CN105726532A - Simvastatin composition and application thereof in preparation of medicine for treating osteoporotic fracture - Google Patents
Simvastatin composition and application thereof in preparation of medicine for treating osteoporotic fracture Download PDFInfo
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- CN105726532A CN105726532A CN201610073825.5A CN201610073825A CN105726532A CN 105726532 A CN105726532 A CN 105726532A CN 201610073825 A CN201610073825 A CN 201610073825A CN 105726532 A CN105726532 A CN 105726532A
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- simvastatin
- bromo
- osteoporotic fracture
- medicine
- fracture
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
Abstract
The invention discloses a simvastatin composition and application thereof in preparation of medicine for treating an osteoporotic fracture.The composition is prepared from active ingredients of simvastatin and medicinal auxiliary materials.Accordingly, the purpose of treating osteoporosis or promoting healing of the osteoporotic fracture can be achieved through the mechanisms of promoting bone formation and transformation, enhancing the osteoblast activity, inhibiting osteoclast differentiation and the like.
Description
Technical field
The invention belongs to pharmaceutical technology field, in particular to a kind of simvastatin composite and the application in the medicine of preparation treatment osteoporotic fracture thereof.
Background technology
Osteoporotic fracture (OPF) is that with age growth, bone amount reduces one, bone microstructure is abnormal, bone fragility increases, only because of fracture that Mild Violence or non-wound factor cause, also known as fragility fractures, clinical data shows that osteoporosis is the main cause (Ma Junling of fracture, Guo Haiying, Yang Xiaodong. the Epidemiology [J] of osteoporosis. China's general family medicine, 2009,12 (9): 1744-1746).In recent years, osteoporotic fracture has become as the harm able-bodied killer of old people, has a strong impact on middle-aged and elderly people quality of life.Estrogen deficiency is considered as the primary cause of disease of post menopausal OPF, but concrete mechanism of action still imperfectly understands.
The clinical Therapeutic Method for fracture is more, but the treatment for osteoporosis and caused fracture thereof really acquires a certain degree of difficulty.Due to the patient groups of osteoporotic fracture all there is age height, the feature such as health status is poor, operation risk is high, postoperative not easily recovery, and the ill concealment of osteoporosis, very easily ignored by people, in clinical treatment, to osteoporotic understanding deficiency, doctor is often made to ignore osteoporotic treatment the therapeutic purposes of fracture, therefore, constantly increasing the weight of of osteoporosis degree, even fractures, all bring sizable difficulty to clinical treatment, and secondary fracture very easily occurs.Although there being some Chinese Patent Medicines kind also to have been used for osteoporotic preventing and treating, but treatment aspect also lacks method desirable, reliable, treatment especially for osteoporotic fracture is still a great problem, therefore, exploitation has prevention and treatment osteoporosis, fracture, particularly effective medicine for the treatment of osteoporotic fracture and preventing secondary fracture, this is particularly important.
Existing research finds, oral statins can increase bone density, improves bone mechanical properties.Further investigation revealed that, simvastatin can partly stop ovariectomized female rats bone amount to be lost and show certain effect trend promoting union of fracture, but the not notable (MUNDYG of effect, GARRETTR, HARRISS, etal.Stimulationofboneformationinvitroandinrodentsbystat ins [J] .Science, 1999,286 (5446): 1946-1949).Safety based on the medication clinically of simvastatin for many years, it is necessary to by furtheing investigate the treatment that this medicine is used for osteoporotic fracture.
Additionally, Chinese patent CN102558059A discloses a kind of bromo-4-trifluoromethyl indazole of indazole compounds 5-, it is with 2-methyl-3-nitro trifluoromethylbenzene for initiation material, prepare target compound indazole derivative, and disclose its physiologically active in arthritis, antitumor and town are told etc., but do not report this compound improving bone density, promote the biological activity in osteoporotic fracture.
Summary of the invention
It is an object of the invention to provide a kind of simvastatin composite and the application in the medicine of preparation treatment osteoporotic fracture thereof, said composition is with the bromo-4-trifluoromethyl indazole of simvastatin and 5-for active component, formation and the conversion of bone can be effectively facilitated, thus reaching the purpose for the treatment of osteoporotic fracture.
