CN104587470A - 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
- Publication number
- CN104587470A CN104587470A CN201510088461.3A CN201510088461A CN104587470A CN 104587470 A CN104587470 A CN 104587470A CN 201510088461 A CN201510088461 A CN 201510088461A CN 104587470 A CN104587470 A CN 104587470A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- statins
- ketorolac tromethamine
- bone
- promote
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 medical art, be specifically related to a kind of for the pharmaceutical composition after fracture operation and promoting the application in osteoporotic fracture Postoperative Bone healing etc.
Background technology
Osteoporosis (osteoporosis, OP) be a kind of general bone metabolism disease, it is thinning with bone amount minimizing in unit volume, bone trabecula decreased number, cortical bone, osseous tissue fine structure destroys, medullary cavity is broadening, bone fragility increases and risk of fractures probability increases to feature, is commonly encountered diseases clinical at present, frequently-occurring disease.Fracture is the most serious consequence of osteoporosis, and phase compared with normal indolence after there is fracture.At present, the whole world about has more than 200,000,000 patients with osteoporosis, and account for 33% in the women of its fracture caused more than 50 years old, male is 20%.The medicine of traditional treatment osteoporosis has: anti-bone resorption medicine Diphosphonate, calcitonin, calcium vitamin D and metabolite thereof; The medicine of promoting bone growing---fluoride.
In recent years, have scholar to find under study for action, statins can reduce the loss of bone amount, the generation of prevention fracture and the healing of acceleration fracture.Statins is the inhibitor of 3-hydroxyl-3-methylglutaryl coenzyme A A, reduce the generation of cholesterol, interleukin product can be decomposed simultaneously, reduce the generation of cytokine, research finds statins also by promoting bone morphogenetic protein (bone morphogenetic protein2, BMP-2) gene expression, acting on osteoblast increases the mechanism such as the expression of Bone Gla protein (OPG) gene to reach increase bone amount, improves the object of bone density.
Although many research confirms that statins has ossification potential, but the drug level that systemic administration arrives osseous tissue is too low, limited (the von Stechow D of skeletonization effect, Fish S, Yahalom D, et al.Does simvastatinstimulate bone formation in vivo [J] BMC Musculoskelet Disord, 2003,4:8.); If increase dosage, then there will be unacceptable toxic and side effects.Drug combination is address this problem to provide new thinking (Abdul-Majeed S, Mohamed N, Soelaiman IN.Effects of tocotrienoland lovastatincombination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis [J] .EvidBased Complement Alternat Med, 2012,2012:960742.).
At present, treat osteoporosis or union of osteoportic fracture aspect at home and abroad, not yet find using statins and ketorolac tromethamine coupling as the medicine of main active.
Summary of the invention
Statins can be used for controlling raising bone density, but due to the drug level arriving osseous tissue after the administration of oral administration mode too low, and the toxic and side effects that heavy dose of administration brings, because which limit statins application in this respect.The present inventor is surprised to find that in clinical application, and fracture surgery adopts ketorolac tromethamine analgesic simultaneously, and it significantly can strengthen the curative effect that statins promotes the healing of osteoporotic fracture Postoperative Bone.
In further animal experiment research, after inventor finds significantly to reduce statins dosage, with ketorolac tromethamine drug combination, there is the synergism promoting that osteoporotic fracture Postoperative Bone heals.For this reason, the present inventor using ketorolac tromethamine with low dose of statins as active component, thus provide the low pharmaceutical composition of a kind of good effect, toxic and side effects and promoting the application in osteoporotic fracture Postoperative Bone healing etc.Its concrete technical scheme is as follows:
Promote the pharmaceutical composition that osteoporotic fracture Postoperative Bone heals, it contains statins and ketorolac tromethamine.Preferably, the active component of pharmaceutical composition described above is made up of statins and ketorolac tromethamine.
