CN105902525A - Application of chlorogenic acid nano powder inhalation in medicine for treating acute lung injury - Google Patents
Application of chlorogenic acid nano powder inhalation in medicine for treating acute lung injury Download PDFInfo
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Abstract
The invention discloses an application of a chlorogenic acid nano powder inhalation in a medicine for treating acute lung injury. The chlorogenic acid nano powder inhalation is prepared with a chlorogenic acid nano medicine delivery system selected from the dosage forms of lipidosomes, nano-particles, nano-emulsions and micro-emulsions with or without addition of an auxiliary material. The medicine delivery system is dried into solid powder and is then mixed with a carrier to prepare the chlorogenic acid nano powder inhalation. The nano powder inhalation is stable, is easy to enter the deep parts of lung tissue, allows targeted positioning, is convenient to carry and use and has advantages on treatment of the acute lung injury. The chlorogenic acid nano powder inhalation is used for treating acute lung injuries caused by infection, shock, smoking, wound, poisoning, inhalation of simulative gas, irradiation, high-oxygen and low-oxygen atmospheres and the like. The simulative gas herein comprises phosgene, diphosgene, triphosgene, chlorine, nitrogen oxides, formaldehyde, dimethyl sulfate, hydrogen chloride, hydrogen bromide, hydrogen fluoride, ammonia, ozone and sulfur dioxide.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to chlorogenic acid nanometer powder spray and the application in the medicine for the treatment of acute lung injury thereof.
Background technology
Chlorogenic acid is widely distributed in plant, all has to pteridophyta from high dicotyledon, is primarily present in Caprifoliaceae Radix Ophiopogonis
Belong to, in Compositae artemisia and Eucommiaceae Cortex Eucommiae platymiscium, the plant that content is higher mainly have Semen Helianthi, cacao bean, coffee bean,
Fructus Hippophae and Chinese traditional herbs, such as Flos Lonicerae, the Cortex Eucommiae.The chlorogenic acid entitled 3-O-coffee phthalein quinic acid of chemistry, the dissolubility in water
It is 4%, is soluble in ethanol, acetone, is slightly soluble in ethyl acetate, be insoluble in the lipophylic organic solvents such as chloroform, ether, benzene, be
Flaxen solid.Have now been found that chlorogenic acid has antibacterial, antiviral, hepatic cholagogic, antitumor, lowering blood pressure and blood fat etc. to live
Property.Chlorogenic acid has a good pharmacological effect function, but chlorogenic acid poorly water-soluble, external instability, oxidizable, oral after at stomach
Being metabolized inactivation in intestinal, absorbance is the lowest, limits clinical practice, brings challenges also to chlorogenic acid preparation research.
The particle diameter of administration nano-drug administration system is nanoscale, and therefore its specific surface area is very big, with the connecing of site of action after entering human body
Contacting surface is actively big, can be greatly increased dissolution and the absorption of medicine.Administration nano-drug administration system also can solve many medicine poorly water-soluble, suction
The problem such as astigmat, instability.The material major part preparing nanosystems is biocompatibility macromolecular carrier, and medicine is wrapped up it
In, reduce drug degradation, improve stability；Promote that medicine enters intracellular, increase and absorb.Administration nano-drug administration system is inhaled for lung
Enter administration and have outstanding advantage.It can enter lung tissue deep after inhalation, directly contacts with alveolar, and contact area is big.
Therefore medicine is greatly increased in the concentration of alveolar tissue, can fast onset drug effect.Lung sucks administration nano-drug administration system often with powder spray shape
Formula is administered, and will mix with powder spray carrier, be drawn in lung by oral cavity after medicine is prepared as nanoparticle.Nanometer is administered system
System includes the dosage forms such as liposome, nanoparticle, microemulsion.