In order to realize the purpose of the present invention, active constituents of medicine is studied by lot of experiments and explores by inventor, is finally obtained following technical scheme:
A kind of pharmaceutical composition treating osteoporotic fracture, is prepared from by active component and pharmaceutic adjuvant, and described active component comprises simvastatin and the bromo-4-trifluoromethyl indazole of 5-.Preferably, treating the pharmaceutical composition of osteoporotic fracture as mentioned above, active component therein is made up of the bromo-4-trifluoromethyl indazole of simvastatin and 5-.
It is further preferred that treat the pharmaceutical composition of osteoporotic fracture as mentioned above, wherein simvastatin is 1～8:1 with the quality amount ratio of the bromo-4-trifluoromethyl indazole of 5-.Further preferably, treating the pharmaceutical composition of osteoporotic fracture as mentioned above, wherein simvastatin is 1～4:1 with the quality amount ratio of the bromo-4-trifluoromethyl indazole of 5-.
In a preferred effect test example in present invention research, treating the pharmaceutical composition of osteoporotic fracture as mentioned above, wherein simvastatin is 2:1 with the quality amount ratio of the bromo-4-trifluoromethyl indazole of 5-.
The pharmaceutical composition for the treatment of osteoporotic fracture of the present invention is tablet, capsule or granule；The pharmaceutic adjuvant adopted includes filler, disintegrating agent, binding agent, sweeting agent and lubricant.It is further preferred that treat the pharmaceutical composition of osteoporotic fracture as mentioned above, wherein said filler is selected from following one or more: microcrystalline Cellulose, pregelatinized Starch, hydroxypropylcellulose, Polyethylene Glycol；Described disintegrating agent is selected from following one or more: carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose；Described binding agent is alcoholic solution, Gonak, povidone solution；Described sweeting agent is selected from stevioside；Described lubricant is selected from following one or more: magnesium stearate, Pulvis Talci and micropowder silica gel.
Finding in experimental study of the present invention compared with model control group, the bromo-4-trifluoromethyl indazole of 5-or itself and simvastatin conjunctive use can be effectively increased BGP and ALP content in osteoporotic fracture model mouse serum.BGP is by a kind of noncollagen protein of ripe osteoblast synthesis secretion, rich content in osseous tissue, after being synthesized by osteoblast, about 20% is directly entered blood from osseous tissue, therefore in blood, the concentration of BGP and carboxylated grade can reflect the state of os in os calcium element, and its physiological function is relevant with bone conversion.Measuring serum BGP to have great importance for the curative effect evaluating Drug therapy osteoporosis, BGP level rises and points out the medicine irritation formation of bone.ALP is one of osteoblast maturation and active mark, is usually used in evaluating bone formation and bone conversion, is commonly used to the reference index as diagnosing osteoporosis in clinic.Therefore from this interpretation of result, the bromo-4-trifluoromethyl indazole of 5-or itself and simvastatin use in conjunction can effectively promote formation and the conversion of bone in osteoporotic fracture tissue, it is enhanced to bone cell activity and suppresses the differentiation of osteoclast, thus reaching the purpose for the treatment of osteoporosis and osteoporotic fracture.Therefore, further object is that the bromo-4-trifluoromethyl indazole of 5-or its pharmaceutical applications with simvastatin coupling are provided, it may be assumed that the bromo-4-trifluoromethyl indazole of 5-treats the application in the medicine of osteoporosis as active component in preparation.Or, the bromo-4-trifluoromethyl indazole of 5-treats the application in the medicine of osteoporotic fracture as active component in preparation.Or, simvastatin treats application in the medicine of osteoporosis as active component in preparation with the bromo-4-trifluoromethyl indazole of 5-.Or, simvastatin treats application in the medicine of osteoporotic fracture as active component in preparation with the bromo-4-trifluoromethyl indazole of 5-.
Compared with prior art, the present invention can pass through to promote formation and the conversion of bone, the mechanism such as the differentiation being enhanced to bone cell activity and suppress osteoclast, reach treatment osteoporosis or promote the healing of osteoporotic fracture, being especially suitable for the osteoporotic fracture that treatment estrogen deficiency causes.Further, simvastatin obtains, with the bromo-4-trifluoromethyl indazole of 5-, the synergy promoting union of osteoportic fracture do coupling.
Detailed description of the invention
The following is animal experiment example, in order to the technique effect of the present invention to be described.Inventor is by as follows to animal experiment process and the interpretation of simvastatin coupling 5-bromo-4-trifluoromethyl indazole treatment osteoporotic fracture:
SPF level 6 monthly age Adult female rats 32, weight 260～300g, it is randomly divided into following five groups: model control group, simvastatin group, methylindazole group, pungent cut down-indazole group, often organize each 8, set up osteoporotic fracture model as follows: rat is fasting 6h before anesthesia, with 10% chloral hydrate (4mL/kg), rat being carried out intraperitoneal anesthesia afterwards, anaesthetize successfully after 3～5min, its extremity are fixed on operating-table by abdominal part upward.At rat Ventral Midline position preserved skin, then with iodine tincture and 70% alcohol disinfecting, aseptically with medical scissors crosscut opening, cutting skin, superficial fascia and deep fascia respectively, arrive Musclar layer, strip off muscle finds fallopian tube, ovary is found along fallopian tube end, with silk thread in isthmus of uterine tube ligation, cut off ovary with shears, completely extract bilateral ovaries.Tubal ligation and [Dan, after flushing, suture muscles, depth fascia, last skin suture, bind up a wound.After raising 3 months before anesthesia Rat Fast 6h, carrying out sucking either shallow anesthesia to rat with ether afterwards, anaesthetize after successfully, patient is fixing hip joint on the other hand, on the other hand fixing knee joint in right lateral side femur on 1/3 place fracture and set up closed fracture model, postoperative rearing conditions is constant.
Fracture, simvastatin group gives simvastatin gavage by the dosage of 20mg/ (kg d)；Methylindazole group gives 5-bromo-4-trifluoromethyl indazole gavage by the dosage of 5mg/ (kg d)；Pungent cut down-indazole group gives simvastatin gavage by the dosage of 10mg/ (kg d), and methylindazole group gives 5-bromo-4-trifluoromethyl indazole gavage by the dosage of 5mg/ (kg d)；Model control group all gives isopyknic normal saline.Each group after fracture operation next day start administration, administration time is 6 weeks.After last is administered, 24h carries out plucking eyeball and takes blood, 3000r/min frozen centrifugation, takes Virus monitory Bone Gla protein (BGP) and alkali phosphatase (ALP).Result of the test shows: after treating 6 weeks, each medication therapy groups serum BGP, ALP relatively model control group decline, especially pungent cut down-indazole group decline degree adopts more merely simvastatin or single medicine group more notable (P < 0.01 or P < 0.05) of 5-bromo-4-trifluoromethyl indazole treatment, it is shown that the synergism of the bromo-4-trifluoromethyl indazole promotion union of osteoportic fracture of simvastatin coupling 5-.
Table 1 is respectively organized serum osteocalcin, alkaline phosphatase levels in rat and is compared
Each medicine group compares with model control group,*P < 0.05,**P < 0.01；
Pungent cut down-indazole group compares with simvastatin group,#P < 0.05,##P < 0.01；
Pungent cut down-indazole group compares with methylindazole group,$P < 0.05,$$P < 0.01.
It addition, study of histological morphology finds, pungent cut down-indazole group rat fracture after 7d, be the cellulose after hematoma and machine thereof between the broken ends of fractured bone, have monocyte infiltration.Visible a large amount of Hematoma Cells and inflammatory cell in defective region.14d after fracture: the outer periosteum of all specimen all thickens, the outer periosteum of part specimen thickens more than 4 layers, and the outer notable hypertrophy of Osteoblastic Cells Derived from Periosteum of minority specimen, proliferative cell is fused into a piece of, and bone matrix is calm, forms osteoid, cartilage and bone trabecula；All specimen perimyelis thicken, and have area of new bone girder to generate in major part specimen medullary cavity, and part specimen area of new bone girder is full of medullary cavity.28d after fracture, most specimen fracture site fibroblasts and fibrous tissue and osteoid are increased, and the outer notable hypertrophy of Osteoblastic Cells Derived from Periosteum of all specimen, proliferative cell is fused into a piece of, and bone matrix is calm, forms osteoid tissue, cartilage and bone trabecula.After fracture 42d, woven bone is formed, and the bone trabecula in medullary cavity attenuates, and medullary cavity is led to again, and woven bone changes to lamellar bone gradually.