Further preferably, statins of the present invention is selected from one or more of simvastatin, lovastatin and Atorvastatin calcium.When described statins is simvastatin, the mass ratio of simvastatin and ketorolac tromethamine is (2-10): 1; The mass ratio of preferred simvastatin and ketorolac tromethamine is (4-6): 1.When described statins is lovastatin, the mass ratio of lovastatin and ketorolac tromethamine is (1-5): 1; The mass ratio of preferred lovastatin and ketorolac tromethamine is (2-3): 1.When described statins is Atorvastatin calcium, the mass ratio of Atorvastatin calcium and ketorolac tromethamine is (0.1-0.8): 1; The mass ratio of preferred Atorvastatin calcium and ketorolac tromethamine is (0.2-0.4): 1.
Have owing to being administered systemically to fracture Local delivery few, implement the advantages such as convenient and easy, therefore the pharmaceutical composition of promotion osteoporotic fracture Postoperative Bone healing of the present invention is oral formulations, and described oral formulations comprises tablet, capsule, granule, dry suspension, oral liquid.These oral formulations all on the basis of above-mentioned active component, can add adjuvant available on pharmaceutics, as included but are not limited to filler, disintegrating agent, lubricant, binding agent etc., are prepared from by the conventional formulation technique of this area.In the most preferred example of formulations of the present invention, the oral formulations described in per unit contains lovastatin 5mg, ketorolac tromethamine 2mg.
The present inventor selects castration osteoporosis model when animal experiment, this model is mainly used in the research of post menopausal and senile osteoporosis, natural life-span due to rat is 2 ~ 3 years, female rats entered osteogenesis resting stage 6 ~ 9 months time, after there are some researches show rat spay, 8-9 is all, and skeleton can occur that bone metabolism enlivens, and bone conversion strengthens, there is obvious bone loss in spongy bone, the biochemical indicator of bone density value and bone metabolism all goes out significance and changes.The bone loss state of height conversion type osteoporosis when this characteristic has imitated the normal menopause of people preferably, therefore, the female rats of castration is the ideal animals model of the research primary osteoporosis of generally acknowledging at present.Found by this test, the bone density of ovariectomized rat reduces, result of the test display ketorolac tromethamine significantly can strengthen low dose of statins increases bone amount, improve the effect of bone density, namely the bone loss that oophorectomize causes is offset, maintain close to normal thighbone density, thus at maintenance Bones morphology, improve in osteoplastic speed there is significant curative effect, and then promote that osteoporotic fracture Postoperative Bone heals.
Based on the result of animal experiment and clinical practice, two of object of the present invention is to provide the pharmaceutical applications of statins and ketorolac tromethamine; That is: 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; Or the compositions that statins and ketorolac tromethamine form is preparing the application in the medicine for the treatment of osteoporosis as active component; Or the compositions that statins and ketorolac tromethamine form is preventing and treating the application in the osteoporotic medicine of diabetics as active component.
In a word, pharmaceutical composition of the present invention adopts statins and ketorolac tromethamine use in conjunction, not only improves the bone amount of sufferers of osteoporosis face to a greater extent, also accelerates the healing of osteoporotic fracture on this basis, improve its mechanical property.In addition, decrease the using dosage of statins, thus the expense of patient medication is reduced, reduce the toxic and side effects of statins simultaneously, add the safety of medication and the compliance of patient.
Detailed description of the invention
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.It should be understood that described embodiment is only exemplary, any restriction is not formed to protection scope of the present invention.It will be understood by those skilled in the art that and do not departing under spirit of the present invention and can modify to the details of technical scheme and form or replace, but these amendments or replacement all fall into protection scope of the present invention.
Embodiment 1: lovastatin coupling ketorolac tromethamine is tested the impact of castration osteoporotic fracture model
Choose 7 monthly age cleaning grade SD rat 40, female, weight 280 ~ 320g, is divided into sham operated rats, model control group, lovastatin group, ketorolac tromethamine group, therapeutic alliance group at random, often organizes 8.
