CN117838672B - Tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension and preparation method thereof - Google Patents
Tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension and preparation method thereof Download PDFInfo
- Publication number
- CN117838672B CN117838672B CN202410257806.2A CN202410257806A CN117838672B CN 117838672 B CN117838672 B CN 117838672B CN 202410257806 A CN202410257806 A CN 202410257806A CN 117838672 B CN117838672 B CN 117838672B
- Authority
- CN
- China
- Prior art keywords
- tilmicosin
- solution
- core
- type brown
- shell
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 title claims abstract description 143
- 229960000223 tilmicosin Drugs 0.000 title claims abstract description 142
- 229920001542 oligosaccharide Polymers 0.000 title claims abstract description 75
- -1 alginate oligosaccharide Chemical class 0.000 title claims abstract description 55
- 229940072056 alginate Drugs 0.000 title claims abstract description 53
- 235000010443 alginic acid Nutrition 0.000 title claims abstract description 53
- 229920000615 alginic acid Polymers 0.000 title claims abstract description 53
- 239000000443 aerosol Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000000725 suspension Substances 0.000 title description 12
- 239000002105 nanoparticle Substances 0.000 claims abstract description 79
- 239000011258 core-shell material Substances 0.000 claims abstract description 69
- 229920001661 Chitosan Polymers 0.000 claims abstract description 43
- 239000006070 nanosuspension Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 105
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 48
- 239000010410 layer Substances 0.000 claims description 27
- 239000012792 core layer Substances 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- 229920001577 copolymer Polymers 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 238000005507 spraying Methods 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 33
- 229940079593 drug Drugs 0.000 abstract description 24
- 150000002482 oligosaccharides Chemical class 0.000 abstract description 20
- 241000199919 Phaeophyceae Species 0.000 abstract description 19
- 238000007590 electrostatic spraying Methods 0.000 abstract description 15
- 230000001580 bacterial effect Effects 0.000 abstract description 6
- 235000019629 palatability Nutrition 0.000 abstract description 6
- 239000008280 blood Substances 0.000 abstract description 4
- 210000004369 blood Anatomy 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 239000012876 carrier material Substances 0.000 abstract description 3
- 244000005700 microbiome Species 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000002195 synergetic effect Effects 0.000 abstract description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000005303 weighing Methods 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 8
- 239000006069 physical mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 238000005538 encapsulation Methods 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 238000011068 loading method Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 235000019658 bitter taste Nutrition 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 206010048610 Cardiotoxicity Diseases 0.000 description 3
- 206010036790 Productive cough Diseases 0.000 description 3
- 229940124350 antibacterial drug Drugs 0.000 description 3
- 231100000259 cardiotoxicity Toxicity 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- 210000003802 sputum Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 229930194936 Tylosin Natural products 0.000 description 2
- 239000004182 Tylosin Substances 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 238000011056 performance test Methods 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 229960004059 tylosin Drugs 0.000 description 2
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 description 2
- 235000019375 tylosin Nutrition 0.000 description 2
- 238000001132 ultrasonic dispersion Methods 0.000 description 2
- ZMOUALJOEYJPSZ-BDMZYGHZSA-N (4r,5s,6s,7r,9r,11e,13e,15s,16r)-6-[(2r,3r,4s,5s,6r)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-7-[2-[(3s,5r)-3,5-dimethylpiperidin-1-yl]ethyl]-16-ethyl-4-hydroxy-15-[(2s,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxy-5,9,13-trimeth Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)O[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O ZMOUALJOEYJPSZ-BDMZYGHZSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000204022 Mycoplasma gallisepticum Species 0.000 description 1
- 241000202934 Mycoplasma pneumoniae Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, and provides tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nano suspension and a preparation method thereof. According to the invention, chitosan and PLGA are used as carrier materials, core-shell nanoparticles loaded with tilmicosin are prepared by a coaxial electrostatic spraying method, and then the core-shell nanoparticles are dispersed in a G-type brown algae oligosaccharide solution, so that the tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension is obtained. The invention adopts the coaxial electrostatic spraying technology to construct the indissolvable drug tilmicosin atomized inhalation nano preparation for the first time, and solves the problems of low bioavailability, poor palatability and the like of tilmicosin; tilmicosin is coated in the nanoparticles to play a role in slow release so as to maintain longer effective blood concentration and reduce the administration times; the G-type brown alginate oligosaccharides can destroy bacterial biomembrane, and increase the sensitivity of microorganisms to medicines while playing a synergistic effect; the medicine can directly act on the focus by the administration mode of aerosol inhalation, and the bioavailability of the medicine is improved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nano suspension and a preparation method thereof.
Background
Tilmicosin (Timicosin) is a macrolide antibiotic which is synthesized by the hydrolysis of tylosin, has stronger antibacterial activity compared with tylosin, and particularly has stronger antibacterial effect on mycoplasma gallisepticum, mycoplasma pneumoniae, mycoplasmal, spirochete and all gram-positive bacteria. Tilmicosin has wide antibacterial spectrum, strong antibacterial activity, low drug resistance, good tissue penetrating power and pharmacokinetics characteristics, and no adverse reaction of teratogenesis, carcinogenesis and mutagenesis, so that the tilmicosin is widely applied to the prevention and treatment of livestock and poultry respiratory diseases. The prior dosage forms on the market comprise tilmicosin premix, solution, injection, soluble powder and the like, but the oral administration of tilmicosin has heavier bitter taste and seriously affects the feed intake of animals, so that the bioavailability is low, and the injection administration is easy to generate cardiotoxicity. On the other hand, tilmicosin is a time-dependent antibacterial drug, and an effective therapeutic amount can be achieved only by multiple administrations, and toxic and side effects such as cardiotoxicity can be generated when the administration dosage or the administration frequency is increased. Therefore, development of a new formulation capable of masking the bitter taste of tilmicosin, enhancing palatability, and having a sustained-release effect is urgently needed to maintain a longer steady-state concentration, reduce the number of administration times, and reduce toxic and side effects.
