Traditional Chinese medicine composition and application thereof in delayed fracture healing

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a traditional Chinese medicine composition and application thereof in delayed fracture healing. The traditional Chinese medicine composition is prepared from the following raw materials: trogopterus dung, ardisia dodecandrum, pseudo-ginseng, rhizoma drynariae, curcuma zedoary, eucommia ulmoides, morinda officinalis, madder, radix paeoniae rubra, leech, scorpio, platycodon grandiflorum, liquorice and kadsura pepper stem. The traditional Chinese medicine composition is mainly used for promoting blood circulation to remove blood stasis, promoting reunion of fractured tendons and bones and tonifying kidney and strengthening bones, is rigorous in compatibility of monarch, minister, assistant and guide, and has obvious curative effect in clinical use; pharmacological experiments show that the prescription has a remarkable curative effect on delayed fracture healing, the preparation process of the prescription is simple, and the prescription has a good foundation when being used for many years in a hospital.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a traditional Chinese medicine composition and its application in the treatment of delayed fracture healing. Background Art

[0002] Delayed fracture healing is mostly classified into the categories of "bone flaccidity" and "bone impediment" in traditional Chinese medicine. The main pathogenesis is qi stagnation and blood stasis, as well as spleen and kidney deficiency. Chen Shiduo in the Qing Dynasty pointed out in "Record of Syndrome Differentiation": "In the internal treatment method, it is necessary to prioritize promoting blood circulation to remove blood stasis first. If the blood is not activated, the stasis cannot be removed. If the stasis is not removed, the bone cannot be connected." Shi Yangshan, a master of traditional Chinese medicine, said: "The essence is deficient and cannot irrigate, the blood is deficient and cannot nourish, the qi is deficient and cannot reach, and there is no way to generate marrow to nourish the bone", emphasizing the treatment from deficiency, especially focusing on the spleen and kidney. Applying traditional Chinese medicine to patients with delayed fracture healing after surgery has a high efficiency, can avoid secondary surgery, and reduce the pain of patients.

[0003] Delayed union and nonunion after fracture surgery are common complications in orthopedic clinics, with an incidence of about 5%-10%. Its occurrence mechanism is complex, involving insufficient local blood supply, poor mechanical stability, infection, metabolic diseases (such as diabetes, osteoporosis) and biological factors (such as lack of growth factors). Traditional treatment methods include prolonging the fixation time, bone grafting surgery (autologous / allogeneic bone grafting), extracorporeal shock wave therapy (ESWT) and low-intensity pulsed ultrasound (LIPUS), but there are problems such as large trauma, long cycle and unstable curative effect.

[0004] In recent years, drug treatment has gradually become an important auxiliary means. Especially the development of chemical drugs and biological drugs has provided new intervention strategies for delayed fracture healing. However, existing therapeutic drugs still have limitations, such as narrow indications, high prices or obvious side effects.

[0005] In terms of traditional Chinese medicine, Chinese Patent CN107890511A discloses a traditional Chinese medicine composition for treating rapid fracture healing, belonging to the field of traditional Chinese medicine. The traditional Chinese medicine composition for treating rapid fracture healing of the present invention is composed of the following components in parts by weight: 5-10 parts of moschus, 2-8 parts of bezoar, 3-6 parts of fritillaria cirrhosa, 1-3 parts of crab shell, 1-4 parts of cucumber seeds, 1-3 parts of borneol, 1-4 parts of drynaria rhizome, 4-8 parts of coptis chinensis, 5-10 parts of liquorice, 5-10 parts of pumpkin seeds. The ingredients contain precious medicinal materials such as bezoar and moschus, and the cost is relatively high; Chinese Patent CN102526405A discloses a traditional Chinese medicine composition for accelerating fracture healing, which relates to the technical field of traditional Chinese medicine. It is prepared from the following Chinese medicinal materials in parts by weight: 12-15 parts of frankincense, 12-15 parts of myrrh, 12-15 parts of angelica sinensis, 4-6 parts of asarum, 12-18 parts of dragon's blood, 10-14 parts of speranskia tuberculata, 8-12 parts of notoginseng, 12-15 parts of clerodendrum bungei, 12-15 parts of kusnezoff monkshood, 4-8 parts of borneol. The prescription contains Chinese medicinal materials with great toxic effects of asarum, and the dosage exceeds the requirements of the pharmacopoeia, and there are certain safety hazards in clinical practice. Summary of the Invention

[0006] The purpose of the present invention is to address the deficiencies of the prior art. The present invention provides a traditional Chinese medicine composition for promoting fracture healing after fracture. The composition is prepared into a decoction or granules, which has a definite curative effect on the healing of fractures and bone injuries, shortens the fracture healing time, can accelerate the growth of callus, and has a definite clinical effect, and is suitable for further popularization and application.

[0007] Specifically, the technical solution of the present invention is realized as follows:

[0008] A traditional Chinese medicine composition for treating delayed fracture healing, characterized in that the traditional Chinese medicine composition is made from the following raw materials: trogopterus dung, small umbrella, notoginseng, drynaria rhizome, zedoary, eucommia ulmoides, morinda officinalis, madder, red peony root, leech, scorpion, platycodon grandiflorum, liquorice and kadsura pepper stem.

[0009] Furthermore, in the preferred embodiment of the present invention, the traditional Chinese medicine composition contains the following components: 15-25 parts by weight of trogopterus dung, 10-30 parts by weight of small umbrella, 5-15 parts by weight of notoginseng, 8-12 parts by weight of drynaria rhizome, 5-10 parts by weight of zedoary, 10-15 parts by weight of eucommia ulmoides, 7-12 parts by weight of morinda officinalis, 2-8 parts by weight of madder, 4-7 parts by weight of red peony root, 1-3 parts by weight of leech, 1-3 parts by weight of scorpion, 3-8 parts by weight of platycodon grandiflorum, 5-15 parts by weight of liquorice, 5-10 parts by weight of kadsura pepper stem.

