CN107308118A - A kind of Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons and preparation method thereof - Google Patents
A kind of Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons and preparation method thereof Download PDFInfo
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- CN107308118A CN107308118A CN201710551086.0A CN201710551086A CN107308118A CN 107308118 A CN107308118 A CN 107308118A CN 201710551086 A CN201710551086 A CN 201710551086A CN 107308118 A CN107308118 A CN 107308118A
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- Prior art keywords
- plga
- sulphuric acid
- preparation
- cephalosporium quinol
- lung targeting
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 241001619326 Cephalosporium Species 0.000 title claims abstract description 66
- 239000001117 sulphuric acid Substances 0.000 title claims abstract description 66
- 235000011149 sulphuric acid Nutrition 0.000 title claims abstract description 66
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 title claims abstract description 61
- 210000004072 lung Anatomy 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 230000008685 targeting Effects 0.000 title claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 93
- 229940079593 drug Drugs 0.000 claims abstract description 57
- 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 40
- 229950009592 cefquinome Drugs 0.000 claims abstract description 40
- 238000000498 ball milling Methods 0.000 claims abstract description 33
- 239000002270 dispersing agent Substances 0.000 claims abstract description 20
- 239000012046 mixed solvent Substances 0.000 claims abstract description 20
- 239000007788 liquid Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 238000013019 agitation Methods 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 238000001694 spray drying Methods 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000011805 ball Substances 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 238000002604 ultrasonography Methods 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000012530 fluid Substances 0.000 claims description 11
- 239000011806 microball Substances 0.000 claims description 9
- 238000013022 venting Methods 0.000 claims description 8
- 238000003801 milling Methods 0.000 claims description 7
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 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 4
- 230000008859 change Effects 0.000 claims description 2
- 206010001497 Agitation Diseases 0.000 claims 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
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 239000004005 microsphere Substances 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 10
- 238000011084 recovery Methods 0.000 abstract description 8
- 241001465754 Metazoa Species 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 238000005538 encapsulation Methods 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 238000011017 operating method Methods 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract 1
- 210000001519 tissue Anatomy 0.000 description 36
- 239000000523 sample Substances 0.000 description 25
- 241000700159 Rattus Species 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 13
- 238000009826 distribution Methods 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000005507 spraying Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000012224 working solution Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003182 parenteral nutrition solution Substances 0.000 description 3
- 239000012071 phase Substances 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
- 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 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 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
- 238000003556 assay Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000009472 formulation Methods 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
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000004885 tandem mass spectrometry Methods 0.000 description 2
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 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
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 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
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000000502 dialysis Methods 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
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 238000000265 homogenisation 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
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 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
- 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
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000010415 tropism 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
- 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
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a kind of Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons and preparation method thereof, belong to animal antibiotic targeting preparation technical field, preparation method is：Bulk drug is mixed with dispersant, and ball milling volatilizes liquid, obtains raw materials treated medicine Cefquinome；PLGA and PLA are weighed as carrier, the carrier is dissolved in the mixed solvent, until completely dissolved, bulk drug is added, adds glidant, mixed and be spray-dried by ultrasonic wave, while carrying out magnetic agitation, microballoon is then obtained by whirlpool separator.The microsphere encapsulation rate of the present invention is more than 95%, and drugloading rate more than 20%, more than 85% microspherulite diameter is distributed in the range of 10~25um；Operating method is easy, it is high to prepare microspheres efficiency, and obtained microballoon dispersiveness is preferable, with excellent slow release effect and lung targeted characteristic.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 PLGA 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.The preparation of Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons before
Also there are some defects, being applied in effect also needs further raising.
The content of the invention
It is an object of the invention to provide a kind of Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons 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
PLGA microballoons, preparation method comprises the following steps：
Bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling, during grinding
Between be ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine Cefquinome；According to than
Example weighs PLGA and PLA as carrier, and the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, treated
After fully dissolved, Cefquinome bulk drug is proportionally added into, glidant is added, is mixed by ultrasonic wave, low-power 300-400w
Ultrasonic 1-1.5min, high power 800-1000w ultrasound 0.5-1min, then carry out spraying dry using two-fluid spray drying machine
Dry, while carrying out magnetic agitation, spray drying sample introduction speed is 8ml/min, then obtains Lung targeting sulphur by whirlpool separator
Sour Cefquinome PLGA microballoon microballoons.
