CN104587470B - Pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of pharmaceutical composition - Google Patents
Pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of pharmaceutical composition Download PDFInfo
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- CN104587470B CN104587470B CN201510088461.3A CN201510088461A CN104587470B CN 104587470 B CN104587470 B CN 104587470B CN 201510088461 A CN201510088461 A CN 201510088461A CN 104587470 B CN104587470 B CN 104587470B
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- statinses
- pharmaceutical composition
- ketorolac tromethamine
- knitting
- lovastatin
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Abstract
The invention discloses a pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of the pharmaceutical composition. The pharmaceutical composition comprises statins and ketorolac tromethamine, wherein the statins are selected from one or more of simvastatin, lovastatin and atorvastatin. The pharmaceutical composition has the advantages of improving the bone mass of osteoporosis patients to a greater extent and accelerating the healing of osteoportic fracture to improve the mechanical property.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of pharmaceutical composition for after fracture operation and its promoting
Enter the application of the aspects such as the postoperative knitting of osteoporotic fracture.
Background technology
Osteoporosis (osteoporosis, OP) are a kind of general bone metabolism diseases, and it is with bone amount in unit volume
Reduce, bone trabecula number is reduced, cortical bone is thinning, osseous tissue fine structure is destroyed, medullary cavity is broadening, bone fragility increases and is fractured
Dangerous probability increase is characterized, and is current clinical commonly encountered diseases, frequently-occurring disease.Fracture is osteoporosis most serious consequence, and is sent out
Normal indolence is compared after bone growth promoting folding.At present, the whole world about has more than 200,000,000 patients with osteoporosis, fracture caused by its institute
33% is accounted in women more than 50 years old, male is 20%.The medicine of traditional treatment osteoporosis has：Anti- bone resorption medicine is double
Phosphate, calcitonin, calcium vitamin D and its metabolite；The medicine of promoting bone growing --- fluoride.
In recent years, have scholar to find under study for action, statinses can reduce the loss of bone amount, prevent the generation of fracture with
And the healing of acceleration fracture.Statinses are the inhibitor of 3-hydroxyl-3-methylglutaryl coenzyme A A, reduce the life of cholesterol
Into, while interleukin product can be decomposed, the generation of cytokine being reduced, research finds that statinses can also be by promoting
The gene expression of bone morphogenetic protein (bone morphogenetic protein2, BMP-2), acts on osteoblast increasing
Plus the mechanism such as the expression of Bone Gla protein (OPG) gene is reaching increase bone amount, improve the purpose of bone density.
Although many research confirms that statinses have ossification potential, systemic administration reaches the medicine of osseous tissue
Thing concentration is too low, and skeletonization effect is limited (von Stechow D, Fish S, Yahalom D, et al.Does simvastatin
stimulate bone formation in vivo[J]BMC Musculoskelet Disord,2003,4:8.)；If increased
Plus dosage, then unacceptable toxic and side effects occur.Drug combination provides new thinking 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] .Evid Based Complement Alternat Med, 2012,2012:960742.).
At present, osteoporosis or union of osteoportic fracture aspect are at home and abroad treated, is not yet found with Statins
Medicine is combined the medicine as main active with ketorolac tromethamine.
The content of the invention
Statinses can be used to controlling raising bone density, but it is dense that the medicine of osseous tissue is reached after being administered due to mode by oral administration
Low, and toxic and side effects that heavy dose of administration brings are spent, therefore limits statinses application in this respect.The present inventor
It was unexpectedly observed that while fracture surgery is eased pain using ketorolac tromethamine, it can significantly increase statin in clinical application
Class medicine promotes the curative effect of the postoperative knitting of osteoporotic fracture.
In the research of further animal experiment, inventor has found to be greatly lowered after statinses dosage, coughs up with ketone
Sour trometamol drug combination has the synergism for promoting the postoperative knitting of osteoporotic fracture.For this purpose, the present inventor with
Ketorolac tromethamine with low dose statinses as active component, so as to provide a kind of good effect, toxic and side effects
Low pharmaceutical composition and its in the application for promoting the aspects such as the postoperative knitting of osteoporotic fracture.Its specific technical scheme
It is as follows：
A kind of pharmaceutical composition for promoting the postoperative knitting of osteoporotic fracture, it contains statinses and ketorolac
Trometamol.Preferably, the active component of pharmaceutical composition as described above is made up of statinses and ketorolac tromethamine.