[0010] Further, in a preferred embodiment of the present invention, the traditional Chinese medicine composition contains the following components: 20 parts by weight of Trogopterus dung, 20 parts by weight of Ardisia quinquegona Blume, 10 parts by weight of Panax notoginseng, 10 parts by weight of Drynaria fortunei (Kunze) J. Sm., 7.8 parts by weight of Curcuma zedoaria (Christm.) Rosc., 12.5 parts by weight of Eucommia ulmoides Oliv., 15.5 parts by weight of Morinda officinalis How, 5 parts by weight of Rubia cordifolia L., 5.5 parts by weight of Paeonia lactiflora Pall., 1.5 parts by weight of Whitmania pigra Whitman, 1.5 parts by weight of Scorpio, 6.5 parts by weight of Platycodon grandiflorus (Jacq.) A. DC., 10 parts by weight of Glycyrrhiza uralensis Fisch., 7.5 parts by weight of Piper kadsura (Choisy) Ohwi.

[0011] Further, in a preferred embodiment of the present invention, the traditional Chinese medicine composition contains the following components: 15 parts by weight of Trogopterus dung, 10 parts by weight of Ardisia quinquegona Blume, 5 parts by weight of Panax notoginseng, 8 parts by weight of Drynaria fortunei (Kunze) J. Sm., 5 parts by weight of Curcuma zedoaria (Christm.) Rosc., 10 parts by weight of Eucommia ulmoides Oliv., 7 parts by weight of Morinda officinalis How, 2 parts by weight of Rubia cordifolia L., 4 parts by weight of Paeonia lactiflora Pall., 1 part by weight of Whitmania pigra Whitman, 1 part by weight of Scorpio, 3 parts by weight of Platycodon grandiflorus (Jacq.) A. DC., 5 parts by weight of Glycyrrhiza uralensis Fisch., 5 parts by weight of Piper kadsura (Choisy) Ohwi.

[0012] Further, in a preferred embodiment of the present invention, the traditional Chinese medicine composition contains the following components: 25 parts by weight of Trogopterus dung, 30 parts by weight of Ardisia quinquegona Blume, 15 parts by weight of Panax notoginseng, 12 parts by weight of Drynaria fortunei (Kunze) J. Sm., 10 parts by weight of Curcuma zedoaria (Christm.) Rosc., 15 parts by weight of Eucommia ulmoides Oliv., 12 parts by weight of Morinda officinalis How, 8 parts by weight of Rubia cordifolia L., 7 parts by weight of Paeonia lactiflora Pall., 3 parts by weight of Whitmania pigra Whitman, 3 parts by weight of Scorpio, 8 parts by weight of Platycodon grandiflorus (Jacq.) A. DC., 15 parts by weight of Glycyrrhiza uralensis Fisch., 10 parts by weight of Piper kadsura (Choisy) Ohwi.

[0013] Further, in an embodiment of the present invention, the Panax notoginseng is raw Panax notoginseng powder. The method of taking the decoction is as follows: other drugs except Panax notoginseng are decocted with water, and then Panax notoginseng powder is added for taking after decoction; the method of taking the granule is to take it together with excipients (sucrose or dextrin).

[0014] The traditional Chinese medicine composition is prepared into a clinically acceptable preparation after being mixed with and / or without pharmaceutically acceptable excipients.

[0015] The preparations include but are not limited to granules, capsules, tablets, oral liquids, mixtures, syrups, decoctions, and are further preferably granules or decoctions.

[0016] The pharmaceutical composition or extract of the present invention is combined with and / or chemical drugs, biological drugs; preferably, the chemical drugs and biological drugs are drugs for treating delayed union of fractures; more preferably, the chemical drug is any one or more of teriparatide, abaloparatide, zoledronic acid, misoprostol.

[0017] The traditional Chinese medicine composition is directly prepared into a decoction, and the volume of the decoction is 100 - 300 mL; the daily dosage is 100 mL - 300 mL; twice a day.

[0018] The monarch, minister, assistant, and envoy herbs in the present invention are completely compatible. In the formula, the monarch, minister, assistant, and envoy herbs are all present. Specifically, the monarch herbs, namely Trogopterus Dung and Ardisia quinquegona Blume, promote blood circulation to remove stasis, repair tendons and bones, and directly promote local blood circulation and callus formation; among the minister herbs, Panax notoginseng and Rhizoma Curcumae assist the monarch herbs in promoting blood circulation to remove stasis, and Drynaria fortunei, Eucommia ulmoides Oliv., and Morinda officinalis How strengthen the kidney and bones, taking both the symptoms (stasis) and root causes (deficiency) into consideration; the assistant herbs are divided into two groups. Rubia cordifolia L., Radix Paeoniae Rubra, Whitmania pigra Whitman, and Scorpio enhance the power of promoting blood circulation to remove stasis and dredging collaterals, Platycodon grandiflorum A. DC. guides the herbs to the affected meridians, and Glycyrrhiza uralensis Fisch. harmonizes the properties of the herbs; the envoy herb, Piper kadsura (Choisy) Ohwi, guides the herbs to enter the muscles and bones. Promoting blood circulation to remove stasis does not damage healthy qi, and tonifying the kidney does not stagnate stasis. Whitmania pigra Whitman and Scorpio search for and remove deep-seated stasis, targeting stubborn delayed healing; Piper kadsura (Choisy) Ohwi guides the medicinal power to focus on the affected area. It is applicable to cases of long-term retention of blood stasis and slow healing after fracture (local swelling and pain, sparse callus), and needs to be added or subtracted according to the syndrome: add Olibanum if stasis is severe, and add Cornu Cervi Colla if kidney deficiency is present. It is contraindicated for pregnant women, and the weak should use insect drugs with caution.