For many years, nanoparticle-based drug delivery systems are mostly administered by systemic routes such as oral administration or injection, and have the disadvantage of poor targeted delivery ability of drugs to the lungs. In contrast, the drug-carrying nano particles are delivered to the lung through the atomizer, so that the high-concentration antibacterial drug can be directly and locally delivered to the periphery of infected cells and bacteria, the effect is quick, and the bioavailability of the drug is improved; meanwhile, the inhalable nano-carrier has a better slow release effect, can maintain longer effective blood concentration, and further reduces the administration times.
G-type brown algae oligosaccharide (Guluronate oligosaccharides), also called guluronic acid oligosaccharide, has effects of enhancing immunity, resisting tumor, virus and oxidation, and has multiple biological activities such as immunoregulation, antiinflammatory, protecting nerve, and destroying drug-resistant bacteria biomembrane. In respiratory diseases, the sputum viscoelasticity can be effectively reduced; destroying drug-resistant bacteria biomembrane, and enhancing the sterilizing effect of antibiotics; lowering pulmonary inflammatory cell, igE and histamine levels, and inhibiting asthma by modulating Th1/Th2 associated factors. The G-type brown alginate oligosaccharides are not absorbed by the organism, are discharged along with sputum after being used, have no chemical residues, and can be combined with antibiotics to improve the sensitivity of the antibiotics to drug-resistant bacteria. Currently, there are researches on the application of G-type brown alginate oligosaccharides to inhalation preparations, for example, in 2007, G-type brown alginate oligosaccharide inhalants are marketed as orphan drugs for treating cystic fibrosis of lung for the first time, and patent publications such as nebulizers, nebulizing concentrate, liquid dressing and the like based on G-type brown alginate oligosaccharides are also disclosed, but the application is limited to the use of G-type brown alginate oligosaccharides alone or in combination with water-soluble antibacterial drugs. Tilmicosin is a poorly soluble drug, and the G-type brown alginate oligosaccharides with bacterial biofilm disruption and the poorly soluble drug tilmicosin nano-preparation are used as lung inhalation preparations, and are locally administered through a lung inhalation route, so that the treatment effect can be enhanced. However, how to prepare tilmicosin and G-type brown alginate oligosaccharides into nano suspension solves the problems of low bioavailability, poor palatability and the like of tilmicosin, and still belongs to a difficult problem in the field.
Disclosure of Invention
In view of the above, the invention provides an aerosol inhalation nano suspension of tilmicosin/G-type brown alginate oligosaccharides and a preparation method thereof. The invention adopts the electrostatic spraying technology to construct the aerosol inhalation nanometer suspension of the indissolvable drug tilmicosin for the first time, can mask the bitter taste of the tilmicosin, has good palatability and has slow release effect.
In order to achieve the above object, the present invention provides the following technical solutions:
A preparation method of tilmicosin/G-type brown alginate oligosaccharides aerosol inhalation nanosuspension comprises the following steps:
Mixing chitosan, tilmicosin and acetic acid solution to obtain a nuclear layer solution; the concentration of chitosan in the nuclear layer solution is 1-5 mg/mL, and the concentration of tilmicosin is 0.2-1 mg/mL;
mixing polylactic acid-glycolic acid copolymer, tilmicosin and acetone to obtain a shell solution; the concentration of the polylactic acid-glycolic acid copolymer in the shell solution is 5-10 mg/mL, and the concentration of tilmicosin is 2-10 mg/mL;
Coaxially and electrostatically spraying the core layer solution and the shell layer solution to obtain core-shell nanoparticles;
Dispersing the core-shell nano particles in a G-type brown alginate oligosaccharide solution to obtain an aerosol inhalation nano suspension of the tilmicosin/G-type brown alginate oligosaccharide; the concentration of the G-type brown alginate oligosaccharides in the G-type brown alginate oligosaccharide solution is 30-110 mg/mL.
Preferably, the mass fraction of acetic acid in the acetic acid solution is 0.5% -1%.
Preferably, the pushing speed of the core layer solution in the coaxial electrostatic spraying is 0.03-0.1 mm/min, and the pushing speed of the shell layer solution is 0.1-0.3 mm/min.
Preferably, the voltage of the coaxial electrostatic spraying is 16-20V, and the receiving distance is 7-8 cm.
Preferably, the concentration of tilmicosin in the tilmicosin/G-type brown alginate oligosaccharides aerosol inhalation nanosuspension is 4-16 mug/mL.
The invention also provides tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension prepared by the preparation method.
