CN101219206A - Application of recombinant human vascular endothelial inhibin in pharmacy - Google Patents
Application of recombinant human vascular endothelial inhibin in pharmacy Download PDFInfo
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- CN101219206A CN101219206A CNA2008100060628A CN200810006062A CN101219206A CN 101219206 A CN101219206 A CN 101219206A CN A2008100060628 A CNA2008100060628 A CN A2008100060628A CN 200810006062 A CN200810006062 A CN 200810006062A CN 101219206 A CN101219206 A CN 101219206A
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- vascular endothelial
- recombinant human
- human vascular
- endothelial inhibin
- inhibin
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Abstract
The invention relates to an application of recombinant human vascular endothelial inhibin in pharmacy, and particularly discloses an application of recombinant human vascular endothelial inhibin in preparing a medicament for treating angiogenic ocular fundus diseases. The angiogenesis ocular fundus disease is treated by the vitreal injection of the recombinant human vascular endothelial inhibin, and the angiogenesis ocular fundus disease can be effectively inhibited from proliferating, so that the angiogenesis ocular fundus disease is treated and the symptoms are improved. The method has strong specificity, high efficiency, and no obvious adverse side effect.
Description
Technical field
The present invention relates to biological product technical field, be specifically related to the pharmaceutical applications of recombinant human vascular endothelial inhibin, this medicine can be used for the treatment of angiogenic retinopathy.
Background technology
Retinopathy is a kind of very high ocular disease of blind rate of complexity, and present most Epidemiological study result shows that domestic retinopathy causes the ratio of low vision and blinding in rising trend.Eyeball is a spheric object, and the vitreous body at its rear portion, retina, choroid etc. partly are the optical fundus, and there are blood vessel, optic nerve, macula lutea portion in the optical fundus, and the pathological changes at these positions just is called retinopathy.Comprise age-related macular degeneration, diabetic retinopathy, retinochoroiditis, proliferative vitreoretinopathy, detachment of retina, retinoblastoma, anterior ischemic optic neuropathy etc.Wherein there are some relevant, as age-related macular degeneration, the exudative retinochoroiditis of centrality, proliferative vitreoretinopathy and retinoblastoma etc., i.e. angiogenic retinopathy with angiogenesis.
Age-related macular degeneration (age-related macular degeneration, AMD) be that senile degeneration of macula is called age-related macular degeneration again, it is the retinopathy of the chronic visual deterioration of a kind of painless property, became gradually in recent years and caused person's visual deterioration even blind main cause at advanced age, thereby receive much concern, but its cause of disease is at present also indeterminate.AMD mainly is divided into atrophic type and exudative type, wherein atrophic type mainly is meant the atrophy of retinal pigment epithelium, choriocapillary plate, newborn irrelevant with choroidal artery, exudative type then mainly is owing to the macula lutea portion the person at advanced age, stretches new vessels to retinal pigment epithelium or under retina and causes hemorrhage or the exudative type pathological changes from choroid.
The exudative chorioretinopathy of centrality claims Rieger central serous chorioretinopathy, youth's property hemorrhagic Maculopatliy again.Be generally simple eye morbidity clinically, the age is many at the right side of fifty.Mainly betide the upright exudative chorioretinopathy kitchen range of macula lutea portion and arc on every side thereof, with new vessels under the retina and hemorrhage.
Proliferative vitreoretinopathy (proliferative vitreoretinopathy, PVR) be meant after rhegmatogenous detachment of retina or reattachment of retina operation, and after the ocular injury, owing to reach the hyperplasia and the contraction of retinal surface in the vitreous body, cause the pathological changes of traction detachment of retina.The treatment of PVR mainly is an operative treatment, although but adopted many operation methods to impel the reattachment of retina of proliferative vitreoretinopathy, can still have 1/3 case operative failure, though being operation on vitreous, its reason can excise established propagation film, but can not remove proliferative cell fully, even also stimulate it to produce differentiation, propagation, therefore, medical treatment PVR is very important.
(retinoblastoma is a kind of embryo's property malignant tumor that originates from retina stratum nucleare primordial stem cell RB) to retinoblastoma, shows as retina cell and grows uncontrollably, has heritability, accounts for the first place of eye neoplasms.These sick many morbidities before three years old, occasionally in the adult, asexuality difference, eyes while or first sequela person account for 1/4.
Human Endostatin (endostatin) is that the segment molecule amount size of collagen XVIII c-terminus is the enzyme action product of 20kDa, having the activity that suppresses angiogenesis in vascular endothelial cell proliferation, migration and the body, is present the strongest known endogenous vascularization inhibitive factor.