It is further preferred that statinses of the present invention are selected from simvastatin, lovastatin and atorvastatin
One or more of calcium.When described statinses are simvastatins, the quality of simvastatin and ketorolac tromethamine
Than for (2-10)：1；It is preferred that simvastatin is (4-6) with the mass ratio of ketorolac tromethamine：1.When described statinses
When being lovastatin, lovastatin is (1-5) with the mass ratio of ketorolac tromethamine：1；It is preferred that lovastatin and Ketoralac ammonia
The mass ratio of butantriol is (2-3)：1.When described statinses are Atorvastatin calciums, Atorvastatin calcium is coughed up with ketone
The mass ratio of sour trometamol is (0.1-0.8)：1；It is preferred that Atorvastatin calcium is with the mass ratio of ketorolac tromethamine
(0.2-0.4)：1.
There is, therefore of the present invention rush few, easy to implement easy to Local delivery of fracturing due to being administered systemically
The pharmaceutical composition for entering the postoperative knitting of osteoporotic fracture is oral formulations, and described oral formulations include tablet, capsule
Agent, granule, dry suspension, oral liquid.These oral formulations can add pharmaceuticss on the basis of above-mentioned active component
Upper available adjuvant, such as includes but are not limited to filler, disintegrating agent, lubricant, binding agent, by the routine system of this area
Agent technique is prepared from.In most preferably example of formulations of the invention, the oral formulations described in per unit contain Lip river and cut down him
Spit of fland 5mg, ketorolac tromethamine 2mg.
The present inventor selects castration osteoporosis model, this model to be mainly used in post menopausal and old age in animal experiment
Property osteoporosis research, due to rat natural life-span be 2～3 years, female rats at 6～9 months enter osteogenesis
Resting stage, there are some researches show that 8-9 is all after rat excision ovary, skeleton may occur in which that bone metabolism is enlivened, and bone conversion strengthens, spongy bone
The biochemical indicator for obvious bone loss, bone density value and bone metabolism occur goes out and significantly sexually revises.This characteristic is preferably
The bone loss state of high conversion type osteoporosis when having imitated people's normal menopause, therefore, the female rats of castration are current public affairs
The ideal animals model of the research primary osteoporosis recognized.Found by this test, the bone density of ovariectomized rat is reduced,
Result of the test shows that ketorolac tromethamine can significantly increase low dose of statinses and increase bone amount, improves the effect of bone density
Really, that is, bone loss caused by ovary excision is offset, is maintained Jie Jin normal thighbone density, so as to maintaining Bones morphology, improving
Osteoplastic speed aspect has significant curative effect, and then promotes the postoperative knitting of osteoporotic fracture.
Based on animal experiment and the result of clinical practice, the second object of the present invention is to provide statinses and ketorolac
The pharmaceutical applications of trometamol；I.e.：Statinses are being made with the compositionss of ketorolac tromethamine composition as active component
For the application in the medicine for promoting the postoperative knitting of osteoporotic fracture；Or, statinses and ketorolac tromethamine
Application of the compositionss of composition as active component in the medicine for preparing treatment osteoporosis；Or, statinses with
Application of the compositionss of ketorolac tromethamine composition as active component in the osteoporotic medicine of preventing and treating diabeticss.
In a word, pharmaceutical composition of the invention adopts statinses and ketorolac tromethamine use in conjunction, not only more
The bone amount of sufferers of osteoporosis face is improve to limits, the healing of osteoporotic fracture is also accelerated on this basis, improved
Its mechanical property.In addition, the using dosage of statinses is reduced, so that the expense of patient medication is reduced, while reducing
The toxic and side effects of statinses, increased the safety of medication and the compliance of patient.