The invention provides a preparation method of tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension, which comprises the following steps: mixing chitosan, tilmicosin and acetic acid solution to obtain a nuclear layer solution; the concentration of chitosan in the nuclear layer solution is 1-5 mg/mL, and the concentration of tilmicosin is 0.2-1 mg/mL; mixing polylactic acid-glycolic acid copolymer (PLGA), tilmicosin and acetone to obtain a shell solution; the concentration of the polylactic acid-glycolic acid copolymer in the shell solution is 5-10 mg/mL, and the concentration of tilmicosin is 2-10 mg/mL; coaxially and electrostatically spraying the core layer solution and the shell layer solution to obtain core-shell nanoparticles; dispersing the core-shell nano particles in a G-type brown alginate oligosaccharide solution to obtain an aerosol inhalation nano suspension of the tilmicosin/G-type brown alginate oligosaccharide; the concentration of the G-type brown alginate oligosaccharides in the G-type brown alginate oligosaccharide solution is 30-110 mg/mL. According to the invention, chitosan and PLGA are used as carrier materials, and core-shell nanoparticles loaded with tilmicosin medicaments are prepared by a coaxial electrostatic spraying technology, so that the core-shell nanoparticles have a certain slow release effect, can maintain the effective blood concentration for a longer time, and reduce the administration dosage and times, thereby reducing the cardiotoxicity of the tilmicosin medicaments; the bitter taste of the medicine can be covered by the encapsulation, so that the problem of poor palatability of tilmicosin due to bitter taste is solved. Meanwhile, the novel G-type brown alginate-oligose material is jointly applied, so that bacterial biomembrane can be destroyed, the viscoelasticity of sputum and the inflammatory cell level of lung can be reduced, the sensitivity of microorganism to antibiotics can be enhanced, the secretion of respiratory tract can be reduced, the function of resolving phlegm and expelling phlegm can be achieved, and a certain protection effect on mucous membrane can be realized. Compared with the prior tilmicosin premix, solution, injection and the like on the market, the tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension prepared by the invention can directly deliver drug-carrying nanometer particles to the lung and directly act on the periphery of infected cells and bacteria. In addition, compared with the traditional oral administration and intravenous injection administration routes, the aerosol inhalation can avoid systemic circulation, thereby reducing the toxicity of the medicine, improving the bioavailability of the medicine and meeting the clinical needs.
Drawings
FIG. 1 is a transmission electron microscope image of the core-shell nanoparticles prepared in example 1-example 5;
FIG. 2 is a particle size histogram of core-shell nanoparticles prepared in examples 1-5;
FIG. 3 is a potential histogram of the core-shell nanoparticles prepared in examples 1-5;
FIG. 4 is a FTIR plot of tilmicosin, chitosan, PLGA, core-shell nanoparticles (TNPs) prepared in example 2, and physical mixture (mix) prepared in comparative example 1;
FIG. 5 is an XRD pattern of tilmicosin, chitosan, PLGA, core-shell nanoparticles (TNPs) prepared in example 2, and physical mixture (mix) prepared in comparative example 1;
FIG. 6 is a TG plot of tilmicosin, chitosan, PLGA, core-shell nanoparticles (TNPs) prepared in example 2, and physical mixture (mix) prepared in comparative example 1;
FIG. 7 is a DSC of tilmicosin, chitosan, PLGA, core-shell nanoparticles (TNPs) prepared in example 2, and physical mixtures (mix) prepared in comparative example 1;
FIG. 8 is an in vitro cumulative release profile of tilmicosin and core-shell nanoparticles prepared in examples 1-5;
Figure 9 shows the in vitro bacteriostatic effect of tilmicosin drug substance, tilmicosin core-shell nanoparticles and nanosuspension on escherichia coli and staphylococcus aureus.
Detailed Description
The invention provides a preparation method of tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension, which comprises the following steps:
Mixing chitosan, tilmicosin and acetic acid solution to obtain a nuclear layer solution; the concentration of chitosan in the nuclear layer solution is 1-5 mg/mL, and the concentration of tilmicosin is 0.2-1 mg/mL;
mixing polylactic acid-glycolic acid copolymer, tilmicosin and acetone to obtain a shell solution; the concentration of the polylactic acid-glycolic acid copolymer in the shell solution is 5-10 mg/mL, and the concentration of tilmicosin is 2-10 mg/mL;
Coaxially and electrostatically spraying the core layer solution and the shell layer solution to obtain core-shell nanoparticles;
Dispersing the core-shell nano particles in a G-type brown alginate oligosaccharide solution to obtain an aerosol inhalation nano suspension of the tilmicosin/G-type brown alginate oligosaccharide; the concentration of the G-type brown alginate oligosaccharides in the G-type brown alginate oligosaccharide solution is 30-110 mg/mL.
According to the invention, chitosan, tilmicosin and acetic acid solution are mixed to obtain a nuclear layer solution. In the invention, the molecular weight of the chitosan is preferably 100 ten thousand, the molecular formula is (C 6H11NO4)n, CAS number is 9012-76-4, the molecular formula of the tilmicosin is C 46H80N2O13, the molecular weight is 869.15, CAS number is 108050-54-0, the mass fraction of acetic acid in the acetic acid solution is preferably 0.5% -1%, more preferably 0.6% -0.8%, the concentration of chitosan in the core layer solution is 1-5 mg/mL, preferably 2-4 mg/mL, and the concentration of tilmicosin is 0.2-1 mg/mL, preferably 0.4-0.8 mg/mL.