Liposome is the vesicle that phospholipid bilayer is constituted.Medicine can be encapsulated in interior aqueous phase or lipid film according to character.Liposome
Being made up of biodegradable material (phospholipid), to human non-toxic, histocompatibility is good.Liposome and cell membrane affinity
By force, the ability of medicine permeates cell membranes of being wrapped can be increased.Liposome technology can solve some fat-soluble medicine and be insoluble in water
A difficult problem.The drug encapsulation that some are unstable, oxidizable in liposome, medicine because being protected by lipid film, stability
Strengthen.
Nanoparticle refers generally to be the scattered solids of nanoscale, and due to its high dispersion, it is improved medicine as pharmaceutical carrier
The features such as thing bioavailability, intensifier target tropism.Solid lipid nanoparticle uses the compatible matrix material of human body as major auxiliary burden
Forming nanoparticle, have the feature of common nanoparticle and the feature of good biocompatibility, Recent study is more.Nanocapsule refers in particular to
Pharmaceutical pack is rolled in filmogen the nanoparticle formed, and has the inside and outside feature of nanoparticle equally.
Nano-emulsion refers to the system of particle diameter emulsion droplet composition below 200 nanometers, can be wrapped in emulsion droplet by fat-soluble medicine.
Nano-emulsion is high dispersion, is improved the feature such as drug bioavailability, intensifier target tropism as pharmaceutical carrier.Nano-emulsion can
Make insoluble medicine content in the formulation significantly increase, the absorption of active substance also can be made substantially to accelerate.Microemulsion refers to that particle diameter is 100
The system of the emulsion droplet composition below nanometer, has the feature of nano-emulsion equally.
Lung sucks preparation and is developed rapidly in recent years.Except obtaining in addition to effective general action, lung inhalation approach be asthma,
The most direct therapeutic modality of the pulmonary disease such as emphysema, chronic obstructive pulmonary disease, acute lung injury.Medicine can be directly to reach target
Position, rapid-action, reduce dosage and toxicity and untoward reaction.There are more than one hundred million alveolars in pulmonary, and absorption area is big；Blood flow
Greatly, the absorption of beneficially medicine；It is directly entered blood circulation after the transpulmonary absorption of medicine, it is to avoid the first pass effect of liver, improves
The bioavailability of medicine, the most existing a lot of pulmonary inhalation listing.The technology of Pulmonary inhalation mainly has 3 kinds: (1) mist
Change inhaler；(2) metered dose inhaler；(3) powder spray.Nebulizer needs ultrasonic atomizing device, in-convenience in use.Fixed
Containing propellant freon in amount inhalant disabled, effect duration is short, easily reveals.Powder spray is the research of pulmonary administration in recent years
Focus dosage form, its advantage is drug substance stable (solid state), easily enters lung tissue deep, absorbs rapidly, and targeting positions, takes
Band is with easy to use.
Acute lung injury be by many reasons cause based on diffusivity lung cellular damage, lung tissue structure occur distinctive
Pathological change, pulmonary edema and lung be micro-not to be opened for pathological characters, affect rapidly gas exchange function and is clinical characters pneumonia and leads to
Property increases syndrome thoroughly.The pathological characteristic of acute lung injury is alveolar capillary endotheliocyte and alveolar epithelial cells damage, table
It is now extensive pulmonary edema and microatelectasis.Its pathophysiological change is mainly QS pulmonary shunt and increases and lung compliance decline.It
Show as hypoxemia clinically, breathe frequency speed and x-ray rabat appearance double lung diffusivity infiltration.
The cause of disease of acute lung injury is complicated, and mortality rate is high, severe infections, shock, wound, smoking, toxic poisoning, radiation
Beta radiation, hyperoxia etc. all can cause acute lung injury, but its pathomechanism illustrates the most completely.Although 10 years lung preversation in recent years
Ventilation has obtained certain popularization, and the mortality rate of acute lung injury is under control, but its mortality rate is still up to 30～40%.At present
There is no the specific medicament for acute lung injury clinically.
Summary of the invention
The inventors discovered that acute lung injury can substantially be treated by chlorogenic acid.The invention discloses chlorogenic acid nanometer powder spray anxious in treatment
Application in the medicine of property injury of lung.
