipsacus asperoides (scalded bone), add 10 times the amount of water and decoct twice, each time for 1.2 hours. Combine the decoctions and concentrate them under reduced pressure to an aqueous extract with a relative density of 1.20 at 60℃.

[0029] (III) Pill making: Combine the above alcohol extract and water extract, add Panax notoginseng fine powder, natural copper and peach kernel mixed fine powder and refined honey (add 30g of refined honey for every 100g of medicinal powder), mix well to make soft material, and make pills by pan-frying method; dry under reduced pressure at 48℃ to 8% moisture content, coat with film, and package to obtain water-honey pills, each bag weighing 6g.

[0030] Example 2: Water-honey pills Prescription: Panax notoginseng 20g, Drynaria fortunei 20g, Calcined natural copper 20g, Dipsacus asper 15g, Sappanwood 15g, Stir-fried peach kernel 9g, Carthamus tinctorius 9g, Angelica sinensis 9g, Salvia miltiorrhiza 9g, Lycopus lucidus 9g, Corydalis yanhusuo (processed with vinegar) 9g, Boswellia carterii (processed with vinegar) 4g, Commiphora myrrha (processed with vinegar) 4g.

[0031] The preparation process is the same as in Example 1 (freezing and embrittlement at -15°C for 3 hours; the composite impregnation solution is a 60% ethanol aqueous solution containing 0.15% L-cysteine, 1.5% erythritol, and 0.2% sodium bicarbonate, pH 7.0, material-to-liquid ratio 1:4.5, impregnation at 15°C for 0.5 hours; the step-temperature drying conditions are the same as in Example 1; pulverization until all particles pass through a 100-mesh sieve), and water-honey pills are made.

[0032] Example 3: Concentrated Pills Prescription: Panax notoginseng 30g, Drynaria fortunei 30g, Calcined natural copper 30g, Dipsacus asper 25g, Sappanwood 25g, Stir-fried peach kernel 15g, Safflower 15g, Angelica sinensis 15g, Salvia miltiorrhiza 15g, Lycopus lucidus 15g, Corydalis yanhusuo (vinegar-processed) 15g, Boswellia carterii (vinegar-processed) 8g, Commiphora myrrha (vinegar-processed) 8g.

[0033] The preparation process is the same as in Example 1. Concentrated pills are made by combining alcohol extract and water extract and concentrating under reduced pressure to a relative density of 1.35 at 60°C. Then, fine powder of Panax notoginseng, mixed fine powder and appropriate amount of dextrin are added, pills are made, and dried under reduced pressure at 48°C to a moisture content of 8%.

[0034] Example 4 Pharmacodynamic Test Laboratory animals, test drugs and dosing regimens (1) Experimental animals and environment: SPF grade mice (body weight 18-22g) and SPF grade SD rats (body weight 220-260g), Laboratory Animal Use License No.: SYXK(Lu) 2023 0023 (barrier environment). After purchase, the animals were adaptively reared in the barrier environment animal room for 3 days, with rearing conditions of temperature 22-25℃, relative humidity 50%-65%, 12h / 12h light-dark cycle, and free access to food and water.

[0035] (2) Preparation of test drugs: (1) Group of Example 1 of the present invention: The bone-setting analgesic pills prepared according to Example 1 are taken and ground into fine powder, and before use, the powder is triturated with 0.5% sodium carboxymethyl cellulose (CMC-Na) solution to prepare a suspension of the required concentration, with a administration dose of 0.5g / kg (calculated as the pill, the intragastric administration volume is 20mL / kg for mice and 10mL / kg for rats).

[0036] (2) Original prescription group: The original prescription is the Xinshang Xuduan Decoction recorded in "Lectures on Traumatology of Traditional Chinese Medicine", whose prescription is: 12g Angelica sinensis root tail, 6g Eupolyphaga, 3g Olibanum, 3g Myrrha, 6g Salvia miltiorrhiza, 12g Native Copper (vinegar calcined), 12g Rhizoma Drynariae, 6g Herba Lycopi, 6g Rhizoma Corydalis, 10g Sappan Lignum, 10g Radix Dipsaci, 12g Ramulus Mori, 6g Semen Persicae (the whole prescription has 13 ingredients, totaling 104g). Preparation method: Take the above thirteen ingredients and perform purification; break the vinegar-calcined Native Copper, place it in a decoction container and decoct first for 30 minutes; add water to the remaining medicinal ingredients and soak for 30 minutes, the added water level is about 5cm above the medicinal surface, boil with strong fire then turn to gentle fire to decoct twice, 1 hour for the first time and 40 minutes for the second time, add Olibanum and Myrrha later and wrap them for decoction during the second decoction; combine the two decoctions, filter, concentrate the filtrate under reduced pressure until each 1mL is equivalent to 1.0g of crude drug, to obtain the original prescription aqueous concentrated decoction, store at 4℃, and dilute to the required concentration with distilled water before use. The original prescription group is administered at the same dose as the group of the present invention in terms of crude drug amount.

