CN107157940A - A kind of Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere and preparation method thereof - Google Patents
A kind of Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere and preparation method thereof Download PDFInfo
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- CN107157940A CN107157940A CN201710551087.5A CN201710551087A CN107157940A CN 107157940 A CN107157940 A CN 107157940A CN 201710551087 A CN201710551087 A CN 201710551087A CN 107157940 A CN107157940 A CN 107157940A
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- sulphuric acid
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- cephalosporium quinol
- acid cephalosporium
- gelatine microsphere
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Links
- 241001619326 Cephalosporium Species 0.000 title claims abstract description 62
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 239000001117 sulphuric acid Substances 0.000 title claims abstract description 62
- 235000011149 sulphuric acid Nutrition 0.000 title claims abstract description 62
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229920000159 gelatin Polymers 0.000 title claims abstract description 56
- 235000019322 gelatine Nutrition 0.000 title claims abstract description 56
- 239000004005 microsphere Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 239000001828 Gelatine Substances 0.000 title claims abstract description 37
- 210000004072 lung Anatomy 0.000 title claims abstract description 35
- 230000008685 targeting Effects 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 82
- 229940079593 drug Drugs 0.000 claims abstract description 50
- YWKJNRNSJKEFMK-PQFQYKRASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 YWKJNRNSJKEFMK-PQFQYKRASA-N 0.000 claims abstract description 25
- 229950009592 cefquinome Drugs 0.000 claims abstract description 25
- 238000000498 ball milling Methods 0.000 claims abstract description 21
- 108010010803 Gelatin Proteins 0.000 claims abstract description 19
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002270 dispersing agent Substances 0.000 claims abstract description 19
- 239000008273 gelatin Substances 0.000 claims abstract description 19
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 19
- 239000007788 liquid Substances 0.000 claims abstract description 15
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 14
- 239000000661 sodium alginate Substances 0.000 claims abstract description 14
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000013019 agitation Methods 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000007921 spray Substances 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 239000012153 distilled water Substances 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000002604 ultrasonography Methods 0.000 claims description 20
- 239000011805 ball Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 15
- 239000011806 microball Substances 0.000 claims description 8
- 238000001694 spray drying Methods 0.000 claims description 8
- 238000013022 venting Methods 0.000 claims description 8
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims 1
- 239000000194 fatty acid Substances 0.000 claims 1
- 229930195729 fatty acid Natural products 0.000 claims 1
- 150000004665 fatty acids Chemical class 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 238000011084 recovery Methods 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 7
- 241001465754 Metazoa Species 0.000 abstract description 6
- 238000005538 encapsulation Methods 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 210000001519 tissue Anatomy 0.000 description 38
- 239000000523 sample Substances 0.000 description 18
- 241000700159 Rattus Species 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000012224 working solution Substances 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003182 parenteral nutrition solution Substances 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000003672 processing method Methods 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 210000005003 heart tissue Anatomy 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010010254 Concussion Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000001033 granulometry Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000010827 pathological analysis Methods 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011410 subtraction method Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a kind of Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere and preparation method thereof, belong to animal antibiotic targeting preparation technical field, preparation method comprises the following steps：Bulk drug is mixed with dispersant, and ball milling volatilizes liquid, obtains raw materials treated medicine；Gelatin and sodium alginate are weighed as carrier, it is dissolved under the conditions of 40 50 DEG C in distilled water, heating stirring is until completely dissolved, Cefquinome is added, glidant is added, mixed, add glutaraldehyde solution, then it is spray-dried using double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.The microsphere encapsulation rate of the present invention is more than 90%, and drugloading rate more than 20%, more than 90% microspherulite diameter is distributed in the range of 10 ~ 25um, and this preparation method is easy to operate, it is high to prepare microspheres efficiency, with preferable slow release effect and targeting；The tissue Chinese medicine object detecting method specificity set up is good, and sensitivity and the rate of recovery are high, and precision is excellent.
Description
Technical field
The present invention relates to antibiotic targeting preparation technical field, more particularly to a kind of Lung targeting sulphuric acid cephalosporium quinol gelatin are micro-
Ball and preparation method thereof.
Background technology
Cefquinome (Cefquinome), also known as Cefquinome, are German Hoechst Roussel Vet companies exploitations
The 1st generation cephalosporins of animal specific the 4th, it is domestic because of its strong antibacterial activity, wide antimicrobial spectrum and low drug resistance
The outer respiratory disease for being widely used in treating domestic animal.