Chlorogenic acid of the present invention, its molecular characterization is:
Chlorogenic acid is widely present in various plant, including some Chinese medicine, vegetable, fruit etc..Carried by conventional effective ingredient
The technology of taking can be obtained by chlorogenic acid.Purer chlorogenic acid can be obtained after extraction process is optimized, can be used for entering of medicine
One step processing, as being prepared as the compositions of various dosage form.A lot of disclosed documents it has been reported how to extract from plant obtain green
Ortho acid, and be purified.The chlorogenic acid raw material that purity is higher it has been commercially available in market.
The preparation process of chlorogenic acid nanometer powder spray does not limit, as long as obtaining corresponding chlorogenic acid administration nano-drug administration system, and prepares
Obtain chlorogenic acid nanometer powder spray and just can meet the requirement of the present invention.Usually, the preparation of chlorogenic acid nanometer powder spray can use
Following steps:
(1) chlorogenic acid administration nano-drug administration system is prepared；
(2) chlorogenic acid administration nano-drug administration system is dried to powder；
(3) chlorogenic acid administration nano-drug administration system powder is mixed with carrier.
Above-mentioned steps (2) is when dry, according to the character of chlorogenic acid administration nano-drug administration system, can add or without the most auxiliary
Material, for the purpose of the powder obtaining the thin good fluidity of granule；The method being dried is selected from lyophilization and spray drying.
In some cases, it is not necessary to carrier participates in, and independent chlorogenic acid administration nano-drug administration system powder can serve as chlorogenic acid nanometer
Powder spray.Therefore, the preparation of chlorogenic acid nanometer powder spray can also use following steps:
(1) chlorogenic acid administration nano-drug administration system is prepared；
(2) chlorogenic acid administration nano-drug administration system is dried to powder.
The explanation of above-mentioned steps (2) is identical with aforesaid preparation process with requirement.
Chlorogenic acid administration nano-drug administration system is selected from chlorogenic acid liposome, chlorogenic acid nanoparticle, chlorogenic acid nano-emulsion, chlorogenic acid microemulsion,
Preferably chlorogenic acid liposome.
Adjuvant described in step prepared above selected from saccharide, alcohols, amino acids, phospholipid, pulmonary surfactant,
Cyclodextrin, polymer substance, fluidizer, antioxidant, citric acid and salt thereof, phosphate.Saccharide selected from lactose, galactose,
Glucose, fructose, sucrose, trehalose, Raffinose.Alcohols is selected from mannitol, xylitol, maltose alcohol, sorbitol.On
Amino acids described in face, selected from glycine, Aspartic Acid, alanine, tryptophan, threonine, glutamic acid, phenylalanine,
Leucine, isoleucine, cystine, lysine, proline, arginine.Phospholipid is selected from soybean phospholipid, lecithin, phospholipid
Phatidylcholine, PHOSPHATIDYL ETHANOLAMINE, synthetic phospholipid.Pulmonary surfactant is selected from dipalmitoyl phosphatidyl choline, two Laurels
Phosphatidyl choline, cholesterol.Cyclodextrin is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, large cyclodextrin, various replacement
The alpha-cyclodextrin derivant of degree, the beta-cyclodextrin derivative of various substitution value, the gamma-cyclodextrin derivant of various substitution value, hydroxypropyl
Group-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched cyclodextrin, methylated cyclodextrin, dimethyl-β-cyclodextrin, ethoxy ring
Dextrin, low-molecular-weight beta cyclo dextrin polymer (molecular weight is 3000-6000), ethyl cyclodextrin, acetyl group cyclodextrin, ion
Property cyclodextrin derivative, carboxymethyl cyclodextrin, sulfuric ester cyclodextrin.Polymer substance is selected from biodegradable polymer substance
Such as albumin, dextrin, polyvinylpyrrolidone, cellulose derivative, starch derivatives, polylactic acid, polylactic acid-glycolic base second
Acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, sodium alginate.Fluidizer is selected from micropowder silica gel, Talcum
Powder, hard magnesium, stearic acid, hard ester fumaric acid sodium.Antioxidant is selected from vitamin C, sodium L-ascorbate-2-phosphate, vitamin
The each analog derivative of C, coenzyme Q10, vitamin E, polyethylene glycol 1000 vitamin E succinic acid ester, vitamin E are all kinds of derivative
Thing.
