CN109908085A - A kind of pharmaceutical carrier of respiratory tract administration, preparation method and its application in preparation treatment cardiotropic formulation - Google Patents
A kind of pharmaceutical carrier of respiratory tract administration, preparation method and its application in preparation treatment cardiotropic formulation Download PDFInfo
- Publication number
- CN109908085A CN109908085A CN201910330644.XA CN201910330644A CN109908085A CN 109908085 A CN109908085 A CN 109908085A CN 201910330644 A CN201910330644 A CN 201910330644A CN 109908085 A CN109908085 A CN 109908085A
- Authority
- CN
- China
- Prior art keywords
- phosphatide
- pharmaceutical carrier
- drug
- respiratory tract
- emulsion
- 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
- 210000002345 respiratory system Anatomy 0.000 title claims abstract description 50
- 239000003937 drug carrier Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 230000001426 cardiotropic effect Effects 0.000 title abstract description 3
- 238000009472 formulation Methods 0.000 title abstract description 3
- 239000000203 mixture Substances 0.000 title abstract description 3
- 239000000839 emulsion Substances 0.000 claims abstract description 73
- 239000003814 drug Substances 0.000 claims abstract description 49
- 229940079593 drug Drugs 0.000 claims abstract description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 4
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 claims description 58
- 102000004169 proteins and genes Human genes 0.000 claims description 33
- 108090000623 proteins and genes Proteins 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 16
- 239000006071 cream Substances 0.000 claims description 11
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 11
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 10
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 10
- -1 small molecule compound Chemical class 0.000 claims description 10
- 239000007908 nanoemulsion Substances 0.000 claims description 6
- 229920001184 polypeptide Polymers 0.000 claims description 6
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 4
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 4
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 4
- FRKBLBQTSTUKOV-UHFFFAOYSA-N diphosphatidyl glycerol Natural products OP(O)(=O)OCC(OP(O)(O)=O)COP(O)(O)=O FRKBLBQTSTUKOV-UHFFFAOYSA-N 0.000 claims description 4
- 229940067606 lecithin Drugs 0.000 claims description 4
- 239000000787 lecithin Substances 0.000 claims description 4
- 235000010445 lecithin Nutrition 0.000 claims description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 4
- 229940067626 phosphatidylinositols Drugs 0.000 claims description 4
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 4
- PRPAGESBURMWTI-UHFFFAOYSA-N [C].[F] Chemical compound [C].[F] PRPAGESBURMWTI-UHFFFAOYSA-N 0.000 claims description 3
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 2
- 102000007079 Peptide Fragments Human genes 0.000 claims description 2
- 108010033276 Peptide Fragments Proteins 0.000 claims description 2
- 230000008827 biological function Effects 0.000 claims description 2
- 230000004217 heart function Effects 0.000 claims description 2
- 102000039446 nucleic acids Human genes 0.000 claims description 2
- 108020004707 nucleic acids Proteins 0.000 claims description 2
- 150000007523 nucleic acids Chemical class 0.000 claims description 2
- 150000003384 small molecules Chemical class 0.000 claims description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 2
- 210000004072 lung Anatomy 0.000 abstract description 10
- 150000003904 phospholipids Chemical class 0.000 abstract description 6
- 102100035846 Pigment epithelium-derived factor Human genes 0.000 description 22
- 108090000102 pigment epithelium-derived factor Proteins 0.000 description 22
- 210000001519 tissue Anatomy 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 10
- 206010061216 Infarction Diseases 0.000 description 9
- 230000007574 infarction Effects 0.000 description 9
- 239000002504 physiological saline solution Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 210000004165 myocardium Anatomy 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 235000010469 Glycine max Nutrition 0.000 description 5
- 230000005540 biological transmission Effects 0.000 description 5
- 230000000747 cardiac effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000003387 muscular Effects 0.000 description 5
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229940083466 soybean lecithin Drugs 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 210000004413 cardiac myocyte Anatomy 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 210000005003 heart tissue Anatomy 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 210000003437 trachea Anatomy 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 244000046052 Phaseolus vulgaris Species 0.000 description 2
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 2
- 230000009692 acute damage Effects 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- VBVAVBCYMYWNOU-UHFFFAOYSA-N coumarin 6 Chemical compound C1=CC=C2SC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 VBVAVBCYMYWNOU-UHFFFAOYSA-N 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000020195 rice milk Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a kind of pharmaceutical carrier of respiratory tract administration, preparation method and its applications in preparation treatment cardiotropic formulation, including perfluor carbons compound, phosphatide, it is prepared into emulsion, the pharmaceutical carrier has continuous water phase and discontinuous perfluor carbon phase；Wherein, quality accounting of the perfluor carbons compound in the pharmaceutical carrier is 1%~60%；The accounting of the sum of the phosphatide and perfluor carbons compound quality in the pharmaceutical carrier is no more than 70%, and the ratio between phosphatide and perfluor carbons compound quality are 1: 30~30: 1；Surplus is water.Drug and phospholipid substance are formed drug phosphatide complexes by the present invention, the lipophilicity of drug can be enhanced, to allow medicament to improve delivery efficiency steadily in O/W emulsion oil phase, it is thus achieved that delivering the purpose of drug to heart in such a way that respiratory tract fills lung.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of pharmaceutical carrier of respiratory tract administration, its preparation side
Method and its application in preparation treatment cardiotropic formulation.
Background technique
With the appearance of protein science, the therapy field based on proteins/peptides is concerned, by grinding to macromolecular drug
Study carefully and develop peptides drug candidate, the application value of proteins/peptides is got more and more attention, but at present clinically there has been no safety,
The noninvasive proteins/peptides administration mode for heart disease.Current respiratory tract administration mode effectively can not be such that drug reaches
Heart.
Ideally it is necessary to have pharmaceutical carrier protected protein matter/peptide of biocompatibility and biodegradability,
Its dosage as much as possible is set to reach target tissue, reduction and treatment-related cost, and pharmaceutical carrier will not normal tissue production
Raw toxic side effect.
Summary of the invention
The purpose of this section is to summarize some aspects of the embodiment of the present invention and briefly introduce some preferable implementations
Example.It may do a little simplified or be omitted to avoid our department is made in this section and the description of the application and the title of the invention
Point, the purpose of abstract of description and denomination of invention it is fuzzy, and this simplification or omit and cannot be used for limiting the scope of the invention.
In view of above-mentioned technological deficiency, the present invention is proposed.
Therefore, as one aspect of the present invention, the present invention provides a kind of pharmaceutical carrier of respiratory tract administration.
In order to solve the above technical problems, the present invention provides the following technical scheme that a kind of pharmaceutical carrier of respiratory tract administration,
It includes perfluor carbons compound, phosphatide, is prepared into emulsion, and the pharmaceutical carrier has continuous water phase and discontinuous perfluor
Carbon phase；
Wherein, quality accounting of the perfluor carbons compound in the pharmaceutical carrier is 1%~60%；The phosphatide
It is no more than 70% with the accounting of the sum of perfluor carbons compound quality in the pharmaceutical carrier, phosphatide and perfluor carbons compound
Mass ratio is 1:30~30:1；Surplus is water.
A kind of preferred embodiment of pharmaceutical carrier as respiratory tract administration of the present invention: further including drug, the medicine
The mass ratio of object and phosphatide is 100:1~1:100.
A kind of preferred embodiment of pharmaceutical carrier as respiratory tract administration of the present invention: the matter of the drug and phosphatide
Amount is than being 1:(1~30), quality accounting of the perfluor carbons compound in the pharmaceutical carrier is 1%~20%, described
Quality accounting of the phosphatide in the pharmaceutical carrier is no more than 20%.
A kind of preferred embodiment of pharmaceutical carrier as respiratory tract administration of the present invention: the emulsion includes common
Cream, Submicron Emulsion, nano-emulsion, average grain diameter are 30nm~250nm.
A kind of preferred embodiment of pharmaceutical carrier as respiratory tract administration of the present invention: the drug, including have
One or more of the high molecular weight protein of biological function, polypeptide, small molecule peptide fragment, nucleic acid, small molecule compound.
A kind of preferred embodiment of pharmaceutical carrier as respiratory tract administration of the present invention: the phosphatide includes lecithin
Rouge, phosphatidyl choline (PC), phosphatidyl-ethanolamine (PE), phosphatidylserine (PS), phosphatidylinositols (PI), phosphatidyl glycerol
(PG), one or more of diphosphatidylglycerol (DG).
A kind of preferred embodiment of pharmaceutical carrier as respiratory tract administration of the present invention: the phosphatide includes that hydrogenation is big
Beans lecithin and/or egg yolk lecithin.
As one aspect of the present invention, the present invention provides the side of the pharmaceutical carrier of the preparation respiratory tract administration
Method.
In order to solve the above technical problems, the present invention provides the following technical scheme that the medicine of respiratory tract administration described in preparation
The method of object carrier comprising, phosphatide, perfluor carbons compound, water are uniformly mixed, oil-in-water type perfluorocarbon emulsion is prepared；
Or,
Drug is uniformly mixed with phosphatide and prepares drug phosphatide complexes, by the drug phosphatide complexes and perfluor carbons
Compound, water are uniformly mixed, and prepare oil-in-water type perfluorocarbon emulsion；Or,
Drug is uniformly mixed with phosphatide and prepares drug phosphatide complexes, by the drug phosphatide complexes and phosphatide, complete
Fluorine carbon compound, water are uniformly mixed, and prepare oil-in-water type perfluorocarbon emulsion.
As one aspect of the present invention, the present invention provides the pharmaceutical carrier in the drug for preparing respiratory tract administration
In application.
In order to solve the above technical problems, the present invention provides the following technical scheme that the pharmaceutical carrier is breathed in preparation
Application in the drug of canal drug administration.
A kind of preferred embodiment as application of the pharmaceutical carrier of the present invention in the drug for preparing respiratory tract administration:
The drug of the respiratory tract administration is protected for cardiac function.
Beneficial effects of the present invention: drug is loaded in the oily phase of O/W emulsion by the present invention, is enhanced drug lipophilicity, is being protected
On the basis of demonstrate,proving good biocompatibility and patient compliance, the delivery capability and efficiency of drug are improved.It allows medicament to stablize
Ground is in O/W emulsion oil phase, improves delivery efficiency, it is thus achieved that delivering drug to heart in such a way that respiratory tract fills lung
Purpose.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, required use in being described below to embodiment
Attached drawing be briefly described, it should be apparent that, drawings in the following description are only some embodiments of the invention, for this
For the those of ordinary skill of field, without any creative labor, it can also be obtained according to these attached drawings other
Attached drawing.Wherein:
Fig. 1 is transmission electron microscope observation bovine serum albumin(BSA) (BSA) phosphatide complexes perfluorocarbon emulsion emulsion droplet form.
Fig. 2 is that perfluorocarbon emulsion is detected by fluorescence microscope in the transmitting result of cellular level.
Fig. 3 is that fluorescence microscope is detected through respiratory tract application Cy5-BSA phosphatide complexes perfluorocarbon emulsion.
Fig. 4 was Western Blot method, was detected after respiratory tract application PEDF phosphatide complexes perfluorocarbon emulsion 8h, with
Control group is compared, the expression of results of rat heart muscle tissue PEDF.
Fig. 5 is the size for comparing infarct size after acute myocardial infarction AMI 6h by TTC experiment.
Fig. 6 is to be tested by CCK-8, detects influence of the perfluorocarbon emulsion to the cell activity of H9C2 cell.Control generation
Table control group, Saline represent physiological saline group, and PFOB represents perfluorocarbon emulsion group.
Fig. 7 is to be assessed complete through respiratory tract application Cy5-BSA phosphatide complexes by om observation lung tissue HE stained slice
To the influence of lung tissue after fluorocarbon emulsion 6h.Control, which is represented, does not process group normally；Saline represents physiological saline group；
PFOB represents perfluorocarbon emulsion group；Bar=50um.
Specific embodiment
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, right combined with specific embodiments below
A specific embodiment of the invention is described in detail.
In the following description, numerous specific details are set forth in order to facilitate a full understanding of the present invention, but the present invention can be with
Implemented using other than the one described here other way, those skilled in the art can be without prejudice to intension of the present invention
In the case of do similar popularization, therefore the present invention is not limited by the specific embodiments disclosed below.
Secondly, " one embodiment " or " embodiment " referred to herein, which refers to, may be included at least one realization side of the invention
A particular feature, structure, or characteristic in formula." in one embodiment " that different places occur in the present specification not refers both to
The same embodiment, nor the individual or selective embodiment mutually exclusive with other embodiments.
Embodiment 1:
The preparation of protein, phospholipid compound:
Bovine serum albumin(BSA) (Bovine serum albumin, BSA) 1mg is dissolved in the sodium dihydrogen phosphate of 3mlPH=6.5
(NaH2P04) in buffer, hydrogenated soy phosphatidyl choline 20mg is dissolved in 300ul dehydrated alcohol, and reaction, reaction controlling is mixed
Mass ratio is 1:20, is freeze-dried after reaction, and 21mgBSA phosphatide complexes are obtained.
Embodiment 2:
The preparation of perfluorocarbon emulsion:
Perfluoro bromide octane (PFOB) is emulsified with hydrogenated soy phosphatidyl choline, specifically: it is hydrogenated using 60 μ lPFOB, 40mg big
Beans lecithin, 940 μ l distilled water obtain 1000 μ l perfluorocarbon emulsions.
Operating process: mixing hydrogenated soy phosphatidyl choline (40mg), PFOB (60 μ l) and distilled water (940 μ l), magnetic agitation
Uniformly, it is squeezed out 15 times repeatedly using Avanti liposome extruder (0.1 μm), is oil-in-water type cream to obtain perfluorocarbon emulsion
Agent.