Polylactic acid-glycolic acid copolymer (PLGA), tilmicosin and acetone are mixed to obtain a shell solution. In the invention, the molecular formula of PLGA is (C 3H4O2)n(C2H2O2)m, the molecular weight is preferably 4 ten thousand, the CAS number is 34346-01-5; the concentration of polylactic acid-glycolic acid copolymer in the shell solution is 5-10 mg/mL, preferably 6-10 mg/mL, the concentration of tilmicosin is 2-10 mg/mL, preferably 3-10 mg/mL. In the embodiment of the invention, PLGA is preferably dissolved in acetone first, then tilmicosin is added, and ultrasonic or magnetic stirring is carried out to dissolve the tilmicosin, thus obtaining the shell solution.
After a core layer solution and a shell layer solution are obtained, the core layer solution and the shell layer solution are subjected to coaxial electrostatic spraying to obtain the core-shell nanoparticle. In the invention, the pushing speed of the core layer solution in the coaxial electrostatic spraying is preferably 0.03-0.1 mm/min, more preferably 0.05-0.08 mm/min, and the pushing speed of the shell layer solution is preferably 0.1-0.3 mm/min, more preferably 0.15-0.25 mm/min; the voltage of the coaxial electrostatic spray is preferably 16-20V, more preferably 17-19V, and the receiving distance is preferably 7-8 cm. After coaxial electrostatic spraying is finished, the method is used for preferentially collecting the obtained solution, centrifuging the obtained solution, collecting the precipitate, washing the precipitate by deionized water, and freeze-drying to obtain the core-shell nanoparticle; the rotational speed of the centrifugation is preferably 12000r/min and the time is preferably 30min. According to the invention, the indissolvable drug tilmicosin is prepared into the core-shell nanoparticles, and the nanoparticles are used as the carrier of the tilmicosin, so that the drug can be embedded or dissolved in the nanoparticles in the form of small enough particles, and the specific surface area of the drug is increased to increase the solubility of the drug.
After obtaining core-shell nanoparticles, dispersing the core-shell nanoparticles in a G-type brown alginate oligosaccharide solution to obtain the tilmicosin/G-type brown alginate oligosaccharide atomized inhalation nanometer suspension. In the invention, the G-type brown alginate oligosaccharide is also called as G Duan Guluo uronic acid oligosaccharide, and the molecular weight of the G-type brown alginate oligosaccharide is preferably less than or equal to 8000Da, more preferably 7000-8000 Da; the concentration of the G-type brown alginate oligosaccharides in the G-type brown alginate oligosaccharide solution is 30-110 mg/mL, preferably 40-100 mg/mL; the solvent of the G-type brown alginate oligosaccharide solution is water; the concentration of tilmicosin in the tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nano suspension is preferably 4-16 mug/mL, more preferably 8 mug/mL, and the concentration of tilmicosin in the finally obtained suspension is controlled within the range by controlling the proportion of core-shell nanoparticles and G-type brown alginate oligosaccharide solution; the dispersion mode is preferably ultrasonic dispersion, the condition of ultrasonic dispersion is not required, and the core-shell nanoparticles can be uniformly dispersed.
The invention also provides tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension prepared by the preparation method; the tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension comprises water, G-type brown alginate oligosaccharides and core-shell nanoparticles, wherein a core layer of the core-shell nanoparticles comprises chitosan and tilmicosin, and a shell layer comprises PLGA and tilmicosin; the particle size of the core-shell nanoparticle is preferably 170-210 nm.
The invention adopts the coaxial electrostatic spraying technology to construct the aerosol inhalation nano preparation of the indissolvable drug tilmicosin for the first time, and solves the problems of low bioavailability, poor palatability and the like of the tilmicosin; the tilmicosin is coated in the nanoparticles to play a role in slow release so as to maintain longer effective blood concentration and reduce the administration times; the G-type brown algae oligosaccharide can destroy bacterial biomembrane, and increase the sensitivity of microorganisms to medicines while playing a synergistic effect; the medicine can directly act on the focus part by the administration mode of aerosol inhalation, thereby improving the bioavailability of the medicine and meeting the clinical needs.
The following description of the embodiments of the present invention will clearly and fully describe the technical solutions of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examples, the molecular weight of chitosan was 100 ten thousand, the molecular weight of PLGA was 4 ten thousand, and the molecular weight of G-type brown alginate oligosaccharides was 7000Da.
Example 1
Accurately weighing 5mg of chitosan, dissolving in 5mL of 0.5wt% acetic acid solution to make the concentration of chitosan be 1mg/mL, adding 5mg of tilmicosin, and performing ultrasonic dissolution to obtain a core layer solution; weighing 50mg of PLGA, dissolving in 5mL of acetone to make the concentration of PLGA be 10mg/mL, adding 50mg of tilmicosin, and taking the solution as a shell solution after ultrasonic dissolution; setting coaxial electrostatic spraying parameters, wherein the pushing speed of the core layer solution is 0.1mm/min, the pushing speed of the shell layer solution is 0.2mm/min, the voltage is 18V, the receiving distance is 8cm, collecting the solution after the pushing is finished, centrifuging for 30min after 12000r/min, collecting the precipitate, washing with deionized water, and freeze-drying to obtain core-shell nanoparticles, which are recorded as TNPs-1; and ultrasonically dispersing the prepared core-shell nano particles in 90mg/mL G-type brown algae oligosaccharide solution to obtain tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension, and controlling the content of tilmicosin in the obtained tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension to be 8 mug/mL.