Wherein, in the 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, PLGA and PLA mass ratio is 1 in the microball preparation carrier:4-1:10.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 40-200 DEG C, and rate of venting is 400-
1000%, 20-50 DEG C of leaving air temp.
Wherein, the volume fraction of the in the mixed solvent dichloromethane and methanol is 1:3-1:10.
Wherein, the mass ratio of Cefquinome bulk drug medicine and carrier is 1:2-1:10.
Wherein, the glidant is magnesium stearate or talcum powder, and carrier is 1-5 with its mass ratio:0.01-0.1.
In addition, present invention also offers the preparation method of described Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons, wherein, system
Preparation Method comprises the following steps：
Bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling, during grinding
Between be ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine Cefquinome；According to than
Example weighs PLGA and PLA as carrier, and the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, treated
After fully dissolved, Cefquinome bulk drug is proportionally added into, glidant is added, is mixed by ultrasonic wave, low-power 300-400w
Ultrasonic 1-1.5min, high power 800-1000w ultrasound 0.5-1min, then carry out spraying dry using two-fluid spray drying machine
Dry, while carrying out magnetic agitation, spray drying sample introduction speed is 8ml/min, then obtains Lung targeting sulphur by whirlpool separator
Sour Cefquinome PLGA microballoon microballoons.
Beneficial effects of the present invention are：Prepared microsphere encapsulation rate is more than 95%, drugloading rate more than 20%, 85% with
On microspherulite diameter be distributed in the range of 10~25um, this preparation method has that operating method is easy, it is high to prepare microspheres efficiency, system
The advantages of standby mild condition, and reappearance is high, and stable, preferably, outward appearance is homogeneous for the Cefquinome microballoon dispersiveness prepared,
Through release in vitro research and rat distribution research show, prepared microball preparation have excellent slow release effect and
Lung targeted characteristic.
Brief description of the drawings
Fig. 1 is microspherulite diameter distribution map；
Fig. 2 is the drug-eluting speed for carrying medicine PLGA microballoons；
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 PLGA microballoons 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 PLGA microballoons
With the section of blank pathologic.
Embodiment
The present invention is realized by following measure：A kind of Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons, preparation method bag
Include following steps：
Bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling, during grinding
Between be ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine Cefquinome；According to than
Example weighs PLGA and PLA as carrier, and the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, treated
After fully dissolved, Cefquinome bulk drug is proportionally added into, glidant is added, is mixed by ultrasonic wave, low-power 300-400w
Ultrasonic 1-1.5min, high power 800-1000w ultrasound 0.5-1min, then carry out spraying dry using two-fluid spray drying machine
Dry, while carrying out magnetic agitation, spray drying sample introduction speed is 8ml/min, then obtains Lung targeting sulphur by whirlpool separator
Sour Cefquinome PLGA microballoons.
Wherein, in the 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, PLGA and PLA mass ratio is 1 in the microball preparation carrier:4-1:10.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 40-200 DEG C, and rate of venting is 400-
1000%, 20-50 DEG C of leaving air temp.
Wherein, the volume fraction of the in the mixed solvent dichloromethane and methanol is 1:3-1:10.
Wherein, the mass ratio of Cefquinome bulk drug medicine and carrier is 1:2-1:10.
Wherein, the glidant is magnesium stearate or talcum powder, and carrier is 1-5 with its mass ratio:0.01-0.1.
In addition, present invention also offers the preparation method of described Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons, wherein, system
Preparation Method comprises the following steps：
Bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling, during grinding
Between be ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine Cefquinome；According to than
Example weighs PLGA and PLA as carrier, and the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, treated
After fully dissolved, Cefquinome bulk drug is proportionally added into, glidant is added, is mixed by ultrasonic wave, low-power 300-400w
Ultrasonic 1-1.5min, high power 800-1000w ultrasound 0.5-1min, then carry out spraying dry using two-fluid spray drying machine
Dry, while carrying out magnetic agitation, spray drying sample introduction speed is 8ml/min, then obtains Lung targeting sulphur by whirlpool separator
Sour Cefquinome PLGA microballoon microballoons.