[0019] Research has found that the increase in insect drugs in traditional Chinese medicine can especially accelerate the blood circulation in the local fracture area, further accelerate the absorption of hematoma in the swollen area, and can also stimulate the activity of osteoblasts in the fracture area. By enhancing the power of dredging collaterals and penetrating, it relieves deep stasis, and the clinical efficacy is remarkable. The composition of the present invention pays attention to the theory of traditional Chinese medicine that "new growth occurs when stasis is removed, and bones unite when collaterals are dredged". It is applicable to cases of delayed healing with a long course of disease and sticky blood stasis in this hospital, and has achieved good results.

[0020] Modern pharmacology has confirmed that Trogopterus Dung, Panax notoginseng, and Rhizoma Curcumae in the prescription of the present invention can promote bone formation and mineralization, inhibit inflammatory factors such as TNF-α and IL-6, reduce local inflammatory response through the NF-κB pathway, up-regulate the expression of BMP-2 and Runx2, and promote osteogenic differentiation. While Drynaria fortunei, Eucommia ulmoides Oliv., and Morinda officinalis How activate the Wnt / β-catenin pathway, enhance the activity of osteoblasts, increase the levels of serum calcium and phosphorus, and promote the deposition of hydroxyapatite; Whitmania pigra Whitman, Scorpio, and Rubia cordifolia L. inhibit platelet aggregation, dilate microvessels through the NO / cGMP pathway, promote angiogenesis at the fracture end, and enhance the mechanical strength of callus. Piper kadsura (Choisy) Ohwi, as a guiding herb, can increase the enrichment of drugs in bone tissue and improve bioavailability.

[0021] Compared with the prior art, the present invention has outstanding technical effects, which are mainly reflected in the following aspects

[0022] 1) The formula of the present invention is reasonable and hits the mechanism. On the basis of promoting blood circulation to remove stasis as the main treatment method, it also dredges collaterals. Through clinical drug use experiments, the treatment effect is remarkable. In the treatment of delayed fracture healing, promoting blood circulation to remove stasis and tonifying the spleen and kidney are the main methods. Clinical research shows that this scheme can significantly improve local blood circulation, and the total effective rate reaches more than 95%, and no obvious adverse reactions are found.

[0023] 2) In terms of animal experiment verification, a standard fracture model was used for systematic evaluation. The experimental data show that there are significant differences in biochemical indexes such as the maximum load, maximum stress, and maximum displacement of the composition of the present invention compared with the model group (P<0.01).

[0024] 3) The compositions of the present invention have been prepared into dosage forms such as decoctions and granules. The therapeutic effects of many dosage forms are similar. The granule dosage form is entrusted to the National Key Laboratory for the Integration and Innovation of Classical Prescriptions and Modern Chinese Medicine in our province for production, with strict quality control; the decoction strictly follows the traditional decocting process and is uniformly prepared by the pharmacy of our hospital. The preparation process is relatively simple and suitable for large-scale production. Description of the Drawings

[0025] Figure 1 : Evaluation standard scores for the therapeutic effects of Johner-Wruh fractures in the experimental group and the control group before and after treatment.

[0026] Figure 2 : Statistical results of the clinical healing dates in the experimental group and the control group.

[0027] Figure 3 : Comparison of the growth of callus observed by X-ray in the experimental group and the control group.

[0028] Figure 4 : Statistical results of the treatment conditions in the experimental group and the control group.

[0029] Figure 5 : Test results of the maximum load (N) of each example.

[0030] Figure 6 : Test results of the maximum stress (Mpa) of each example.

[0031] Figure 7 : Test results of the maximum displacement (mm) of each example.

[0032] Figure 8 : Fracture healing condition of Shuai in the experimental group.

[0033] Figure 9 : Fracture healing condition of Yang in the experimental group. Detailed Embodiments

[0034] The present invention will be further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. After reading the present invention, various equivalent modifications made by those skilled in the art to the present invention fall within the scope defined by the appended claims of this application.

[0035] Example 1: A traditional Chinese medicine decoction for treating delayed fracture healing, with the composition, dosage, and preparation method as follows:

[0036] Trogopterus dung 20g, Ardisia quinquegona Blume 20g, Notoginseng 10g, Drynaria fortunei (Kunze) J. Sm. 10g, Rhizoma Curcumae 7.8g, Eucommia ulmoides Oliv. 12.5g, Morinda officinalis How 15.5g, Rubia cordifolia L. 5g, Radix Paeoniae Rubra 5.5g, Hirudo 1.5g, Scorpio 1.5g, Platycodon grandiflorus (Jacq.) A. DC. 6.5g, Glycyrrhiza uralensis Fisch. 10g, Piper kadsura (Choisy) Ohwi 7.5g.

[0037] Preparation process: Decoct with water twice, filter, add notoginseng powder, stir evenly to obtain 200 ml of decoction, take it separately, twice a day, in the morning and evening, 200 ml each time.

[0038] Example 2: A traditional Chinese medicine decoction for treating delayed fracture healing, the ingredients, dosages and preparation method are as follows:

[0039] Trogopterus dung 15 g, Ardisia quinquegona Blume 10 g, Notoginseng 5 g, Drynaria fortunei (Kunze) J. Sm. 8 g, Curcuma zedoaria (Christm.) Rosc. 5 g, Eucommia ulmoides Oliv. 10 g, Morinda officinalis How 7 g, Rubia cordifolia L. 2 g, Paeonia lactiflora Pall. 4 g, Hirudo 1 g, Scorpio 1 g, Platycodon grandiflorus (Jacq.) A. DC. 3 g, Glycyrrhiza uralensis Fisch. 5 g, Piper kadsura (Choisy) Ohwi 5 g.

[0040] Preparation process: Decoct with water twice, filter, add notoginseng powder, stir evenly to obtain 400 ml of decoction, take it separately, twice a day, in the morning and evening, 100 ml each time.