Except sham operated rats, other is group row bilateral ovaries enucleation respectively, and step is: by rat with 10% chloral hydrate by 2m1/kg weight intraperitoneal injection of anesthesia, after preserved skin, row abdominal cavity hits exactly stringer otch, be about 3cm, successively cut, expose abdominal visceral browser, find metraterm with aseptic cotton carrier respectively to both sides, excision is attached to the bilateral ovaries tissue of metraterm completely, and with silk thread by stump ligation, thoroughly stop blooding, return to receive after abdominal viscera and successively close otch.Postoperatively give penicillin 800,000 unit, intramuscular injection, 2 times/d, continuous 3d.
After bilateral ovaries enucleation, freely activity and feed 2 months, then respectively organize the sawed-off art of rats underwent femur, step is: then 10% chloral hydrate 2mL/kg intraperitoneal anesthesia, bilateral femur stage casing row stringer otch respectively, cuts skin, subcutaneous tissue and deep fascia, is separated and exposes femur in spatium intermusculare.Cut periosteum in femur mid point, walk crosswise sawed-off femur, fix with diameter 1.2mm intramedullary needle immediately, close otch successively.Postoperatively give penicillin 800,000 unit, intramuscular injection, 2 times/d, continuous 3d.
The sawed-off postoperative freely movable and feed of femur, sham operated rats and model control group give normal saline gavage by 2mL/kg simultaneously; Lovastatin group (Lov group) gavage gives lovastatin 10mg/kg; Ketorolac tromethamine group (Keto group) gavage gives ketorolac tromethamine 2mg/kg; Therapeutic alliance group (Lov-Keto group) gavage gives lovastatin 5mg/kg and ketorolac tromethamine 2mg/kg Combination intervention, equal every day 1 time.Continuous gavage gave corresponding tested material after 6 weeks, gets whole femur on the right side of each group of rat respectively, Dual-energy X-rays absorptionmetry measures bone mineral density of proximal femur.In addition, get the capable three-point bending test of right side femur of all rats, fulcrum span is 20mm, and central vertical (femur and load are at an angle of 90) imposed load, speed 10mm/min, directly obtains maximum load in software.
Bone density and the peak load of table 1 each group osteoporotic fracture rat model compare
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 group compares with Lov group,
$p < 0.05,
$ $p < 0.01;
Lov-Keto group compares with Keto group,
aMP.AMp.Ampp < 0.05,
aMP.AMp.Amp &p < 0.01.
Known by the result of the test of table 1, after administration terminates, the bone density of each group of osteoporotic fracture rat model and the display of peak load comparative result, compare with sham operated rats, bone density and the peak load of model control group significantly decline (P < 0.01), illustrate that castration osteoporosis model copies successfully; Compared with model control group, Keto group does not have a significant effect (P > 0.05) to the bone density of rat fracture and peak load, the peak load of Lov group and bone density have certain increase, but the increase of bone density does not have significant difference (P > 0.05); And the bone density of Lov-Keto group and peak load have the improvement of significance, no matter compare model control group or single medicine group (Lov group, Keto group), it all has significant difference (P < 0.05 or P < 0.01); This shows that lovastatin group coupling ketorolac tromethamine can the sedimentation rate of synergitic quickening bone ore deposit composition, improves bone density, thus promotes the healing of fracture.