Example 2
Accurately weighing 5mg of chitosan, dissolving in 5mL of 0.5wt% acetic acid solution to make the concentration of chitosan be 1mg/mL, adding 1.67mg of tilmicosin, and performing ultrasonic dissolution to obtain a core layer solution; weighing 50mg of PLGA, dissolving in 5mL of acetone to make the concentration of PLGA be 10mg/mL, adding 16.67mg of tilmicosin, and taking the solution as a shell solution after ultrasonic dissolution; setting coaxial electrostatic spraying parameters, wherein the pushing speed of the core layer solution is 0.1mm/min, the pushing speed of the shell layer solution is 0.2mm/min, the voltage is 18V, the receiving distance is 8cm, collecting the solution after the pushing is finished, centrifuging for 30min after 12000r/min, collecting the precipitate, washing with deionized water, and freeze-drying to obtain core-shell nanoparticles, which are recorded as TNPs-2; and ultrasonically dispersing the prepared core-shell nano particles in 90mg/mL G-type brown algae oligosaccharide solution to obtain tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension, and controlling the content of tilmicosin in the obtained tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension to be 8 mug/mL.
Example 3
Accurately weighing 5mg of chitosan, dissolving in 5mL of 0.5wt% acetic acid solution to make the concentration of chitosan be 1mg/mL, adding 1mg of tilmicosin, and performing ultrasonic dissolution to obtain a core layer solution; weighing 50mg of PLGA, dissolving in 5mL of acetone to make the concentration of PLGA be 10mg/mL, adding 10mg of tilmicosin, and taking the solution as a shell solution after ultrasonic dissolution; setting coaxial electrostatic spraying parameters, wherein the pushing speed of the core layer solution is 0.1mm/min, the pushing speed of the shell layer solution is 0.2mm/min, the voltage is 18V, the receiving distance is 8cm, collecting the solution after the pushing is finished, centrifuging for 30min after 12000r/min, collecting the precipitate, washing with deionized water, and freeze-drying to obtain core-shell nanoparticles, which are recorded as TNPs-3; and ultrasonically dispersing the prepared core-shell nano particles in 90mg/mL G-type brown algae oligosaccharide solution to obtain tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension, and controlling the content of tilmicosin in the obtained tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension to be 8 mug/mL.
Examples 4 and 5 are examples carried out to examine the release of tilmicosin in the core and shell layers, and are specifically as follows:
example 4 Shell-only contains tilmicosin
Accurately weighing 5mg of chitosan, dissolving in 5mL of 0.5wt% acetic acid solution to make the concentration of chitosan be 1mg/mL, and performing ultrasonic dissolution to obtain a nuclear layer solution; weighing 50mg of PLGA, dissolving in 5mL of acetone to make the concentration of PLGA be 10mg/mL, adding 16.67mg of tilmicosin, and taking the solution as a shell solution after ultrasonic dissolution; setting coaxial electrostatic spraying parameters, wherein the pushing speed of the core layer solution is 0.1mm/min, the pushing speed of the shell layer solution is 0.2mm/min, the voltage is 18V, the receiving distance is 8cm, collecting the solution after the pushing is finished, centrifuging for 30min after 12000r/min, collecting the precipitate, washing with deionized water, and freeze-drying to obtain core-shell nanoparticles, which are recorded as TNPs-4; and ultrasonically dispersing the prepared core-shell nano particles in 90mg/mL G-type brown algae oligosaccharide solution to obtain tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension, and controlling the content of tilmicosin in the obtained tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension to be 8 mug/mL.
Example 5 only the core layer contains tilmicosin
Accurately weighing 5mg of chitosan, dissolving in 5mL of 0.5wt% acetic acid solution to make the concentration of chitosan be 1mg/mL, adding 1.67mg of tilmicosin, and performing ultrasonic dissolution to obtain a core layer solution; weighing 50mg of PLGA, dissolving in 5mL of acetone to make the concentration of PLGA be 10mg/mL, and taking the PLGA as a shell solution after ultrasonic dissolution; setting coaxial electrostatic spraying parameters, wherein the pushing speed of the core layer solution is 0.1mm/min, the pushing speed of the shell layer solution is 0.2mm/min, the voltage is 18V, the receiving distance is 8cm, collecting the solution after the pushing is finished, centrifuging for 30min after 12000r/min, collecting the precipitate, washing with deionized water, and freeze-drying to obtain core-shell nanoparticles, wherein the number of the core-shell nanoparticles is TNPs-5; and ultrasonically dispersing the prepared core-shell nano particles in 90mg/mL G-type brown algae oligosaccharide solution to obtain tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension, and controlling the content of tilmicosin in the obtained tilmicosin/G-type brown algae oligosaccharide aerosol inhalation nano suspension to be 8 mug/mL.
Comparative example 1
Tilmicosin, chitosan, and PLGA were physically mixed, and the amounts of tilmicosin, chitosan, and PLGA were the same as those prescribed in example 2, and the resultant mixture was designated as mix.
Performance test:
1. Characterization of
FIG. 1 is a transmission electron microscope image of the core-shell nanoparticles prepared in example 1-example 5; according to fig. 1, it can be seen that the core-shell nanoparticles prepared according to the invention have good dispersibility, and the nanoparticles are not adhered to each other and have uniform spherical structures.
FIG. 2 is a particle size histogram of core-shell nanoparticles prepared in examples 1-5; according to fig. 2, the particle size range of the core-shell nanoparticles with different prescriptions is 170-210 nm.
FIG. 3 is a potential histogram of the core-shell nanoparticles prepared in examples 1-5; according to the graph 3, the Zeta potential of the core-shell nano particles prepared by the invention with different prescriptions is about-15 mV, and the dispersibility and the stability are good.