Recombinant human vascular endothelial inhibin is to utilize DNA recombined engineering technology, with protokaryon or carrier for expression of eukaryon, and the protein that the angiogenesis inhibiting activity form is arranged that the human Endostatin gene is obtained through clone, expression and purification.
(patent publication No. is CN1324818A to Chinese invention patent, it open day was calendar year 2001 December 5 days, denomination of invention is " method of producing endostatin ") a kind of improvement is provided, with the method for higher productive rate and simpler purifying process production recombinant human endothelial inhibin.This invention utilizes DNA recombined engineering technology, with escherichia expression system, produce the human Endostatin (wherein Xaa represents neutral amino acid or do not exist) that N-terminal has the additional aminoacid sequence of (Met) GlyGlyXaaHisHisHisHisHis in enormous quantities with simple method and lower cost, not only kept the biologic activity completely of endostatin, and do not produced because of adding immunity in the body due to the additional N terminal sequence.Above-mentioned additional aminoacid sequence has not only improved transcribing and translation initiation efficient of endostatin structural gene, help the purification of recombiant protein, and the structure of additional aminoacid sequence has also increased the stability of recombiant protein.
The method that is used at present to prevent and treats the angiogenic retinopathy mainly comprises medicine, laser therapy, isotope therapy, operation etc., but these methods all have shortcoming separately, bigger etc. as injuring adjacent tissue, curative effect instability, risk easily, therefore finding specificity is good, evident in efficacy, side effect is little Therapeutic Method is the focus paid close attention to of researcher both at home and abroad at present.
Summary of the invention
Though the propagation of retinopathy position new life's blood capillary all appears in angiogenic retinopathy pathogenesis difference, new vessels becomes that the state of an illness takes place and the key factor of development.Consider from this mechanism,, then may bring new breakthrough for the treatment of angiogenic retinopathy if can suppress the propagation of optical fundus focus new vessels specifically with some treatment means.
In order to overcome the bigger defective of traditional remedies instability, risk of angiogenic retinopathy, the invention provides a kind of pharmaceutical applications of recombinant human vascular endothelial inhibin, specifically be to use the pharmaceutical applications of the medicine of recombinant human vascular endothelial inhibin preparation treatment angiogenic retinopathy, this medicine has high specificity, nontoxic, the advantage that has no drug resistance.
Technical solution of the present invention relates to the application of recombinant human vascular endothelial inhibin in the medicine of preparation treatment angiogenic retinopathy.
Described herein recombinant human vascular endothelial inhibin has kept the biologic activity completely of endostatin, can use genetic engineering means to obtain, it is gene constructed in escherichia coli (E.Coli) or Pichia sp. (Pichia pastoris) expression system maybe will to change the human Endostatin of structure by the vascellum esoderma inhibin gene with the people, by fermentation, means such as separation, purification obtain.
Preferred recombinant human vascular endothelial inhibin is to add 0-4 arbitrary amino acid and 2-8 histidine sequence behind the initial amino acid Me of human Endostatin encoding amino acid sequence t successively among the present invention.The same Chinese invention patent of its preparation method (patent publication No. is CN1324818A, open day be calendar year 2001 December 5 days, and denomination of invention is " method of production endostatin ").
The initial amino acid Met of above-mentioned recombinant human vascular endothelial inhibin may be cut, and reason is may be deleted in the course of processing behind the protein translation in expressive host.
The aminoacid sequence of the preferred recombinant human vascular endothelial inhibin of the present invention is shown in SEQID NO:1, this sequence is identical with the disclosed SEQ IDNO:2 of Chinese invention patent (patent publication No. is CN1324818A), and the proteinic preparation method that this sequence constitutes is identical with the preparation embodiment of above-mentioned publication.
The preparation of the medicine of above-mentioned treatment angiogenic retinopathy can be injection or lyophilized formulations.The described active component of stating medicine can be recombinant human vascular endothelial inhibin or the recombinant human vascular endothelial inhibin microsphere that recombinant human vascular endothelial inhibin, PEG modify.The molecular weight of described PEG is 5000-30000, and PEG links to each other with recombinant human vascular endothelial inhibin by covalent bond (as: succinimido or sulfydryl etc.).Described recombinant human vascular endothelial inhibin microsphere is to be mixed with by host material and recombinant human vascular endothelial inhibin to form, and its host material can be polylactic-co-glycolic acid block copolymer (PLGA), polyglycolic acid (PLA) etc.