Carrier described in step prepared above is selected from lactose, arabic gum, xylitol, glucosan, mannitol, trehalose,
It preferably is selected from lactose, mannitol, most preferably lactose.Chlorogenic acid administration nano-drug administration system powder is the strictest with the weight ratio of carrier
Regulation, as long as meeting good fluidity, pulmonary deposition effect higher position is permissible.Usually, chlorogenic acid administration nano-drug administration system powder and load
The part by weight of body is 1: 50～50: 1, preferably 1: 20～10: 1, most preferably 1: 10～5: 1.
Chlorogenic acid nanometer powder spray is packaged in capsule or bubble-cap or Diskus, it is possible to carry easily and use.
Chlorogenic acid nanometer powder spray is prepared by chlorogenic acid administration nano-drug administration system.Chlorogenic acid administration nano-drug administration system dosage form is selected from lipid
Body, nanoparticle, nano-emulsion, microemulsion, namely selected from chlorogenic acid liposome, chlorogenic acid nanoparticle, chlorogenic acid nano-emulsion, green
Ortho acid microemulsion, preferably chlorogenic acid liposome.Therefore, chlorogenic acid nanometer powder spray is selected from chlorogenic acid liposome powder spray, green
Ortho acid nanoparticle powder spray, chlorogenic acid nano-emulsion powder spray, chlorogenic acid microemulsion powder spray, preferably chlorogenic acid liposome dust cloud
Agent.
When being chlorogenic acid liposome when selecting chlorogenic acid administration nano-drug administration system dosage form, preparation method is steamed selected from film dispersion method, anti-phase
Send out method, multi-emulsion method, fusion method, injection method, freeze-drying, surfactant facture, centrifuging, pro-liposome method,
The pressurization technology such as extrusion molding, calcium fusion method, preferably is selected from film dispersion method, reverse phase evaporation, injection method, pressurization extrusion molding, more
Preferably film dispersion method.These preparation methoies are referred to relevant speciality books and document, by professional and technical personnel design and
Operation completes.Chlorogenic acid liposome in the present invention, its particle diameter is 1～1000 nanometers, preferably 10～600 nanometers, more
Preferably 20～300 nanometers.The amount of chlorogenic acid liposome Content of Chlorogenic Acid, the amount of adjuvant do not limit, preferred chlorogenic acid fat
Containing the chlorogenic acid of 0.1%～50% weight ratio, 50%～99.9% lipid, 0%～50% other of weight ratio of weight ratio in plastid
The most acceptable adjuvant.Other the most acceptable adjuvant selected from adsorbent, solubilizing agent, cosolvent, preservative,
One or more in stabilizer, freeze drying protectant, surfactant.
Chlorogenic acid liposome in the present invention, wherein prepares the lipid of liposome selected from lecithin, PHOSPHATIDYL ETHANOLAMINE, Semen sojae atricolor phosphorus
Fat, cholesterol, cephalin, cholesterol acetyl fat, cupreol, natrii tauroglycocholas, Yolk lecithin, two lauroyl phospholipid
Phatidylcholine, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, two palmityl phosphorus
Phosphatidyl glycerol, DSPG, DPPA, Phosphatidylserine, phosphatidylinositols, nerve sheath phosphorus
Fat, sphingo, two Cetyl Phosphates, stearmide, preferably be selected from lecithin, soybean phospholipid, cholesterol, two lauroyl phosphorus
Phosphatidylcholine, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, more preferably certainly
Lecithin, soybean phospholipid, cholesterol, dipalmitoyl phosphatidyl choline, most preferably from soybean phospholipid and cholesterol.Big when using
When fabaceous lecithin and cholesterol prepare chlorogenic acid liposome, the molar ratio of soybean phospholipid and cholesterol is selected from 100: 1～1: 100,
It preferably is selected from 20: 1～1: 5, more preferably from 10: 1～1: 1.Other additives can also be added, specifically in chlorogenic acid liposome
Kind is unrestricted, such as vitamin E, 18-amine..