[0037] (3) Positive control group: Commercially available Jiegu Qili Tablets are taken, the coating is removed, ground into fine powder, and prepared into a suspension with 0.5% CMC-Na solution by the same method, with a administration dose of 0.5g / kg (calculated as the tablet).

[0038] (4) Model group: Administer an equal volume of 0.5% CMC-Na solution.

[0039] (5) Blank group: Administer an equal volume of 0.5% CMC-Na solution.

[0040] The above four groups are administered by intragastric gavage once a day, and the general condition, food and water intake, and body weight change of the animals are observed daily during the administration period.

[0041] Anti-inflammatory test SPF-grade mice, weighing 18–22 g, were randomly divided into a model group, a positive control group, a parent formulation group, and the present invention group (Example 1 group), with 10 mice in each group. Xylene-induced ear swelling was used to establish the mouse model, and each group was given the corresponding test substance. Ten mice in the blank group were administered the drug for 7 consecutive days. Thirty minutes after the last administration, 0.05 mL of xylene was evenly applied to both sides of the right ear to induce inflammation. The left ear served as a control. One hour later, the mice were euthanized by cervical dislocation, and both ears were cut off along the auricle baseline. Ear pieces were taken from the same location using an 8 mm punch, accurately weighed, and the difference in weight between the left and right ears was used as the degree of swelling. The swelling inhibition rate was also calculated. The results are shown in Table 1.

[0042] Table 1. Degree of ear swelling in mice Note: Compared with the model group, *p<0.01.

[0043] The xylene-induced ear swelling model primarily reflects the degree of acute inflammatory exudation. After intervention with Jiegu Zhitong Wan (a traditional Chinese medicine formula), ear swelling in mice was significantly suppressed, and its anti-inflammatory and swelling-reducing effects were superior to those of the positive control group and the parent formula group, indicating that this preparation has a good controlling effect on the early inflammatory response after injury.

[0044] Analgesia trial Acetic acid-induced writhing in mice was used to establish the model. The experimental animals, grouping, and administration were the same as above, with 10 mice in each group. Thirty minutes after the last administration, each mouse was intraperitoneally injected with 0.2 mL of 0.6% acetic acid solution. The number of writhing episodes within 20 minutes after injection was recorded (a typical writhing response involving abdominal concavity, trunk and hind limb extension, and hip elevation was considered one episode). The results are shown in Table 2.

[0045] Table 2 Number of writhing movements in mice Note: Compared with the model group, *p<0.01.

[0046] In an acetic acid-induced writhing pain model, Jiegu Zhitong Wan reduced the writhing response in mice, demonstrating a good analgesic effect. The analgesic effect was more pronounced than that of the positive control group and the parent formula group, suggesting that it can be used to relieve pain in the early and middle stages of fractures, dislocations, or muscle injuries.

[0047] Fracture healing promotion test SPF-grade female SD rats with a body weight of 220-260 g are selected, and the experimental animal use license number is SYXK(Lu) 20230023. After the rats are anesthetized by intraperitoneal injection of 3% sodium pentobarbital (40 mg / kg), blunt dissection is performed through a medial knee joint incision under aseptic conditions, a Kirschner wire with a diameter of 1.0 mm is inserted retrogradely into the right femoral medullary cavity, a closed transverse fracture is created at the middle femur using a special fracture forceps, and the incision is sutured; after the operation, sodium penicillin (40,000 U / animal) is intramuscularly injected for 3 consecutive days to prevent infection. The blank group receives sham operation treatment. After modeling, the rats are randomly divided into 4 groups according to body weight: model group, positive control group, mother prescription group and the present invention group, with 10 rats in each group. Starting from the 2nd day after operation, the corresponding test substances are administered by gavage as described above, once a day, for 6 consecutive weeks. Anteroposterior X-ray films of the right femur are taken at the 2nd, 4th and 6th weeks respectively, and two radiologists unaware of the grouping independently perform callus scoring according to the Lane-Sandhu standard, and the average value is taken; the clinical fracture healing time is recorded; at the end of the 6th week, the animals are sacrificed, the right femur is taken and the soft tissue is removed, and a three-point bending test (span 20 mm, loading rate 2 mm / min) is performed to record the maximum load. The results are shown in Table 3.