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 PLGA microballoon drug contents 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
PLGA microballoon microsphere particle size measurement results are shown in Fig. 1 respectively.
By Fig. 1, it is seen that the PLGA microsphere particle size narrow distributions of preparation, granularity 7~35 μ m microballoons account for 80.0% with
On.
1.3.2 microballoon drugloading rate, envelop rate analysis
The load medicine situation of table 1-3PLGA microballoons
| Title | Theoretical drugloading rate (%) | Actual drugloading rate (%) | Envelop rate (%) |
| PLGA microballoons | 20.0% | 18.2% | 91.0% |
From table 1-3, PLGA microballoon microsphere encapsulation rates prepare microballoon drug carrying ability preferable more than 85%.
1.3.3 drug-eluting rate analysis
The drug-eluting rate analysis of PLGA microballoon microballoons is shown in Fig. 2 respectively.
From Figure 2 it can be seen that PLGA microballoons are compared with Cefquinome bulk drug, PLGA microsphere drug dissolution rates are significantly slowed,
When 0.5h insoluble drug releases are 16.4%, 48h, insoluble drug release is 97.8%, and Cefquinome bulk drug insoluble drug release in 4h
For 98.9%, it is seen that PLGA microballoons have 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 PLGA microballoon microballoons prepared
It is uniform in size, distribution relatively concentrate between 7-35 μm (2) drugloading rate, envelop rate result prove prepare PLGA microballoons 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 PLGA microballoons prepared have slow releasing function, has obvious slow release effect, PLGA 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
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
| Title | Producer | Model |
| LC-MS instrument | Anjelen Sci. ＆ Tech. Inc | BC-J80S |
| High-speed homogenization machine | Wuxi Wo Xin Instrument Ltd. | FSH-2A |
| Assay balance | Mettler Toledo Inc. of Switzerland | ME203E |
| Centrifuge | Town in Shanghai booth | TDL-40C |
| Micropipettor | Eppendorf | 5415R |
2.2 experimental method
2.2.1UPLC/MS/MS the foundation of detection method
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 1000ppm standard reserving solution, is saved backup in -20 DEG C of refrigerators.Taking-up mobile phase before use
It is diluted to 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, 1.7um)
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 PLGA microballoon groups, 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 2-15.
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 PLGA microballoons 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.
It is visible by Fig. 4,5, after injection sulphuric acid cephalosporium quinol PLGA microball preparations, noted with positive controls sulphuric acid cephalosporium quinol
Liquid phase ratio (Fig. 4) is penetrated, lung tissue drug concentration is very high relative to the drug concentration of other internal organs, targeting and slow release effect
Substantially.
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 PLGA microballoons, effectively enhances sulphuric acid cephalosporium quinol medicine target
Tropism 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.Preparation method efficient stable, successfully obtains one kind
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：
Bulk drug 3.7g and dispersant 15ml is mixed, and is put into frequency conversion planetary ball mill, ball milling, milling time is ball milling
2h, interval 1h, then ball milling 2h, volatilize liquid, obtain raw materials treated medicine Cefquinome；PLGA and PLA are weighed as carrier, will
The carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, until completely dissolved, adds Cefquinome raw material
Medicine, adds 0.15g glidants, is mixed by ultrasonic wave, low-power 300w ultrasound 1min, high power 800w ultrasound 0.5min,
Then it is spray-dried using two-fluid spray drying machine, while carrying out magnetic agitation, spray drying sample introduction speed is 8ml/
Min, then obtains Lung targeting sulphuric acid cephalosporium quinol PLGA microballoon microballoons by whirlpool separator.
Wherein, in the dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 5:2:1.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, PLGA12g, PLA3g in the microball preparation carrier.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 50 DEG C, and rate of venting is 700%, leaving air temp
30℃。
Wherein, the volume fraction of the in the mixed solvent dichloromethane and methanol is 1:5.
Wherein, the glidant is magnesium stearate.
The microballoon of above-mentioned preparation, 13.45 μm of average grain diameter, 88.43% 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 16.86%, and envelop rate is 84.3%, and drug release in vitro is reachable
More than 24h.
