CN107320452A - A kind of Lung targeting sulphuric acid cephalosporium quinol EC microballoons and preparation method thereof - Google Patents
A kind of Lung targeting sulphuric acid cephalosporium quinol EC microballoons and preparation method thereof Download PDFInfo
- Publication number
- CN107320452A CN107320452A CN201710550821.6A CN201710550821A CN107320452A CN 107320452 A CN107320452 A CN 107320452A CN 201710550821 A CN201710550821 A CN 201710550821A CN 107320452 A CN107320452 A CN 107320452A
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- China
- Prior art keywords
- sulphuric acid
- cephalosporium quinol
- acid cephalosporium
- microballoons
- preparation
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- Granted
Links
- 241001619326 Cephalosporium Species 0.000 title claims abstract description 69
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 239000001117 sulphuric acid Substances 0.000 title claims abstract description 69
- 235000011149 sulphuric acid Nutrition 0.000 title claims abstract description 69
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 210000004072 lung Anatomy 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 230000008685 targeting Effects 0.000 title claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 83
- 239000003814 drug Substances 0.000 claims abstract description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229940079593 drug Drugs 0.000 claims abstract description 52
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 38
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 38
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 38
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 38
- 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 34
- 229950009592 cefquinome Drugs 0.000 claims abstract description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000498 ball milling Methods 0.000 claims abstract description 21
- 102000009027 Albumins Human genes 0.000 claims abstract description 17
- 108010088751 Albumins Proteins 0.000 claims abstract description 17
- 239000004005 microsphere Substances 0.000 claims abstract description 17
- 239000007788 liquid Substances 0.000 claims abstract description 16
- 239000002245 particle Substances 0.000 claims abstract description 16
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000013019 agitation Methods 0.000 claims abstract description 11
- 230000004087 circulation Effects 0.000 claims abstract description 10
- 239000000523 sample Substances 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 29
- 238000001694 spray drying Methods 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000002270 dispersing agent Substances 0.000 claims description 16
- 239000012530 fluid Substances 0.000 claims description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 238000012545 processing Methods 0.000 claims description 8
- 238000013022 venting Methods 0.000 claims description 8
- -1 wherein Chemical compound 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
- 238000005507 spraying Methods 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000001828 Gelatine Substances 0.000 claims 3
- 229920000159 gelatin Polymers 0.000 claims 3
- 235000019322 gelatine Nutrition 0.000 claims 3
- 238000001514 detection method Methods 0.000 abstract description 9
- 238000011084 recovery Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 241001465754 Metazoa Species 0.000 abstract description 6
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 238000005538 encapsulation Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 239000000375 suspending agent Substances 0.000 abstract 1
- 210000001519 tissue Anatomy 0.000 description 36
- 235000019441 ethanol Nutrition 0.000 description 23
- 239000011805 ball Substances 0.000 description 17
- 241000700159 Rattus Species 0.000 description 16
- 238000007792 addition Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 13
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 239000003937 drug carrier Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 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
- 238000010253 intravenous injection Methods 0.000 description 5
- 239000003182 parenteral nutrition solution Substances 0.000 description 5
- 239000011806 microball Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000013641 positive control Substances 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
- 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
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- 230000001575 pathological effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000003672 processing method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 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
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000000605 extraction Methods 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
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 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
- 230000008859 change 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
- 230000006378 damage Effects 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
- 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
- 239000004744 fabric Substances 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
- 238000001033 granulometry Methods 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
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000002156 mixing 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
- 230000008569 process Effects 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
- 229940126585 therapeutic drug Drugs 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
- A61K9/0002—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
- 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
- A61K9/14—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
Abstract
The invention provides a kind of Lung targeting sulphuric acid cephalosporium quinol EC microballoons and preparation method thereof, belong to animal antibiotic targeting preparation technical field, preparation method is：Bulk drug and ethanol：Isopropanol：Dichloromethane mixes ball milling, volatilizes liquid, obtains raw materials treated medicine.Take ethyl cellulose and albumin as carrier, be dissolved in ethanol solution, after heating stirring is to be dissolved, add Cefquinome, with ultrasonic circulation, fully mix, add glidant and suspending agent, mix, it is spray-dried, while needing magnetic agitation, microballoon is then received to obtain by whirlpool separator.The microsphere encapsulation rate of the present invention is more than 90%, and drugloading rate more than 15%, more than 90% microspherulite diameter is distributed in the range of 10 ~ 25um.Easy to operate, efficiency high, mild condition, particle size are easy to control etc., and preferably, outward appearance is homogeneous, safe and reliable with preferable slow release effect and targeting, and detection method specificity is good for dispersiveness, and sensitivity and the rate of recovery are high.