[0041] Example 3: A traditional Chinese medicine decoction for treating delayed fracture healing, the ingredients, dosages and preparation method are as follows:

[0042] Trogopterus dung 25 g, Ardisia quinquegona Blume 30 g, Notoginseng 15 g, Drynaria fortunei (Kunze) J. Sm. 12 g, Curcuma zedoaria (Christm.) Rosc. 10 g, Eucommia ulmoides Oliv. 15 g, Morinda officinalis How 12 g, Rubia cordifolia L. 8 g, Paeonia lactiflora Pall. 7 g, Hirudo 3 g, Scorpio 3 g, Platycodon grandiflorus (Jacq.) A. DC. 8 g, Glycyrrhiza uralensis Fisch. 15 g, Piper kadsura (Choisy) Ohwi 10 g.

[0043] Preparation process: Decoct with water twice, filter, add notoginseng powder, stir evenly to obtain 300 ml of decoction, take it separately, twice a day, in the morning and evening, 300 ml each time.

[0044] Example 4: A traditional Chinese medicine granule for treating delayed fracture healing, the ingredients, dosages and preparation method are as follows:

[0045] Trogopterus dung 20 g, Ardisia quinquegona Blume 20 g, Notoginseng 10 g, Drynaria fortunei (Kunze) J. Sm. 10 g, Curcuma zedoaria (Christm.) Rosc. 7.8 g, Eucommia ulmoides Oliv. 12.5 g, Morinda officinalis How 15.5 g, Rubia cordifolia L. 5 g, Paeonia lactiflora Pall. 5.5 g, Hirudo 1.5 g, Scorpio 1.5 g, Platycodon grandiflorus (Jacq.) A. DC. 6.5 g, Glycyrrhiza uralensis Fisch. 10 g, Piper kadsura (Choisy) Ohwi 7.5 g.

[0046] Preparation process:

[0047] 1) Grind notoginseng, hirudo and scorpio into fine powder, and set aside the mixture.

[0048] 2) Decoct the remaining herbs except notoginseng, hirudo and scorpio with water, filter the decoction, concentrate it to a thick paste with a relative density of 1.10 - 1.15 (40 °C), dry it, and pulverize it into fine powder.

[0049] 3) Add the fine powder from step 2), the mixture from step 1), an appropriate amount of sucrose powder and dextrin (where the weight ratio of sucrose powder to dextrin is 5:1), and the weight of the two accounts for 60 - 80% of the total drug. Mix well, granulate, dry, and make 1000 g to obtain the granule.

[0050] Example 5: A traditional Chinese medicine capsule for treating delayed fracture healing, with the ingredients, dosages, and preparation method as follows:

[0051] 20 g of Trogopterus Dung, 20 g of Ardisia quinquegona Blume, 10 g of Notoginseng, 10 g of Drynaria rhizome, 7.8 g of Curcuma zedoaria, 12.5 g of Eucommia ulmoides, 15.5 g of Morinda officinalis, 5 g of Rubia cordifolia, 5.5 g of Red Peony Root, 1.5 g of Whitmania pigra Whitman, 1.5 g of Scorpio, 6.5 g of Platycodon grandiflorum, 10 g of Licorice Root, 7.5 g of Piper kadsura.

[0052] Preparation process:

[0053] 1) Grind Notoginseng, Whitmania pigra Whitman, and Scorpio into fine powder and set aside the mixture.

[0054] 2) Except for Notoginseng, Whitmania pigra Whitman, and Scorpio, decoct the remaining medicinal materials with water, filter the decoction, concentrate it to a thick paste with a relative density of 1.10 - 1.15 (40 °C), dry it, and pulverize it into fine powder.

[0055] 3) Add the fine powder from step 2), the mixture from step 1), an appropriate amount of sucrose powder and dextrin (where the weight ratio of sucrose powder to dextrin is 5:1), and the weight of the two accounts for 20 - 50% of the total drug. Mix well, granulate, dry, make 1000 g, and fill it into capsules to obtain the capsules.

[0056] Comparative Example 1: A traditional Chinese medicine capsule for treating delayed fracture healing, with the ingredients, dosages, and preparation method as follows:

[0057] 25 g of Carthamus tinctorius, 30 g of Prunus persica, 15 g of Notoginseng, 12 g of Drynaria rhizome, 10 g of Curcuma zedoaria, 15 g of Eucommia ulmoides, 12 g of Morinda officinalis, 8 g of Rubia cordifolia, 7 g of Red Peony Root, 3 g of Whitmania pigra Whitman, 3 g of Scorpio, 8 g of Platycodon grandiflorum, 15 g of Licorice Root, 10 g of Piper kadsura.

[0058] Preparation process: Decoct with water twice, filter, add Notoginseng powder, and stir evenly to obtain 300 ml of decoction.

[0059] Comparative Example 2: A traditional Chinese medicine decoction for treating delayed fracture healing, with the ingredients, dosages, and preparation method as follows:

[0060] 25 g of Trogopterus Dung, 30 g of Typha angustifolia, 15 g of Notoginseng, 12 g of Drynaria rhizome, 10 g of Curcuma zedoaria, 15 g of Eucommia ulmoides, 12 g of Morinda officinalis, 8 g of Rubia cordifolia, 7 g of Red Peony Root, 3 g of Whitmania pigra Whitman, 3 g of Scorpio, 8 g of Platycodon grandiflorum, 15 g of Licorice Root, 10 g of Piper kadsura.

[0061] Preparation process: Decoct with water twice, filter, add notoginseng powder, and stir evenly to obtain 300 ml of decoction.

[0062] Comparative Example 3: A traditional Chinese medicine decoction for treating delayed fracture healing, with the composition, dosage, and preparation method as follows:

[0063] Trogopterus dungarensis 25 g, Ardisia quinquegona Blume 30 g, Panax notoginseng 15 g, Drynaria fortunei (Kunze) J. Sm. 12 g, Curcuma zedoaria (Christm.) Rosc. 10 g, Eucommia ulmoides Oliv. 15 g, Morinda officinalis How 12 g, Rubia cordifolia L. 8 g, Paeonia lactiflora Pall. 7 g, Platycodon grandiflorus (Jacq.) A. DC. 8 g, Glycyrrhiza uralensis Fisch. 15 g, Piper kadsura (Choisy) Ohwi 10 g.