When being chlorogenic acid nanoparticle when selecting chlorogenic acid administration nano-drug administration system dosage form, preparation method has a variety of, according to nanoparticle
Material is different with requirement, refers to pertinent literature and professional technique books.Chlorogenic acid nanoparticle selected from chlorogenic acid polymer nanoparticle,
Chlorogenic acid solid lipid nanoparticle, chlorogenic acid inorganic nano-particle, chlorogenic acid nanocapsule, chlorogenic acid nanosuspension.Chlorogenic acid gathers
The preparation method of compound nanoparticle is selected from polymerization, the sedimentation method, solvent evaporation method, salting out method.Chlorogenic acid solid lipid nanoparticle
Preparation method selected from film ultrasound, high-pressure stripping, melted newborn even method, freezing newborn even method, emulsification-evaporation method, receive
Rice breast method.The preparation method of chlorogenic acid inorganic nano-particle can use the sedimentation method.The method of chlorogenic acid nanocapsule is gathered selected from monomer interface
Legal and polymer interface nano-precipitation method.The preparation method of chlorogenic acid nanosuspension is selected from polishing, high pressure homogenization method, breast
Change method.Some stabilizers such as poloxamer, Polysorbate can be added in chlorogenic acid nanosuspension preparation process.
Solid lipid nanoparticle preferred as chlorogenic acid nanoparticle dosage form in the present invention.Usually, by under chlorogenic acid and room temperature
For the lipid of solid-state, such as phospholipid, fatty acid, glyceride, jointly add heat fusing, be subsequently adding water or suitable buffer, adding
In the case of heat, on high pressure dispersing emulsification machine, circulating emulsion repeatedly, forms the emulsion droplet of nano-dispersed, cools down rapidly, be allowed to solidify, to obtain final product
To chlorogenic acid solid lipid nanoparticle.Also chlorogenic acid solid lipid nanoparticle can be prepared by microemulsion method.
When being chlorogenic acid nano-emulsion when selecting chlorogenic acid administration nano-drug administration system dosage form, preparation method refers to pertinent literature and specialty skill
Physicopsychic training techniques evidence.Usually, emulsifying agent, co-emulsifier, oil phase, aqueous phase, medicine are included at chlorogenic acid nano-emulsion.Typically in choosing
After selecting suitable prescription, chlorogenic acid nano-emulsion can be readily formed.If selecting suitable prescription, generally comprise emulsifying agent,
Co-emulsifier, oil phase, it is also possible to composition chlorogenic acid is from nanometer emulsified system, and after adding suitable quantity of water solution, system can be voluntarily
It is dispersed into chlorogenic acid nano-emulsion.
When being chlorogenic acid microemulsion when selecting chlorogenic acid administration nano-drug administration system dosage form, preparation method refers to pertinent literature and professional technique
Data.Usually, emulsifying agent, co-emulsifier, cosolvent, oil phase, aqueous phase, medicine are included at chlorogenic acid microemulsion.Typically
After selecting suitable prescription, chlorogenic acid microemulsion can be readily formed.If selecting suitable prescription, generally comprise emulsifying agent,
Co-emulsifier, cosolvent, oil phase, it is also possible to composition chlorogenic acid self-microemulsifying system, after adding suitable quantity of water solution, system can
Chlorogenic acid microemulsion is become with self-dispersing.After oil phase, aqueous phase, emulsifying agent and co-emulsifier determine, quasi-ternary phase can be passed through
Figure finds out microemulsion region.