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 EC microballoons
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 content of the invention
It is an object of the invention to provide a kind of Lung targeting sulphuric acid cephalosporium quinol EC 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
EC microballoons, it is characterised in that preparation method comprises the following steps：
The first step, by bulk drug and dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary type ball-milling
Machine, ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, and 60-80 DEG C of heating stirring is waited to be completely dissolved
Afterwards, the Cefquinome after being handled in the addition of pharmaceutical carrier ratio, with ultrasonic probe in ultrasonic power 600-800W, ultrasonic 6-8s,
Stop 4-6s 25 circulations, it is mixture fully to mix, and adds glidant, mixes, then enters using two-fluid spray drying machine
Row spray drying, while needing magnetic agitation, then receives to obtain Lung targeting sulphuric acid cephalosporium quinol EC microballoons by whirlpool separator.
Wherein, in the first step, the dispersant is the mixture of ethanol, isopropanol and dichloromethane, wherein, ethanol：It is different
Propyl alcohol：Methylene chloride volume ratio is 5-10:1-3:0.5-2.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, in the second step, the carrier is the mixture of ethyl cellulose and albumin, wherein ethyl cellulose
Quality parts ratio with albumin is：5:1-20:1.
Wherein, in second step, medicine is 1 with carrier ratio:1-1:10.
Wherein, the spray drying condition is：Inlet temperature is 40-200 DEG C, and rate of venting is 400-1000%, sample introduction
Speed is 10-60%, 20-40 DEG C of leaving air temp.
Wherein, the particle diameter of the microballoon is at 10-25 μm.
Wherein, the glidant is magnesium stearate or talcum powder, and carrier is 1-10 with its mass ratio:0.01-0.1.
In order to achieve the above object, present invention also offers a kind of preparation side of Lung targeting sulphuric acid cephalosporium quinol EC microballoons
Method, wherein, preparation method comprises the following steps：
The first step, by bulk drug and solvent 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, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, and 60-80 DEG C of heating stirring is waited to be completely dissolved
Afterwards, the Cefquinome after being handled in the addition of pharmaceutical carrier ratio, with ultrasonic probe in ultrasonic power 600-800W, ultrasonic 6-8s,
Stop 4-6s 25 circulations, it is mixture fully to mix, and adds glidant, mixes, then enters using two-fluid spray drying machine
Row spray drying, while needing magnetic agitation, then receives to obtain Lung targeting sulphuric acid cephalosporium quinol EC microballoons by whirlpool separator.
Beneficial effects of the present invention are：Prepared microsphere encapsulation rate is more than 90%, more than 90% microspherulite diameter point
Cloth is in the range of 10~25um.This preparation method has that operating method is easy, preparing microspheres efficiency, high, preparation condition is gentle, micro-
The advantages of spherolite footpath size is easy to control, and reappearance is high, and stable, the Cefquinome microballoon dispersiveness prepared is preferable,
Outward appearance is homogeneous.Contrasted by positive control medicine sulphuric acid cephalosporium quinol parenteral solution, through group in release in vitro research and rat body
Knit distribution result of study to show, with preferable slow release effect and targeting, can be drawn by tissue pathological slice, Lung targeting
Microballoon will not cause damage to tissue, safe and reliable.Detection method specificity is good, sensitivity (test limit 1 μ g/kg, the μ of quantitative limit 3
G/kg) and the rate of recovery it is high (>80%), the excellent (CV of precision<10%) 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 Ethylcellulose Microspheress.
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 rat after single dose (6mg CEQ/kg B.W.) intravenous injection sulphuric acid cephalosporium quinol Ethylcellulose Microspheress
The distribution of medicine in tissue.
Fig. 6 is rat after single dose (6mg CEQ/kg B.W.) intravenous injection sulphuric acid cephalosporium quinol Ethylcellulose Microspheress
Lung tissue and the section of blank pathologic.