FIG. 4 is a FTIR plot of Tilmicosin (TMS), chitosan (CTS), PLGA, core-shell nanoparticles (TNPs) prepared in example 2, and physical mixture (mix) prepared in comparative example 1; as can be seen from fig. 4, the FTIR curve of tilmicosin: the free hydroxyl groups have telescopic vibration absorption near 3450 cm -1, -CH 3 and-CH 2 have telescopic vibration absorption near 2930 cm -1 and 2840 cm -1, the carbon-carbon double bonds have unsaturated telescopic vibration near 1740 cm -1, the carbonyl groups have telescopic vibration near 1673 cm -1, the sharp absorption peaks at 1589 cm -1 and 1455 cm -1 are the vibration absorption peaks of N-H and C-H, and the C-O-C has telescopic vibration absorption near 1060 cm -1. FTIR profile of chitosan: at 2872 cm -1 -CH stretching vibrations are shown, 1650 cm -1、1600 cm-1、1420 cm-1 for amide I, II, III bands, 1070 cm -1 for C-O stretching vibrations, respectively. In the FTIR profile of PLGA: 2949 cm -1 is the C-H stretching vibration of methyl, c=o characteristic peak at 1745 cm -1,1090 cm-1 is the C-O stretching vibration peak. The FTIR curve at TNPs shows the methyl C-H, C =o and C-O stretching vibration peaks of PLGA, and no characteristic peaks of tilmicosin and chitosan appear, indicating encapsulation in core-shell nanoparticles. The above results show that the core-shell nanoparticle prepared by the invention has no chemical reaction between the drug and the carrier material.
FIG. 5 is an XRD pattern of Tilmicosin (TMS), chitosan (CTS), PLGA, core-shell nanoparticles (TNPs) prepared in example 2, and physical mixture (mix) prepared in comparative example 1; as can be seen from fig. 5, tilmicosin has no characteristic diffraction peak, is amorphous, and is an amorphous substance; chitosan and PLGA show broad peaks at 20 ° and 21 °, which are amorphous diffraction peaks; the prepared core-shell nano-particles exist in an amorphous form.
FIG. 6 is a TG plot of Tilmicosin (TMS), chitosan (CTS), PLGA, core-shell nanoparticles (TNPs) prepared in example 2, and physical mixture (mix) prepared in comparative example 1; according to fig. 6, it can be seen that the core-shell nanoparticle prepared by the method has good thermal stability at 0-250 ℃.
FIG. 7 is a DSC of Tilmicosin (TMS), chitosan (CTS), PLGA, core-shell nanoparticles (TNPs) prepared in example 2, and physical mixture (mix) prepared in comparative example 1; as can be seen from fig. 7, chitosan has a hot melt absorption peak at 324 ℃ and the absorption peak disappears in the core-shell nanoparticle, indicating that the core-shell nanoparticle exists in an amorphous form.
2. Drug loading and encapsulation efficiency test
Table 1 shows the results of the Drug Loading (DL) and Encapsulation Efficiency (EE) tests of the core-shell nanoparticles prepared in examples 1 to 5.
TABLE 1 drug loading and encapsulation efficiency of core-shell nanoparticles obtained in example 1 to example 5
| Core-shell nanoparticles | DL（%） | EE（%） |
| TNPs-1 | 36.79±1.18 | 88.83±1.03 |
| TNPs-2 | 25.30±0.96 | 96.82±0.59 |
| TNPs-3 | 16.84±1.08 | 97.13±0.24 |
| TNPs-4 | 21.43±0.13 | 93.53±0.56 |
| TNPs-5 | 3.14±0.42 | 97.90±0.05 |
According to the data in Table 1, it can be seen that the core-shell nanoparticle prepared by the invention has higher drug-loading rate and encapsulation efficiency, wherein TNPs-5 only the core layer contains tilmicosin, so that the drug-loading rate is lower.
3. In vitro Release Performance test
Calculating the dosage of the nanoparticles in the in-vitro release according to the drug loading quantity of the core-shell nanoparticles in table 1, and determining the in-vitro release characteristics of the nanoparticles by a dialysis bag method, wherein the dosage is as follows: 1.5mg TMS, 4.1mg TNPs-1, 5.9mg TNPs-2, 8.9mg TNPs-3, 7.0mg TNPs-4, 47.8mg TNPs-5, respectively, were dispersed in 2mL of release medium (PBS buffer, pH7.4, containing 0.5% Tween 80), added to a pre-treated dialysis bag (MWCO, 8-12 kDa), placed in a conical flask containing 28mL of the same release medium, and shaken at (37.+ -. 0.5) DEG.C, 100 r/min, and constant temperature. 2mL were sampled at 0, 0.25, 0.5, 0.75, 1,2, 4, 6, 8, 12, 24, 48h, respectively, while fresh aliquots of the above release medium were replenished. The cumulative release rate was calculated and examined in vitro release behavior by repeating 3 times in parallel.
FIG. 8 is an in vitro cumulative release profile of tilmicosin and core-shell nanoparticles prepared in examples 1-5; according to fig. 8, it can be seen that core-shell nanoparticles prepared according to different prescriptions have a certain slow release effect, and examples 4 and 5 are core-shell nanoparticles prepared for examining the release conditions of tilmicosin in the core layer and the shell layer, and according to fig. 8, TNPs-5 is a nanoparticle only containing tilmicosin in the core layer, and the release of the drug in the core layer is slower.