Also contain protective agent and pH value regulator in the medicine of above-mentioned treatment angiogenic retinopathy.Described protective agent is selected from polyhydric alcohol, saccharide, aminoacid, surfactant, human albumin, EDTA and NaCl.The pH value scope of described medicine is 4.0-8.5.
Above-mentioned described angiogenic retinopathy comprises at least a in age-related macular degeneration, the exudative retinochoroiditis of centrality, proliferative vitreoretinopathy and the retinoblastoma, and other retinopathy relevant with angiogenesis also belongs to indication of the present invention.
The medicine of the angiogenic retinopathy of treatment described in the present invention can with traditional Therapeutic Method use in conjunction, as with operation or the medication combined application of conventional therapy.
The invention also discloses a kind of prescription for the treatment of the recombinant human vascular endothelial inhibin injection of angiogenic retinopathy, be formulated by recombinant human vascular endothelial inhibin and pharmaceutic adjuvant, wherein contain recombinant human vascular endothelial inhibin 0.2mg～10mg by every milliliter of injection, mannitol 60mg～80mg, it is 4.0～8.5 that the PH regulator is regulated pH value.
Also disclose the preparation technology of recombinant human vascular endothelial inhibin lyophilized formulations in the embodiments of the invention, the lyophilized formulations product stability that this technology makes is good, can long preservation.Lyophilized formulations need be dissolved in the water for injection when using, and use amount takes the circumstances into consideration to use according to lesion degree.
The present invention is applicable to the treatment of the angiogenic retinopathy that a variety of causes causes, therapeutic dose can be taken the circumstances into consideration plus-minus according to the state of an illness, and recombinant human vascular endothelial inhibin treatment valid density is 0.2mg/ml～10mg/ml, generally adopts the medication of retinopathy local injection.
For better explanation the present invention, its purposes in the medicine of preparation treatment angiogenic retinopathy is described below in conjunction with drug study, zoopery and clinical experiment.Employed recombinant human vascular endothelial inhibin has the aminoacid sequence shown in the SEQ ID NO:1 among experimental example hereinafter and the preparation embodiment.If no special instructions, hereinafter related experiment all can obtain by commercial sources with material.
1, recombinant human vascular endothelial inhibin albumen suppresses experiment to vascular endothelial cell proliferation
The trophophase Human umbilical vein endothelial cells of taking the logarithm (HUVEC) is adjusted density to 1 * 10
4/ ml, be inoculated in 96 orifice plates, the 160ul/ hole, in the hole, add 40ul/ hole different dilution 5mg/ml, 2.5mg/ml, 1.25mg/ml, 0.625mg/ml, 0.313mg/ml, 0.156mg/ml recombinant human vascular endothelial inhibin albumen (being that protein concentration is followed successively by 1000 μ g/ml, 500 μ g/ml, 250 μ g/ml, 125 μ g/ml, 62.5 μ g/ml, 31.25 μ g/ml in the hole) respectively, in 37 ℃, 5%CO
2Cultivate in the incubator after 4 days and measure absorbance in the 490nm place, and calculate cell proliferation inhibition rate with MTT (tetramethyl azo azoles salt) method.Suppression ratio=1-(experimental group OD/ matched group OD).The mtt assay result shows, the vascellum esoderma inhibin albumen of each extension rate all can effectively suppress the propagation of vascular endothelial cell, the highest suppression ratio can reach 87.5% (seeing Table 1), morphologic observation shows the apoptosis of this inhibitory action with cell, behind the effect 96h, cell promptly becomes circle fully, and concentration phenomena appears in nuclear, and the blank group does not then have this phenomenon.
Table 1: recombinant human vascular endothelial inhibin is to the suppression ratio of HUVEC
| Recombinant human vascular endothelial inhibin dosage (μ g/ml) | Suppression ratio (%) |
| 31.25 62.5 125 250 500 1000 | 10.9 19.5 33.2 52.6 64.3 87.5 |
2, cornea rebirth blood vessel rabbit model experiment
Get 36 of healthy male new zealand white rabbits, eye is normal.Be divided into recombinant human vascular endothelial inhibin high dose experimental group, middle dosage experiments group, low dosage experimental group, photodynamic therapy group (positive controls), normal saline matched group (matched group) and blank group (blank group) at random, 6 every group (12 eyes).Bury suture in corneal stroma under the aseptic condition, the same day is respectively to high, medium and low dosage experiments group lagophthalmos intravitreal injection 0.5ml recombinant human vascular endothelial inhibin after the operation, concentration is followed successively by 80 μ g/ml, 40 μ g/ml, 20 μ g/ml, and injection in per two days is once injected 10 times continuously.And simultaneously to matched group lagophthalmos intravitreal injection normal saline 0.5ml.Positive controls is then implemented photodynamic therapy, promptly earlier photosensitizer is injected the patient vessel, then with black light lamp or long-wave band laser irradiation hemangioma zone.Photosensitizer activate the back produce photochemical reaction and cause hemangioma portion tunica intima and between matter the photosensitiveness process appears, make the vessel lumen obturation, to reach therapeutic purposes.Blank group lagophthalmos is left intact.