Embodiment
The present invention is realized by following measure：A kind of Lung targeting sulphuric acid cephalosporium quinol EC microballoons, it is characterised in that system
Preparation Method comprises the following steps：
The first step, by bulk drug and dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary type ball-milling
Machine, ball milling 1-3h, interval 0.5-1.5h, then ball milling 1-3h, volatilize liquid, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, and 60-80 DEG C of heating stirring is waited to be completely dissolved
Afterwards, the Cefquinome after being handled in the addition of pharmaceutical carrier ratio, with ultrasonic probe in ultrasonic power 600-800W, ultrasonic 6-8s,
Stop 4-6s 25 circulations, it is mixture fully to mix, and adds glidant, mixes, then enters using two-fluid spray drying machine
Row spray drying, while needing magnetic agitation, then receives to obtain Lung targeting sulphuric acid cephalosporium quinol EC microballoons by whirlpool separator.
Wherein, in the first step, the dispersant is the mixture of ethanol, isopropanol and dichloromethane, wherein, ethanol：It is different
Propyl alcohol：Methylene chloride volume ratio is 5-10:1-3:0.5-2.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, in the second step, the carrier is the mixture of ethyl cellulose and albumin, wherein ethyl cellulose
Quality parts ratio with albumin is：5:1-20:1.
Wherein, in second step, medicine is 1 with carrier ratio:1-1:10.
Wherein, the spray drying condition is：Inlet temperature is 40-200 DEG C, and rate of venting is 400-1000%, sample introduction
Speed is 10-60%, 20-40 DEG C of leaving air temp.
Wherein, the particle diameter of the microballoon is at 10-25 μm.
Wherein, the glidant is magnesium stearate or talcum powder, and carrier is 1-10 with its mass ratio:0.01-0.1.
In order to achieve the above object, present invention also offers a kind of preparation side of Lung targeting sulphuric acid cephalosporium quinol EC microballoons
Method, wherein, preparation method comprises the following steps：
The first step, by bulk drug and solvent 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, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, and 60-80 DEG C of heating stirring is waited to be completely dissolved
Afterwards, the Cefquinome after being handled in the addition of pharmaceutical carrier ratio, with ultrasonic probe in ultrasonic power 600-800W, ultrasonic 6-8s,
Stop 4-6s 25 circulations, it is mixture fully to mix, and adds glidant, mixes, then enters using two-fluid spray drying machine
Row spray drying, while needing magnetic agitation, then receives to obtain Lung targeting sulphuric acid cephalosporium quinol EC microballoons by whirlpool separator.
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 particle diameter distribution Fig. 1.
1.2.2 the measure of microballoon drugloading rate, envelop rate
The assay method of Ethylcellulose Microspheress drug content crushes the method for microballoon, specific method using Probe Ultrasonic Searching
It is as follows：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 Fig. 2, produces dissolution bent
Line.
1.3 experimental results and analysis
1.3.1 microsphere particle size is analyzed
Ethylcellulose Microspheress granulometry result is shown in Fig. 1 respectively.
By Fig. 1, it is seen that the Ethylcellulose Microspheress narrower particle size distribution of preparation, granularity is accounted in 7~35 μ m microballoons
More than 80.0%.
1.3.2 microballoon drugloading rate, envelop rate analysis
The load medicine situation of table 1-3 Ethylcellulose Microspheress
| Title | Theoretical drugloading rate (%) | Actual drugloading rate (%) | Envelop rate (%) |
| Ethylcellulose Microspheress | 16.6% | 14.2% | 85.5% |
From table 1-3, Ethylcellulose Microspheress envelop rate prepares microballoon drug carrying ability preferable more than 85%.
1.3.3 drug-eluting rate analysis
The drug-eluting rate analysis of Ethylcellulose Microspheress is shown in Fig. 2 respectively.
