CN108653283A - Rapamycin and its derivative are preparing the purposes in treating bone loss disorders drug - Google Patents
Rapamycin and its derivative are preparing the purposes in treating bone loss disorders drug Download PDFInfo
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- CN108653283A CN108653283A CN201810400174.5A CN201810400174A CN108653283A CN 108653283 A CN108653283 A CN 108653283A CN 201810400174 A CN201810400174 A CN 201810400174A CN 108653283 A CN108653283 A CN 108653283A
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- Prior art keywords
- rapamycin
- purposes
- mouse
- ovx
- bone loss
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
The invention mainly relates to the purposes of rapamycin; claimed technical solution is that rapamycin and its derivative are preparing the purposes of the purposes in treating bone loss disorders drug, especially rapamycin in preparing treatment companion's iron accumulation bone loss disorders drug.The present invention tests the bone loss for showing that rapamycin can significantly be alleviated with iron accumulation.
Description
Technical field
The invention belongs to technical field of pharmaceutical biotechnology, and in particular to a kind of rapamycin and its derivative are treated preparing
Purposes in bone loss disorders drug.
Background technology
Rapamycin (Rapamycin, RAPA) also known as sirolimus, its chemical name be (3S, 6R, 7E, 9R,
10R, 12R, 14S, 15E, 17E, 19E, 21S, 23S, 26R, 27R, 34aS) -9,10,12,13,14,21,22,23,24,25,
26,27,32,33,34,34a- ten hexahydro -9,27- dihydroxy -3- [(1R) -2- [(1S, 3R, 4R) -4- hydroxyl -3- cyclohexyl methoxies
Hexyl] -1- Methylethyls] -10,21- dimethoxies -6,8,12,14,20,26- hexamethyl -23,27- epoxy -3H- pyridos
31 cyclenes -1,5 of [2,1-c] [Isosorbide-5-Nitrae] oxazepine, 11,28,29 (4H, 6H, 31H)-pentanones, molecular formula are
C51H79NO13, molecular weight 914.172, chemical structural formula is as follows：
Rapamycin is a kind of immunosuppressor, the triene macrolide class compound being made of 31 membered rings, containing special
α, beta diketone second nipecotic acid amide molecule cover hemiketal.Rapamycin is white crystalline solid, and lipophilicity is slightly soluble in
Water, oral administration are absorbed rapidly, are often used with cyclosporine and corticosteroids, in vivo conventionally used for inhibiting organ
Immunological rejection after transplanting.Rapamycin and FKBP compounds are combined that the costimulations such as IL-2, IL-15 can be blocked with mTOR
The immune response that pathway activation mTOR accesses are caused, to play powerful immunosuppressive effect.
After rapamycin is clinically mainly used for organ transplant, inhibit the immunological rejection after organ transplant, in addition thunder
The antiproliferative effect of pa mycin can be used for the coating of coronary stent, to prevent coronary artery sacculus angioplasty can
The restenosis of the formation of energy.
Invention content
The present invention's solves the problems, such as that being to provide rapamycin and its derivative is preparing treatment bone loss disorders medicine
Purposes in object.
In order to solve the problems, such as it is in the prior art these, the technical scheme is that：Rapamycin and its derivative exist
Prepare the purposes in treatment bone loss disorders drug
In the preferred technical solution of the present invention, rapamycin is preparing treatment in iron accumulation bone loss disorders drug
Purposes.
In the preferred technical solution of the present invention, rapamycin derivative includes tamiros, everolimus, sirolimus.
Results of animal and the rapamycin clinical application of osteoporosis are accumulated with iron according to rapamycin treatment
Method, the present invention when treatment accumulates bone loss disorders with iron, the qf oral administration dosage of the rapamycin can according to
Prescription formula, the age weight of patient, coincident with severity degree of condition and other relevant factors and change, when oral medication, recommends agent
Amount is 1~50mg/ days.