[0048] Table 3 Clinical fracture healing time and maximum load at 6 weeks Note: Compared with the model group, *p<0.01.

[0049] Comprehensively judged from the imaging callus formation, clinical healing process and biomechanical strength of the healed bone, the Bone-setting and Pain-relieving Pill can promote fracture repair, accelerate healing and improve the quality of the healed bone, and the overall effect is superior to that of the model group, positive control group and mother prescription group.

[0050] Example 5 Clinical Observation A randomized controlled method is adopted, a total of 60 patients in the early and middle stages of fracture, dislocation or soft tissue injury are enrolled, and randomly divided into a treatment group and a control group according to the consultation order, with 30 cases in each group. The baselines (age, gender, injury type, disease course) of the two groups are balanced and comparable (p>0.05). The treatment group takes the Bone-setting and Pain-relieving Pill prepared according to Example 1 orally (6 g each time, 3 times a day); the control group takes Jiegu Qili Tablets orally (1.5 g each time, 2 times a day). The treatment course of both groups is 6 weeks. Observation indicators: swelling subsidence time, VAS pain score, clinical fracture healing time and comprehensive curative effect (total effective rate = sum of clinical control, markedly effective and effective / total number of cases). The results are shown in Table 4.

[0051] Table 4 Observation indicators of clinical cases In clinical observation, the Bone-setting and Pain-relieving Pill is superior to Jiegu Qili Tablets in terms of swelling subsidence, pain relief, fracture healing and comprehensive curative effect, bringing more obvious clinical benefits to patients, which supports its application in the treatment of early and middle stages of fracture, dislocation or soft tissue injury.

[0052] Example 6 Comparative study on disassembled formulas of monarch-minister-assistant-guide compatibility The experimental animals were SPF-grade Kunming mice and SD rats, with the experimental animal use license number: SYXK(Lu) 20230023. To verify the effect of the monarch-minister-assistant-guide compatibility of the present invention, the following comparative examples are set; to ensure the same dosage form for easy comparison, all groups are made into pills according to the same process as in Example 1, and the administration dosage of each group is converted to be consistent based on the raw drug amount: Comparative Example 1: Notoginseng is removed from the prescription of the present invention, and the remaining medicinal materials and dosages remain unchanged.

[0053] Comparative Example 2: Stir-baked peach kernel and safflower are removed from the prescription of the present invention, and the remaining medicinal materials and dosages remain unchanged.

[0054] Comparative Example 3: Processed Rhizoma Drynariae, Radix Dipsaci, and Calcined Pyritum are removed from the prescription of the present invention, and the remaining medicinal materials and dosages remain unchanged.

[0055] The anti-inflammatory swelling inhibition rate, analgesic inhibition rate, 6-week callus score and healing time of each group were determined according to the method in Example 4, and the results are shown in Table 5.

[0056] Table 5 Anti-inflammatory swelling inhibition rate, analgesic inhibition rate, 6-week callus score and healing time of each group After the formula is disassembled, the groups missing the monarch drug, the minister drug or the three key bone-knitting drugs all show different degrees of decline in anti-inflammatory, analgesic, callus formation and healing progress, indicating that each medicinal material in the prescription has a clear division of labor and is indispensable; the full-formula compatibility can maintain the overall efficacy better than the disassembled formulas.

[0057] Example 7 Single-factor comparative study on Notoginseng treatment To verify the effect of the "four-step combined" treatment of the monarch drug Notoginseng of the present invention, the following comparative examples are set with the same batch of Notoginseng medicinal materials, and the remaining medicinal materials and subsequent pill-making processes are the same as those in Example 1: Comparative Example 4: Notoginseng is directly pulverized after being purified, all of which pass through a 100-mesh sieve, without freeze embrittlement, impregnation and stepwise variable temperature drying.