From Figure 2 it can be seen that Ethylcellulose Microspheress are compared with Cefquinome bulk drug, Ethylcellulose Microspheress drug-eluting speed
Rate is significantly slowed, and when 0.5h insoluble drug releases are 2.8%, 48h, insoluble drug release is 96.7%, and Cefquinome bulk drug is in 4h
Insoluble drug release is 98.9%, it is seen that Ethylcellulose Microspheress 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 that the ethyl cellulose prepared is micro-
Ball is uniform in size, and distribution relatively concentrates between 7-35 μm the Ethylcellulose Microspheress that (2) drugloading rate, envelop rate result prove to prepare
Drugloading rate and envelop rate are higher, and drugloading rate is between 10-20%, and envelop rate is between 80-95%.(3) microsphere drug dissolution speed
Rate measurement result proves that the Ethylcellulose Microspheress prepared have slow releasing function, has compared with Cefquinome bulk drug obvious
Slow release effect, Ethylcellulose Microspheress are complete in 48h 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 Wietar 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 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, 1.7um)
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 sample 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 Ethylcellulose Microspheress 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 after administration
0.0833rd, 0.25,0.5,1,2,4,6,8,10,12,14,16,20,24,36,48h, by femoral artery sacrificed by exsanguination animal.Immediately
Point 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 addition concentration concentration and linear relationship of peak area between 3-500ppb are good in lung tissue
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 2-13,2-14.
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
Rat after table 2-14 single doses (6mg CEQ/kg B.W.) intravenous injection sulphuric acid cephalosporium quinol Ethylcellulose Microspheress
Organize 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 Ethylcellulose Microspheress preparation, compared with positive controls sulphuric acid cephalosporium quinol parenteral solution
(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 obvious.
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 that rat injects Ethylcellulose Microspheress, effectively enhances sulphuric acid cephalosporium quinol targeting and sustained release is imitated
Really.
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.Finally with Lung targeting sulphur efficient, stably, environmentally friendly
Sour Cefquinome microball preparation preparation method (spray drying process), successfully obtains a kind of sulphuric acid cephalosporium quinol lung-targeted microspheres system
Agent.
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 4.8g is mixed with dispersant 24ml, is put into frequency conversion planetary ball mill, ball milling 1h,
Interval 0.5h, then ball milling 1h, volatilize liquid, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, and 60 DEG C of heating stirrings until completely dissolved, are pressed
Cefquinome after pharmaceutical carrier ratio addition processing, with ultrasonic probe in ultrasonic power 600W, ultrasonic 6s, stop 4s 25 follow
Ring, it is mixture fully to mix, and adds 0.24g glidants, mixes, and it is dry then to carry out spraying using two-fluid spray drying machine
It is dry, while needing magnetic agitation, Lung targeting sulphuric acid cephalosporium quinol EC microballoons are then received to obtain by whirlpool separator.
Wherein, in the first step, the dispersant is the mixture of ethanol, isopropanol and dichloromethane, wherein, ethanol：It is different
Propyl alcohol：Methylene chloride volume ratio is 5:1:0.5.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, in the second step, the carrier is the mixture of ethyl cellulose and albumin, wherein ethyl cellulose
20g, albumin 4g.
Wherein, the spray drying condition is：Inlet temperature is 120 DEG C, and rate of venting is 700%, and sample rate is
40%, 30 DEG C of leaving air temp.
Wherein, the particle diameter of the microballoon is at 10-25 μm.
Wherein, the glidant is magnesium stearate.
The microballoon of above-mentioned preparation, 15.67 μm of average grain diameter, 80.32% 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 12.24%, and envelop rate is 73.42%, and drug release in vitro can
Up to more than 24h.
Embodiment 2
Preparation method comprises the following steps：
The first step, bulk drug 4.9g is mixed with dispersant 15ml, is put into frequency conversion planetary ball mill, ball milling 3h,
Interval 1.5h, then ball milling 3h, volatilize liquid, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, 80 DEG C of heating stirrings until completely dissolved, plus
Enter the Cefquinome after processing, with ultrasonic probe in ultrasonic power 800W, ultrasonic 8s, stop 6s 25 circulations, fully mixing is
Mixture, adds 0.079g glidants, mixes, and is then spray-dried using two-fluid spray drying machine, while needing magnetic
Power is stirred, and then receives to obtain Lung targeting sulphuric acid cephalosporium quinol EC microballoons by whirlpool separator.
Wherein, in the first step, the dispersant is the mixture of ethanol, isopropanol and dichloromethane, wherein, ethanol：It is different
Propyl alcohol：Methylene chloride volume ratio is 10:3:2.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, in the second step, the carrier is the mixture of ethyl cellulose and albumin, wherein ethyl cellulose
18g, albumin 1.8g.