Chlorogenic acid nanometer powder spray is used for treating infection, shock, smoking, wound, toxic poisoning, suction irritative gas, spoke
Penetrate, acute lung injury that hyperoxia, hypoxia etc. cause.Suck irritative gas can be phosgene, surpalite, triphosgene, chlorine,
Nitrogen oxides, formaldehyde, dimethyl sulfate, hydrogen chloride, hydrogen bromide, fluohydric acid gas, ammonia, ozone, sulfur dioxide one therein
Or it is several.Radiation includes ionizing radiation and ionizing radiation, or both is comprehensive.Ionizing radiation is produced after including nuclear accident or nuclear explosion
Raw external exposure, because the radiation cure that carries out of disease treatment or medical inspection and inspection, various radionuclides are inhaled by human body
The internal radiation produced after receipts.
Accompanying drawing explanation
Fig. 1. chlorogenic acid liposome transmission electron microscope photo
Fig. 2. transmission electron microscope photo after the redissolution of chlorogenic acid liposome powder spray
Fig. 3. each group lung tissue of rats W/D ratio (N=5)
Fig. 4. blank group (A group) lung tissue of rats HE dyeing pathological section photo (× 200)
Fig. 5. model group (B group) lung tissue of rats HE dyeing pathological section photo (× 200)
Fig. 6. chlorogenic acid suspension treatment group (C group) lung tissue of rats HE dyeing pathological section photo (× 200)
Fig. 7. chlorogenic acid liposome powder spray treatment group (D group) lung tissue of rats HE dyeing pathological section photo (× 200)
Detailed description of the invention
Embodiment 1. chlorogenic acid liposome powder spray
Take chlorogenic acid 80mg, soybean phospholipid 300mg, cholesterol 20mg are placed in eggplant-shape bottle, add 10ml ethanol the hottest
Being completely dissolved, be injected in 40 DEG C of water of 50ml by several times with 1ml syringe, marginal not enters limit stirring, ultrasonic disperse after injection
10min, and under the conditions of 37 DEG C, decompression removes major part ethanol, obtains chlorogenic acid liposome turbid liquor.By chlorogenic acid liposome
Chlorogenic acid liposome powder spray is obtained with spray drying method.Spray drying parameters is as follows: inlet temperature: 100 DEG C, leaving air temp:
50 DEG C, power of fan: 55Hz, peristaltic pump rotating speed: 280mL/h, striker is spaced: 2 seconds.
Chlorogenic acid liposome (Fig. 1) and chlorogenic acid liposome powder spray before electromicroscopic photograph display spray drying rebuild suspension (figure
2) all spherical in Regularia, particle diameter is about 30 nanometers.
Embodiment 2. chlorogenic acid solid lipid nanoparticle powder spray
Take chlorogenic acid 50mg, glyceryl monostearate 0.7g, Tween 80 0.03g are heated to 80 DEG C in beaker, are gradually added into
80 DEG C of water 10ml containing sodium lauryl sulphate 10mg, keep temperature-resistant, transparent liquid；Again it is injected with syringe
Contain in 0 DEG C of water of 1.2g lactose to high-speed stirred, transparent liquid；Observe under a scanning electron microscope, mostly be 100 and receive
The particle that rice is following.Chlorogenic acid solid lipid nanoparticle spray drying method is obtained chlorogenic acid solid lipid nanoparticle powder spray.
Spray drying parameters is as follows: inlet temperature: 100 DEG C, leaving air temp: 50 DEG C, power of fan: 55Hz, peristaltic pump rotating speed:
280mL/h, striker is spaced: 2 seconds.
Embodiment 3. chlorogenic acid nano-emulsion powder spray
Take chlorogenic acid 50mg to be dissolved in 5ml ethyl oleate/alcohol mixed solvent, add appropriate polyoxyethylene castor oil and monoglyceride,
Heated and stirred becomes solution, under the conditions of high-speed stirred, adds about 4ml water, continuously stirred, obtains translucent dispersing liquid.