Observe the cornea rebirth blood vessel growing state every day, continuous 20 days.Postoperative was put to death rabbit on the 20th day, extractd eyeball, observed the eyeball situation, respectively organized the maximum growth area and the most long-living long length of cornea new vessels.Simultaneously when extracing eyeball, also to get its internal organs (heart, liver,kidney,spleen, lung), so that carry out the whether research of toxic side effect.
The result: the new vessels of normal saline matched group corneal stroma is more than experimental group, and tube chamber is big, and the corneal epithelial cell of each dosage experiments group is normal, new vessels is less, poor growth and sparse (table 2), hyperemia and edema phenomenon do not appear in conjunctive bulbi substantially, and cornea is muddy, edema not, and there is dose dependent in effect.After positive controls was carried out optical dynamic therapy, the inflammatory reaction of laser zone partly disappeared, and sealing of part new vessels and stenosis are narrow, in the narrow new vessels tube chamber fiber-like material is arranged, but slight damage appear in endothelial cell and surrounding tissue.Blank group corneal transparency, no blood vessel.In addition, the result of internal organs pathology detection shows, each dosage experiments group, positive controls, normal saline matched group and blank group do not have obvious difference, and this also just illustrates that recombinant human vascular endothelial inhibin injection among the present invention does not have obvious toxic and side effects to the important organ of health.
Table 2 cornea rebirth blood vessel maximum growth area and the most long-living length
| Group | n | Maximum growth area (mm2) | The most long-living length (mm) |
| The normal saline matched group | 6 | 25.22±4.06 | 6.72±2.03 |
| Dosage experiments group * low dosage experimental group * positive controls among the high dose experimental group * | 6 6 6 6 | 7.83±2.93 10.69±3.59 12.01±3.34 19.72±3.82 | 3.53±1.65 4.49±1.22 5.13±1.79 5.65±1.36 |
* group and the maximum growth area of positive controls (photodynamic therapy group) relatively p＜0.05,
* group compares p＜0.05 with the most long-living length of positive controls (photodynamic therapy group).
Experimental study shows: by the cornea rebirth blood vessel rabbit model of lagophthalmos portion cornea suture preparation, its corneal stroma is by artificial suture, cause the angiogenic retinopathy, after the recombinant human vascular endothelial inhibin injection is injected into lagophthalmos portion, can suppress the formation of diseased region new vessels significantly, the most long-living length and the maximum growth area of its blood vessel all are starkly lower than the normal saline matched group, obviously improved the symptom of angiogenic retinopathy, have curative effect preferably, and do not have obvious toxic and side effects.
Conclusion: recombinant human vascular endothelial inhibin can suppress the formation of position, optical fundus new vessels significantly, its effect is better than the optical dynamic therapy method, effectively reach the purpose of treatment angiogenic retinopathy, and this injection there is not obvious toxic-side effects to the important organ of health.
Below set forth the beneficial effect of medicine of the present invention by test case and clinical observation on the therapeutic effect.
Case one
The patient, man, 59 years old.The patient because of the right eye blurred vision unclear and the distortion, after half a year in hospital admission.On inspection, left vision 1.0, right vision 0.2, eyes prosthomere and left eye optical fundus all do not occur unusual, and it is clear that the nipple limit is looked at position, right eye optical fundus, and the temporo side is light slightly, blood vessel is walked to act charitably, the reflective summary of arterial wall is strong, the macular area filth, visible glass-film wart, pigment disorder, yellow-white exudate, hemorrhage, form the machine dissipating rashes, the central fovea of macula luminous reflectance disappears substantially.FFA checks and shows that macula lutea portion fluorescein oozes out formation than hyperfluorescence, the hemorrhage fluorescence that covers.The patient is irascible temperament usually, suffers from coronary heart disease and myocardial ischemia 3 years, and follows soreness of the waist and knees dizziness, pale tongue.Clinical diagnosis: right eye age-related macular degeneration (exudative type).Treatment: agree that through patient and family members thereof to patient's right eye intravitreal injection 3mg/ml recombinant human vascular endothelial inhibin injection 0.5ml, per 3 weeks inject once, 2 months is a course of treatment.After first course of treatment, the situation of patient's readme metamorphopsia disappears, and it is clear than before to look thing, and the checking eyesight result is a left eye 1.0, right eye 0.5, and hemorrhage of the optical fundus macular area is dwindled, and the glass-film wart reduces.After continuing a course of treatment, it is clear that thing is looked in patient's readme, and the checking eyesight result is a left eye 1.0, right eye 0.9, and macular area oozes out and hemorrhage basic absorption at the bottom of the right eye, the basic noresidue of glass-film wart.
Case two
The patient, woman, 1 years old.Infant ophthalmalgia, the uneasiness of crying and screaming.The white pupil companion of patient's left eye visual deterioration was gone to see a doctor after one week.Check result is: eyes external eyes no abnormality seen, and conjunctiva of left eye hyperemia, the nethike embrane Mild edema, pupil is 6mm, conceals and sees the nethike embrane protuberance.High density soft tissue sample shadow slightly appears in all visible diffusivity increase in density shadow of double eyeball in the vitreous chamber, crystalline lens shows normal, and retinal telangiectasia has ill-defined yellow-white protuberance lump on the retina, and the calcification of patch shape appears in the eyeball rear wall.Tumor has expansion and shifts sign.CT diagnosis: retina of both eyes blastoma.Treatment: agree that through the patient monitoring people respectively to patient's eyes intravitreal injection 1mg/ml recombinant human vascular endothelial inhibin injection 0.5ml, per 3 weeks inject once, 2 months is a course of treatment.After the course of treatment, patient tumors does not enlarge and shifts, and the lump on the retina reduces density reduction in the double eyeball, calcified plaque sx.After continuing to treat 1 course of treatment, each symptom is all obviously improved, and for preventing recurrence, continues to have injected 2 courses of treatment again, and pathological changes is suppressed substantially fully, and symptoms such as infant ophthalmalgia, headache obviously alleviate.
105 routine age-related macular degeneration clinical observation experiments:
To 105 examples (114 suffer from eye) age-related macular degeneration (AMD) patient (clinical diagnosis standard foundation: ophthalmology branch of Chinese Medical Association retinopathy group. senile degeneration of macula clinical diagnosis standard. retinopathy, 1987,3: inside back cover) carry out the intravitreal injection recombinant human vascular endothelial inhibin, suffer from the each 1.5mg of eye, per 4 week injections 1 time, after the administration 3 months, the result shows that the average central retina thickness of patient drops to 235 ± 99 μ m from injecting preceding 305 ± 89 μ m, and mean vision has increased by 1.69 row (p=0.001).Wherein remarkable result 39 examples (43 eyes) improve 3 row above (comprising 3 row) before vision is injected, retinal thickness decline, and macula lutea portion glass-film wart obviously reduces, and oozes out stagnation, and General Symptoms disappears substantially.Effective 60 examples (64 eyes), vision is than preceding raising 1～2 row, and macula lutea portion glass-film wart reduces, and oozes out minimizing, and General Symptoms obviously improves.DeGrain 6 examples (7 eyes), vision does not have obvious raising, and the optical fundus symptom does not have obvious improvement, needs to continue injection.The result of follow up survey shows in three months of administration, 54% patient is in 1 week of treatment back retinal thickness decline＞10%, 4 weeks, back 52 trouble eyes retina edema, subretinal fluid (SRF) and pigment epithelium disengaging (PED) symptoms obviously alleviated, even disappear, there are 36 above-mentioned symptoms of suffering from eye to disappear after 8 weeks again.
The present invention directly carries out intravitreal injection with recombinant human vascular endothelial inhibin and treats the angiogenic retinopathy, and its beneficial effect that brings is:
1) excavates the therapeutic use of the new indication of recombinant human vascular endothelial inhibin, opened up a new application.
2) propagation of the special inhibition of recombinant human vascular endothelial inhibin of the present invention optical fundus focus new vessels, safety non-toxic has no drug resistance, and indicating has good application prospects.
3) the present invention directly carries out intravitreal injection with recombinant human vascular endothelial inhibin and treats the angiogenic retinopathy, and Therapeutic Method is simple and efficient, and produce effects is fast, and it is wide to be suitable for the disease scope.