Wherein, the spray drying condition is：Inlet temperature is 130 DEG C, and rate of venting is 600%, and sample rate is
40%, 30 DEG C of leaving air temp.
Wherein, the particle diameter of the microballoon is at 10-25 μm.
Wherein, the glidant is magnesium stearate.
The microballoon of above-mentioned preparation, 16.32 μm of average grain diameter, 81.34% 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 16.56%, and envelop rate is 82.80%, and drug release in vitro can
Up to more than 30h.
Embodiment 3
Preparation method comprises the following steps：
The first step, bulk drug 7.5g and dispersant 30ml ratio are mixed, and are put into frequency conversion planetary ball mill, ball
2h, interval 1h, then ball milling 2h are ground, liquid is volatilized, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, and 70 DEG C of heating stirrings until completely dissolved, are pressed
Cefquinome after pharmaceutical carrier ratio addition processing, with ultrasonic probe in ultrasonic power 700W, ultrasonic 7s, stop 5s 25 follow
Ring, it is mixture fully to mix, and adds 0.0675g glidants, mixes, and it is dry then to carry out spraying using two-fluid spray drying machine
It is dry, while needing magnetic agitation, Lung targeting sulphuric acid cephalosporium quinol EC microballoons are then received to obtain by whirlpool separator.
Wherein, in the first step, the dispersant is the mixture of ethanol, isopropanol and dichloromethane, wherein, ethanol：It is different
Propyl alcohol：Methylene chloride volume ratio is 6:2:1.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, in the second step, the carrier is the mixture of ethyl cellulose and albumin, wherein ethyl cellulose
20g, albumin 2.5g.
Wherein, the spray drying condition is：Inlet temperature is 140 DEG C, and rate of venting is 800%, and sample rate is
40%, 30 DEG C of leaving air temp.
Wherein, the particle diameter of the microballoon is at 10-25 μm.
Wherein, the glidant is talcum powder.
The microballoon of above-mentioned preparation, 15.86 μm of average grain diameter, 90.83% 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 23.89%, and envelop rate is 95.57%, and drug release in vitro can
Up to more than 48h.
Embodiment 4
Preparation method comprises the following steps：
The first step, bulk drug 7.8g and dispersant 39ml ratio are mixed, and are put into frequency conversion planetary ball mill, ball
2h, interval 1h, then ball milling 2h are ground, liquid is volatilized, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, and 65 DEG C of heating stirrings until completely dissolved, are pressed
Cefquinome after pharmaceutical carrier ratio addition processing, with ultrasonic probe in ultrasonic power 700W, ultrasonic 7s, stop 5s 25 follow
Ring, it is mixture fully to mix, and adds 0.079g glidants, mixes, and it is dry then to carry out spraying using two-fluid spray drying machine
It is dry, while needing magnetic agitation, Lung targeting sulphuric acid cephalosporium quinol EC microballoons are then received to obtain by whirlpool separator.
Wherein, in the first step, the dispersant is the mixture of ethanol, isopropanol and dichloromethane, wherein, ethanol：It is different
Propyl alcohol：Methylene chloride volume ratio is 5:3:1.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, in the second step, the carrier is the mixture of ethyl cellulose and albumin, wherein ethyl cellulose
15g, albumin 0.75g.
Wherein, the spray drying condition is：Inlet temperature is 150 DEG C, and rate of venting is 600%, and sample rate is
40%, 30 DEG C of leaving air temp.
Wherein, the particle diameter of the microballoon is at 10-25 μm.
Wherein, the glidant is talcum powder.
The microballoon of above-mentioned preparation, 15.86 μm of average grain diameter, 79.83% 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 23.89%, and envelop rate is 71.67%, and drug release in vitro can
Up to more than 24h.
Embodiment 5
Preparation method comprises the following steps：
The first step, bulk drug 5.5g and dispersant 22ml ratio are mixed, and are put into frequency conversion planetary ball mill, ball
2h, interval 1h, then ball milling 2h are ground, liquid is volatilized, the bulk drug Cefquinome after being handled；Second step, weighs carrier, is dissolved in
In 500ml95% ethanol solution, 70 DEG C of heating stirrings until completely dissolved, in the addition of pharmaceutical carrier ratio handle after cephalo
Quinoline promise, with ultrasonic probe in ultrasonic power 750W, ultrasonic 7s, stops 5s 25 circulations, it is mixture fully to mix, and is added
0.17g glidants, are mixed, and are then spray-dried using two-fluid spray drying machine, while magnetic agitation is needed, Ran Houtong
Cross whirlpool separator and receive to obtain Lung targeting sulphuric acid cephalosporium quinol EC microballoons.