Embodiment 2
Preparation method comprises the following steps：
Bulk drug 4g and dispersant 20ml is mixed, and is put into frequency conversion planetary ball mill, ball milling, and milling time is ball milling 2h,
Interval 1h, then ball milling 2h, volatilize liquid, obtain raw materials treated medicine Cefquinome；Proportionally weigh PLGA10g and PLA2g
As carrier, the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, until completely dissolved, in proportion
Cefquinome bulk drug is added, 0.3g glidants is added, is mixed by ultrasonic wave, low-power 350w ultrasounds 1min, high power
900w ultrasound 1min, are then spray-dried using two-fluid spray drying machine, while progress magnetic agitation, be spray-dried into
Sample speed is 8ml/min, then obtains Lung targeting sulphuric acid cephalosporium quinol PLGA microballoon microballoons by whirlpool separator.
Wherein, in the 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 60 DEG C, and rate of venting is 600%, sample rate
For 8ml/min, 30 DEG C of leaving air temp.
Wherein, the volume fraction of the in the mixed solvent dichloromethane and methanol is 1:5.
Wherein, the glidant is talcum powder.
The microballoon of above-mentioned preparation, 14.56 μm of average grain diameter, 79.73% 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 19.84%, and envelop rate is 79.36%, and drug release in vitro can
Up to more than 36h.
Embodiment 3
Preparation method comprises the following steps：
Bulk drug 3g is mixed with dispersant according to 15ml, is put into frequency conversion planetary ball mill, ball milling, milling time is ball milling
2h, interval 1h, then ball milling 2h, volatilize liquid, obtain raw materials treated medicine Cefquinome；Weigh PLGA14g and PLA1.4g conducts
Carrier, the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, until completely dissolved, is proportionally added into
Cefquinome bulk drug, adds 0.205g glidants, is mixed by ultrasonic wave, low-power 300w ultrasounds 1min, high power
800w ultrasound 1min, are then spray-dried using two-fluid spray drying machine, while progress magnetic agitation, be spray-dried into
Sample speed is 8ml/min, then obtains Lung targeting sulphuric acid cephalosporium quinol PLGA microballoon microballoons by whirlpool separator.
Wherein, in the dispersant, ethanol：Isopropanol：Methylene chloride volume ratio is 5:3:1.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, the conditional parameter of the spray drying is：Inlet temperature is 100 DEG C, and rate of venting is 800%, sample introduction speed
Rate is 8ml/min, 30 DEG C of leaving air temp.
Wherein, the volume fraction of the in the mixed solvent dichloromethane and methanol is 1:7.
Wherein, the glidant is magnesium stearate.
The microballoon of above-mentioned preparation, 16.03 μm of average grain diameter, 88.24% 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 11.65%, and envelop rate is 69.88%, and drug release in vitro can
Up to more than 24h.
Embodiment 4
Preparation method comprises the following steps：
Bulk drug 6g and dispersant 24ml is mixed, and is put into frequency conversion planetary ball mill, ball milling, and milling time is ball milling 3h,
Interval 1h, then ball milling 2h, volatilize liquid, obtain raw materials treated medicine Cefquinome；PLGA16g and PLA2g are weighed as carrier,
Carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, until completely dissolved, Cefquinome bulk drug is added,
0.324g glidants are added, are mixed by ultrasonic wave, low-power 350w ultrasound 1min, high power 900w ultrasound 1min, then
It is spray-dried using two-fluid spray drying machine, while carrying out magnetic agitation, spray drying sample introduction speed is 8ml/min,
Then Lung targeting sulphuric acid cephalosporium quinol PLGA microballoon microballoons are obtained by whirlpool separator.
Wherein, in the 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 60 DEG C, and rate of venting is 750%, sample rate
For 8ml/min, 30 DEG C of leaving air temp.
Wherein, the volume fraction of the in the mixed solvent dichloromethane and methanol is 1:6.
Wherein, the glidant is magnesium stearate.
The microballoon of above-mentioned preparation, 16.03 μm of average grain diameter, 88.24% 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 24.22%, and envelop rate is 96.88%, and drug release in vitro can
Up to more than 48h.