[0058] Comparative Example 5: Notoginseng is subjected to freeze embrittlement in step (1) of Example 1 and then pulverized, all of which pass through a 100-mesh sieve, without impregnation and stepwise variable temperature drying.

[0059] Comparative Example 6: Notoginseng is subjected to impregnation and draining in step (2) of Example 1, then dried under normal pressure at 60°C until the water content is about 7.5%, and pulverized to all pass through a 100-mesh sieve, without freeze embrittlement and stepwise variable temperature drying.

[0060] Comparative Example 7: Notoginseng is subjected to stepwise variable temperature drying (without freeze embrittlement and impregnation) in step (3) of Example 1 and then pulverized, all of which pass through a 100-mesh sieve.

[0061] The pulverizing equipment, feed amount (24g), and sieve size (100 mesh) were the same for all comparative examples. The total amount of notoginsenosides (notoginsenoside R1 + ginsenoside Rg1 + ginsenoside Rb1) and the content of rare saponins (ginsenoside Rg3 + Rh2) in the obtained Panax notoginseng powder were determined for each treatment. The contents mentioned are the extractable amounts determined by HPLC. The results are shown in Table 6.

[0062] Table 6 Total content of Panax notoginseng saponins and content of ginsenoside Rg3+Rh2 After freezing and embrittlement, compound impregnation, step-temperature drying, and pulverization and sieving, the retention of saponin components and the enrichment of rare saponins in Panax notoginseng are significantly better than those of conventional pulverization and treatment using only some steps. This indicates that the pretreatment route is beneficial to improving the component quality of Panax notoginseng, the principal ingredient.

[0063] Example 8: Comparative Study on the Composition of Panax notoginseng Ternary Composite Impregnation Solution To verify the effects of L-cysteine, erythritol, and sodium bicarbonate in the composite impregnation solution of this invention, the same batch of Panax notoginseng was used as the subject. The three steps of freezing and embrittlement (-15℃, 3 hours), step temperature variable pressure drying (40℃ for 2 hours / 55℃ for 1.5 hours / 70℃ for 0.5 hours, vacuum degree -0.07MPa), and pulverization and sieving (pulverizing until all passed through a 100-mesh sieve) were exactly the same as in Example 1. Only the composition of the impregnation solution in step (2) was changed. The impregnation conditions were uniformly set as follows: material-to-liquid ratio 1:4.5, 15℃, 1 hour, and stirring once every 30 minutes. Comparative Example 8: Soaked in 108 mL of purified water.

[0064] Comparative Example 9: Impregnated with 108 mL of 60% (v / v) aqueous ethanol solution, without the addition of any protective components.

[0065] Comparative Example 10: 60% ethanol contains 0.2% (g / mL) sodium bicarbonate.

[0066] Comparative Example 11: 60% ethanol contains 0.15% (g / mL) L-cysteine.

[0067] Comparative Example 12: 60% ethanol contains 1.5% (g / mL) erythritol.

[0068] Comparative Example 13: 60% ethanol contains 0.2% sodium bicarbonate and 0.15% L-cysteine.

[0069] Comparative Example 14: 60% ethanol contains 0.2% sodium bicarbonate and 1.5% erythritol.

[0070] Comparative Example 15: 60% ethanol contains 0.15% L-cysteine ​​and 1.5% erythritol.

[0071] Comparative Example 16: 60% ethanol contains 1.0% L-cysteine, 8.0% erythritol, and 1.0% sodium bicarbonate.

[0072] Determination Items and Methods: (i) pH of the impregnation solution: determined by pH meter at the beginning of impregnation; (ii) Total saponin content (notoginsenoside R1 + ginsenoside Rg1 + ginsenoside Rb1) and rare saponin content (ginsenoside Rg3 + Rh2) in Panax notoginseng powder: determined by high performance liquid chromatography, the content is the extractable amount determined by HPLC; (iii) Browning index: 0.5g of Panax notoginseng powder was taken, 10mL of 70% ethanol was added, ultrasonically treated for 30 minutes, filtered, and the absorbance A of the filtrate was measured at 420nm. 420 The degree of enzymatic browning and oxidation was characterized. The results are shown in Table 7.