Specific embodiment
Further describe the present invention with reference to specific embodiment, advantages of the present invention and feature will be with description and
It is apparent.It should be understood that the embodiment is only exemplary, any restriction is not constituted to protection scope of the present invention.This
Art personnel should be understood that the details of technical scheme and form can be carried out without departing from the spirit of the invention
Modification is replaced, but these modifications or replacement each fall within protection scope of the present invention.
Embodiment 1：Lovastatin is combined impact test of the ketorolac tromethamine to castration osteoporotic fracture model
7 monthly age cleaning grade SD rats 40 are chosen, female, 280～320g of weight is randomly divided into sham operated rats, model
Matched group, lovastatin group, ketorolac tromethamine group, therapeutic alliance group, 8 per group.
In addition to sham operated rats, other each group row bilateral ovaries enucleation, step is：Rat is pressed with 10% chloral hydrate
2m1/kg weight intraperitoneal injection of anesthesia, row abdominal cavity center stringer otch, is about 3cm after preserved skin, successively cuts, and exposes intraperitoneal
Internal organs, metraterm is found with aseptic cotton carrier to both sides respectively, and excision completely is attached to the bilateral ovaries tissue of metraterm, and
Stump is ligatured with silk thread, thoroughly hemostasis, return to receive and successively close otch after abdominal viscera.It is postoperative to give the unit of penicillin 800,000,
Intramuscular injection, 2 times/d, continuous 3d.
After bilateral ovaries enucleation, freedom is movable and takes food 2 months, then the sawed-off art of each group rats underwent femur, and step is：
Then 10% chloral hydrate 2mL/kg intraperitoneal anesthesias, bilateral femur stage casing row stringer otch respectively, cut skin, subcutaneous tissue and
Deep fascia, separates exposure femur in spatium intermusculare.Periosteum is cut in femur midpoint, the sawed-off femur of row uses immediately diameter 1.2mm
Intramedullary needle is fixed, and otch is closed successively.It is postoperative to give the unit of penicillin 800,000, intramuscular injection, 2 times/d, continuous 3d.
The sawed-off postoperative freely activity of femur and feed, while sham operated rats and model control group give physiology salt by 2mL/kg
Water gavage；Lovastatin group (Lov groups) gavage gives lovastatin 10mg/kg；Ketorolac tromethamine group (Keto groups) gavage
Give ketorolac tromethamine 2mg/kg；Therapeutic alliance group (Lov-Keto groups) gavage gives lovastatin 5mg/kg and ketorolac
Trometamol 2mg/kg Combination interventions, once a day.After continuous gavage gives corresponding tested material 6 weeks, each group Rat Right is taken respectively
Side whole femur, determines bone mineral density of proximal femur on Dual-energy X-rays absorptionmetry.In addition, taking the right side femur row of all rats
Three-point bending test, fulcrum span is 20mm, central vertical (femur with load at an angle of 90) imposed load, speed 10mm/min,
Maximum load is directly obtained in software.
The bone density and peak load of each group osteoporotic fracture rat model of table 1 compares
Model control group compares with sham operated rats,*P ＜ 0.05,**P ＜ 0.01；
Each administration group compares with model control group,#P ＜ 0.05,##P ＜ 0.01；
Lov-Keto groups compare with Lov groups,$P ＜ 0.05,$$P ＜ 0.01；
Lov-Keto groups compare with Keto groups,&P ＜ 0.05,&&P ＜ 0.01.
By the result of the test of table 1, after administration terminates, the bone density of each group osteoporotic fracture rat model and
Peak load comparative result shows, compares with sham operated rats that the bone density and peak load of model control group significantly decline (P
＜ 0.01), illustrate that castration osteoporosis model is replicated successfully；Compared with model control group, bone of the Keto groups to rat fracture
Density and peak load have not significant impact (P ＞ 0.05), and the peak load and bone density of Lov groups have certain increase, but bone
The increase of density does not have significant difference (P ＞ 0.05)；And the bone density and peak load of Lov-Keto groups have significance
Improve, either compare model control group or single medicine group (Lov groups, Keto groups), it there are significant difference (P ＜ 0.05 or P
＜ 0.01)；This show lovastatin group combination ketorolac tromethamine can with it is synergitic quickening bone ore deposit composition sedimentation rate,
Bone density is improved, so as to the healing for promoting to fracture.