Result of study of the present invention is shown, in animal experiment, the transgenosis for causing endogenous high ferro is knocked out by hepcidin
The mTOR levels of mouse model will be apparently higher than the mouse normally organized, and bone loss is even more serious, by being knocked out to hepcidin
Transgenic mice inject suitable rapamycin, the bone amount of mouse, which is reduced, significantly to be mitigated.
The osteoporosis animal model accumulated with iron with rapamycin intervention finds that there is certain anti-sclerotin to dredge for it
Pine effect.This discovery by being accumulated with iron the research of bone loss disorders and treatment generate significant impact, and have clinic
Practical value opens new clinical application for rapamycin.Since the individual absorptivity of rapamycin differs greatly, to make
Absorption difference minimize, and should consistently be taken with or without food is same, consistent as possible to the time is wanted, and periodic measurement blood medicine is dense
Degree.It should be noted that grapefruit juice can slow down by the metabolism of the CYP3A4 rapamycins adjusted, thus it is not useable for taking or dilutes
Rapamycin.
In above-mentioned technical proposal, the rapamycin drug composition can be by purity 98% (mass percent) more than
Rapamycin add general medicinal auxiliary element, suspension oral solution, tablet, capsule, electuary, drops, freeze-drying is made
Object, granule, ointment or injection.
Pharmaceutical composition according to the present invention can work with whole body and/or locally, for this purpose, can be with suitable side
Formula, such as taken by the approach of mouth, parenteral, lung or nose, composition according to the present invention may adapt to these administrations
The form of taking of approach is taken.
It is to be worked according to state of the art and promptly and/or with improved procedure discharge the present invention suitable for what is taken orally
Pharmaceutical composition form of medication, and include such as the tablet (nothing to crystallize and/or unbodied and/or dissolved form
Coating or cated tablet, such as with resistance gastric juice or delayed dissolved or undissolved coating, it is according to the present invention
Composition discharges), tablet or diaphragm broken rapidly, film/lyophilized products, capsule (such as hard or soft capsule), sugar-coat in mouth
The pharmaceutical composition according to the present invention of piece, particle, piller, powder, emulsion, suspension, smoke agent or solution.
Parenteral admistration can to avoid absorption step (such as intravenous, intra-arterial is intracardiac, in intraspinal either waist or
It is intra-articular) or include absorbing (such as intramuscular, subcutaneously, intradermal, in percutaneous or peritonaeum) to carry out simultaneously.It is suitable for stomach
The suitable form of taking of outer medication is particularly useful for injecting and inject with solution, suspension, emulsion, lyophilized products or
The preparation of aseptic powdery form.
Be suitable for another administration route is the medicament forms for example for sucking, such as powder inhalator or mist
Change device, or the medicament forms that can be taken with nose, typing drops, solution or spray.
It is an advantage of the invention that：1, rapamycin is as clinical application, compared with traditional immunosuppressor, takes orally
Convenient, dosage is few, Small side effects；2, rapamycin can significantly alleviate the bone loss with iron accumulation.Rapamycin or
Preparation prepared by its pharmaceutically acceptable carrier has the application prospect for the treatment of medicine for treating osteoporosis.
Description of the drawings
The invention will be further described with reference to the accompanying drawings and embodiments：
Fig. 1 is enzyme linked immunosorbent assay test experience each group mice serum ferritin levels.
Fig. 2 is enzyme linked immunosorbent assay test experience each group mice serum mTOR horizontal.
The distal part of femur of Fig. 3 Micro-CT scanning experiment each group mouse simultaneously rebuilds 3-D view, and Fig. 3 A are OVX groups, Fig. 3 B
For OVX+ △ Hep groups, Fig. 3 C are OVX+ △ Hep+Rapa groups.