The specific embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment 1
Preparation contains the injection of recombinant human vascular endothelial inhibin, makes its every milliliter to contain vascellum esoderma inhibin 2mg, mannitol 8mg, and adding concentration is 6.5 for 10mM sodium acetate adjusting pH value.Filtration sterilization, sterile filling, every 3ml.
Usage and consumption: this medicine is injected normal saline or glucose injection, intravitreal injection, consumption is taken the circumstances into consideration plus-minus according to the state of an illness, per 4 weeks 1 time.
Embodiment 2
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 151.5ml concentration after using acetic acid-sodium acetate buffer system about 30mM pH5.5 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 9.9mg/ml, add 20% mannitol 60ml and 20% sucrose solution 7.5ml, add the acetic acid-sodium-acetate buffer 2.98ml about 1.5M pH5.5, add injection water to 300ml.Through 0.22 μ m microporous filter membrane aseptic filtration, be sub-packed in the pre-encapsulated injector, in 4 ℃ of preservations.
Embodiment 3:
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 90.9ml concentration after using acetic acid-sodium acetate buffer system about 30mM pH5.5 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 9.9mg/ml, add 20% mannitol 60ml, add the acetic acid-sodium-acetate buffer 4.20ml about 1.5M pH5.5, add injection water to 300ml.Through 0.22 μ m microporous filter membrane aseptic filtration, be sub-packed in the cillin bottle, add butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-40 ℃, keeps 3-4 hour, evacuation, the dividing plate heating makes products temperature be increased to-20 ℃, kept 8 hours, continue heating elevated temperature to 25 ℃, kept 6 hours, change when little to vacuum, take out after the vacuum tamponade, roll lid.
Embodiment 4:
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 151.5ml concentration after using acetic acid-sodium acetate buffer system about 30mM pH5.5 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 9.9mg/ml, add 20% mannitol 60ml and 20% sucrose solution 15ml, add the acetic acid-sodium-acetate buffer 2.98ml about 1.5M pH5.5, add injection water to 300ml.Through 0.22 μ m microporous filter membrane aseptic filtration, be sub-packed in the cillin bottle, add butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-40 ℃, keeps 4-5 hour, evacuation, the dividing plate heating makes products temperature be increased to-25 ℃, kept 10 hours, continue heating elevated temperature to 30 ℃, kept 4 hours, change when little to vacuum, take out after the vacuum tamponade, roll lid.
Embodiment 5:
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 97.8ml concentration after using acetic acid-sodium acetate buffer system about 30mM pH5.5 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 30.61mg/ml, add 20% mannitol 60ml and 20% sucrose solution 60ml, add the acetic acid-sodium-acetate buffer 4.04ml about 1.5M pH5.5, add injection water to 300ml.Through 0.22 μ m microporous filter membrane aseptic filtration, be sub-packed in the cillin bottle, add butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-45 ℃, keeps 6 hours, evacuation, the dividing plate heating makes products temperature be increased to-30 ℃, kept 6 hours, the reheat elevated temperature kept 6 hours to-25 ℃, continue heating elevated temperature to 25 ℃, kept 8 hours, and changed when little to vacuum and take out after the vacuum tamponade, roll lid.
Embodiment 6:
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 147ml concentration after using acetic acid-sodium acetate buffer system about 30mM pH5.5 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 30.61mg/ml, add 20% mannitol 60ml, 20% sucrose solution 60ml and 20% aqueous trehalose 30ml, add the acetic acid-sodium-acetate buffer 3.06ml about 1.5M pH5.5, add injection water to 300ml.Through 0.22 μ m microporous filter membrane aseptic filtration, be sub-packed in the cillin bottle, add butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-45 ℃, keeps 2-4 hour, evacuation, the dividing plate heating makes products temperature be increased to-30 ℃, kept 12 hours, continue heating elevated temperature to 30 ℃, kept 6 hours, change when little to vacuum, take out after the vacuum tamponade, roll lid.
Embodiment 7:
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 30ml concentration after using citric acid-sodium citrate buffer system about 10mM pH6.0 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 9.9mg/ml, add 2% glycine 15ml, tween 80 0.15ml, add the citric acid-sodium citrate buffer 2.70ml about 1.0M pH6.5, add injection water to 300ml.Through 0.22 μ m microporous filter membrane aseptic filtration, be sub-packed in the cillin bottle, add butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-40 ℃, keeps 2-4 hour, evacuation, the dividing plate heating makes products temperature be increased to-30 ℃, kept 8 hours, continue heating elevated temperature to 30 ℃, kept 8 hours, change when little to vacuum, take out after the vacuum tamponade, roll lid.