Research and development of the China to Cefquinome and its preparation are relatively later, at present only sulphuric acid cephalosporium quinol bulk drug and
Its injection (suspension injection, injection powder injection) obtains Ministry of Agriculture's approval and produces and sells license, matched formulation
Species is fewer.Cefquinome oral absorption is bad, and injection absorbs more rapid, and half-life period is shorter in vivo, and only 1~3 is small
When.To reach effective treatment concentration, it is necessary to which multiple injection administration, very big inconvenience is brought to clinical practice.Therefore, exploitation tool
There is the preparation of target slow-release performance extremely urgent.
Lung-targeted microspheres can be trapped in lung, made the drug-rich of load in lung, effectively improved therapeutic drug level,
Substantially reduce toxic side effect of the medicine to non-target organ；Meanwhile, the sustained release performance of microballoon can make medicine reach long-acting purpose,
And then avoid the inconvenience of frequent drug administration.
To solve the limitation present in domestic animal sulphuric acid cephalosporium quinol ordinary preparation, its application value is improved, depth is opened
The novel formulation using it as raw material is sent out, and is applied in produce reality, these problems are the research points of the present invention.
The content of the invention
It is an object of the invention to provide a kind of Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere and preparation method thereof.
For achieving the above object, the present invention is realized by following measure：A kind of Lung targeting sulphuric acid cephalosporium quinol
Gelatine microsphere, preparation method comprises the following steps：
The first step, bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling
1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine；
Second step, weighs gelatin and sodium alginate as carrier, is dissolved under the conditions of 40-50 DEG C in distilled water, heating
Stirring until completely dissolved, is proportionally added into Cefquinome bulk drug, mixed by ultrasonic wave, low-power 300-400w ultrasounds 1-
2min, high power 600-1000w ultrasound 1-2min, add glidant, mix as mixture, add glutaraldehyde solution, then
It is spray-dried using double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.
Wherein, in dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 5-10:1-3:0.5-2.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 100-200 DEG C, and rate of venting is 400-
1000%, sample rate is 10-60%, 20-40 DEG C of leaving air temp.
Wherein, in the microball preparation carrier, the mass ratio of sodium alginate and gelatin is 1:3-1:10.
Wherein, the mass ratio of Cefquinome and carrier is 1:1-1:50.
Wherein, the glutaraldehyde consumption is the 1%-10% of volume of mixture.
Wherein, the glidant is magnesium stearate or talcum powder, and gelatin is 1-10 with its mass ratio:0.01-0.1.
Wherein, in the microballoon, more than 90% particle diameter distribution is in the range of 10~25um.
In addition, the invention provides the preparation method of described Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere, wherein, prepare
Method comprises the following steps：The first step, bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into the planetary ball of frequency conversion
Grinding machine, ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine；
Second step, weighs gelatin and sodium alginate as carrier, is dissolved under the conditions of 40-50 DEG C in distilled water, heating
Stirring until completely dissolved, is proportionally added into Cefquinome bulk drug, mixed by ultrasonic wave, low-power 300-400w ultrasounds 1-
2min, high power 600-1000w ultrasound 1-2min, add glidant, mix as mixture, add glutaraldehyde solution, then
It is spray-dried using double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.
Beneficial effects of the present invention are：Microsphere encapsulation rate prepared by the present invention is more than 90%, more than 90% microballoon
Particle diameter distribution is in the range of 10~25um, this preparation method, with operating method simplicity, prepares microspheres efficiency height, preparation condition
Gently, the advantages of microspherulite diameter size is easy to control, and reappearance is high, and stable, the Cefquinome microballoon prepared disperses
Property preferably, outward appearance is homogeneous, shows through release in vitro research and rat distribution result of study, prepared microball preparation
With preferable slow release effect and targeting, it can be drawn by tissue pathological slice, lung-targeted microspheres will not be caused to tissue
Damage, it is safe and reliable.The tissue Chinese medicine object detecting method specificity set up is good, sensitivity (the μ g/kg of test limit 1, quantitative limit 3
μ g/kg) and rate of recovery height (>90%), the excellent (CV of precision<8%) it, ensure that accurate, reliable testing result.