Embodiment 3:
The preparation of protein, phospholipid compound perfluorocarbon emulsion (is illustrated by taking protein as an example, originally in specification embodiment
Field technical staff is obviously able to know that, present protein is replaced with polypeptide or other drugs molecule equally can
Implement):
Protein, phospholipid compound, the 940 μ l distilled water prepared using 60 μ lPFOB, 41mg embodiment 1 obtain 1000 μ l eggs
White phosphorus fat complexes perfluorocarbon cream.
Mixed protein phosphatide complexes (21mg), hydrogenated soy phosphatidyl choline (20mg), PFOB (60 μ l) and distilled water (940
μ l), magnetic agitation is uniform, is squeezed out 15 times repeatedly using Avanti liposome extruder (0.1um), compound to obtain BSA phosphatide
Object perfluorocarbon cream.
Perfluorocarbon cream is observed by transmission electron microscope (transmission electron microscope, TEM)
The form of agent.Firstly, taking the copper mesh for having been coated with agraphitic carbon to infiltrate 5- in lotion for 100 times of preparation diluent of preparation
10min is placed in the culture dish for being placed with filter paper, spontaneously dries, then sample is put into transmission electron microscope sample slot, is seen
It examines.The results show that the emulsion droplet size of the perfluorocarbon emulsion is about 100nm, Fig. 1 is seen.
Embodiment 4:
The preparation of protein, phospholipid compound perfluorocarbon emulsion:
The protein, phospholipid compound and 20mg hydrogenated soy phosphatidyl choline, 940 μ prepared using 60 μ lPFOB, 21mg embodiment 1
L distilled water obtains 1000 μ l protein, phospholipid compound perfluorocarbon creams.
Mixed protein phosphatide complexes (41mg), PFOB (60 μ l) and distilled water (940 μ l), magnetic agitation is uniform.It uses
Avanti liposome extruder (0.1um) squeezes out 15 times repeatedly, to obtain protein, phospholipid compound perfluorocarbon lotion.
Embodiment 5:
The transmitting of perfluorocarbon emulsion prepared by embodiment 3 on a cellular level:
It is dissolved in 60 μ lPFOB with particle fluorescence substance coumarin 6, the perfluorocarbon of preparation 1000 μ l coumarin 6s label is received
The emulsion (100 μ l) is added in H9C2 Tissue Culture Dish for rice milk agent, insulating box incubation 4h, fluorescence microscopy microscopic observation, this
Experiment is repeated 4 times, and fluorescence results are shown in Fig. 2.The result shows that perfluorocarbon emulsion can be smoothly by cellular uptake.
Embodiment 6:
Perfluorocarbon emulsion prepared by embodiment 3 is for passing through respiratory tract mode transferrin matter to heart:
Flower cyanogen dyestuff Cy5 label BSA:BSA is dissolved in the sodium dihydrogen phosphate (NaH of PH=6.52P04) in buffer, magnetic force stirs
It mixes down, Cy5-NHS solution (1mg/ml, DMSO) slowly is added thereto, 25 DEG C, react 12h.Reaction controlling mass ratio is 200:
1.Mixing sample is placed in bag filter (MW:14000Da) after reaction, then bag filter is placed in is equipped with 1L concentration
It dialyses 2 days, stirs in the aqueous acetic acid of 1% (V/V), every 12h replaces an aqueous acetic acid.It is freezed after dialysis dry
It is dry to get Cy5-BSA.
Prepare Cy5-BSA phosphatide complexes with Cy5-BSA and soybean lecithin: with Cy5-BSA phosphatide complexes (42mg),
Cy5-BSA phosphatide complexes perfluorocarbon cream is made in soybean lecithin (40mg), PFOB (120 μ l), distilled water (1880 μ l)
Agent (2000 μ l), then carries out In vivo study.
Tracheal instillation perfluorocarbon emulsion: after rat (250g) anesthesia, trachea cannula, instillation Cy5-BSA phosphatide complexes
Perfluorocarbon emulsion (500 μ l), using 6h after instiling as point of observation, experimental group rat quantity is 4.
It can be transferred to cardiac muscular tissue by respiratory tract for evaluation protein, after tracheal instillation nanoemulsion 6h, removed
Heart tissue cooks frozen section, and under the microscope, fluorescence results are shown in Fig. 3 to fluorescence microscopy.Cy5-BSA is through respiratory tract success as the result is shown
Rat heart muscle tissue is reached, and is absorbed and used, shows that protein can be by non-intrusion type mode application, from respiratory tract approach
It is transferred to cardiac muscular tissue.
Embodiment 7:
The transmitting of therapeutic protein:
The transmitting of example therapeutic protein: pigment epidermal derived factors (Pigment Epithelium-Derived
Factor, PEDF) cardiac muscle cell's glycometabolism can be reduced under anoxic conditions, the cardiac muscle after heart infarction occurs has protective effect.
The perfluorocarbon emulsion carrier prepared through the invention is transferred to heart by respiratory tract, the cardiac muscle cell after protection heart infarction generation.
It prepares PEDF phosphatide complexes perfluorocarbon emulsion: being prepared with pedf protein (2mg), soybean lecithin (40mg)
PEDF phosphatide complexes (42mg).With PEDF phosphatide complexes (42mg), soybean lecithin (40mg), PFOB (120 μ l), distillation
PEDF phosphatide complexes perfluorocarbon emulsion (2000 μ l) is made in water (1880 μ l), then carries out In vivo study.
Tracheal instillation perfluorocarbon emulsion: after rat (250g) anesthesia, trachea cannula, instillation PEDF phosphatide complexes perfluor
Carbon nanoemulsion (500 μ l), using 8h after instiling as point of observation.
The transmitting result of exemplary treatment protein: it can be transferred to by respiratory tract for evaluation human cytokines PEDF
Heart tissue is removed after tracheal instillation nanoemulsion 8h by cardiac muscular tissue, row protein immunoblotting (Western Blot,
WB) method detects, and as a result sees Fig. 4.
The treatment results of exemplary treatment protein: it can be transferred to by respiratory tract for evaluation human cytokines PEDF
Cardiac muscular tissue, and the protective effect of the cardiac muscle cell after heart infarction occurs is played, after tracheal instillation nanoemulsion 8h, ligation is big
Mouse ramus descendens anterior arteriae coronariae sinistrae causes myocardial infarction and ischemia model, and 6h removes heart tissue, and row TTC decoration method calculates infarct size.It is right
According to group not do myocardial ischemia 6h group after any processing group, tracheal instillation physiological saline 8h normally, TTC result is shown in Fig. 5.As a result it shows
Show by way of respiratory tract administration, human cytokines PEDF effectively reduces the infarct size of rat heart muscle.
Embodiment 8:
The toxicity detection of perfluorocarbon emulsion:
Influence of the perfluorocarbon emulsion to cell activity:
It is inoculated with H9C2 cell suspension in 96 orifice plates, 5000/hole of quantity is inoculated with, by culture plate in cell incubator (37
DEG C, 5%CO2) in culture for 24 hours.
1ml perfluorocarbon emulsion is prepared according to above-described embodiment method, 10ul is added in every hole in culture plate, continues to cultivate
24h.Same amount of normal saline is added without any processing, physiological saline group in control group.
Under the conditions of being protected from light, 10ulCCK-8 solution is added to every hole, culture plate is incubated for 2h in incubator.
The absorbance at 450nm is measured with microplate reader, which is repeated 3 times, and as a result sees Fig. 6.Perfluorocarbon as the result is shown
Emulsion does not impact the cell activity of H9C2 cell.
Influence of the perfluorocarbon emulsion to animal:
2ml perfluorocarbon emulsion is prepared according to above-described embodiment method, then carries out animal In vivo study.
Tracheal instillation perfluorocarbon emulsion: after rat (250g ± 15g) anesthesia, trachea cannula, instillation perfluorocarbon cream
Agent (500 μ l), abdominal aorta sacrificed by exsanguination after 6h remove lung tissue, and sterile buffer is rinsed, and 4% paraformaldehyde is fixed, and
Routine paraffin wax embedding and HE dyeing processing, light microscopic observation pulmonary morphology are carried out afterwards.The experiment is repeated 3 times, and as a result sees Fig. 7.
Perfluorocarbon emulsion does not cause acute injury to lung tissue as the result is shown.
Compared to w/o type emulsion, O/W emulsion of the present invention has better biocompatibility and patient compliance.However it passes
The hydrophilic protein matter of system O/W emulsion is always present in water phase, is unable to reach and is passed using emulsion realization by respiratory tract albumen
It send to the purpose of heart, delivery efficiency is caused to decline or fail.Therefore, the present invention is by protein, polypeptide or other molecular drugs
It is loaded in the oily phase of O/W emulsion, enhances drug lipophilicity, on the basis of guaranteeing good biocompatibility and patient compliance,
Improve the delivery capability and efficiency of protein or polypeptide.The drugs such as protein or polypeptide and phospholipid substance are formed medicine by the present invention
Object phosphatide complexes, can enhance the lipophilicity of drug, to allow medicament to improve steadily in O/W emulsion oil phase
Delivery efficiency, it is thus achieved that delivering the purpose of drug to heart in such a way that respiratory tract fills lung.
Fig. 1 has by transmission electron microscope observation BSA phosphatide complexes perfluorocarbon emulsion emulsion droplet form, emulsion droplet
The diameter of 100nm or so.Bar=50nm.
Fig. 2 detects perfluorocarbon emulsion in the transmitting result of H9C2 cellular level by fluorescence microscope.Arrow meaning represents
Fluorescent material coumarin 6, bar=20um.
Fig. 3 is detected by fluorescence microscope through respiratory tract application Cy5-BSA phosphatide complexes perfluorocarbon emulsion, is passed after 6h
It is handed to the result of rat heart muscle tissue.Arrow meaning represents Cy5-BSA, bar=20um.
Fig. 4 is detected after respiratory tract application PEDF phosphatide complexes perfluorocarbon emulsion 8h by Western Blot method, with
Control group is compared, the expression of results of rat heart muscle tissue PEDF.His-tag represents the distinctive histidine tag of exogenous PEDF.
Control, which is represented, does not process group normally；Saline represents physiological saline group；PEDF represents PEDF phosphatide complexes perfluorocarbon cream
Agent group.As can be seen from the figure human cytokines PEDF can be transferred to cardiac muscular tissue by respiratory tract.
Fig. 5 compares the size of infarct size after acute myocardial infarction AMI 6h by TTC experiment, verifies through respiratory tract application PEDF
Protective effect after phosphatide complexes perfluorocarbon emulsion, to heart.Control, which is represented, does not process group normally；Saline is represented
Physiological saline group；PEDF represents PEDF phosphatide complexes perfluorocarbon emulsion group.It is black-and-blue to represent normal area；Red represents ischemic
Area；White represents infarct size.From attached drawing it can be seen that by way of respiratory tract administration, human cytokines PEDF is effectively reduced
The infarct size of rat heart muscle.
Fig. 6 is to be tested by CCK-8, detects influence of the perfluorocarbon emulsion to the cell activity of H9C2 cell.Control generation
Table control group, Saline represent physiological saline group, and PFOB represents perfluorocarbon emulsion group.Perfluorocarbon emulsion is not to H9C2 as the result is shown
The cell activity of cell impacts.
Fig. 7 is to be assessed complete through respiratory tract application Cy5-BSA phosphatide complexes by om observation lung tissue HE stained slice
To the influence of lung tissue after fluorocarbon emulsion 6h.Control, which is represented, does not process group normally；Saline represents physiological saline group；
PFOB represents perfluorocarbon emulsion group；Bar=50um.Perfluorocarbon emulsion does not cause acute injury to lung tissue as the result is shown.
Perfluorocarbon emulsion of the present invention using protein, phosphatide, PFC, water as raw material, the emulsion of formation have continuous water phase and
Discontinuous perfluor carbon phase, final product are that protein, phospholipid compound is loaded in the oil-in-water emulsion in perfluorocarbon emulsion droplet.The cream
Agent property is stablized, and is easy to save, and production method is simple, low for equipment requirements, is conducive to continuous production, is the clinic of protein
Using the new mode of offer.
It should be noted that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to preferable
Embodiment describes the invention in detail, those skilled in the art should understand that, it can be to technology of the invention
Scheme is modified or replaced equivalently, and without departing from the spirit and scope of the technical solution of the present invention, should all be covered in this hair
In bright scope of the claims.
Claims (10)
1. a kind of pharmaceutical carrier of respiratory tract administration, it is characterised in that: including perfluor carbons compound, phosphatide, it is prepared into emulsion,
The pharmaceutical carrier has continuous water phase and discontinuous perfluor carbon phase；
Wherein, quality accounting of the perfluor carbons compound in the pharmaceutical carrier is 1%~60%；The phosphatide and complete
Accounting of the sum of the fluorine carbon compound quality in the pharmaceutical carrier is no more than 70%, phosphatide and perfluor carbons compound quality
The ratio between be 1:30~30:1；Surplus is water.
2. the pharmaceutical carrier of respiratory tract administration as described in claim 1, it is characterised in that: further include drug, the drug with
The mass ratio of phosphatide is 100:1~1:100.
3. the pharmaceutical carrier of respiratory tract administration as claimed in claim 2, it is characterised in that: the mass ratio of the drug and phosphatide
For 1:(1~30), quality accounting of the perfluor carbons compound in the pharmaceutical carrier is 1%~20%, the phosphatide
Quality accounting in the pharmaceutical carrier is no more than 20%.
4. the pharmaceutical carrier of respiratory tract administration according to any one of claims 1 to 3, it is characterised in that: the emulsion packet
Common cream, Submicron Emulsion, nano-emulsion are included, average grain diameter is 30nm~250nm.
5. the pharmaceutical carrier of respiratory tract administration according to any one of claims 1 to 3, it is characterised in that: the drug, packet
Include one or more of high molecular weight protein with biological function, polypeptide, small molecule peptide fragment, nucleic acid, small molecule compound.
6. the pharmaceutical carrier of respiratory tract administration according to any one of claims 1 to 3, it is characterised in that: the phosphatide packet
Include lecithin, phosphatidyl choline (PC), phosphatidyl-ethanolamine (PE), phosphatidylserine (PS), phosphatidylinositols (PI), phosphatide
One or more of acyl glycerol (PG), diphosphatidylglycerol (DG).
7. the pharmaceutical carrier of respiratory tract administration according to any one of claims 1 to 3, it is characterised in that: the phosphatide packet
Include hydrogenated soy phosphatidyl choline and/or egg yolk lecithin.
8. the method for preparing the pharmaceutical carrier of respiratory tract administration described in claim 1, it is characterised in that: including by phosphatide, entirely
Fluorine carbon compound, water are uniformly mixed, and prepare oil-in-water type perfluorocarbon emulsion；Or,
Drug is uniformly mixed with phosphatide and prepares drug phosphatide complexes, by the drug phosphatide complexes and perfluor carbons chemical combination
Object, water are uniformly mixed, and prepare oil-in-water type perfluorocarbon emulsion；Or,
Drug is uniformly mixed with phosphatide and prepares drug phosphatide complexes, by the drug phosphatide complexes and phosphatide, perfluorocarbon
Class compound, water are uniformly mixed, and prepare oil-in-water type perfluorocarbon emulsion.
9. application of the pharmaceutical carrier according to any one of claims 1 to 8 in the drug for preparing respiratory tract administration.
10. application of the pharmaceutical carrier as claimed in claim 9 in the drug for preparing respiratory tract administration, it is characterised in that: institute
The drug for stating respiratory tract administration is protected for cardiac function.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910330644.XA CN109908085B (en) | 2019-04-23 | 2019-04-23 | Respiratory tract administration medicine carrier, its preparation method and application in preparing medicine for treating heart disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910330644.XA CN109908085B (en) | 2019-04-23 | 2019-04-23 | Respiratory tract administration medicine carrier, its preparation method and application in preparing medicine for treating heart disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109908085A true CN109908085A (en) | 2019-06-21 |
| CN109908085B CN109908085B (en) | 2021-12-03 |
Family
ID=66978253
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910330644.XA Active CN109908085B (en) | 2019-04-23 | 2019-04-23 | Respiratory tract administration medicine carrier, its preparation method and application in preparing medicine for treating heart disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109908085B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112190547A (en) * | 2020-09-30 | 2021-01-08 | 北京诺康达医药科技股份有限公司 | Lipid microsphere composition and preparation method thereof |
| WO2024046999A1 (en) | 2022-08-31 | 2024-03-07 | Johann Wolfgang Goethe-Universität Frankfurt am Main | Lecithin-modified nanoscale oxygen carriers (lenox) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1195981A (en) * | 1995-06-07 | 1998-10-14 | 联合药品公司 | Reverse fluorocarbon emulsion compositions for drug delivery |
| WO2015034940A1 (en) * | 2013-09-03 | 2015-03-12 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Cardioprotectant to reduce damage from heart attack |
| CN105343001A (en) * | 2015-11-02 | 2016-02-24 | 上海交通大学 | Oxygen-carried fluorocarbon emulsion and preparation method thereof |
| CN109620818A (en) * | 2018-01-19 | 2019-04-16 | 中国药科大学 | Lipid nanometer emulsion for pulmonary drug delivery enhancing pulmonary drug accumulation |
-
2019
- 2019-04-23 CN CN201910330644.XA patent/CN109908085B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1195981A (en) * | 1995-06-07 | 1998-10-14 | 联合药品公司 | Reverse fluorocarbon emulsion compositions for drug delivery |
| WO2015034940A1 (en) * | 2013-09-03 | 2015-03-12 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Cardioprotectant to reduce damage from heart attack |
| CN105343001A (en) * | 2015-11-02 | 2016-02-24 | 上海交通大学 | Oxygen-carried fluorocarbon emulsion and preparation method thereof |
| CN109620818A (en) * | 2018-01-19 | 2019-04-16 | 中国药科大学 | Lipid nanometer emulsion for pulmonary drug delivery enhancing pulmonary drug accumulation |
Non-Patent Citations (4)
| Title |
|---|
| DIANE L NELSON,ET AL.,: "In vitro evaluation of lysophosphatidic acid delivery via reverse perfluorocarbon emulsions to enhance alveolar epithelial repair", 《COLLOIDS SURF B BIOINTERFACES》 * |
| 代坤坤: "蜂毒素全氟碳纳米囊的制备及评价", 《安徽医科大学学报》 * |
| 林典义主编: "《呼吸内科疾病诊疗新进展》", 31 January 2015, 西安交通大学出版社 * |
| 王晓波主编: "《药物运释系统》", 31 August 2007, 中国医药科技出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112190547A (en) * | 2020-09-30 | 2021-01-08 | 北京诺康达医药科技股份有限公司 | Lipid microsphere composition and preparation method thereof |
| WO2024046999A1 (en) | 2022-08-31 | 2024-03-07 | Johann Wolfgang Goethe-Universität Frankfurt am Main | Lecithin-modified nanoscale oxygen carriers (lenox) |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109908085B (en) | 2021-12-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6433079B2 (en) | Drug carrier and drug carrier kit for suppressing fibrosis | |
| Kong et al. | Cationic solid lipid nanoparticles derived from apolipoprotein-free LDLs for target specific systemic treatment of liver fibrosis | |
| Zhao et al. | Experiment on the feasibility of using modified gelatin nanoparticles as insulin pulmonary administration system for diabetes therapy | |
| CN108451929B (en) | Recombinant lipoprotein with solid-phase kernel entrapped and preparation and application thereof | |
| CN106333926A (en) | Brain tumor multiple targeting drug delivery system of stability polypeptide mediated cross-barrier film | |
| CN109908085A (en) | A kind of pharmaceutical carrier of respiratory tract administration, preparation method and its application in preparation treatment cardiotropic formulation | |
| CN101394861A (en) | Extended release of neuregulin for improved cardiac function | |
| CN110960688A (en) | Low-toxicity bionic nano system for improving curative effect of pancreatic cancer and preparation method thereof | |
| CN108187061B (en) | Drug delivery system targeting brown adipose tissue | |
| CN111450061A (en) | Hybrid mesenchymal stem cell exosome drug delivery system and preparation method and application thereof | |
| JP3910646B2 (en) | "Composition for gene transfer into cells" | |
| Zhao et al. | Construction of functional targeting daunorubicin liposomes used for eliminating brain glioma and glioma stem cells | |
| CN115252582A (en) | Preparation and application of erythrocyte membrane heterozygosis pH liposome coated oncolytic virus preparation | |
| JP2008050375A (en) | Drug carrier and drug carrier kit for inhibiting fibrosis | |
| CA2356701C (en) | Gene therapy for diabetic ischemic disease | |
| Navarro et al. | Cell tolerability and biodistribution in mice of indocyanine green-loaded lipid nanoparticles | |
| CN103040910B (en) | Cervus and cucumis polypeptide liposome injection | |
| CN114848831A (en) | Coated nano preparation and preparation method and application of carrier thereof | |
| CN114533760A (en) | Manganese-based nanoenzyme as iron death inhibitor and application thereof in liver injury | |
| CN108096189A (en) | A kind of elaioplast nanometer particle and its pharmaceutical composition and application | |
| CN107334739A (en) | A kind of fibroblast growth factor liposome freeze-dried powder for preventing and treating alopecia and preparation method thereof | |
| CN108853054A (en) | A kind of gambogicacid nano structured lipid carrier and preparation method thereof of cyclic peptide modification | |
| CN110279661A (en) | A kind of Nanoparticulate compositions delivery system, preparation method and its usage | |
| CN105832702B (en) | For the protein nano magnetic crust core capsule of drug delivery and its application | |
| CN112569189A (en) | Low-toxicity biomimetic nano system capable of simultaneously regulating tumor microenvironment and killing tumor cells in targeted manner and construction method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200527 Address after: No. 38, Hequn lane, Quanshan District, Xuzhou City, Jiangsu Province Applicant after: Chen Changshun Address before: 221000 No. 209 Copper Mountain Road, Jiangsu, Xuzhou Applicant before: XUZHOU MEDICAL University |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200630 Address after: Room 601, unit 3, building 2, 50 jiaheqian street, Quanshan District, Xuzhou City, Jiangsu Province Applicant after: Dong Hongyan Address before: No. 38, Hequn lane, Quanshan District, Xuzhou City, Jiangsu Province Applicant before: Chen Changshun |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230424 Address after: Floor 2, Building 10, Huaihai Health Industrial Park, No. 118 Huanghe West Road, Quanshan District, Xuzhou City, Jiangsu Province, 221000 Patentee after: Huarong (Xuzhou) Biomedical Technology Development Research Institute Co.,Ltd. Address before: Room 601, unit 3, building 2, 50 jiaheqian street, Quanshan District, Xuzhou City, Jiangsu Province, 221000 Patentee before: Dong Hongyan |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240507 Address after: Room 601, Unit 3, Building 2, No. 50 Jiaheqian Street, Quanshan District, Xuzhou City, Jiangsu Province, 221002 Patentee after: Dong Hongyan Country or region after: China Address before: Floor 2, Building 10, Huaihai Health Industrial Park, No. 118 Huanghe West Road, Quanshan District, Xuzhou City, Jiangsu Province, 221000 Patentee before: Huarong (Xuzhou) Biomedical Technology Development Research Institute Co.,Ltd. Country or region before: China |
|
| TR01 | Transfer of patent right |