4. Antibacterial effect test
The test method is as follows: bacterial liquid (10 8 CFU/mL,100 mu L) and PBS, tilmicosin bulk drug (TMS), tilmicosin core-shell nanoparticles (TNPs) prepared in example 2 and tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanosuspension (TNPs@GOS) prepared in example 2 are added into a shaking tube, wherein the addition amount of PBS, TMS, TNPs and TNPs@GOS is 900 mu L, the concentration of TMS, TNPs and TNPs@GOS is 8 mu G/mL based on the content of tilmicosin, and the solvent adopted by TMS and TNPs is PBS. Placing at 37 ℃ and vibrating at constant temperature. After 12h, the bacterial solution was diluted to 10 5 CFU/mL with PBS (pH 7.4), 80. Mu.L was added dropwise to an agar plate and spread and cultured uniformly for 24h for observation.
FIG. 9 shows the in vitro antibacterial effect of tilmicosin drug substance, tilmicosin core-shell nanoparticles and nanosuspension on E.coli and Staphylococcus aureus, wherein Control is the experimental group with PBS; as can be seen from the graph 9, the tilmicosin nano/G-type brown alginate oligosaccharides aerosol inhalation suspension has better antibacterial effect compared with tilmicosin bulk drug and tilmicosin core-shell nanoparticles.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (6)
1. The preparation method of the tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanosuspension is characterized by comprising the following steps of:
Mixing chitosan, tilmicosin and acetic acid solution to obtain a nuclear layer solution; the concentration of chitosan in the nuclear layer solution is 1-5 mg/mL, and the concentration of tilmicosin is 0.2-1 mg/mL;
mixing polylactic acid-glycolic acid copolymer, tilmicosin and acetone to obtain a shell solution; the concentration of the polylactic acid-glycolic acid copolymer in the shell solution is 5-10 mg/mL, and the concentration of tilmicosin is 2-10 mg/mL;
Coaxially and electrostatically spraying the core layer solution and the shell layer solution to obtain core-shell nanoparticles;
Dispersing the core-shell nano particles in a G-type brown alginate oligosaccharide solution to obtain an aerosol inhalation nano suspension of the tilmicosin/G-type brown alginate oligosaccharide; the concentration of the G-type brown alginate oligosaccharides in the G-type brown alginate oligosaccharide solution is 30-110 mg/mL.
2. The preparation method according to claim 1, wherein the mass fraction of acetic acid in the acetic acid solution is 0.5% -1%.
3. The method according to claim 1, wherein the injection speed of the core layer solution in the coaxial electrostatic spray is 0.03-0.1 mm/min, and the injection speed of the shell layer solution is 0.1-0.3 mm/min.
4. The method according to claim 1, wherein the coaxial electrostatic spray has a voltage of 16-20 v and a receiving distance of 7-8 cm.
5. The preparation method of claim 1, wherein the concentration of tilmicosin in the tilmicosin/G-type brown alginate oligosaccharides in the aerosol inhalation nanosuspension is 4-16 μg/mL.
6. The tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanosuspension prepared by the preparation method according to any one of claims 1 to 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410257806.2A CN117838672B (en) | 2024-03-07 | 2024-03-07 | Tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410257806.2A CN117838672B (en) | 2024-03-07 | 2024-03-07 | Tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117838672A CN117838672A (en) | 2024-04-09 |
| CN117838672B true CN117838672B (en) | 2024-05-10 |
Family
ID=90536445
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410257806.2A Active CN117838672B (en) | 2024-03-07 | 2024-03-07 | Tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117838672B (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747738A (en) * | 2002-10-29 | 2006-03-15 | 川塞夫有限公司 | Sustained release of antifectives |
| WO2009064469A1 (en) * | 2007-11-14 | 2009-05-22 | Nektar Therapeutics | Pulmonary delivery of a macrolide antibiotic |
| WO2010005740A2 (en) * | 2008-06-16 | 2010-01-14 | Bind Biosciences, Inc. | Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic targeted nanoparticles |
| WO2010139959A2 (en) * | 2009-06-03 | 2010-12-09 | Algipharma Ipr As | Alginate oligomers for the inhibition of microbial adherence to surfaces |
| CN102458474A (en) * | 2009-06-03 | 2012-05-16 | 阿尔吉法玛公司 | Treatment of acinetobacter with alginate oligomers and antibiotics |
| CN106029079A (en) * | 2014-02-28 | 2016-10-12 | 阿尔吉法玛公司 | Use of alginate oligomers in the treatment of cystic fibrosis and other conditions associated with defective cftr ion channel function |
| CN112691087A (en) * | 2021-01-25 | 2021-04-23 | 潍坊医学院 | Natamycin nanoparticles and preparation method thereof |
| CN115581688A (en) * | 2022-11-25 | 2023-01-10 | 山东国邦药业有限公司 | Tilmicosin dry powder inhalant and preparation method thereof |
| CN115671291A (en) * | 2022-06-12 | 2023-02-03 | 深圳三林生物技术有限公司 | Atomizing agent and atomizing agent concentrated solution based on G-type brown alginate oligosaccharides as well as preparation methods and applications of atomizing agent and atomizing agent concentrated solution |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050191359A1 (en) * | 2001-09-28 | 2005-09-01 | Solubest Ltd. | Water soluble nanoparticles and method for their production |