[0073] Table 7. pH, total saponins, Rg3+Rh2, and browning index of the examples and comparative examples. The composition and pH of the impregnation solution significantly affect the retention of Panax notoginseng components, the formation of rare saponins, and the degree of browning. A suitable concentration of L-cysteine, erythritol, and sodium bicarbonate can reduce oxidative browning and promote saponin retention and the enrichment of rare saponins; the absence of any component or excessive concentration is detrimental to the improvement of component quality.

Claims

1. A bone-setting and pain-relieving pill, characterized in that, The bone-setting and pain-relieving pills are water-honey pills or concentrated pills, made from raw materials and pharmaceutically acceptable excipients. The raw materials consist of the following medicinal materials in parts by weight: Panax notoginseng 20-30 parts, Drynaria fortunei 20-30 parts, Calcined natural copper 20-30 parts, Dipsacus asper 15-25 parts, Sappanwood 15-25 parts, stir-fried peach kernel 9-15 parts, Carthamus tinctorius 9-15 parts, Angelica sinensis 9-15 parts, Salvia miltiorrhiza 9-15 parts, Lycopus lucidus 9-15 parts, vinegar-processed Corydalis yanhusuo 9-15 parts, vinegar-processed frankincense 4-8 parts, and vinegar-processed myrrh 4-8 parts. The Panax notoginseng is obtained by processing it into fine powder through the following steps: (1) Take clean Panax notoginseng and freeze it at -10℃ to -20℃ for 2 to 4 hours; (2) Immerse the frozen Panax notoginseng in a compound impregnation solution, wherein the compound impregnation solution is a 55%~65% v / v ethanol aqueous solution containing L-cysteine, erythritol and sodium bicarbonate, wherein the concentration of L-cysteine ​​is 0.1%~0.2% g / mL, the concentration of erythritol is 1%~2% g / mL, the concentration of sodium bicarbonate is 0.1%~0.3% g / mL, the material-liquid ratio of Panax notoginseng to compound impregnation solution is 1:3~1:6 g / mL, immerse at 10~20℃ for 0.5~1.5 hours, filter and drain. (3) After draining, the Panax notoginseng is dried at 40℃ for 1.5-2.5 hours, at 55℃ for 1-2 hours, and at 70℃ for 0.5-1 hour in sequence, and then dried under reduced pressure until the moisture content is no more than 8.0%; (4) Grind until all of them pass through a 100-mesh sieve.

2. The bone-setting and pain-relieving pill according to claim 1, characterized in that, The raw materials are composed of the following medicinal materials in parts by weight: 24 parts of Panax notoginseng, 24 parts of Drynaria fortunei, 24 parts of calcined natural copper, 20 parts of Dipsacus asper, 20 parts of Sappanwood, 12 parts of stir-fried peach kernel, 12 parts of safflower, 12 parts of Angelica sinensis, 12 parts of Salvia miltiorrhiza, 12 parts of Lycopus lucidus, 12 parts of vinegar-processed Corydalis yanhusuo, 6 parts of vinegar-processed frankincense, and 6 parts of vinegar-processed myrrh.

3. The bone-setting and pain-relieving pill according to claim 1, characterized in that, In step (2), the composite impregnation solution contains 60% ethanol by volume, 0.15% L-cysteine ​​by volume, 1.5% erythritol by volume, and 0.2% sodium bicarbonate by volume.

4. The bone-setting and pain-relieving pill according to claim 1, characterized in that, The pH of the composite impregnation solution in step (2) is 7.

0.

5. The bone-setting and pain-relieving pill according to claim 1, characterized in that, In step (2), the ratio of Panax notoginseng to the compound impregnation solution is 1:4.5 g / mL, the impregnation temperature is 15℃, the impregnation time is 1 hour, and the mixture is stirred every 30 minutes during the impregnation period; in step (1), the freezing temperature is -15℃ and the freezing time is 3 hours; in step (3), the mixture is dried at 40℃ for 2 hours, at 55℃ for 1.5 hours, and at 70℃ for 0.5 hours in sequence, and the vacuum degree of the vacuum drying is -0.06~-0.08 MPa.