Fig. 4 is by the 3-D view of Micro-CT scan rebuildings to the bone density of each experiment mice, diaphysis fraction, bone
Trabecular number and bone trabecula thickness carry out quantitative analysis, and Fig. 4 A are the bone density for testing each group mouse, and Fig. 4 B are that experiment each group is small
The diaphysis fraction of mouse, Fig. 4 C are the bone trabecula number for testing each group mouse, and Fig. 4 D are the bone trabecula thickness for testing each group mouse
Degree.
Fig. 5 is the osteogenic activity index of enzyme linked immunosorbent assay test experience each group mouse --- before I procollagen type N-terminal
Peptide (I NP of P) is horizontal.
Specific implementation mode
Said program is described further below in conjunction with specific embodiment.It should be understood that these embodiments are for illustrating
The present invention and be not limited to limit the scope of the invention.The implementation condition used in embodiment can be according to the condition of specific producer
Further adjustment is done, the implementation condition being not specified is usually the condition in routine experiment.
It introduces and summarizes
The present invention by way of example rather than provides the mode of limitation to illustrate.It should be noted that in present disclosure
" one " or "an" embodiment is not necessarily referring to same specific implementation mode, and refers at least a kind of.
One, material
1. experimental animal
C57 mouse, 8, female, 17 week old, 18~25g of weight, cleaning grade are limited by Shanghai Si Laike experimental animals
Company provides.Experimental animal production licence number (SCXK (Shanghai) 2012-0002).
20 ± 3.2 DEG C of receptacle temperature during experiment, relative humidity are 65~75%, freely ingest and drink water.
△ Hep transgenic mices, 16, female, 17 week old, 18~25g of weight, cleaning grade, by the big gene of Cambridge-Soviet Union
Group resource center provides.Experimental animal production licence number (SCKX (Soviet Union) 2017-0006).Receptacle temperature 20 during experiment
± 3.2 DEG C, relative humidity is 65~75%, freely ingests and drinks water.
2, drug and reagent：
2.1 drug
Sirolimus piece, trade name rapammune, tablet, 1mg/ pieces are carried by Wyeth of the U.S. (China) Co., Ltd
For 4 DEG C of refrigerators preserve.
2.2 reagent
Rapamycin, white powder, purity >=95%, 1mg/ bottle are provided, product by Sigma-Aldrich
Number is V900930, and -20 DEG C of refrigerators are kept in dark place.
MTOR ELISA kits are provided by abcam companies of the U.S., and product article No. is ab206311.
Ferritin ELISA kit is provided by abcam companies of the U.S., and product article No. is ab157713.
2.3 instrument
Micro-CT scanners (Micro-CT scanning), model：GE explore Locus SP types, instrument number：PT004938,
It is ground and is provided by University Of Suzhou's bone.
Microplate reader (multi-functional micropore board detector), model：TecanM200PRO types, originate from Austria,
It is provided by No.2 Hospital Attached To Suzhou Univ. experimental center.
Two, experimental method
1, modeling and administration
Experiment packet situation is as follows：Osteoporosis model removal ovary OVX groups, removal ovary add endogenous high ferro iron tune
Element knocks out (OVX+ △ Hep) group and rapamycin treatment group (OVX+ △ Hep+RAPA) group, each 8 of every group of mouse.
OVX groups：Mouse is the common C57 mouse of 17 week old, and when 8 week old, mouse bilateral is cut off after cutting skin, muscle
Ovary causes castration osteoporosis model；
OVX+ △ Hep groups：Mouse is the transgenic mice △ Hep of the 17 systemic knockouts of week old hepcidin；Incision skin,
Mouse bilateral ovaries are cut off after muscle, cause castration osteoporosis model；
OVX+ △ Hep+Rapa groups：Mouse is the transgenic mice of the 17 systemic knockouts of week old hepcidin, when 8 week old,
Bilateral ovaries are cut off, castration osteoporosis model is caused, give rapamycin (being dissolved in DMSO) intraperitoneal injection, dosage after a week
Continue 8 weeks altogether 3 times a week for 3mg/kg.
2, experiment each group mouse sample is taken
Serum specimen is taken：Using eye socket blood taking method, mouse is pressed on mouse cage with left hand, uses thumb
Finger, index finger fix the head of mouse, hold neck, and compressing neck both sides are allowed to exophthalmos, socket of the eye is quiet
Arteries and veins clump is congested, and the right hand holds capillary from eye medial canthal, and with mouse face angle at 45 °, rotation is pierced into, fixed mouse body,
Hind leg is pushed down, finger is loosened, capillary is adjusted, is that blood stream Channel Group goes out, after the completion of taking blood, taking out neck pressure immediately will
Hemostix is extracted, and hemostasis by compression immediately, jog blood sample pipe, is stood 30 minutes on ice, 4 DEG C, 3000rpm, centrifugation 20
Minute, it is serum sample to take supernatant.
Mouse femur sample is taken：By mouse using cervical dislocation put to death, cut mouse lower limb proximal skin and
Muscle fully exposes femur and hip joint, carefully isolates femur, completely takes out femur, and rejects muscle and its
His soft tissue, preservation is fixed with 4%PFA.
3, the results of animal of osteoporosis according to rapamycin treatment with iron accumulation and facing for rapamycin
Bed administrated method, the present invention can be used rapamycin and take orally in bone loss disorders of the treatment with iron accumulation, 1~2mg/
It.
Three, experimental result
3.1 hepcidin knock-out mice serum ferritin levels are significantly raised
Each experimental mice serum ferritin level is detected with enzyme linked immunosorbent assay (ELISA).
As shown in Figure 1, compared with OVX groups, the serum levels of iron egg for the transgenic mice (OVX+ △ Hep groups) that hepcidin knocks out
White level can obviously rise (P<0.05), and injectable rapamycin mycin to the serum ferritin of hepcidin knock-out mice without apparent shadow
It rings；The experimental result prompts：The transgene mouse model of endogenous high ferro, that is, hepcidin knock-out mice model is successful.
The serum mTOR levels of 3.2 hepcidin knock-out mices increase, and Rapa can effectively reduce the blood of hepcidin knock-out mice
Clear mTOR is horizontal.
We have detected each experimental mice serum mTOR levels with enzyme linked immunosorbent assay (ELISA), as shown in Fig. 2,
The serum mTOR levels that hepcidin knocks out the mouse (OVX+ △ Hep groups) for causing endogenous high ferro significantly increase compared with OVX groups
(P<0.05), in addition, the mTOR of OVX+ △ Hep+Rapa group mouse is horizontal to be declined (P than OVX+ △ Hep groups again<0.05)；
The result shows endogenous high ferro can be such that mTOR levels increase, and Rapa can effectively reduce the high mTOR water caused by high ferro
It is flat.
3.3 endogenous high ferros can aggravate the osteoporosis degree of castration mouse, and RAPA can partly restore mouse because iron overloads
Caused bone loss.
As shown in figure 3, scan the distal part of femur of above-mentioned three groups of experiment mices with Micro-CT and carry out three-dimensional reconstruction and
Quantitative analysis, can accurate description bone density and bone microstructure, to judge the degree of osteoporosis.Graphics
As rebuilding display：Compared with OVX groups, its bone trabecula number of the OVX+ △ Hep groups mouse of hepcidin knockout, which significantly reduces, to attenuate,
Almost disappear.And compared with OVX+ △ Hep groups, the bone trabecula for giving the OVX+ △ Hep+Rapa groups after Rapa intervenes obviously increases
It thickens more.In addition, the OVX+ △ Hep+Rapa group Mouse Bone Trabecular numbers and thickness after Rapa interventions are still less than OVX groups.
In order to further verify 3-D view as a result, we quantitatively analyze the bone density of each experiment mice, diaphysis
Fraction, bone trabecula number and bone trabecula thickness.As shown in figure 4, compared with OVX groups, OVX+ △ Hep groups and OVX+ △ Hep+
Bone density, diaphysis fraction, bone trabecula number and the bone trabecula thickness of Rapa groups all significantly reduce (P<0.05).And and OVX+
△ Hep groups are compared, and bone density, diaphysis fraction, bone trabecula number and the bone trabecula of OVX+ △ Hep+Rapa group mouse femurs are thick
Degree, which has, significantly restores (P<0.05).The above results illustrate that the endogenous caused by the transgenic mice that hepcidin knocks out is high
Iron can aggravate the degree of its osteoporosis, give the quality of cancellous bone after Rapa intervenes and can be obviously improved, but can not restore
To the level of simple removal ovary OVX groups, therefore we conclude that, the treatment of Rapa anti-osteoporosis is effective.
3.4RAPA can significantly improve osteogenic activity.
As shown in figure 5, we have detected each I procollagen type of experimental mice serum with enzyme linked immunosorbent assay (ELISA)
N-terminal propetide (I NP of the P) bone turnover marker is horizontal, the osteogenic activity of key reaction body.As a result, it has been found that compared with OVX groups,
I NP levels of P are decreased obviously in OVX+ △ Hep group mice serums；Prompt, the skeletonization that endogenous high ferro significantly reduces body are lived
Property (P<0.05)；After Rapa intervenes, I NP levels of OVX+ △ Hep+Rapa group mice serums P are significantly gone up compared with OVX+ △ Hep groups
(P<0.05), this result illustrates again, and Rapa can have function of resisting osteoporosis by improving mouse osteogenic activity,
This effect may be related with mTOR contents in Mice Body are reduced.
Specific embodiment described above is only the preferred embodiment of the present invention, it is noted that for the art
For those of ordinary skill, without departing from the principle of the present invention, several improvement or replacement can also be made, these change
Into or replace should also be as being considered as protection scope of the present invention.
Claims (4)
1. rapamycin and its derivative are preparing the purposes in treating bone loss disorders drug.
2. purposes according to claim 1, which is characterized in that rapamycin is preparing treatment with iron accumulation osteoporosis disease
Purposes in medicine.
3. purposes according to claim 1, which is characterized in that rapamycin derivative include tamiros, everolimus,
Sirolimus.
4. purposes according to claim 1, which is characterized in that rapamycin is administered orally.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810400174.5A CN108653283A (en) | 2018-04-28 | 2018-04-28 | Rapamycin and its derivative are preparing the purposes in treating bone loss disorders drug |
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| CN201810400174.5A CN108653283A (en) | 2018-04-28 | 2018-04-28 | Rapamycin and its derivative are preparing the purposes in treating bone loss disorders drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110151747A (en) * | 2019-03-29 | 2019-08-23 | 徐又佳 | Purposes of the Ferrostatin-1 in treatment bone loss disorders |
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| CN1820011A (en) * | 2003-07-08 | 2006-08-16 | 诺瓦提斯公司 | Use of rapamycin and rapamycin derivatives for the treatment of bone loss |
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| MENG QI ET AL: "Autophagy Maintains the Function of Bone Marrow Mesenchymal Stem Cells to Prevent Estrogen Deficiency-Induced Osteoporosis", 《THERANOSTICS》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110151747A (en) * | 2019-03-29 | 2019-08-23 | 徐又佳 | Purposes of the Ferrostatin-1 in treatment bone loss disorders |
| CN110151747B (en) * | 2019-03-29 | 2021-05-11 | 徐又佳 | Application of Ferrostatin-1 in treating osteoporosis diseases |
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Inventor after: Wang Aifei Inventor after: Wang Xiao Inventor after: Li Guangfei Inventor after: Chen Bin Inventor after: Yang Fan Inventor after: Xu Youjia Inventor after: Yi Nan Inventor before: Wu Jiadong Inventor before: Wang Aifei Inventor before: Wang Xiao Inventor before: Li Guangfei Inventor before: Chen Bin Inventor before: Yang Fan Inventor before: Xu Youjia Inventor before: Yi Nan |
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Application publication date: 20181016 |