[0064] Preparation process: Decoct with water twice, filter, add notoginseng powder, and stir evenly to obtain 300 ml of decoction.

[0065] Comparative Example 4: A traditional Chinese medicine decoction for treating delayed fracture healing, with the composition, dosage, and preparation method as follows:

[0066] Trogopterus dungarensis 10 g, Ardisia quinquegona Blume 40 g, Panax notoginseng 5 g, Drynaria fortunei (Kunze) J. Sm. 20 g, Curcuma zedoaria (Christm.) Rosc. 5 g, Eucommia ulmoides Oliv. 20 g, Morinda officinalis How 12 g, Rubia cordifolia L. 18 g, Paeonia lactiflora Pall. 7 g, Hirudo nipponia Whitman 0.5 g, Scorpio 0.5 g, Platycodon grandiflorus (Jacq.) A. DC. 8 g, Glycyrrhiza uralensis Fisch. 15 g, Piper kadsura (Choisy) Ohwi 10 g.

[0067] Preparation process: Decoct with water twice, filter, add notoginseng powder, and stir evenly to obtain 300 ml of decoction.

[0068] Comparative Example 5: A traditional Chinese medicine decoction for treating delayed fracture healing, with the composition, dosage, and preparation method as follows:

[0069] Prunus persica (L.) Batsch 10 g, Carthamus tinctorius L. 6 g, Rehmannia glutinosa Libosch. 10 g, Paeonia lactiflora Pall. 10 g, Ligusticum wallichii Franch. 6 g, Eupolyphaga sinensis Walker 10 g, Pyritum 10 g, Dipsacus asperoides C. Y. Cheng et T. M. Ai 10 g, Hirudo nipponia Whitman 3 g, Spatholobus suberectus Dunn 15 g.

[0070] Preparation process: Decoct with water twice, filter, add notoginseng powder, and stir evenly to obtain 300 ml of decoction.

[0071] Comparative Example 6: A traditional Chinese medicine decoction for treating delayed fracture healing, with the composition, dosage, and preparation method as follows:

[0072] Trogopterus dungarensis 25 g, Ardisia quinquegona Blume 30 g, Panax notoginseng 15 g, Dipsacus asperoides C. Y. Cheng et T. M. Ai 15 g, Spatholobus suberectus Dunn 12 g, Curcuma zedoaria (Christm.) Rosc. 10 g, Eucommia ulmoides Oliv. 15 g, Morinda officinalis How 12 g, Plantago asiatica L. 8 g, Paeonia lactiflora Pall. 7 g, Hirudo nipponia Whitman 3 g, Scorpio 3 g, Schizonepeta tenuifolia Briq. 8 g, Saposhnikovia divaricata (Turcz.) Schischk. 15 g, Aurantii Fructus Immaturus 10 g, Glycyrrhiza uralensis Fisch. 20 g.

[0073] Preparation process: Decoct with water twice, filter, add notoginseng powder, and stir evenly to obtain 300 ml of decoction.

[0074] I. Clinical Experiments

[0075] 1. Basic information:

[0076] The inventor's unit of this application, the Affiliated Hospital of Shandong University of Traditional Chinese Medicine, has screened 68 patients with unsatisfactory fracture healing for clinical medication observation and treatment from May 2023 to the present. The age range is 25 - 47 years old, with an average age of 36.8 years. There are 34 male patients and 34 female patients, and all patients have fractures of the tibia and / or fibula.

[0077] 2. Diagnostic criteria:

[0078] Refer to the 6th edition of "Surgery" (edited by Wu Zhaide and Wu Zhaohan, People's Medical Publishing House, 2003) and adopt the Johner - Wruh fracture efficacy evaluation standard. See Table 1 for details.

[0079] Table 1 Johner - Wruh fracture efficacy evaluation standard

[0080]

[0081] 3. Grouping and treatment methods:

[0082] Randomly divided into 2 groups. There are no significant differences in age, condition, gender, etc. between the two groups (P > 0.05). Randomly divided into two groups, with 34 cases in the experimental group (17 males and 17 females); 34 cases in the observation group (17 males and 17 females). After closed reduction and percutaneous pinning internal fixation.

[0083] Experimental group: Oral administration of aspirin, and one dose (200 ml) of the decoction of Example 1 per day, taken orally in 2 divided doses, once in the morning and once in the evening. 15 days is one course of treatment, and an X - ray review is conducted 3 days after the end of 2 courses of treatment.

[0084] Control group: Adopt conventional oral administration of aspirin and placebo.

[0085] After statistical analysis, there are no significant differences in gender, age, and fracture site between the experimental group and the control group by statistical X 2 (chi - square test) (P > 0.05), and they are comparable.

[0086] 4. Detection methods and indicators:

[0087] 4.1. Johner - Wruh fracture efficacy evaluation standard scoring method

[0088] According to the Johner - Wruh fracture efficacy evaluation standard, let the patient state their own numerical value based on their own perceived characteristics, which is the score value. The higher the score value, the better the treatment effect.

[0089] 4.2. Clinical healing date

[0090] For patients with unsatisfactory fracture healing (deformation and pain still present 30 days after the fracture), if the fracture site remains unchanged after continuous observation for 2 weeks, the first day of observation is defined as the clinical healing date, marked as the number of days after the fracture occurred.

[0091] 4.3. Observe the growth of callus by X-ray

[0092] Anteroposterior and lateral radiographs of the fracture site were taken under the same conditions at the 1st week, 2nd week, and 4th week of treatment respectively to observe the growth of callus. Evaluation criteria: ① The fracture line is clearly visible and there is no obvious callus growth, scored 0 points; ② The fracture line is blurred and there is a small amount of callus growth, scored 1 point; ③ The fracture line is blurred and there is a moderate amount of callus growth, scored 1.5 points; ④ The fracture line disappears and there is continuous callus growth, scored 2 points.