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104587470A true CN104587470A (en) | 2015-05-06 |
| CN104587470B CN104587470B (en) | 2017-04-19 |
Family
ID=53113740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510088461.3A Expired - Fee Related CN104587470B (en) | 2015-02-26 | 2015-02-26 | Pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104587470B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105726532A (en) * | 2016-02-03 | 2016-07-06 | 张少峰 | Simvastatin composition and application thereof in preparation of medicine for treating osteoporotic fracture |
| CN106333977A (en) * | 2015-07-06 | 2017-01-18 | 陕西天奎生物医药科技有限公司 | Natural drug composition for treatment of osteoporotic fracture and/or osteoarthritis and application thereof |
| WO2023021514A1 (en) * | 2021-08-18 | 2023-02-23 | Orthotreat Ltd. | Composition of β-caryophyllene and a statin, and methods of using same |
-
2015
- 2015-02-26 CN CN201510088461.3A patent/CN104587470B/en not_active Expired - Fee Related
Non-Patent Citations (4)
| Title |
|---|
| HO ML,ET AL: "Effects of ketorolac on bone repair:A radiographic study in modeled demineralized bone matrix grafted rabbits", 《PHARMACOLOGY》 * |
| 张春玉等: "阿托伐他汀钙对糖尿病骨质疏松大鼠骨代谢的影响", 《中国临床康复》 * |
| 王建卫等: "辛伐他汀对大鼠骨质疏松性骨折愈合质量的影响", 《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》 * |
| 黄娅娟等: "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", 《临床急诊杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106333977A (en) * | 2015-07-06 | 2017-01-18 | 陕西天奎生物医药科技有限公司 | Natural drug composition for treatment of osteoporotic fracture and/or osteoarthritis and application thereof |
| 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 |
| WO2023021514A1 (en) * | 2021-08-18 | 2023-02-23 | Orthotreat Ltd. | Composition of β-caryophyllene and a statin, and methods of using same |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104587470B (en) | 2017-04-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8933028B2 (en) | Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue | |
| CN105263500A (en) | Bone-selective osteogenic oxysterol-bone targeting agents | |
| AU2022203758B2 (en) | Compositions and methods to promote bone formation | |
| Huang et al. | Combination therapy with BMP‑2 and psoralen enhances fracture healing in ovariectomized mice | |
| CN104587470A (en) | Pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of pharmaceutical composition | |
| Kimura et al. | Gelatin hydrogel as a carrier of recombinant human fibroblast growth factor-2 during rat mandibular distraction | |
| Yu et al. | Use of BMPs and bisphosphonates to improve bone fracture healing | |
| TWI382841B (en) | Pharmaceutical composition for inhibiting inflammation | |
| CN108653263B (en) | Application of chlorogenic acid and composition thereof in preparing medicine for treating sarcoma | |
| Park et al. | Effect of a selective estrogen receptor modulator on bone formation in osteoporotic spine fusion using an ovariectomized rat model | |
| CN100348207C (en) | Use of sea-buckthorn fruit oil and/or fruit slag oil in preparing medicine for treating osteoporosis | |
| Faraco-Schwed et al. | Removal torque analysis of implants in rabbit tibia after topical application of simvastatin gel | |
| WO2017019709A1 (en) | Composition and method for reducing scarring | |
| Bottai et al. | Use of teriparatide in preventing delayed bone healing in complex biosseous leg fracture: a case report | |
| CN110876766A (en) | Application of peony seed oil in preparation of medicines and health-care foods for improving biomechanical properties of male bones | |
| Love et al. | Mesenchymal stem cells enhance targeted bone growth from injectable hydrogels with BMP‐2 peptides | |
| WO2005074944A1 (en) | Use of sodium neridronate to promote new bone formation | |
| KR102451667B1 (en) | Formulation for regeneration of bone, cartilage, teeth, and periodontium and treatment of tumors and cysts | |
| Singh et al. | A Comparative Study to Evaluate the Role of Teriparatide in Post-Operative Intertrochanteric Fracture Healing | |
| CN113712953B (en) | Pharmaceutical composition for rapidly healing osteoporotic fracture | |
| JP2010275308A (en) | Agent for preventing forearm bone fracture, which comprises eldecalcitol | |
| Sallam | The influence of oral administration of simvastatin on delayed non-union facial fractures—clinical study | |
| Kim et al. | Effects of Yuhyangjeongtong-san on Fracture Healing in Rats | |
| RU2155588C2 (en) | Method for increasing bone tissue mass in fracture cases | |
| Zahid et al. | Efficacy of Bisphosphonates and Recombinant Parathyroid Hormone in Treatment of Osteoporosis in Pakistan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170419 |