Granulometry result shows that major part particle, at below 120nm, is chlorogenic acid nano-emulsion.Take 100mg mannitol and add 4ml
Dissolving in chlorogenic acid nano-emulsion, in freeze dryer, lyophilization obtains the chlorogenic acid nano-emulsion powder of good fluidity.Take chlorogenic acid to receive
The Inhalac230 model lactose 100mg that rice emulsifiable powder end 100mg and Mei Jile company produces mixes, and obtains chlorogenic acid nanometer milk powder
Mist agent.
Experimental example. chlorogenic acid liposome powder spray treatment hydrochloric acid causes the Acute Lung Injury test of pesticide effectiveness
20 female rats (average weight 180 ± 20g/ is only) are randomly divided into 4 groups, often group 5, after etherization, A
Group gives normal saline by trachea, B, C, D group reference literature method at the uniform velocity note to tracheal strips people's dilute hydrochloric acid (pH 1.25,
1.2mL/kg).Injecting after dilute hydrochloric acid completes each group of rat and be administered immediately, administering mode is to be injected by trachea or spray into medicine
Mode, wherein A, B two groups gives normal saline, and C group gives chlorogenic acid-sodium carboxymethyl cellulose suspension (chlorogenic acid concentration
5mg/mL, 0.32mL/ are only), D group gives the chlorogenic acid liposome powder spray (chlorogenic acid 1.6mg/ is only) of embodiment 1 preparation.
Each group rat has been administered rear 4h and has put to death each group of rat.Quickly opening breast and take out right lung, filter paper blots surface moisture, is placed in and is dried title
Claim to obtain weight in wet base W on amount paper, put 80 DEG C of baking ovens baking 48h to weighing dry weight D after constant weight, and calculate lung tissue wet/dry weight value (W/D)
(Fig. 3), W/D value shows the most greatly to damage the most serious.Put to death the rat left lung tissue of taking-up and put in formalin fixing, conventional de-
Light Microscopic observation pathologic metamorphosis (Fig. 4-Fig. 7) after water, embedding, Hematoxylin-eosin (HE) dyeing.
Experiment empty matched group (A group) rat lung is cerise, without edema.After rat trachea injects hydrochloric acid 4h, model
Group (B group) rat lung is kermesinus, edema, and volume increases, and W/D value significantly increases, and lung surface visible point lamellar is hemorrhage.
Chlorogenic acid suspension treatment group (C group) is similar to B group, pulmonary edema occurs, but makes moderate progress, and W/D value and B group are without notable
Sex differernce.Chlorogenic acid liposome powder spray treatment group (D group) rat lung substantially alleviates than B group, and there is congested water accidental local
Swell, and W/D value has significance to reduce (p ＜ 0.01) compared with B group.
A group lung tissue of rats (see Fig. 4) structural integrity, alveolar space is complete, without oozing out.B group lung tissue of rats (see Fig. 5) can
See major part alveolar space in be full of pink transudate, a large amount of cell infiltration, including neutrophilic granulocyte, eosinophilic granulocyte and
Mononuclear phagocyte, bronchial epithelial cells at different levels are downright bad and come off in tube chamber, also show transudate, and visible vessels in it
Dilatation and congestion and hemorrhage.Lung tissue (see Fig. 6) pathological changes of C group rat is similar with model group, but slightly alleviates.The lung of D group rat
Tissue (see Fig. 7) pathological changes relatively model group alleviates, and especially exudative process significantly alleviates, and the necrosis of human airway epithelial cells comes off also
Alleviate, only observed focal oozing out and the phenomenon of a small amount of cell infiltration.
Pathology section examination result show chlorogenic acid in suspension with proto-drug enter internal after be difficult to be absorbed by lesions position,
To pneumonia limited efficacy.After chlorogenic acid is prepared as Liposome for Pulmonary Delivery, it is possible to overcome chlorogenic acid poor stability, easy oxygen
Change, the shortcoming that absorbance is low, powder spray can directly act on lesions position by medicine after pulmonary administration, plays and preferably controls
Treatment effect, reaches to alleviate pulmonary inflammatory effect.
Use above-mentioned identical experiment, it was demonstrated that chlorogenic acid solid lipid nanoparticle powder spray and chlorogenic acid nano-emulsion powder spray have very equally
Good treatment acute lung injury effect.