[0093] 4.4. Efficacy diagnosis

[0094] Cured: Based on X-ray images, the fracture line is blurred, there is continuous callus passing through the fracture line, and the swelling and pain disappear.

[0095] The patient can move freely normally;

[0096] Markedly effective: Callus formation is obvious, surrounding the fracture end, the swelling and pain disappear, and the patient can move locally;

[0097] Ineffective: No callus formation or only a small amount of callus formation, and the swelling and pain are obvious.

[0098] Effective rate = (Cured + Markedly effective) / Number of cases in this group

[0099] 5. Statistical processing standard:

[0100] GraphPad Prism 6 software was used to perform statistical analysis on the obtained data. Measurement data were expressed as (x±s). One-way ANOVA was used for comparison among multiple groups, and independent sample T-test was used for comparison between two groups. P<0.05 was considered statistically significant.

[0101] 6. Results and conclusions

[0102] 6.1 Johner-Wruh fracture efficacy evaluation standard score

[0103] The statistical results and comparative treatments are as Figure 1 shown in Table 2

[0104] Table 2 Comparison of pain scores between two groups of patients

[0105]

[0106] Note: Compared with the control group, @ P < 0.05, @@P < 0.01; compared with before treatment, *P < 0.05,

[0107] **P < 0.01

[0108] Table 2 and Figure 1 It can be seen that there are significant differences between the two groups compared with before treatment (P < 0.01), indicating that both treatment methods are effective. Further, there are significant differences between the experimental group and the control group (P < 0.01), indicating that the treatment with traditional Chinese medicine has a better treatment effect than the existing technology.

[0109] 6.2 Clinical healing date:

[0110] Continuously observe the fracture site for 2 weeks without deformation, then the first day of observation is the clinical healing date, marked as the number of days. The specific treatment effects of the clinical healing date are shown in Table 3 and Figure 2 .

[0111] Table 4 Clinical healing date

[0112] Group Clinical healing date Experimental group <![CDATA[3.29±0.43 @@ > Control group 7.99±0.98

[0113] Note: Compared with the control group, @ P < 0.05, @@ P < 0.01;

[0114] Table 4 and Figure 2 It can be seen that there are significant differences in the clinical healing dates between the experimental group and the control group (P < 0.01).

[0115] 6.3 X-ray observation of callus growth

[0116] The statistical results and comparative treatments are as Figure 3 shown in Table 4

[0117] Table 4 X-ray observation of callus growth

[0118]

[0119]

[0120] Note: Compared with the control group, @ P < 0.05, @@ P < 0.01;

[0121] Table 3 and Figure 3 It can be seen that there are significant differences in the X-ray observation of callus growth between the experimental group and the control group. It can be seen that at the 2nd week, there are significant differences (P < 0.05); at the 3rd and 4th weeks, there are significant differences between the experimental group and the control group (P < 0.01). At the 4th week, the callus in the experimental group basically has continuous callus growth.

[0122] 6.4 Statistical Analysis of Treatment

[0123] Table 5 Statistical Analysis of Treatment

[0124] Group Cured Markedly effective Effective Ineffective Experimental group 17 12 4 1 Control group 6 11 10 7

[0125] As can be seen from Tables 1 - 3, after treatment, the pain sensation was significantly reduced, and there were significant differences in the clinical healing date and the callus growth observed by X - ray compared with the control group (P < 0.05). Further, Table 5 and Figure 4 show that through the treatment of Example 3 of the present invention, 17 patients in the experimental group were cured, 12 were markedly effective, 4 were effective, and 1 was ineffective; 6 patients in the control group were cured, 11 were markedly effective, 10 were effective, and 7 were ineffective.

[0126] Typical Clinical Studies:

[0127] 1) Patient Shuai, engaged in the food delivery industry, male, 37 years old. On September 2, 2024, he suffered fractures of the tibia and ankle of the lower leg due to trauma. On the morning of the second day, open reduction and internal fixation of the left tibial fracture was performed (Appendix Figure 8 A). On October 3, 2024, the X - ray review showed no effect on fracture healing. On November 2, 2024, the X - ray review showed unsatisfactory fracture healing (Appendix Figure 8 B), not meeting the expected requirements. On November 2, 2024, he was transferred to our department for treatment, and was given the decoction of Example 1 of the pharmaceutical composition of the present invention. One month later, the X - ray showed good fracture healing (Appendix Figure 8 C).

[0128] 2) Patient Yang, engaged in the food delivery industry, male, 34 years old. On October 1, 2024, due to rushing to deliver orders, he suffered a comminuted fracture of the right clavicle. On the second day, open fracture internal fixation was performed (Appendix Figure 9 A). On December 2, 2024, the clavicle fracture healing was poor after surgery (Appendix Figure 9 B), not meeting the expected requirements. On December 3, 2024, he was transferred to our department for outpatient treatment, and was given the decoction of Example 1 of the pharmaceutical composition of the present invention. One month later, the X - ray showed good fracture healing (Appendix Figure 9 C).

[0129] III. Pharmacological Experiments

[0130] To verify the use and mechanism of the traditional Chinese medicine composition of the present invention in the treatment of fracture healing, the inventors carried out relevant pharmacodynamic experimental studies. The following pharmacodynamic experiments only take some animal models as examples to verify the efficacy of the present invention. For other types of fracture healing mentioned in the present invention, the inventors also carried out relevant pharmacodynamic experiments, and the experimental results showed that they had the same or similar effects. Here, they will not be listed one by one. The following experimental studies were all carried out on the basis of the safety of the drug demonstrated by acute toxicity test and long-term toxicity test, and the administration doses in the experimental studies were all within the safe dose range.

[0131] 1. Modeling and grouping

[0132] Forty-five SPF-grade rats, 6-8 weeks old, with a body weight of 250±10 g, were randomly divided into 9 groups, with 5 rats in each group. The normal control group did not ligate the femoral artery and used the impact method to make a fracture model. The model control group, Examples 1-3 and Comparative Examples 1-5 groups ligated the femoral artery and used the impact method to make a femoral fracture model. Bilateral ovariectomy was performed in each group. After the operation, penicillin was routinely injected to prevent infection, the diet and activities were normal, and the wound was regularly disinfected with iodophor. X-rays were taken weekly to observe the fracture healing situation. After 4 weeks, delayed fracture healing could be observed, and a delayed fracture healing model was established. Another 5 rats were used as the normal control group.

