CN104587470A - Pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of pharmaceutical composition - Google Patents

Abstract

The invention discloses a pharmaceutical composition for promoting bone healing after osteoporotic fracture and its application. The pharmaceutical composition contains statins and ketorolac trometamol, and the statins are selected from octyl One or more of vastatin, lovastatin and atorvastatin calcium. The invention not only improves the bone mass of osteoporosis patients to a greater extent, but also accelerates the healing of osteoporotic fractures and improves their mechanical properties.

Description

A pharmaceutical composition for promoting postoperative bone healing of osteoporotic fracture and its application

technical field

The invention belongs to the technical field of medicine, and in particular relates to a pharmaceutical composition for fracture operation and its application in promoting bone healing after osteoporotic fracture operation and the like.

Background technique

Osteoporosis (OP) is a systemic bone metabolic disease characterized by decreased bone mass per unit volume, decreased number of trabecular bone, thinning of cortical bone, destruction of fine structure of bone tissue, widening of bone marrow cavity, and bone loss. It is characterized by increased fragility and increased risk of fracture, and is a common and frequently-occurring disease in clinical practice. Fractures are the most serious consequence of osteoporosis, and fractures heal more slowly than normal. At present, there are more than 200 million osteoporosis patients in the world, and the fractures caused by it account for 33% of women over the age of 50 and 20% of men. Traditional drugs for the treatment of osteoporosis include: anti-bone resorptive drugs bisphosphonates, calcitonin, calcium vitamin D and their metabolites; drugs that promote bone formation - fluoride.

In recent years, some scholars have found in research that statins can reduce bone loss, prevent fractures and accelerate fracture healing. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A, which can reduce the production of cholesterol, and at the same time can decompose interleukin products and reduce the production of cytokines. Studies have found that statins can also promote bone morphology. The gene expression of bone morphogenetic protein 2 (BMP-2) acts on osteoblasts to increase the expression of osteocalcin (OPG) gene and other mechanisms to increase bone mass and improve bone density.

Although many studies have confirmed that statins have osteogenic potential, the concentration of drugs reaching bone tissue after systemic administration is too low, and the osteogenic effect is limited (von Stechow D, Fish S, Yahalom D, et al. Does simvastatinstimulate bone formation in vivo[J]BMC Musculoskelet Disord,2003,4:8.); if the dosage is increased, unacceptable toxic and side effects will occur. Combined medication provides a new idea to solve this problem (Abdul-Majeed S, Mohamed N, Soelaiman IN. Effects of tocotrienoland lovastatin combination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis[J]. EvidBased Complement Alternat Med, 2012, 2012 :960742.).

At present, in terms of the treatment of osteoporosis or osteoporotic fracture healing at home and abroad, no therapeutic drug with the combination of statins and ketorolac tromethamine as the main active ingredients has been found.

Contents of the invention

Statins can be used to treat and improve bone density, but the drug concentration reaching bone tissue after oral administration is too low, and the toxic and side effects caused by high-dose administration limit the application of statins in this area. The present inventors unexpectedly found in clinical medication that ketorolac tromethamine can significantly enhance the curative effect of statins on promoting bone healing after osteoporotic fracture while it is used for analgesia after fracture surgery.

In a further animal test study, the inventors found that after the dose of statins was greatly reduced, the combination of statins and ketorolac tromethamine had a synergistic effect on promoting bone healing after osteoporotic fracture surgery. For this reason, the present inventor uses ketorolac tromethamine and a small dose of statins as active components, thereby providing a pharmaceutical composition with good curative effect and low toxic and side effects and its role in promoting osteoporotic fracture surgery. Applications in posterior bone healing, etc. Its specific technical scheme is as follows:

A pharmaceutical composition for promoting postoperative bone healing of osteoporotic fractures, which contains statins and ketorolac trometamol. Preferably, the active ingredients of the pharmaceutical composition as described above consist of statins and ketorolac trometamol.

Further preferably, the statin drugs described in the present invention are selected from one or more of simvastatin, lovastatin and atorvastatin calcium. When the statins are simvastatin, the mass ratio of simvastatin and ketorolac tromethamine is (2-10): 1; the quality of simvastatin and ketorolac tromethamine is preferred The ratio is (4-6):1. When the statin is lovastatin, the mass ratio of lovastatin and ketorolac tromethamine is (1-5): 1; the mass of lovastatin and ketorolac tromethamine is preferred The ratio is (2-3):1. When the statin is atorvastatin calcium, the mass ratio of atorvastatin calcium to ketorolac tromethamine is (0.1-0.8): 1; preferably atorvastatin calcium and ketorolac The mass ratio of tromethamine is (0.2-0.4):1.