Wherein, in the first step, dispersant is the mixture of ethanol, isopropanol and dichloromethane, wherein, ethanol：Isopropanol：
Methylene chloride volume ratio is 5:2:2.
Wherein, grinder used is frequency conversion planetary ball mill.
Wherein, in the second step, the carrier is the mixture of ethyl cellulose and albumin, wherein ethyl cellulose
25g, albumin 2.5g.
Wherein, the spray drying condition is：Inlet temperature is 160 DEG C, and rate of venting is 750%, and sample rate is
40%, 30 DEG C of leaving air temp.
Wherein, the particle diameter of the microballoon is at 10-25 μm.
Wherein, the glidant is talcum powder.
The microballoon of above-mentioned preparation, 15.86 μm of average grain diameter, 69.83% 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 10.89%, and envelop rate is 65.32%, and drug release in vitro can
Up to 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 (8)
1. a kind of Lung targeting sulphuric acid cephalosporium quinol EC microballoons, it is characterised in that preparation method comprises the following steps：
The first step, by bulk drug and dispersant according to 1g：2-5ml ratio is mixed, and is put into frequency conversion planetary ball mill, ball
1-3h, interval 0.5-1.5h, then ball milling 1-3h are ground, liquid is volatilized, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, 60-80 DEG C of heating stirring until completely dissolved, by medicine
Cefquinome after thing carrier ratio addition processing, with ultrasonic probe in ultrasonic power 600-800W, ultrasonic 6-8s, stops 4-6s's
25 circulations, it is mixture fully to mix, and adds glidant, mixes, and it is dry then to carry out spraying using two-fluid spray drying machine
It is dry, while needing magnetic agitation, Lung targeting sulphuric acid cephalosporium quinol EC microballoons are then received to obtain by whirlpool separator；
In the second step, the carrier is the mixture of ethyl cellulose and albumin, wherein ethyl cellulose and albumin
Quality parts ratio be：5:1-20:1.
2. Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim 1, it is characterised in that described in the first step
Dispersant is the mixture of ethanol, isopropanol and dichloromethane, wherein, 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 or 2, it is characterised in that grinder used
For frequency conversion planetary ball mill.
4. the Lung targeting sulphuric acid cephalosporium quinol gelatine microsphere according to claim any one of 1-3, it is characterised in that second step
In, medicine is 1 with carrier ratio:1-1:10.
5. the Lung targeting sulphuric acid cephalosporium quinol EC microballoons according to claim any one of 1-4, it is characterised in that the spraying
Drying condition is：Inlet temperature is 40-200 DEG C, and rate of venting is 400-1000%, and sample rate is 10-60%, leaving air temp
20-40℃。
6. the Lung targeting sulphuric acid cephalosporium quinol EC microballoons according to claim any one of 1-5, it is characterised in that the microballoon
Particle diameter at 10-25 μm.
7. the Lung targeting sulphuric acid cephalosporium quinol EC microballoons according to claim any one of 1-6, it is characterised in that described to help stream
Agent is magnesium stearate or talcum powder, and carrier is 1-10 with its mass ratio:0.01-0.1.
8. a kind of preparation method of Lung targeting sulphuric acid cephalosporium quinol EC microballoons, it is characterised in that preparation method comprises the following steps：
The first step, by bulk drug and solvent 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, the bulk drug Cefquinome after being handled；
Second step, weighs carrier, is dissolved in 500ml95% ethanol solution, 60-80 DEG C of heating stirring until completely dissolved, by medicine
Cefquinome after thing carrier ratio addition processing, with ultrasonic probe in ultrasonic power 600-800W, ultrasonic 6-8s, stops 4-6s's
25 circulations, it is mixture fully to mix, and adds glidant, mixes, and it is dry then to carry out spraying using two-fluid spray drying machine
It is dry, while needing magnetic agitation, Lung targeting sulphuric acid cephalosporium quinol EC microballoons are then received to obtain by whirlpool separator.
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