[0133] 2. Group intervention

[0134] Each group was fed normally, and the decoctions of Examples 1-3 and Comparative Examples 1-5 groups were given. The normal control group and the model group were given the same amount of normal saline by gavage.

[0135] Dose control: The administration doses of each traditional Chinese medicine group were converted according to the body weight of humans and rats (human body weight 60 kg), and the equivalent dose ratio was 1:6.25. The daily adult dosage was 200 g. According to the equivalent coefficient, 2.08 g was given by gavage to 100 g rats. Each 100 g rat was given 2.08 mL by gavage every day, once in the morning and once in the evening, and the two gavage doses were the same. They were given by gavage for 8 weeks respectively (200 ml of the decoction is equivalent to 200 g); the model group and the normal control group were given the same dose of normal saline.

[0136] At the end of the experiment, the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate, and then X-rays and micro-CT were taken to observe the fracture line and callus conditions.

[0137] 3. Index detection

[0138] 3.1 Detect the contents of blood and urine calcium and phosphorus in the laboratory;

[0139] By detecting the indicators of blood and urine calcium and phosphorus, it can be determined whether the pharmaceutical composition of the present invention improves delayed fracture healing by regulating mineral metabolism (such as promoting calcium and phosphorus deposition). Abnormal blood calcium / phosphorus levels may indicate parathyroid dysfunction or vitamin D metabolism disorders, both of which can interfere with the callus mineralization process.

[0140] 3.2 Bone metabolism markers include bone formation markers (P1NP), bone resorption markers (β-CTX), and bone turnover markers (25-hydroxyvitamin D3). Observe the effects of the pharmaceutical composition of the present invention on the biochemistry and bone metabolism of rats with delayed fracture healing.

[0141] P1NP (procollagen type I N-terminal propeptide): Reflects osteoblast activity and bone formation efficiency. If P1NP increases, it indicates that the pharmaceutical composition of the present invention may promote bone matrix synthesis.

[0142] β-CTX (collagen type I carboxy-terminal telopeptide): Reflects osteoclast activity and the degree of bone resorption. A decrease in it can indicate that the drug inhibits excessive bone resorption and avoids callus degradation.

[0143] 25-hydroxyvitamin D3: The active form of vitamin D, which regulates calcium absorption and bone mineralization. Low levels are significantly associated with delayed fracture healing.

[0144] 3.3 Calculate the maximum load (N), maximum stress (Mpa), and maximum displacement (mm) to evaluate the effect of the prescription of the present invention on fracture healing in rats with delayed fracture healing.

[0145] Maximum load: The maximum external force borne by the fracture site, reflecting the overall healing quality.

[0146] Maximum stress: The force borne per unit area, reflecting the density and mineralization degree of the callus.

[0147] Maximum displacement: The deformation ability before fracture, indirectly evaluating the toughness of the callus.

[0148] 4. Statistical processing criteria

[0149] Use Graphpad prism 6.0 software to perform statistical analysis on the obtained data. Measurement data are expressed in One-way analysis of variance is used for comparison between multiple groups, and independent sample T-test is used for analysis between two groups. P < 0.05 is considered statistically significant.

[0150] 5. Result analysis

[0151] 5.1 Detection results of the contents of Ca and P in each example

[0152] Table 4 Detection results of the contents of Ca and P in each example

[0153]

[0154]

[0155] Note: Compared with the model group, @ P < 0.01; compared with Comparative Example 1, # P < 0.05, ## P < 0.01; compared with Comparative Example 2, *P < 0.05, **P < 0.01; compared with Comparative Example 3, a P < 0.05, aa P < 0.01; compared with Comparative Example 4, b P < 0.05, bb P < 0.01; compared with Comparative Example 5, c P < 0.05, cc P < 0.01.

[0156] It can be seen from Table 4 that compared with the normal control group, there were significant differences in Ca and P in rats after modeling (P < 0.01), indicating successful modeling. Compared with the model group, Examples 1-3 had the effect of significantly increasing the contents of Ca and P in rats, with significant differences (P < 0.05); compared with Comparative Examples 1-5, the contents of Ca and P in Example 3 were significantly increased, with significant differences (P < 0.05).

[0157] 5.2 Detection results of the contents of OCN, TRAP and Vitamin D in each example

[0158] Table 5 Detection results of the contents of OCN, TRAP and Vitamin D in each example

[0159]

[0160]

[0161] Note: Compared with the model group, @ P < 0.01; compared with Comparative Example 1, # P < 0.05, ## P < 0.01; compared with Comparative Example 2, *P < 0.05, ** P < 0.01; compared with Comparative Example 3, a P < 0.05, aa P < 0.01; compared with Comparative Example 4, b P < 0.05, bb P < 0.01; compared with Comparative Example 5, c P < 0.05, cc P < 0.01.

[0162] As can be seen from Table 5, compared with the normal control group, there were significant differences in the contents of OCN, TRAP, and Vitamin D between the model group (P < 0.01), indicating that the model was successfully established and the experiment could be carried out. Compared with Comparative Examples 1-5, there were no significant differences in OCN in Examples 1-3 (P > 0.05), while there were significant differences between Examples 1-3 and the model group. Compared with Comparative Examples 1-5 and the model group, there were significant differences in TRAP and Vitamin (P < 0.05 or P < 0.01). This shows that the therapeutic effect of the pharmaceutical composition of the present invention is better.