Since systemic administration has the advantages of less local intervention on fractures, convenient implementation, etc., the pharmaceutical composition for promoting bone healing after osteoporotic fractures of the present invention is an oral preparation, and the oral preparation includes tablets, Capsules, granules, dry suspension, oral liquid. These oral preparations can be prepared by adding pharmaceutically available excipients, such as but not limited to fillers, disintegrants, lubricants, binders, etc. become. In the most preferred formulation embodiment of the present invention, each unit of the oral formulation contains 5 mg of lovastatin and 2 mg of ketorolac tromethamine.

The present inventor selects castration osteoporosis model for use in animal experiment, and this model is mainly used in the research of postmenopausal and senile osteoporosis, because the natural lifespan of rat is 2～3 years, female rat is 6 years old. At ~9 months, it enters the quiescent period of bone growth. Studies have shown that 8-9 weeks after ovariectomy in rats, the bone metabolism will be active, the bone turnover will be enhanced, and the cancellous bone will have obvious bone loss. The biochemical indexes of bone metabolism all showed significant changes. This feature better imitates the bone loss state of high turnover osteoporosis during normal menopause. Therefore, castrated female rats are currently recognized as an ideal animal model for primary osteoporosis. Through this experiment, it was found that the bone density of ovariectomized rats decreased. The test results showed that ketorolac tromethamine can significantly enhance the effect of low-dose statins on increasing bone mass and improving bone density, that is, to offset the bone mass caused by ovariectomy Loss, maintain close to normal femoral bone density, thus has a significant effect on maintaining bone shape, increasing the rate of bone formation, and then promote bone healing after osteoporotic fracture.

Based on the results of animal experiments and clinical applications, the second object of the present invention is to provide the pharmaceutical use of statins and ketorolac tromethamine; that is: the composition of statins and ketorolac tromethamine as Application of the active ingredient in the preparation of a drug for promoting bone healing after osteoporotic fracture; or, a composition composed of statins and ketorolac tromethamine as an active ingredient in the preparation of a drug for treating osteoporosis or the application of a composition composed of statins and ketorolac tromethamine as an active ingredient in a drug for preventing and treating osteoporosis in diabetic patients.

In a word, the pharmaceutical composition of the present invention adopts the joint application of statins and ketorolac tromethamine, which not only improves the bone mass of patients with osteoporosis to a greater extent, but also accelerates the rate of osteoporotic fractures on this basis. healing and improve its mechanical properties. In addition, the dosage of statins is reduced, thereby reducing the cost of medication for patients, reducing the toxic and side effects of statins, and increasing the safety of medication and compliance of patients.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments, and the advantages and characteristics of the present invention will become clearer along with the description. However, it should be understood that the embodiments are only exemplary and do not constitute any limitation to the protection scope of the present invention. Those skilled in the art should understand that the details and forms of the technical solution can be modified or replaced without departing from the spirit of the present invention, but these modifications or replacements all fall within the protection scope of the present invention.

Example 1: Effect test of lovastatin combined with ketorolac tromethamine on castrated osteoporotic fracture model

Select 40 7-month-old clean-grade SD rats, female, with a body weight of 280-320 g, and randomly divide them into a sham operation group, a model control group, a lovastatin group, a ketorolac tromethamine group, and a combined treatment group. Group of 8.

Except for the sham operation group, the other groups underwent bilateral ovariectomy. The procedure was as follows: the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate at a weight of 2m1/kg body weight, and a median longitudinal incision was made in the abdominal cavity after skin preparation. 3cm, incision layer by layer, to expose the internal organs of the abdominal cavity, use sterile cotton swabs to find the end of the uterus on both sides, completely resect the bilateral ovarian tissue attached to the end of the uterus, and ligate the stump with silk thread to stop the bleeding completely, and put it back into the abdominal cavity The incision was closed layer by layer behind the viscera. After the operation, 800,000 units of penicillin was given intramuscularly, twice a day for 3 consecutive days.

After bilateral ovariectomies, free movement and eating for 2 months, and then rats in each group were subjected to femoral sawing, the steps are: then 10% chloral hydrate 2mL/kg intraperitoneal anesthesia, bilateral femur mid-section longitudinal incision , cut the skin, subcutaneous tissue and deep fascia, separate and expose the femur in the intermuscular space. The periosteum was incised at the midpoint of the femur, the femur was sawed transversely, and then fixed with a 1.2mm diameter intramedullary nail, and the incisions were closed in turn. After the operation, 800,000 units of penicillin was given intramuscularly, twice a day for 3 consecutive days.