Brief description of the drawings
Fig. 1 is microspherulite diameter distribution map；
Fig. 2 is the drug-eluting speed for carrying medicine gelatine microsphere；
Fig. 3 is the standard curve of addition sulphuric acid cephalosporium quinol in tissue；
Fig. 4 is rat tissue's Chinese medicine after single dose (6mg CEQ/kg B.W.) intravenous injection sulphuric acid cephalosporium quinol parenteral solution
The distribution of thing；
Fig. 5 is that single dose (6mg CEQ/kg B.W.) is injected intravenously after sulphuric acid cephalosporium quinol gelatine microsphere in rat tissue
The distribution of medicine；
Fig. 6 is lung tissue of rats after single dose (6mg CEQ/kg B.W.) intravenous injection sulphuric acid cephalosporium quinol gelatine microsphere
With the section of blank pathologic
Embodiment
The present invention is realized by following measure：A kind of Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere, preparation method bag
Include following steps：
The first step, bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling
1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine；
Second step, weighs gelatin and sodium alginate as carrier, is dissolved under the conditions of 40-50 DEG C in distilled water, heating
Stirring until completely dissolved, is proportionally added into Cefquinome bulk drug, mixed by ultrasonic wave, low-power 300-400w ultrasounds 1-
2min, high power 600-1000w ultrasound 1-2min, add glidant, mix as mixture, add glutaraldehyde solution, then
It is spray-dried using double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.
Wherein, in dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 5-10:1-3:0.5-2.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 100-200 DEG C, and rate of venting is 400-
1000%, sample rate is 10-60%, 20-40 DEG C of leaving air temp.
Wherein, in the microball preparation carrier, the mass ratio of sodium alginate and gelatin is 1:3-1:10.
Wherein, the mass ratio of Cefquinome and carrier is 1:1-1:50.
Wherein, the glutaraldehyde consumption is the 1%-10% of volume of mixture.
Wherein, the glidant is magnesium stearate or talcum powder, and gelatin is 1-10 with its mass ratio:0.01-0.1.
Wherein, in the microballoon, more than 90% particle diameter distribution is in the range of 10~25um.
Performance detection is carried out to the microballoon that the present invention is obtained.
First, microsphere particle size, drugloading rate and the envelop rate analysis of the sulphuric acid cephalosporium quinol microballoon obtained
1.1 materials and instrument
1.1.1 material and reagent
Material needed for experiment is shown in Table 1-1 with reagent.
Table 1-1 experiment materials and reagent
| Title | Producer | Specification |
| Dichloromethane | Chemical Reagent Co., Ltd., Sinopharm Group | Analysis is pure |
| Glacial acetic acid | Chemical Reagent Co., Ltd., Sinopharm Group | Analysis is pure |
| Absolute ethyl alcohol | Chemical Reagent Co., Ltd., Sinopharm Group | Analysis is pure |
| Cefquinome standard items | China Veterinery Drug Inspection Office | 82.6% |
1.1.2 instrument and equipment
Instrument and equipment needed for experiment is shown in Table 1-2.
Table 1-2 laboratory apparatus and equipment
1.2 experimental method
1.2.1 the measure of microspherulite diameter
Weigh appropriate microsphere powder scattered with physiological saline, dipped and be applied on slide with glass bar, with cover glass
Covering, is placed under light microscope, is moved in the visual field according to " bow " font, and the particle diameter of 500 microballoons is asked in the measurement visual field
Mean value calculation particle diameter, and draw grain size distribution.
1.2.2 the measure of microballoon drugloading rate, envelop rate
The method that the assay method of medicine gelatine microsphere drug content crushes microballoon using Probe Ultrasonic Searching is carried, specific method is such as
Under：Accurately weigh 25mg drug bearing microsphere powder to be placed in 50mL centrifuge tubes, first add 1ml dichloromethane, 1000rpm concussions
3min, adds 30mL mobile phases, and Probe Ultrasonic Searching crushes 45 circulations of microballoon, and ultrasonic power 800W, ultrasonic 4s stop 5s, appropriate ice
Bath cooling, is subsequently placed in shaking table and shakes 1h at room temperature, medicine is fully discharged, and is transferred in 50mL volumetric flasks to flow
Phase constant volume, takes supernatant to cross 0.22 μm of filter membrane, and liquid phase detection, combined standard curve calculates drugloading rate according to formula (1) formula (2)
LE% and envelop rate EE%.
The quality * 100% of quality/drug bearing microsphere of medicine in drugloading rate=microballoon；
The quality * 100% of the quality of medicine/addition medicine in envelop rate=microballoon；
1.2.3 the measure of microsphere drug dissolution rate
The external drug-eluting speed of microballoon is determined with dialysis, specific method is as follows, accurately weighs continuous three batches
Each 50mg of microballoon, be respectively charged into three bag filters (molecular cut off 8000-14000Da), separately weigh 50mg blank microballoons
In bag filter, addition appropriate amount of drug (equal with the medicament contg in drug bearing microsphere) is mixed with blank microballoon, is used as blank pair
According to.With pH7.4 PBS 250ml as buffer medium, drug-eluting is carried out in the case where rotating speed is 150rpm with 37 DEG C of constant-temperature tables
The research of speed.It is each in 5min, 15min, 30min, 45min, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h and 72h respectively
1ml is sampled, and adds isometric blank cushioning liquid immediately, the dialyzate outside bag filter is changed per 12h.Sample is entered into HPLC
Analysis, drug-eluting amount is tried to achieve according to standard curve, draws accumulation drug-eluting amount-time drug release profiles figure, produces dissolution bent
Line.
1.3 experimental results and analysis
1.3.1 microsphere particle size is analyzed
Gelatine microsphere granulometry result is shown in Fig. 1 respectively.
By Fig. 1, it is seen that the gelatine microsphere narrower particle size distribution of preparation, granularity 7~35 μ m microballoons account for 85.0% with
On.
1.3.2 microballoon drugloading rate, envelop rate analysis
The load medicine situation of table 1-3 gelatine microspheres
| Title | Theoretical drugloading rate (%) | Actual drugloading rate (%) | Envelop rate (%) |
| Gelatine microsphere | 20.0% | 18.86 | 94.30 |
From table 1-3, gelatine microsphere microsphere encapsulation rate prepares microballoon drug carrying ability preferable more than 85%.
1.3.3 drug-eluting rate analysis
The drug-eluting rate analysis of gelatine microsphere is shown in Fig. 2.
From Figure 2 it can be seen that gelatine microsphere is compared with Cefquinome bulk drug, gelatine microsphere drug-eluting speed is significantly slowed,
When 0.5h insoluble drug releases are 19.3%, 48h, insoluble drug release is 98.5%, and Cefquinome bulk drug insoluble drug release in 4h
For 98.9%, it is seen that gelatine microsphere has preferable slow release effect compared with Cefquinome bulk drug.
1.4 brief summary
This part experiment obtains drawing a conclusion by analysis：(1) microsphere particle size result proves the gelatine microsphere microballoon prepared
It is uniform in size, distribution relatively concentrate between 7-35 μm (2) drugloading rate, envelop rate result prove prepare gelatine microsphere drugloading rate and
Envelop rate is higher, and drugloading rate is between 10-20%, and envelop rate is between 80-95%.(3) microsphere drug dissolution rate determines knot
Fruit proves that the gelatine microsphere prepared has slow releasing function, has obvious slow release effect, gelatin compared with Cefquinome bulk drug
Microballoon is complete in 36h releases.
2nd, the internal lung tissue selective distribution research of the sulphuric acid cephalosporium quinol microballoon prepared
This experiment carries out the internal lung tissue selective distribution examination of sulphuric acid cephalosporium quinol microballoon using Wistar rats as object
Test.
2.1 experiment material
2.1.1 material and reagent
Material needed for experiment is shown in Table 2-1 with reagent.
Table 2-1 experiment materials and reagent
| Title | Producer | Specification |
| Wistar rats | Qingdao great Ren Fu cities herding Co., Ltd | Male and female half and half |
| Grams hundred special | Intervet Internat B. V. | 2.5g/50ml |
| Methanol | Merck | Chromatographically pure |
| Acetonitrile | Merck | Chromatographically pure |
| Sulphuric acid cephalosporium quinol standard items | German DR companies | 95.5% |
| Glacial acetic acid | Chemical Reagent Co., Ltd., Sinopharm Group | Analysis is pure |
| N-hexane | Chemical Reagent Co., Ltd., Sinopharm Group | Analysis is pure |
2.1.2 instrument and equipment
Instrument and equipment needed for experiment is shown in Table 2-2.
Table 2-2 laboratory apparatus and equipment
2.2 experimental method
2.2.1 the foundation of UPLC/MS/MS detection methods
2.2.1.1 standard liquid is configured
Sulphuric acid cephalosporium quinol reference substance is weighed using Subtraction method appropriate into 25ml brown volumetric flasks, be settled to redistilled water
Scale, mixes, is configured to 1000 μ g/ml standard reserving solution, is saved backup in -20 DEG C of refrigerators.Taking-up is flowed before use
Phase dilution is into certain density standard working solution.Storing solution can be used in 1 month.
2.2.1.2 chromatographic condition
Chromatographic condition：
ACQUITY UPLC BEH C18 chromatographic columns (50mm × 2.1mm, 1.7 μm)
Mobile phase：Acetonitrile：0.1% aqueous formic acid (15:85)
Sample size：5ul
Flow velocity：0.2ml/min
Column temperature：30℃
2.2.1.3 tissue sample pre-treatment
Rat tissue 1.0g is taken, appropriate 0.1% formic acid solution is added, is mixed with adjustable high speed refiner, takes homogenate
0.3g is placed in 1.5ml centrifuge tubes, shakes up, and adds extract solution 0.8ml (acetonitriles：Water 95:5), vortex 30s, ultrasonic extraction 15min,
The high speed centrifugation 10min under the conditions of 4 DEG C, 12000rpm, residue repeats extraction 2 times, merges extract solution, and nitrogen drying is added
Redistilled water 1ml, n-hexane 0.5ml, incline n-hexane layer, is then freeze-dried.Plus 1ml (acetonitriles：0.1% formic acid 15:85) it is multiple
It is molten, cross 0.22 μm of filter membrane, HPLC/MS/MS sample detections.
2.2.1.4 the preparation of standard curve
5 parts of blank lung tissue is taken, the sulphuric acid cephalosporium quinol standard working solution of certain volume is added successively so that in lung tissue
Drug concentration is respectively 3,10,50,100,500ug/kg, by processing method under " 2.2.1.3 " item, carry out HPLC detections, record
Chromatogram.Peak area to measure using the concentration of sulphuric acid cephalosporium quinol as abscissa (X), obtains linear regression as ordinate (Y)
Equation simultaneously calculates coefficient correlation.
2.2.1.5 test limit and quantitative limit
1,3ng/g standards addition sample is made with blank tissue, each sample does 3 parallel samples, by " 2.2.1.3 " item
Lower processing method is surveyed.Using signal to noise ratio S/N=3 as test limit (LOD), signal to noise ratio S/N=10 is quantitative limit (LOD).
2.2.1.6 accuracy test
High, medium and low 3 concentration standard liquids are added in blank tissue samples, make its concentration of blank tissue be respectively 10,
20th, 100ug/kg, by processing method under " 2.2.1.3 " item, with the peak area of sulphuric acid cephalosporium quinol in sample divided by standard items
Response, as extraction recovery.
2.2.1.7 precision test
High, medium and low 3 concentration standard liquids are added in blank lung tissue sample, make it be respectively in the concentration of blank tissue
10th, 20,100 μ g/kg, each concentration does 5 repetitions, obtains withinday precision；Do not preparing continuously on the same day and determining 5 analyses
The sample criticized, obtains betweenrun precision.
2.2.2 rat tissue's distribution experiments design.
Rat 288 is taken, body weight 180-200g is randomly divided into 3 groups, and first group is blank control group, and second group is the positive
Control group (sulphuric acid cephalosporium quinol parenteral solution), the 3rd group is sulphuric acid cephalosporium quinol gelatine microsphere group, every group 96, male and female half and half.
Fasting but can be after free water 12h, tail vein injection 12.0mg/kg sulphuric acid cephalosporium quinols, respectively with 0.0833 after administration,
0.25th, 0.5,1,2,4,6,8,10,12,14,16,20,24,36,48h, by femoral artery sacrificed by exsanguination animal.Divide immediately core,
Liver, spleen, lung, kidney, detect each tissue drug content.
2.2.3 rat tissue's pathological analysis.
Left lung is collected by dissecting rat in 48h, and it is fixed in 4% paraformaldehyde, in embedded paraffin, it is cut into 3 μm and cuts
Piece, sections stained with hematoxylin and eosin stains (H and E) are dyed.Disease is identified by Vectra3.0 automatic ration pathology imaging system
Reason change.
2.3 experimental results and analysis
2.3.1 the preparation of sulphuric acid cephalosporium quinol standard curve
By determining, medicine adds concentration between 3-500ppb in lung tissue, and the linear relationship of concentration and peak area is good
It is good.Wherein, in lung tissue medicine coefficient R 2=0.9999, regression equation is y=6.1112x+4.9902.Standard curve
As shown in Figure 3.
2.3.2 sulphuric acid cephalosporium quinol test limit, the measure of quantitative limit
The detection of sulphuric acid cephalosporium quinol in the tissue is limited to 1 μ g/kg (S/N>3) 3 μ g/kg (S/N, are quantitatively limited to>10)
2.3.3 accuracy test
Blank tissue samples are taken, the sulphuric acid cephalosporium quinol standard working solution of certain volume are added so that medicine is dense in sample
Degree respectively 10,20,100ng/g, each concentration are parallel 5 parts, after being handled under " 2.2.1.3 " item, carry out UPLC/MS/MS inspections
Survey, calculated with peak area ratio, obtain the rate of recovery and be shown in Table 2-3 to 2-7.
The rate of recovery of sulphuric acid cephalosporium quinol in table 2-3 heart tissues
The rate of recovery of sulphuric acid cephalosporium quinol in table 2-4 hepatic tissues
The rate of recovery of sulphuric acid cephalosporium quinol in table 2-5 spleen tissues
The rate of recovery of sulphuric acid cephalosporium quinol in table 2-6 lung tissues
The rate of recovery of sulphuric acid cephalosporium quinol in table 2-7 nephridial tissues
2.3.4 precision test
Blank tissue samples are taken, the sulphuric acid cephalosporium quinol standard working solution of certain volume are added so that medicine is dense in sample
Degree respectively 10,20,100ng/g, each concentration put down parallel 5 parts (in a few days) within same working day, in different operating day processing 5
Batch (in the daytime), after method processing under " 2.2.1.3 " item, carries out UPLC/MS/MS detections, calculates and in a few days and in the daytime marks relatively
Quasi- deviation (being shown in Table 2-8 to 2-12).
The precision of sulphuric acid cephalosporium quinol in table 2-8 heart tissues
The precision of sulphuric acid cephalosporium quinol in table 2-9 hepatic tissues
The precision of sulphuric acid cephalosporium quinol in table 2-10 spleen tissues
The precision of sulphuric acid cephalosporium quinol in table 2-11 lung tissues
The precision of sulphuric acid cephalosporium quinol in table 2-12 nephridial tissues
2.3.4 sulphuric acid cephalosporium quinol concentration in organizing
Test after the administration of rat single dose, concentration of the medicine in different tissues is shown in Table 2-13 to 2-14.
Rat tissue's Chinese medicine after table 2-13 single doses (6mg CEQ/kg B.W.) intravenous injection sulphuric acid cephalosporium quinol parenteral solution
Thing concentration
After table 2-14 single doses (6mg CEQ/kg B.W.) intravenous injection sulphuric acid cephalosporium quinol gelatine microsphere in rat tissue
Drug concentration
2.3.5 Tissue distribution figure
Test after the administration of rat single dose, distribution map of the different pharmaceutical preparation in each tissue is shown in Fig. 4 to Fig. 5.
As seen from Figure 5 after injection sulphuric acid cephalosporium quinol gelatine microsphere preparation, injected with positive controls sulphuric acid cephalosporium quinol
Liquid phase ratio (Fig. 4), lung tissue drug concentration is very high relative to the drug concentration of other internal organs, and targeting and slow release effect are bright
It is aobvious.
2.3.6 tissue pathological slice is analyzed
After 48h is administered through tail vein in rat, compared with control group, experimental group does not find pathological change.
2.4 brief summary
This experiment shows after rat injection sulphuric acid cephalosporium quinol gelatine microsphere, effectively enhances sulphuric acid cephalosporium quinol targeting
And slow release effect.
To sum up, the present invention prepares Lung targeting sulphuric acid cephalosporium quinol microball preparation simultaneously, substantially increases sulphuric acid cephalosporium quinol
Targeting and slow release effect, and obtained sulphuric acid cephalosporium quinol microball preparation has positive control medicine to compare in animal body
It is external-there is uniformity in vivo with obvious targeting and slow release effect；It is prepared by Lung targeting sulphuric acid cephalosporium quinol microball preparation
Method efficient stable, successfully obtains a kind of sulphuric acid cephalosporium quinol lung-targeted microspheres preparation.
For the technical characterstic for illustrating this programme can be understood, below by embodiment, this programme is illustrated.
Embodiment 1
Preparation method comprises the following steps：
The first step, bulk drug 3.3g and dispersant 16ml are mixed, and are put into frequency conversion planetary ball mill, ball milling 2h, interval 1h,
Ball milling 2h, volatilizes liquid again, obtains raw materials treated medicine；
Second step, weighs gelatin 10g and sodium alginate 3.3g as carrier, and the double steamings of 250ml are dissolved under the conditions of 50 DEG C
In water, heating stirring until completely dissolved, adds Cefquinome bulk drug, mixed by ultrasonic wave, low-power 400w ultrasounds
1min, high power 1000w ultrasound 1min, add 0.133g glidants, mix as mixture, add glutaraldehyde solution, then
It is spray-dried using double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.
Wherein, in dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 5:2:1.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 150 DEG C, and rate of venting is 800%, sample introduction speed
Rate is 40%, 30 DEG C of leaving air temp.
Wherein, the glutaraldehyde consumption is the 10% of volume of mixture.
Wherein, the glidant is magnesium stearate.
Wherein, in the microballoon, more than 90% particle diameter distribution is in the range of 10~25um.
The microballoon of above-mentioned preparation, 17.78 μm of average grain diameter, 81.35% microballoon is distributed in 10~25 μ ms；Scanning
Electronic Speculum shows outward appearance rounding, and surface compact is bright and clean；Drugloading rate is 15.04%, and envelop rate is 75.2%, and drug release in vitro is reachable
More than 36h.
Embodiment 2
Preparation method comprises the following steps：
The first step, bulk drug 1.1g and dispersant 5ml is mixed, and is put into frequency conversion planetary ball mill, ball milling 1h, interval
0.5h, then ball milling 1h, volatilize liquid, obtain raw materials treated medicine；
Second step, weighs gelatin 10g and sodium alginate 1g as carrier, 250ml distilled waters is dissolved under the conditions of 50 DEG C
In, heating stirring until completely dissolved, adds Cefquinome bulk drug, mixed by ultrasonic wave, low-power 400w ultrasound 2min,
High power 1000w ultrasound 2min, add 0.33g glidants, mix as mixture, glutaraldehyde solution are added, then using double
Stream spray dryer is spray-dried, while needing magnetic agitation, is spray-dried to obtain microballoon.
Wherein, in dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 5:2:2.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 160 DEG C, and rate of venting is 700%, goes out wind-warm syndrome
30 DEG C of degree.
Wherein, the glutaraldehyde consumption is the 8% of volume of mixture.
Wherein, the glidant is talcum powder.
Wherein, in the microballoon, more than 90% particle diameter distribution is in the range of 10~25um.
The microballoon of above-mentioned preparation, 15.63 μm of average grain diameter, 75.38% microballoon is distributed in 10~25 μ ms；Scanning
Electronic Speculum shows outward appearance rounding, and surface compact is bright and clean；Drugloading rate is 7.48%, and envelop rate is 82.31%, and drug release in vitro is reachable
More than 24h.
Embodiment 3
Preparation method comprises the following steps：
The first step, bulk drug 1.5g and dispersant 3ml are mixed, and are put into frequency conversion planetary ball mill, ball milling 2h, interval 1h,
Ball milling 2h, volatilizes liquid again, obtains raw materials treated medicine；
Second step, weighs gelatin 10g and sodium alginate 2g as carrier, 250ml distilled waters is dissolved under the conditions of 45 DEG C
In, heating stirring until completely dissolved, adds Cefquinome bulk drug, mixed by ultrasonic wave, low-power 400w ultrasound 2min,
High power 1000w ultrasound 2min, add 0.3g glidants, mix as mixture, glutaraldehyde solution are added, then using double fluid
Spray dryer is spray-dried, while needing magnetic agitation, is spray-dried to obtain microballoon.
Wherein, in dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 5:3:2.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 140 DEG C, and rate of venting is 600%, goes out wind-warm syndrome
30 DEG C of degree.
Wherein, the glutaraldehyde consumption is the 6% of volume of mixture.
Wherein, the glidant is magnesium stearate.
Wherein, in the microballoon, more than 90% particle diameter distribution is in the range of 10~25um.
The microballoon of above-mentioned preparation, 18.96 μm of average grain diameter, 61.24% microballoon is distributed in 10~25 μ ms；Scanning
Electronic Speculum shows outward appearance rounding, and surface compact is bright and clean；Drugloading rate is 8.71%, and envelop rate is 78.42%, and drug release in vitro is reachable
More than 24h.
Embodiment 4
Preparation method comprises the following steps：
The first step, bulk drug 1.87g and dispersant 7.5ml is mixed, and is put into frequency conversion planetary ball mill, ball milling 2h, interval
1h, then ball milling 2h, volatilize liquid, obtain raw materials treated medicine；
Second step, weighs gelatin 10g and sodium alginate 1.25g as carrier, and the double steamings of 250ml are dissolved under the conditions of 50 DEG C
In water, heating stirring until completely dissolved, adds Cefquinome bulk drug, mixed by ultrasonic wave, low-power 400w ultrasounds
2min, high power 1000w ultrasound 2min, add 0.26g glidants, mix as mixture, add glutaraldehyde solution, then adopt
It is spray-dried with double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.
Wherein, in dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 5:2:1.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 170 DEG C, and rate of venting is 550%, sample introduction speed
Rate is 40%, 30 DEG C of leaving air temp.