[0163] 5.3 Maximum load (N), maximum stress (Mpa), maximum displacement (mm)

[0164] Table 6 Detection of maximum load, maximum stress, and maximum displacement of each example

[0165]

[0166] Note: Compared with the model group, @ P < 0.01; compared with Comparative Example 1, # P < 0.05, ## P <

[0167] 0.01; compared with Comparative Example 2, *P < 0.05, ** P < 0.01; compared with Comparative Example 3, a P < 0.05, aa P < 0.01; compared with Comparative Example 4, bP < 0.05, bbP < 0.01; compared with Comparative Example 5, cP < 0.05, ccP < 0.01.

[0168] As shown in Table 6 and Figures 5 - 7 All indicators (maximum load, maximum stress, maximum displacement) of the model group were significantly lower than those of the normal control group (P < 0.01), indicating that the modeling was successful. Examples 1-3 were significantly superior to the model group and all Comparative Examples 1-5 in terms of maximum load and maximum stress (P < 0.01). In terms of maximum displacement, Example 1 was significantly higher than the model group (P < 0.01) and some Comparative Examples (P < 0.05 or P < 0.01), while Examples 2-3 were only partially significant (P < 0.05 or P < 0.01).

[0169] Compared with Examples 1-3, the effects of all indicators of Comparative Examples 1-5 were significantly worse (P < 0.01). In summary, the performance of Examples 1-3 (especially Example 1) was close to that of the normal control group, significantly superior to the model group and Comparative Examples 1-5, showing a good repair or therapeutic effect. This shows that the therapeutic effect of the pharmaceutical composition of the present invention is better.

Claims

1. A Chinese medicine composition for treating delayed fracture healing, characterized in that: The traditional Chinese medicine composition is prepared from the following raw materials: radix aconiti lobatae, rhizoma scabrae, notoginseng, rhizoma drynariae, zedoariae, eucommia bark, morinda officinalis, madder, red peony root, leech, scorpion, platycodon grandiflorum, liquorice and strychnos auriculatae.

2. The Chinese medicine composition as claimed in claim 1, comprising the following components: 15-25 weight parts of Ophiopogon japonicus, 10-30 weight parts of Rhizoma Cibotii, 5-15 weight parts of Radix Notoginseng, 8-12 weight parts of Rhizoma Drynariae, 5-10 weight parts of Curcuma, 10-15 weight parts of Eucommia ulmoides, 7-12 weight parts of Morinda officinalis, 2-8 weight parts of Rubia cordifolia, 4-7 weight parts of Paeonia lactiflora, 1-3 weight parts of Hirudo, 1-3 weight parts of Scorpio, 3-8 weight parts of Platycodon grandiflorum, 5-15 weight parts of Licorice, and 5-10 weight parts of Caulis Piperis d'Azuricae.

3. The Chinese medicine composition according to claim 1, comprising the following components: 20 weight parts of Ophiopogon japonicus, 20 weight parts of Rhizoma Cibotii, 10 weight parts of Panax notoginseng, 10 weight parts of Drynariae Rhizoma, 7.8 weight parts of Curcuma, 12.5 weight parts of Eucommia ulmoides, 15.5 weight parts of Morinda officinalis, 5 weight parts of Rubia cordifolia, 5.5 weight parts of Paeonia lactiflora, 1.5 weight parts of Leech, 1.5 weight parts of Scorpio, 6.5 weight parts of Platycodon grandiflorum, 10 weight parts of Licorice, and 7.5 weight parts of Caulis Piperis d'Israelii.

4. The Chinese medicine composition as claimed in claim 1, comprising the following components: 15 parts by weight of Rhizoma Cibotii, 10 parts by weight of Rhizoma Cibotii, 5 parts by weight of Rhizoma Notoginseng, 8 parts by weight of Rhizoma Drynariae, 5 parts by weight of Rhizoma Curcumae, 10 parts by weight of Eucommia ulmoides, 7 parts by weight of Morinda officinalis, 2 parts by weight of Rubia cordifolia, 4 parts by weight of Paeonia lactiflora, 1 part by weight of Hirudo, 1 part by weight of Scorpio, 3 parts by weight of Platycodon grandiflorum, 5 parts by weight of Radix Glycyrrhizae, and 5 parts by weight of Caulis Piperis dulse.

5. The Chinese medicine composition as claimed in claim 1, comprising the following components: 25 parts by weight of Rhizoma Cibotii, 30 parts by weight of Rhizoma Cibotii, 15 parts by weight of Radix Notoginseng, 12 parts by weight of Rhizoma Drynariae, 10 parts by weight of Rhizoma Curcumae, 15 parts by weight of Eucommia ulmoides, 12 parts by weight of Morinda officinalis, 8 parts by weight of Rubia cordifolia, 7 parts by weight of Paeonia lactiflora, 3 parts by weight of Hirudo, 3 parts by weight of Scorpio, 8 parts by weight of Platycodon grandiflorum, 15 parts by weight of Glycyrrhizae, and 10 parts by weight of Caulis Piperis d'Israelii.

6. The Chinese medicine composition as claimed in claim 1, wherein the Panax notoginseng is raw Panax notoginseng powder.

7. The Chinese medicine composition according to any one of claims 1 to 6, characterized in that: The Chinese medicine composition is prepared into a clinically acceptable preparation after being mixed with / without pharmaceutically acceptable excipients.

8. The Chinese medicine composition according to claim 7, characterized in that: The preparations include, but are not limited to, granules, capsules, tablets, oral liquids, mixtures, syrups, and decoctions, and are more preferably granules or decoctions.

9. The Chinese medicine composition according to claim 7, characterized in that: The pharmaceutical composition comprises a combination of the traditional Chinese medicine composition and / or chemical drugs and biological drugs as described in any one of claims 1 to 6; preferably, the chemical drugs and biological drugs are drugs for treating delayed fracture healing; more preferably, the chemical drugs are any one or more of teriparatide, abaparatide, zoledronic acid, and misoprostol. The Chinese medicine composition according to claim 6, characterized in that The Chinese medicine composition is directly prepared into a decoction, the volume of the decoction is 100-300 mL, the daily dosage is 100 mL-300 mL, and it is taken twice a day.

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