After femur sawing, free activities and eating, at the same time, the sham operation group and the model control group were given normal saline at 2 mL/kg; the lovastatin group (Lov group) was given lovastatin 10 mg/kg; The butanetriol group (Keto group) was given 2 mg/kg of ketorolac tromethamine by intragastric administration; kg joint intervention, once a day. After continuous intragastric administration of the corresponding test substances for 6 weeks, the right complete femurs of the rats in each group were collected, and the bone density of the proximal femur was measured on a dual-energy X-ray absorptiometry. In addition, three-point bending experiments were performed on the right femurs of all rats. The fulcrum span was 20 mm, and the central load was applied vertically (the femur was at an angle of 90° to the load) at a rate of 10 mm/min. The maximum load was obtained directly in the software.

Table 1 Comparison of bone mineral density and maximum load of osteoporotic fracture model rats in each group

Compared with the model control group and the sham operation group, ^* P<0.05, ^** P<0.01;

Comparing each administration group with the model control group, ^# P<0.05, ^## P<0.01;

Compared between Lov-Keto group and Lov group, ^$ P<0.05, ^$$ P<0.01;

Compared between Lov-Keto group and Keto group, ^& P<0.05, ^&& P<0.01.

It can be seen from the test results in Table 1 that after the administration, the bone mineral density and maximum load comparison results of the osteoporotic fracture model rats in each group showed that compared with the sham operation group, the bone mineral density and maximum load of the model control group were greatly increased. decreased (P<0.01), indicating that the ovariectomized osteoporosis model was replicated successfully; compared with the model control group, the Keto group had no significant effect on the bone mineral density and maximum load at the fracture site of the rats (P>0.05), and the maximum load of the Lov group There was a certain increase in load and bone mineral density, but there was no statistical difference in the increase of bone mineral density (P>0.05); while the bone mineral density and maximum load of the Lov-Keto group were significantly improved, no matter compared with the model control group or the single Drug groups (Lov group, Keto group), there were significant differences (P<0.05 or P<0.01); this shows that lovastatin group combined with ketorolac trometamol can synergistically accelerate bone mineral composition Deposition rate, increase bone density, thereby promoting fracture healing.

Claims (10)

1. promote to it is characterized in that the pharmaceutical composition that osteoporotic fracture Postoperative Bone heals, described pharmaceutical composition contains statins and ketorolac tromethamine.

2. promote the pharmaceutical composition of osteoporotic fracture Postoperative Bone healing according to claim 1, it is characterized in that, described statins is selected from one or more of simvastatin, lovastatin and Atorvastatin calcium.

3. promote the pharmaceutical composition of osteoporotic fracture Postoperative Bone healing according to claim 2, it is characterized in that, described statins is simvastatin, and the mass ratio of simvastatin and ketorolac tromethamine is (2-10): 1.

4. promote the pharmaceutical composition of osteoporotic fracture Postoperative Bone healing according to claim 2, it is characterized in that, described statins is lovastatin, and the mass ratio of lovastatin and ketorolac tromethamine is (1-5): 1.

5. promote the pharmaceutical composition of osteoporotic fracture Postoperative Bone healing according to claim 2, it is characterized in that, described statins is Atorvastatin calcium, and the mass ratio of Atorvastatin calcium and ketorolac tromethamine is (0.1-0.8): 1.

6. according to any one of claim 1-5, promote the pharmaceutical composition that osteoporotic fracture Postoperative Bone heals, it is characterized in that, it is oral formulations, and described oral formulations comprises tablet, capsule, granule, dry suspension, oral liquid.

7. promote the pharmaceutical composition of osteoporotic fracture Postoperative Bone healing according to claim 6, it is characterized in that, the oral formulations described in per unit contains lovastatin 5mg, ketorolac tromethamine 2mg.

8. the compositions that statins and ketorolac tromethamine form is preparing the application in the medicine promoting that osteoporotic fracture Postoperative Bone heals as active component.

9. the compositions that statins and ketorolac tromethamine form is preparing the application in the medicine for the treatment of osteoporosis as active component.

10. the compositions that statins and ketorolac tromethamine form is preventing and treating the application in the osteoporotic medicine of diabetics as active component.