Claims (10)
1. chlorogenic acid nanometer powder spray application in the medicine for the treatment of acute lung injury.
2. the chlorogenic acid nanometer powder spray as claimed in claim 1 application in the medicine for the treatment of acute lung injury, chlorogenic acid therein is received
Rice powder spray, uses following preparation process:
(1) chlorogenic acid administration nano-drug administration system is prepared；
(2) chlorogenic acid administration nano-drug administration system is dried to powder；
(3) chlorogenic acid administration nano-drug administration system powder is mixed with carrier；
Step (2) is when dry, according to the character of chlorogenic acid administration nano-drug administration system, can add or without suitable adjuvant,
For the purpose of the powder obtaining the thin good fluidity of granule；The method being dried is selected from lyophilization and spray drying.
3. the chlorogenic acid nanometer powder spray as claimed in claim 1 application in the medicine for the treatment of acute lung injury, chlorogenic acid therein is received
Rice powder spray, uses following preparation process:
(1) chlorogenic acid administration nano-drug administration system is prepared；
(2) chlorogenic acid administration nano-drug administration system is dried to powder；
Step (2) is when dry, according to the character of chlorogenic acid administration nano-drug administration system, can add or without suitable adjuvant,
For the purpose of the powder obtaining the thin good fluidity of granule；The method being dried is selected from lyophilization and spray drying.
4. the application in the medicine for the treatment of acute lung injury of the chlorogenic acid nanometer powder spray as described in claim 2 and 3, therein green
Ortho acid administration nano-drug administration system is selected from chlorogenic acid liposome, chlorogenic acid nanoparticle, chlorogenic acid nano-emulsion, chlorogenic acid microemulsion.
5. the application in the medicine for the treatment of acute lung injury of the chlorogenic acid nanometer powder spray as described in claim 2 and 3, wherein in step
Suddenly the adjuvant used in (2) selected from saccharide, alcohols, amino acids, phospholipid, pulmonary surfactant, cyclodextrin,
Polymer substance, fluidizer, antioxidant, citric acid and salt thereof, phosphate.
6. the chlorogenic acid nanometer powder spray as claimed in claim 2 application in the medicine for the treatment of acute lung injury, wherein in step (3)
The carrier of middle use is selected from lactose, arabic gum, xylitol, glucosan, mannitol, trehalose.
7. the chlorogenic acid nanometer powder spray as claimed in claim 1 application in the medicine for the treatment of acute lung injury, its Content of Chlorogenic Acid is received
Rice powder spray is micro-selected from chlorogenic acid liposome powder spray, chlorogenic acid nanoparticle powder spray, chlorogenic acid nano-emulsion powder spray, chlorogenic acid
Breast powder spray.
8. the chlorogenic acid nanometer powder spray as claimed in claim 1 application in the medicine for the treatment of acute lung injury, its Content of Chlorogenic Acid is received
Rice powder spray is chlorogenic acid liposome powder spray.
9. the chlorogenic acid nanometer powder spray as claimed in claim 1 application in the medicine for the treatment of acute lung injury, receives selected from chlorogenic acid
Rice powder spray be used for treating infection, shock, smoking, wound, toxic poisoning, suction irritative gas, radiation, hyperoxia,
The application of the medicine of the acute lung injury that hypoxia causes.
10. the chlorogenic acid nanometer powder spray as claimed in claim 9 application in the medicine for the treatment of acute lung injury, wherein sucks stimulation
Property gas selected from phosgene, surpalite, triphosgene, chlorine, nitrogen oxides, formaldehyde, dimethyl sulfate, hydrogen chloride, hydrogen bromide,
Fluohydric acid gas, ammonia, ozone, sulfur dioxide.
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| CN201610248641.8A CN105902525A (en) | 2016-04-21 | 2016-04-21 | Application of chlorogenic acid nano powder inhalation in medicine for treating acute lung injury |
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Application publication date: 20160831 |