Claims (9)
1. a kind of pharmaceutical composition for promoting the postoperative knitting of osteoporotic fracture, it is characterised in that described drug regimen
Thing contains statinses and ketorolac tromethamine, and described statinses are selected from simvastatin, lovastatin and atropic
Cut down statin calcium one or more.
2. the pharmaceutical composition of the postoperative knitting of osteoporotic fracture is promoted according to claim 1, it is characterised in that institute
The statinses stated are simvastatins, and simvastatin is (2-10) with the mass ratio of ketorolac tromethamine：1.
3. the pharmaceutical composition of the postoperative knitting of osteoporotic fracture is promoted according to claim 1, it is characterised in that institute
The statinses stated are lovastatins, and lovastatin is (1-5) with the mass ratio of ketorolac tromethamine：1.
4. the pharmaceutical composition of the postoperative knitting of osteoporotic fracture is promoted according to claim 1, it is characterised in that institute
The statinses stated are Atorvastatin calciums, and Atorvastatin calcium is (0.1-0.8) with the mass ratio of ketorolac tromethamine：
1。
5. the pharmaceutical composition of the postoperative knitting of osteoporotic fracture is promoted according to any one of claim 1-4, and it is special
Levy and be, it is oral formulations, described oral formulations include tablet, capsule, granule, dry suspension, oral liquid.
6. the pharmaceutical composition of the postoperative knitting of osteoporotic fracture is promoted according to claim 5, it is characterised in that every
Oral formulations described in one unit contain lovastatin 5mg, ketorolac tromethamine 2mg.
7. statinses are preparing promotion osteoporotic with the compositionss of ketorolac tromethamine composition as active component
Application in the medicine of fracture surgery knitting, described statinses cut down him selected from simvastatin, lovastatin and atropic
One or more of spit of fland calcium.
8. statinses are preparing treatment osteoporosis with the compositionss of ketorolac tromethamine composition as active component
Medicine in application, the one kind or many of described statinses selected from simvastatin, lovastatin and Atorvastatin calcium
Kind.
9. statinses are preparing preventing and treating diabeticss with the compositionss of ketorolac tromethamine composition as active component
Application in osteoporotic medicine, described statinses are selected from simvastatin, lovastatin and Atorvastatin calcium
One or more.
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| CN201510088461.3A CN104587470B (en) | 2015-02-26 | 2015-02-26 | Pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of pharmaceutical composition |
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| CN106333977B (en) * | 2015-07-06 | 2020-02-21 | 陕西天奎生物医药科技有限公司 | Natural pharmaceutical composition for treating osteoporotic fracture and/or osteoarthritis and application thereof |
| CN105726532A (en) * | 2016-02-03 | 2016-07-06 | 张少峰 | Simvastatin composition and application thereof in preparation of medicine for treating osteoporotic fracture |
| CA3228809A1 (en) * | 2021-08-18 | 2023-02-23 | Orthotreat Ltd. | Composition of ?-caryophyllene and a statin, and methods of using same |
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Non-Patent Citations (4)
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| Effects of ketorolac on bone repair:A radiographic study in modeled demineralized bone matrix grafted rabbits;Ho ML,et al;《Pharmacology》;19980930;第57卷(第3期);第148-159页 * |
| 辛伐他汀对大鼠骨质疏松性骨折愈合质量的影响;王建卫等;《2006年浙江省骨科学术会议暨浙江省脊柱脊髓学术会议论文汇编》;20061031;第11页 * |
| 酮咯酸氨丁三醇不同给药途径用于骨折后疼痛治疗的疗效观察;黄娅娟等;《临床急诊杂志》;20101231;第11卷(第6期);第345-347页 * |
| 阿托伐他汀钙对糖尿病骨质疏松大鼠骨代谢的影响;张春玉等;《中国临床康复》;20030705;第7卷(第15期);第2138-2139页 * |
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