Wherein, the glutaraldehyde consumption is the 6% of volume of mixture.
Wherein, the glidant is talcum powder.
Wherein, in the microballoon, more than 90% particle diameter distribution is in the range of 10~25um.
The microballoon of above-mentioned preparation, 21.96 μm of average grain diameter, 66.71% microballoon is distributed in 10~25 μ ms；Scanning
Electronic Speculum shows outward appearance rounding, and surface compact is bright and clean；Drugloading rate is 8.71%, and envelop rate is 78.42%, and drug release in vitro is reachable
More than 24h.
Embodiment 5
Preparation process is：
The first step, bulk drug 4.2g and dispersant 20ml are mixed, and are put into frequency conversion planetary ball mill, ball milling 2h, interval 1h,
Ball milling 2h, volatilizes liquid again, obtains raw materials treated medicine；
Second step, weighs gelatin 10g and sodium alginate 2.5g as carrier, is dissolved under the conditions of 45 DEG C in distilled water,
Heating stirring until completely dissolved, is proportionally added into Cefquinome bulk drug, mixed by ultrasonic wave, low-power 400w ultrasounds
2min, high power 1000w ultrasound 2min, add 0.025g glidants, mix as mixture, add glutaraldehyde solution, then
It is spray-dried using double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.
Wherein, in dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 6:2:1.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 160 DEG C, and rate of venting is 750%, sample introduction speed
Rate is 40%, 30 DEG C of leaving air temp.
Wherein, the glutaraldehyde consumption is the 5% of volume of mixture.
Wherein, the glidant is talcum powder.
Wherein, in the microballoon, more than 90% particle diameter distribution is in the range of 10~25um.
The microballoon of above-mentioned preparation, 14.63 μm of average grain diameter, 91.71% microballoon is distributed in 10~25 μ ms；Scanning
Electronic Speculum shows outward appearance rounding, and surface compact is bright and clean；Drugloading rate is 23.1%, and envelop rate is 92.42%, and drug release in vitro is reachable
More than 48h.
Technical characteristic of the invention without description can be realized by or using prior art, will not be repeated here, certainly,
Described above is not limitation of the present invention, and the present invention is also not limited to the example above, the ordinary skill of the art
The variations, modifications, additions or substitutions that personnel are made in the essential scope of the present invention, should also belong to the protection model of the present invention
Enclose.
Claims (10)
1. a kind of Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere, it is characterised in that preparation method comprises the following steps：
The first step, bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling 1-
3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine；
Second step, weighs gelatin and sodium alginate as carrier, is dissolved under the conditions of 40-50 DEG C in 250ml distilled waters, heating
Stirring until completely dissolved, is proportionally added into Cefquinome bulk drug, mixed by ultrasonic wave, low-power 300-400w ultrasounds 1-
2min, high power 600-1000w ultrasound 1-2min, add glidant, mix as mixture, add glutaraldehyde solution, then
It is spray-dried using double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.
2. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that in dispersant, ethanol：
Isopropanol：Methylene chloride volume ratio is 5-10:1-3:0.5-2.
3. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that grinder used is change
Frequency planetary ball mill.
4. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that the spray drying
Conditional parameter is：Inlet temperature is 100-200 DEG C, and rate of venting is 400-1000%, and sample rate is 10-60%, leaving air temp
20-40℃。
5. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that the microball preparation is carried
In body, the mass ratio of sodium alginate and gelatin is 1:3-1:10.
6. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that Cefquinome and carrier
Mass ratio be 1:1-1:50.
7. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that the glutaraldehyde consumption
For the 1%-10% of volume of mixture.
8. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that the glidant is hard
Fatty acid magnesium or talcum powder, gelatin are 1-10 with its mass ratio:0.01-0.1.
9. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that in the microballoon, 90%
Above particle diameter distribution is in the range of 10~25um.
10. a kind of preparation method of Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, its feature exists
In preparation method comprises the following steps：The first step, bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion
Planetary ball mill, ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine；
Second step, weighs gelatin and sodium alginate as carrier, is dissolved under the conditions of 40-50 DEG C in distilled water, heating stirring
Until completely dissolved, Cefquinome bulk drug is proportionally added into, is mixed by ultrasonic wave, low-power 300-400w ultrasounds 1-
2min, high power 600-1000w ultrasound 1-2min, add glidant, mix as mixture, add glutaraldehyde solution, then
It is spray-dried using double-current spray dryer, while needing magnetic agitation, is spray-dried to obtain microballoon.
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