Claims (9)
1. treat a pharmaceutical composition for osteoporotic fracture, active component and pharmaceutic adjuvant are prepared from, it is characterised in that described active component comprises simvastatin and the bromo-4-trifluoromethyl indazole of 5-.
2. treat the pharmaceutical composition of osteoporotic fracture according to claim 1, it is characterised in that described active component is made up of the bromo-4-trifluoromethyl indazole of simvastatin and 5-.
3. the pharmaceutical composition for the treatment of osteoporotic fracture according to claim 1 or claim 2, it is characterised in that the quality amount ratio of simvastatin and the bromo-4-trifluoromethyl indazole of 5-is 1～8:1.
4. treat the pharmaceutical composition of osteoporotic fracture according to claim 3, it is characterised in that the quality amount ratio of simvastatin and the bromo-4-trifluoromethyl indazole of 5-is 2～4:1.
5. treat the pharmaceutical composition of osteoporotic fracture according to claim 4, it is characterised in that the quality amount ratio of simvastatin and the bromo-4-trifluoromethyl indazole of 5-is 2:1.
6. simvastatin treats application in the medicine of osteoporosis as active component in preparation with the bromo-4-trifluoromethyl indazole of 5-.
7. simvastatin treats application in the medicine of osteoporotic fracture as active component in preparation with the bromo-4-trifluoromethyl indazole of 5-.
The bromo-4-trifluoromethyl indazole of 8.5-treats the application in the medicine of osteoporosis as active component in preparation.
The bromo-4-trifluoromethyl indazole of 9.5-treats the application in the medicine of osteoporotic fracture as active component in preparation.
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| CN201610073825.5A CN105726532A (en) | 2016-02-03 | 2016-02-03 | Simvastatin composition and application thereof in preparation of medicine for treating osteoporotic fracture |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011072488A1 (en) * | 2009-12-18 | 2011-06-23 | Glaxo Group Limited | Oxadiazole substituted indazole derivatives for use as sphingosine 1-phosphate 1 (s1p1) receptor agonists |
| CN102558059A (en) * | 2011-08-23 | 2012-07-11 | 天津市斯芬克司药物研发有限公司 | Brand-new indazole compound and its synthetic method |
| CN103169972A (en) * | 2011-12-23 | 2013-06-26 | 北京大学第三医院 | New application of statin compound as topical medicine for preventing and curing osteoporotic fracture |
| CN104587470A (en) * | 2015-02-26 | 2015-05-06 | 新乡医学院第一附属医院 | Pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of pharmaceutical composition |
-
2016
- 2016-02-03 CN CN201610073825.5A patent/CN105726532A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011072488A1 (en) * | 2009-12-18 | 2011-06-23 | Glaxo Group Limited | Oxadiazole substituted indazole derivatives for use as sphingosine 1-phosphate 1 (s1p1) receptor agonists |
| CN102558059A (en) * | 2011-08-23 | 2012-07-11 | 天津市斯芬克司药物研发有限公司 | Brand-new indazole compound and its synthetic method |
| CN103169972A (en) * | 2011-12-23 | 2013-06-26 | 北京大学第三医院 | New application of statin compound as topical medicine for preventing and curing osteoporotic fracture |
| CN104587470A (en) * | 2015-02-26 | 2015-05-06 | 新乡医学院第一附属医院 | Pharmaceutical composition for promoting bone healing after osteoportic fracture operations and application of pharmaceutical composition |
Non-Patent Citations (2)
| Title |
|---|
| 于伟利等: "辛伐他汀对骨质疏松大鼠的防治作用", 《西安交通大学学报( 医学版)》 * |
| 马庆芬等: "辛伐他汀对去势大鼠骨质疏松防治作用的试验研究", 《重庆医科大学学报》 * |
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