Embodiment 8:
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 73.5ml concentration after using sodium dihydrogen phosphate-sodium hydrogen phosphate buffer system about 10mM pH7.0 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 30.61mg/ml, add 2%EDTA 30ml, 20% mannitol solution 30ml and 20% sucrose solution 7.5ml, add the sodium dihydrogen phosphate-sodium hydrogen phosphate buffer 2.26ml about 1.5M pH7.0 ± 0.5, add injection water to 300ml.Through 0.22
The aseptic filtration of μ m microporous filter membrane is sub-packed in the cillin bottle, adds butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-45 ℃, keeps 8 hours, evacuation, the dividing plate heating makes products temperature be increased to-30 ℃, kept 12 hours, continue heating elevated temperature to 25 ℃, kept 10 hours, change when little to vacuum, take out after the vacuum tamponade, roll lid.
Embodiment 9:
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 15ml concentration after using acetic acid-sodium acetate buffer system about 30mM pH5.5 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 9.9mg/ml, add 10% glutamic acid 15ml and 10% threonine 15ml, add the acetic acid-sodium-acetate buffer 5.7ml about 1.5M pH5.5, add injection water to 300ml.Through 0.22 μ m microporous filter membrane aseptic filtration, be sub-packed in the cillin bottle, add butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-40 ℃, keeps 4-5 hour, evacuation, the dividing plate heating makes products temperature be increased to-25 ℃, kept 10 hours, continue heating elevated temperature to 30 ℃, kept 4 hours, change when little to vacuum, take out after the vacuum tamponade, roll lid.
Embodiment 10:
Recombinant human vascular endothelial inhibin protein solution ultrafiltration dialysis preparation 151.5ml concentration after using acetic acid-sodium acetate buffer system about 30mM pH5.5 ± 0.5 to purification is the recombinant human vascular endothelial inhibin solution of 9.9mg/ml, add 20% human albumin's solution 30ml, add the acetic acid-sodium-acetate buffer 2.98ml about 1.5M pH5.5, add injection water to 300ml.Through 0.22 μ m microporous filter membrane aseptic filtration, be sub-packed in the cillin bottle, add butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-40 ℃, keeps 4-5 hour, evacuation, the dividing plate heating is increased to products temperature--and 15 ℃, kept 10 hours, continue heating elevated temperature to 20 ℃, kept 10 hours, change when little to vacuum, take out after the vacuum tamponade, roll lid.
Embodiment 11:
Take by weighing recombinant human vascular endothelial inhibin microsphere (PLGA enclose) 30g, interior enclose recombinant human vascular endothelial inhibin 3g, add 20% mannitol 60ml, 20% sucrose solution 15ml adds the acetic acid-sodium-acetate buffer 6.0ml about 1.5MpH5.5, adds injection water to 300ml, be sub-packed in the cillin bottle, add butyl rubber plug, medicinal liquid places in the freeze drying box, and products temperature drops to-40 ℃, kept 4-5 hour, evacuation, the dividing plate heating makes products temperature be increased to-25 ℃, kept 10 hours, continue heating elevated temperature to 30 ℃, kept 4 hours, change when little to vacuum, take out after the vacuum tamponade, roll lid.
Sequence table
＜110〉Shandong Xiansheng Maidejin Biological Pharmaceutical Co., Ltd.
＜120〉application of recombinant human vascular endothelial inhibin in pharmacy
<130>MP071323
<160>1
<170>PatentIn version 3.3
<210>1
<211>192
<212>PRT
<213>Artificial
<220>
＜223〉recombinant human vascular endothelial inhibin
<400>1
Met Gly Gly Ser His His His His His His Ser His Arg Asp Phe Gln
1 5 10 15
Pro Val Leu His Leu Val Ala Leu Asn Ser Pro Leu Ser Gly Gly Met
20 25 30
Arg Gly Ile Arg Gly Ala Asp Phe Gln Cys Phe Gln Gln Ala Arg Ala
35 40 45
Val Gly Leu Ala Gly Thr Phe Arg Ala Phe Leu Ser Ser Arg Leu Gln
50 55 60
Asp Leu Tyr Ser Ile Val Arg Arg Ala Asp Arg Ala Ala Val Pro Ile
65 70 75 80
Val Asn Leu Lys Asp Glu Leu Leu Phe Pro Ser Trp Glu Ala Leu Phe
85 90 95
Ser Gly Ser Glu Gly Pro Leu Lys Pro Gly Ala Arg Ile Phe Ser Phe
100 105 110
Asp Gly Lys Asp Val Leu Arg His Pro Thr Trp Pro Gln Lys Ser Val
115 120 125
Trp His Gly Ser Asp Pro Asn Gly Arg Arg Leu Thr Glu Ser Tyr Cys
130 135 140
Glu Thr Trp Arg Thr Glu Ala Pro Ser Ala Thr Gly Gln Ala Ser Ser
145 150 155 160
Leu Leu Gly Gly Arg Leu Leu Gly Gln Ser Ala Ala Ser Cys His His
165 170 175
Ala Tyr Ile Val Leu Cys Ile Glu Asn Ser Phe Met Thr Ala Ser Lys
180 185 190
Claims (12)
1. the application of recombinant human vascular endothelial inhibin in the medicine of preparation treatment angiogenic retinopathy.