Embodiment 5
Preparation method comprises the following steps：
Bulk drug 2.8g is mixed with dispersant according to 24ml, is put into frequency conversion planetary ball mill, ball milling, milling time is ball
2h, interval 1h, then ball milling 2h are ground, liquid is volatilized, obtains raw materials treated medicine Cefquinome；PLGA20g and PLA2.5g is weighed to make
For carrier, the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, until completely dissolved, cephalo is added
Quinoline promise bulk drug, adds 0.02g glidants, is mixed by ultrasonic wave, low-power 400w ultrasounds 1min, high power 900w ultrasound
1min, is then spray-dried using two-fluid spray drying machine, while carrying out magnetic agitation, spray drying sample introduction speed is
8ml/min, then obtains Lung targeting sulphuric acid cephalosporium quinol PLGA microballoon microballoons by whirlpool separator.
Wherein, in the 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 100 DEG C, and rate of venting is 600%, sample introduction speed
Rate is 8ml/min, 30 DEG C of leaving air temp.
Wherein, the volume fraction of the in the mixed solvent dichloromethane and methanol is 1:5.
Wherein, the glidant is magnesium stearate.
The microballoon of above-mentioned preparation, 16.03 μm of average grain diameter, 78.32% 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 7.72%, and envelop rate is 69.53%, and drug release in vitro is reachable
More than 36h.
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 (9)
1. a kind of Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons, it is characterised in that preparation method comprises the following steps：
Bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling, milling time is
Ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine Cefquinome；Proportionally claim
Take PLGA and PLA as carrier, the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, treat completely molten
Xie Hou, is proportionally added into Cefquinome bulk drug, adds glidant, mixed by ultrasonic wave, low-power 300-400w ultrasounds
1-1.5min, high power 800-1000w ultrasound 0.5-1min, are then spray-dried, together using two-fluid spray drying machine
Shi Jinhang magnetic agitations, spray drying sample introduction speed is 8ml/min, then obtains Lung targeting sulfuric acid cephalo by whirlpool separator
Quinoline promise PLGA microballoon microballoons.
2. Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons according to claim 1, it is characterised in that in the dispersant,
Ethanol：Isopropanol：Methylene chloride volume ratio is 5-10:1-3:0.5-2.
3. Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons according to claim 1, it is characterised in that grinder used is change
Frequency planetary ball mill.
4. Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons according to claim 1, it is characterised in that the microball preparation is carried
PLGA and PLA mass ratio is 1 in body:4-1:10.
5. Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons according to claim 1, it is characterised in that the spray drying
Conditional parameter is：Inlet temperature is 40-200 DEG C, and rate of venting is 400-1000%, 20-50 DEG C of leaving air temp.
6. Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons according to claim 1, it is characterised in that the in the mixed solvent
The volume fraction of dichloromethane and methanol is 1:3-1:10.
7. Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons according to claim 1, it is characterised in that Cefquinome bulk drug
The mass ratio of medicine and carrier is 1:2-1:10.
8. Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons according to claim 1, it is characterised in that the glidant is hard
Fatty acid magnesium or talcum powder, carrier are 1-5 with its mass ratio:0.01-0.1.
9. a kind of preparation method of Lung targeting sulphuric acid cephalosporium quinol PLGA microballoons according to claim 1, it is characterised in that
Preparation method comprises the following steps：
Bulk drug is with dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball milling, milling time is
Ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, obtain raw materials treated medicine Cefquinome；Proportionally claim
Take PLGA and PLA as carrier, the carrier is dissolved in the in the mixed solvent of 200ml dichloromethane and methanol, treat completely molten
Xie Hou, is proportionally added into Cefquinome bulk drug, adds glidant, mixed by ultrasonic wave, low-power 300-400w ultrasounds
1-1.5min, high power 800-1000w ultrasound 0.5-1min, are then spray-dried, together using two-fluid spray drying machine
Shi Jinhang magnetic agitations, spray drying sample introduction speed is 8ml/min, then obtains Lung targeting sulfuric acid cephalo by whirlpool separator
Quinoline promise PLGA microballoon microballoons.
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