6. A method for preparing a bone-setting and pain-relieving pill, wherein the raw material for the bone-setting and pain-relieving pill is composed of the following medicinal materials in parts by weight: The formula comprises 20-30 parts of Panax notoginseng, 20-30 parts of Drynaria fortunei (processed with hot water), 20-30 parts of calcined natural copper, 15-25 parts of Dipsacus asper, 15-25 parts of Sappanwood, 9-15 parts of stir-fried peach kernel, 9-15 parts of safflower, 9-15 parts of Angelica sinensis, 9-15 parts of Salvia miltiorrhiza, 9-15 parts of Lycopus lucidus, 9-15 parts of vinegar-processed Corydalis yanhusuo, 4-8 parts of vinegar-processed frankincense, and 4-8 parts of vinegar-processed myrrh; characterized by the following steps: (1) Freezing and embrittlement: Take clean Panax notoginseng and freeze it at -10℃ to -20℃ for 2 to 4 hours; (2) Composite solution impregnation: The frozen Panax notoginseng is impregnated in a composite impregnation solution, which is a 55%~65% v / v ethanol aqueous solution containing L-cysteine, erythritol and sodium bicarbonate, wherein the concentration of L-cysteine ​​is 0.1%~0.2% g / mL, the concentration of erythritol is 1%~2% g / mL, the concentration of sodium bicarbonate is 0.1%~0.3% g / mL, the material-to-liquid ratio of Panax notoginseng to composite impregnation solution is 1:3~1:6 g / mL, and impregnation is carried out at 10~20℃ for 0.5~1.5 hours, filtered and drained; (3) Step-by-step temperature drying: The drained Panax notoginseng is dried sequentially at 40℃ for 1.5~2.5 hours, 55℃ for 1~2 hours, and 70℃ for 0.5~1 hour, and then dried under reduced pressure until the moisture content is no more than 8.0%; (4) Grinding and sieving: Grind the dried Panax notoginseng until it all passes through a 100-mesh sieve to obtain fine Panax notoginseng powder; (5) Take natural copper, calcine it until it is red-hot, quench it in vinegar 1-3 times, and grind it together with fried peach kernels until all of them pass through a 100-mesh sieve to obtain a mixed fine powder; (6) Alcohol extraction: Take Angelica sinensis, Salvia miltiorrhiza, Carthamus tinctorius, Sappanwood, Lycopus lucidus, Corydalis yanhusuo (vinegar-processed), Boswellia carterii (vinegar-processed), and Commiphora myrrha (vinegar-processed), add 6-10 times their weight of 60%-75% v / v ethanol and reflux extract twice, each time for 1-1.5 hours, filter, combine the filtrates, and concentrate under reduced pressure at a temperature not higher than 60℃ and a vacuum degree of -0.06 to -0.08MPa to obtain an alcohol extract with a relative density of 1.20-1.30 at 60℃; (7) Water extraction: Take Drynaria fortunei and Dipsacus asperoides, add 8 to 12 times the weight of water and decoct twice, each time for 1 to 1.5 hours. Combine the decoctions and concentrate under reduced pressure to a water extract with a relative density of 1.15 to 1.25 at 60°C. (8) Making pills: Combine the alcohol extract obtained in step (6) and the water extract obtained in step (7), add the Panax notoginseng fine powder obtained in step (4), the mixed fine powder obtained in step (5) and the excipients, mix them evenly to make soft material, make pills, dry them at a temperature not higher than 50°C until the moisture content is not greater than 9.0%, coat them with a thin film, and package them to obtain the final product.

7. The preparation method according to claim 6, characterized in that, In step (6), the volume fraction of ethanol is 70%, the amount of ethanol used is 8 times the weight, the reflux extraction is performed for 1.2 hours each time, the temperature of vacuum concentration is 58℃ and the vacuum degree is -0.07MPa, and the relative density of the ethanol extract at 60℃ is 1.25; in step (7), the amount of water used is 10 times the weight, the decoction is performed for 1.2 hours each time, and the relative density of the water extract at 60℃ is 1.

20.

8. The preparation method according to claim 6, characterized in that, The excipient mentioned in step (8) is refined honey. The amount of refined honey used is 25-35g of refined honey per 100g of medicinal powder. The pill making is done by the pan-processing method, and the resulting pills are water-honey pills.

9. The preparation method according to claim 6, characterized in that, In step (8), the combined extract is concentrated under reduced pressure to a relative density of 1.30~1.40 at 60°C. The excipient is dextrin, and the resulting pills are concentrated pills.

10. The use of the bone-setting and pain-relieving pills according to claim 1 in the preparation of drugs for treating early and mid-stage fractures, dislocations or tendon injuries.

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