2. the described application of claim 1 is characterized in that described recombinant human vascular endothelial inhibin is to add 0-4 arbitrary amino acid and 2-8 histidine sequence behind the initial amino acid Met of human Endostatin encoding amino acid sequence successively.
3. the described application of claim 2 is characterized in that the initial amino acid Met of described recombinant human vascular endothelial inhibin can be cut.
4. the described application of claim 2, the aminoacid sequence that it is characterized in that described recombinant human vascular endothelial inhibin is shown in SEQ ID NO:1.
5. each described application of claim 1-4, the preparation that it is characterized in that the medicine of described treatment angiogenic retinopathy is injection or lyophilized formulations.
6. the described application of claim 5, the active component that it is characterized in that described medicine are recombinant human vascular endothelial inhibin or the recombinant human vascular endothelial inhibin microspheres that recombinant human vascular endothelial inhibin, PEG modify.
7. the described application of claim 6, the molecular weight that it is characterized in that described PEG is 5000-30000, PEG links to each other with recombinant human vascular endothelial inhibin by covalent bond.
8. the described application of claim 6 is characterized in that described recombinant human vascular endothelial inhibin microsphere is to be mixed with by host material and recombinant human vascular endothelial inhibin to form.
9. the described application of claim 5 is characterized in that also containing in the described medicine protective agent and pH value regulator.
10. the described application of claim 9 is characterized in that described protective agent is selected from polyhydric alcohol, saccharide, aminoacid, surfactant, human albumin, EDTA and NaCl.
11. the described application of claim 9 is characterized in that the pH value scope of described medicine is 4.0-8.5.
12. the described application of claim 1 is characterized in that described angiogenic retinopathy comprises at least a in age-related macular degeneration, the exudative retinochoroiditis of centrality, proliferative vitreoretinopathy and the retinoblastoma.
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| CN107115522A (en) * | 2016-02-24 | 2017-09-01 | 山东先声生物制药有限公司 | A kind of recombinant human vascular endothelial inhibin pharmaceutical composition |
| CN107148277A (en) * | 2014-11-03 | 2017-09-08 | 清华大学 | A kind of medicine for suppressing Adipocyte Differentiation and insulin resistant |
| WO2018086603A1 (en) * | 2016-11-10 | 2018-05-17 | 北京普罗吉生物科技发展有限公司 | Pegylated endostatin analogue and application thereof |
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2008
- 2008-02-01 CN CNA2008100060628A patent/CN101219206A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107148277A (en) * | 2014-11-03 | 2017-09-08 | 清华大学 | A kind of medicine for suppressing Adipocyte Differentiation and insulin resistant |
| CN114558111A (en) * | 2014-11-03 | 2022-05-31 | 清华大学 | Medicine for inhibiting adipocyte differentiation and insulin resistance |
| CN104548067A (en) * | 2014-12-23 | 2015-04-29 | 浙江省人民医院 | Application of recombinant human endostatin in preparing drugs for treating ocular neovascular diseases |
| CN107115522A (en) * | 2016-02-24 | 2017-09-01 | 山东先声生物制药有限公司 | A kind of recombinant human vascular endothelial inhibin pharmaceutical composition |
| WO2018086603A1 (en) * | 2016-11-10 | 2018-05-17 | 北京普罗吉生物科技发展有限公司 | Pegylated endostatin analogue and application thereof |
| CN109963597A (en) * | 2016-11-10 | 2019-07-02 | 北京普罗吉生物科技发展有限公司 | Pegylation vascellum esoderma inhibin analog and its application |
| CN109963597B (en) * | 2016-11-10 | 2022-08-26 | 北京普罗吉生物科技发展有限公司 | Pegylated endostatin analogs and uses thereof |
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