| CA3094015A1 (en) * | 2018-03-19 | 2019-09-26 | Algipharma As | Use of alginate oligomers to enhance the translocation of micro/nanoparticles across mucus layers |
-
2024
- 2024-03-07 CN CN202410257806.2A patent/CN117838672B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747738A (en) * | 2002-10-29 | 2006-03-15 | 川塞夫有限公司 | Sustained release of antifectives |
| WO2009064469A1 (en) * | 2007-11-14 | 2009-05-22 | Nektar Therapeutics | Pulmonary delivery of a macrolide antibiotic |
| WO2010005740A2 (en) * | 2008-06-16 | 2010-01-14 | Bind Biosciences, Inc. | Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic targeted nanoparticles |
| WO2010139959A2 (en) * | 2009-06-03 | 2010-12-09 | Algipharma Ipr As | Alginate oligomers for the inhibition of microbial adherence to surfaces |
| CN102458474A (en) * | 2009-06-03 | 2012-05-16 | 阿尔吉法玛公司 | Treatment of acinetobacter with alginate oligomers and antibiotics |
| CN106029079A (en) * | 2014-02-28 | 2016-10-12 | 阿尔吉法玛公司 | Use of alginate oligomers in the treatment of cystic fibrosis and other conditions associated with defective cftr ion channel function |
| CN112691087A (en) * | 2021-01-25 | 2021-04-23 | 潍坊医学院 | Natamycin nanoparticles and preparation method thereof |
| CN115671291A (en) * | 2022-06-12 | 2023-02-03 | 深圳三林生物技术有限公司 | Atomizing agent and atomizing agent concentrated solution based on G-type brown alginate oligosaccharides as well as preparation methods and applications of atomizing agent and atomizing agent concentrated solution |
| CN115581688A (en) * | 2022-11-25 | 2023-01-10 | 山东国邦药业有限公司 | Tilmicosin dry powder inhalant and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| Fabrication and Characterization of Chitosan/Poly(Lactic-Co-glycolic Acid) Core-Shell Nanoparticles by Coaxial Electrospray Technology for Dual Delivery of Natamycin and Clotrimazole;Cui Xiaoming et al.;《FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY》;20210315;第9卷;第1-13页 * |
| Overcoming Drug Resistance with Alginate Oligosaccharides Able To Potentiate the Action of Selected Antibiotics;Saira Khan et al.;《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》;20120912;第56卷(第10期);第5134-5141页 * |
| 同轴静电喷雾法制备单分散载药纳米粒进展;蒋屏等;《中南药学》;20180320;第16卷(第3期);第351-354页 * |
| 替米考星新剂型的运用研究进展;汪艳等;《中国畜禽种业》;20190131;第15卷(第1期);第50-51页 * |
| 褐藻胶寡糖的功能特性研究进展;曾斌芬等;《食品研究与开发》;20220710;第43卷(第13期);第210-216页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117838672A (en) | 2024-04-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Pai et al. | Development and evaluation of chitosan microparticles based dry powder inhalation formulations of rifampicin and rifabutin | |
| Douafer et al. | Scope and limitations on aerosol drug delivery for the treatment of infectious respiratory diseases | |
| Wu et al. | Genipin-crosslinked carboxymethyl chitosan nanogel for lung-targeted delivery of isoniazid and rifampin | |
| Goel et al. | Exploring targeted pulmonary delivery for treatment of lung cancer | |
| Forest et al. | Nano-delivery to the lung-by inhalation or other routes and why nano when micro is largely sufficient? | |
| Du et al. | Swellable ciprofloxacin-loaded nano-in-micro hydrogel particles for local lung drug delivery | |
| JP2002543165A (en) | Compositions for aerosolization and inhalation | |
| Miranda et al. | Exploring inhalable polymeric dry powders for anti-tuberculosis drug delivery | |
| NZ504711A (en) | Soft-pellet drug and process for the preparation thereof | |
| Sabuj et al. | Inhaled antibiotic-loaded polymeric nanoparticles for the management of lower respiratory tract infections | |
| Yildiz-Peköz et al. | Preparation and characterization of doripenem-loaded microparticles for pulmonary delivery | |
| US9707228B2 (en) | Dry powder formulation | |
| Mahar et al. | Application of PLGA as a biodegradable and biocompatible polymer for pulmonary delivery of drugs | |
| Almurshedi et al. | Development of inhalable nanostructured lipid carriers for ciprofloxacin for noncystic fibrosis bronchiectasis treatment | |
| US8343551B2 (en) | Nanocomposite particles | |
| Nainwal et al. | Dry powder inhalers of antitubercular drugs | |
| Kanojia et al. | Recent advancements and applications of inhalable microparticles based drug delivery systems in respiratory disorders | |
| CN117838672B (en) | Tilmicosin/G-type brown alginate oligosaccharide aerosol inhalation nanometer suspension and preparation method thereof | |
| WO2011052706A1 (en) | Dry powder inhaler of tranilast having high solubility | |
| Aragao-Santiago et al. | Innovative formulations for controlled drug delivery to the lungs and the technical and toxicological challenges to overcome | |
| Guan et al. | Applications of chitosan in pulmonary drug delivery | |
| Rawat et al. | Nanotechnology-Based Drug Delivery Systems for the Treatment of Pulmonary Diseases | |
| JP5437543B2 (en) | Asthma detection preparation | |
| Mishra et al. | Nanoparticulate delivery systems for the effective treatment of COPD | |
| CN111544420B (en) | Inhalable effervescent powder inhalation and application thereof in preparation of infectious pneumonia medicines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |