CN106580928A - Andrographolide nanometer inhalant and application thereof to treatment of bacterial pneumonia - Google Patents
Andrographolide nanometer inhalant and application thereof to treatment of bacterial pneumonia Download PDFInfo
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- CN106580928A CN106580928A CN201510665631.XA CN201510665631A CN106580928A CN 106580928 A CN106580928 A CN 106580928A CN 201510665631 A CN201510665631 A CN 201510665631A CN 106580928 A CN106580928 A CN 106580928A
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Abstract
The invention discloses an andrographolide nanometer inhalant and an application thereof to treatment of bacterial pneumonia. The andrographolide nanometer inhalant is prepared by an andrographolide nanometer administration system, and the system is selected from andrographolide liposome, andrographolide microemulsion, andrographolide nano-emulsion, andrographolide nonionic surfactant vesicles, andrographolide nanoparticles, and andrographolide nanocapsules. The dosage form of the andrographolide nanometer inhalant is selected from aerosol, water spray, and powder spray. The andrographolide nanometer inhalant can increase bioavailability and reduce stimulation, and is easy to penetrate into deep part of lung tissue; the inhalant can target and locate lesion location, and benefits for treatment of bacterial pneumonia; and the inhalant is convenient to carry and use.
Description
Technical field
The present invention relates to biomedicine field, and in particular to andrographolide nanometer inhalant and its treatment bacterial pneumonia in
Using.
Background technology
Andrographolide (Andrographolide) is active chemical in acanthaceous plant Folium Andrographis, in being China's tradition
One of the effective elements of the medicine.Herba Andrographis are extensively cultivated on China Sichuan, Shaanxi, Beijing and other places, with antiinflammatory, antitumor, guarantor
The pharmacotoxicological effects such as liver function of gallbladder promoting.Up to 1.8%, chemical molecular formula is C to content of the andrographolide composition in Folium Andrographis20H30O5,
Molecular weight is 350.44.Research finds andrographolide, and in vivo toxicity is less, pharmacological action extensively, with antibacterial, antiinflammatory,
Anti-apoptotic, antitumor, regulation immunity, hepatic cholagogic isoreactivity, with great medical value.
Pulmonary infection pathogen is varied, there is antibacterial, virus, mycoplasma, rickettsia, chlamydia, funguses, spiral
Body and parasite etc., wherein bacterium infection is most common, accounts for the 80% of pneumonia sum.The application of a large amount of broad-spectrum antibiotic in recent years,
Pathogenic flora is changed and drug resistance, or even (MDR is referred to resistance to 2 kinds or antibacterials of more than two kinds generation multidrug resistant occurs
By) (PDR is referred to and Tetracyclines, carbapenemss, cephalosporinses, fluoroquinolones and enzyme are pressed down for bacterial strain and general drug resistance
Preparation compound preparation is tolerated) bacterial strain, causes the example of clinical experience medication Endodontic failure of common occurrence.Andrographolide is resistance to
The report of the property of medicine is little.Andrographolide is a kind of diterpenes diterpenoids lactones compound, is insoluble in water, absorbs difficult, vivo biodistribution profit
Expenditure is relatively low, greatly limit its application.
The particle diameter of administration nano-drug administration system is nanoscale, and specific surface area is very big, into after human body with the contact area of site of action
Greatly, the dissolution and absorption of medicine can be greatly increased.Administration nano-drug administration system can also solve many medicine poorly water-solubles, absorption difference,
Unstable the problems such as.The material major part for preparing nanosystems is biocompatibility macromolecular carrier, and medicine is wrapped up wherein, is subtracted
Few drug degradation, raising stability；Promote medicine to enter intracellular, increase and absorb.Administration nano-drug administration system is used for lung inhalation
There is outstanding advantage.It can enter lung tissue deep after inhalation, directly contact with alveolar, and contact area is big.Therefore medicine
Thing is greatly increased in the concentration of alveolar tissue, can fast onset drug effect.Administration nano-drug administration system include liposome, nanoparticle, microemulsion,
The dosage forms such as nano-emulsion.
Nano-emulsion refers to the system of emulsion droplet composition of the particle diameter below 200 nanometers, and fat-soluble medicine can be wrapped in emulsion droplet.
Nano-emulsion is in high dispersion, the features such as being improved drug bioavailability, strengthen targeting as pharmaceutical carrier.Nano-emulsion can
Fat-soluble medicine content in the formulation is significantly increased, the absorption of active substance can also substantially accelerated.Microemulsion refers to that particle diameter exists
The system of less than 100 nanometers of emulsion droplet composition, the characteristics of equally there is nano-emulsion.
Liposome is the vesicle that phospholipid bilayer is constituted.Medicine can be encapsulated in interior water phase or lipid film according to property.Liposome
It is made up of biodegradable material (phospholipid and cholesterol), nontoxic to human body, histocompatibility is good.Liposome and cell membrane
Affinity is strong, can increase the ability for being wrapped medicine permeates cell membranes.It is difficult that liposome technology can solve some fat-soluble medicines
It is dissolved in a difficult problem for water.Nonionic surfactant vesicle (Niosomes) refers to some nonionic surfactants (such as sorbester p18)
It is self-assembled into imitated vesicle structure in water under certain condition, is similar to liposome.It can also serve as pharmaceutical carrier, with similar
Some inside and outside features of liposome.
Nanoparticle refers generally to be the scattered solids of nanoscale that, due to its high dispersion, it is improved medicine as pharmaceutical carrier
The features such as thing bioavailability, enhancing targeting.Solid lipid nanoparticle is using the compatible matrix material of human body as major auxiliary burden
Nanoparticle is formed, with the characteristics of common nanoparticle and the characteristics of good biocompatibility, Recent study is more.Nanocapsule is refered in particular to
Medicine is wrapped in the nanoparticle formed in filmogen, the same inside and outside feature with nanoparticle.
Lung suction preparation is developed rapidly in recent years.In addition to obtaining effective general action, lung inhalation approach be asthma,
The most direct therapeutic modality of the pulmonary disease such as emphysema, chronic obstructive pulmonary disease.Medicine can be directly to up to target site, 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 is big, is conducive to medicine
Absorption；After the transpulmonary absorption of medicine it is directly entered blood circulation, it is to avoid the first pass effect of liver, improves the biological utilisation of medicine
Degree, at present multiple pulmonary inhalation listings.Lung suction preparation formulation mainly has 3 kinds：(1) aerosol；(2) water smoke agent；(3)
Powder spray.
The content of the invention
The invention discloses a kind of andrographolide nanometer inhalant, and andrographolide nanometer inhalant is in the bacillary lung for the treatment of
Application in inflammation.
The preparation process of andrographolide nanometer inhalant is not limited, as long as obtaining corresponding andrographolide nanometer administration system
Uniting, and prepare andrographolide nanometer inhalant can meet the requirement of the present invention.Usually, andrographolide nanometer is inhaled
Entering the preparation of agent can adopt following steps：
(1) andrographolide administration nano-drug administration system is prepared；
(2) andrographolide administration nano-drug administration system is prepared into into andrographolide nanometer inhalant.
Andrographolide administration nano-drug administration system selected from andrographolide nano-emulsion, andrographolide microemulsion, andrographolide liposome,
Andrographolide nonionic surfactant vesicle, andrographolide nanoparticle, preferably andrographolide nanocapsule, punching
Lotus lactone nano-emulsion, andrographolide liposome, more preferably andrographolide liposome.It is administered by andrographolide nanometer
The various dosage forms of system are obtained the andrographolide nanometer inhalant of different dosage form, are chosen in particular from the suction of andrographolide nano-emulsion
Agent, andrographolide microemulsion inhalant, andrographolide liposome inhalant, andrographolide nonionic surfactant vesicle
Inhalant, andrographolide nanoparticle inhalant, preferably andrographolide nanocapsule inhalant, andrographolide nano-emulsion
Inhalant, more preferably andrographolide liposome inhalant, andrographolide liposome inhalant.
The preparation method of andrographolide nano-emulsion refers to pertinent literature and professional technique data.Usually, andrographolide is received
Rice milk contains emulsifying agent, co-emulsifier, oil phase, water phase, andrographolide.Emulsifying agent and co-emulsifier are hard selected from ethylene glycol list
Fat acid ester, ethylene glycol monolaurate, ethylene glycol monoleate, glycol monopalmitate, ethylhydroxyethylcellulose, second
Acylated monoglyceride, diethylene glycol distearate, triethylene glycol dilaurate, triethylene glycol list cinnamate, three second two
Alcohol monolaurate, triethylene glycol monostearate, triethylene glycol dicaprylate, N, N- diethyl lauramides, diacetyl
Monoglyceride, diacetyl tartaric acid (single, double) glyceride, diisopropanolamine (DIPA), sodium lauryl sulphate, lauryl sulphate acid
Magnesium, sodium tetradecyl sulfate, sodium cetostearylsulphate, Emulphor FM, Triglycerol Caprylate-Caprate TCC, trihydroxy
Aminomethane, casein, N-9, Emulsifier LM-102, xylitan monostearate, ethoxylation Pilus Caprae seu Oviss
Fat, ethoxylated hydrogenated lanoline, Hamposyl L, Hamposyl C, Semen Myristicae sarcosine, stearoylketene sarcosine,
Sodium laurate, lauric acid amine, potassium laurate, lauric isopropropanolamide, lauric acid diethyl amide, propylene glycol diacetate,
Propylene glycol monostearate, chitose, methylcellulose, the rosin ester of glycerol three, triolein, the Palmic acid of glycerol three
Ester, glycerol tristearate, triacetin, glyceryl monostearate, glycerin mono-fatty acid ester, Monooctamoin, four
Butanoic acid aldehyde, sorbitan mono-laurate, sorbitan monopalmitate, sorbitan monooleate, Sorbitan
Alcohol trioleate, sorbitan sesquioleate, sorbitan monostearate, anhydrous sorbitol tristearate, field
Cyanines glue, his that glue, Ficus elastica, carbomer, isobutylated lanolin acid esters, isopropanolamine, Furcellaran, lactide ricinoleic acid gather
Glyceride, tragacanth, ethoxylated lanolin alcohol, self-emulsifying monostearate, Resina persicae, malt extract, octoxynol 9,
Bentonite, Bentonite magnesium, carrageenin, tamarind gum, lecithin, hydrogenated soybean lecithin, emulsifing wax, lactic acid fat acid propylene glycol are sweet
Glyceride mixtures, lactic acid fatty glyceride, pectin, loose glue, enuatrol, single double glyceride, POLY-karaya, soft soap, pool
Luo Shamu, citric acid fatty glyceride, cholesteryl palmitat, cholesterol ester stearic acid, cholic acid, sodium cholate bile acid sodium,
Deoxycholic acid, alginic acid, propylene glycol alginate, sodium alginate, calcium alginate, potassium alginate, Sargassum acid amide, fatty acid
Lactoyl ester, polyglycerol fatty acid ester, diglycerol list -2- hexyldecanoic acid esters, two triglycerol monostearates, two contractings three are sweet
Oily monoleate, two triglycerol monolaurates, five contracting six glyceryl monostearates, five contracting six glycerol distearates, nine
Contract the oleate of ten glycerol four, nine contracting the oleates of ten glycerol eight, nine contracting SY-Glyster DAO 750s, nine contract the stearates of ten glycerol ten,
The raw indigo plant of love, hydroxyethylmethyl-cellulose, hydroxylated lecithin, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, Xanthan gum are former, bacterium
Core glucosan, choline chloride, stearmide, palmitamide, stearic acid sodium lactate, lactic acid tetradecane base ester, lactic acid hexadecane
Base ester, sodium stearate, hard soap, curdled milk soap, potassium stearate, stearyl alcohol, coconut monoethanolamide, Oleum Cocois two
Glycollic amide, general Shandong indigo plant, acetyl kip Shandong indigo plant, sodium palmitate, microbial alginate, Carboxymethyl cellulose sodium, caseinic acid
Sodium, guaiac gum, polyethyleneglycol bacteria ether emulsifing wax, Cetomacrogol 1000, polyvinyl alcohol, polysorbate
- 20, polysorbate -40, polysorbate -60, polysorbate -65, Polyoxyethylene Sorbitan Monooleate, polysorbate -85, poly-
Oxygen ethylene (4) laurate, Polyethylene oxide (8) laurate, Polyethylene oxide (12) laurate, Polyethylene oxide (24)
Laurate, Polyethylene oxide (40) laurate, Polyethylene oxide (100) laurate, Polyethylene Glycol (200) list Laurel
Acid esters, Polyethylene Glycol (400) monolaurate, Polyethylene Glycol (600) monolaurate, Polyethylene Glycol (1000) Dan Yue
Cinnamic acid ester, Polyethylene Glycol (6000) monolaurate, polyoxyethylene lauryl ether, polyoxyethylene cetostearyl ether,
The oleyl ether of Polyethylene oxide (30EO) Sorbitol four, the stearyl ether of Polyethylene oxide (60EO) Sorbitol four, Polyethylene oxide (40EO)
It is the oleate ether of Sorbitol four, the oleate of Polyethylene oxide (60EO) Sorbitol four, Emulsifier LT-60M, poly-
Oxygen vinyl alkyl ether, Emulsifier BY Emulsifier MOA, Emulsifier O, Brij -30, Brij -35, Brij -52, Brij -56,
Brij -58, Brij -76, Brij -28, Brij -92, Brij -96, Brij -98, Polyethylene oxide (10) oleyl ether, polyoxy second
Alkene (8) stearate, Polyethylene oxide (12) stearate, Polyethylene oxide (24) stearate, Polyethylene oxide (100)
Stearate, Polyethylene oxide (110) stearate, Polyethylene oxide (40) stearate, Polyethylene oxide (50) stearate,
It is Polyethylene oxide (40) castor oil hydrogenated, Polyethylene oxide (10) castor oil hydrogenated, Polyethylene oxide (30) castor oil hydrogenated, poly-
Oxygen ethylene (50) castor oil hydrogenated, Polyethylene oxide (60) castor oil hydrogenated, Polyethylene oxide (40) Oleum Ricini, Polyethylene oxide
(10) Oleum Ricini, Polyethylene oxide (35) Oleum Ricini, Polyethylene oxide (60) Oleum Ricini, Polyethylene oxide (80) Oleum Ricini,
Polyethylene oxide (90) Oleum Ricini, Polyethylene oxide (100) Oleum Ricini, Polyethylene oxide (300) monoleate, Polyethylene oxide (400)
Monoleate, Polyethylene oxide (600) monoleate, sucrose fatty acid ester, sucrose monolaurate, sucrose palmitic acid ester,
Locust bean gum, sulfonated castor oil, sulfonation castor oil hydrogenated, sodium dioctyl sulfosuccinate, dioctyl sulphosuccinate calcium, sulfo group
Dioctyl succinate potassium, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphocholine.Typically after suitable prescription is selected, i.e.,
Andrographolide nano-emulsion can be readily formed.If selecting suitable prescription, emulsifying agent, co-emulsifier, oil phase are generally comprised,
Andrographolide can also be constituted from nanometer emulsified system, after appropriate aqueous solution is added, system can be with self-dispersing into Herba Andrographis
Lactone nano-emulsion.After oil phase, water phase, emulsifying agent and co-emulsifier are determined, nano-emulsion can be found out by quasi- ternary phase diagrams
Region.Andrographolide nano-emulsion in the present invention, its particle diameter be 1～1000 nanometer, preferably 10～500 nanometers, more
Preferably 10～100 nanometers.The amount of andrographolide, the amount of adjuvant are not limited in andrographolide nano-emulsion, as long as full
The formulation requirements of sufficient andrographolide nanometer inhalant and treatment are required just can be so that preferred Determination of Andrographolide is 0.1%～30%
Weight ratio, preferred Determination of Andrographolide is 0.3%～10% weight ratio, and further preferred Determination of Andrographolide is
1%～5% weight ratio.The adjuvant of andrographolide nano-emulsion inhalant in addition to emulsifying agent, co-emulsifier, can also containing other
Pharmaceutically acceptable adjuvant, and selected from adsorbent, solubilizing agent, cosolvent, preservative, stabilizer, freeze drying protectant,
One or more in surfactant.
The preparation method of andrographolide microemulsion refers to pertinent literature and professional technique data.Usually, andrographolide microemulsion
Containing emulsifying agent, co-emulsifier, cosolvent, oil phase, water phase, medicine.The emulsifying agent and co-emulsifier for preparing microemulsion is referred to
Emulsifying agent and co-emulsifier that andrographolide nano-emulsion is selected.Typically after suitable prescription is selected, you can be readily formed and wear
Heart lotus lactone microemulsion.If selecting suitable prescription, emulsifying agent, co-emulsifier, cosolvent, oil phase are generally comprised, can be with
Composition andrographolide self-microemulsifying system, after appropriate aqueous solution is added, system can be with self-dispersing into andrographolide microemulsion.
After oil phase, water phase, emulsifying agent and co-emulsifier are determined, micro emulsion region can be found out by quasi- ternary phase diagrams.
The preparation method of andrographolide liposome selected from film dispersion method, reverse phase evaporation, multi-emulsion method, fusion method, injection method,
Freeze-drying, surfactant facture, centrifuging, pro-liposome method, pressurization extrusion molding, calcium fusion method, preferably are selected from
Film dispersion method, reverse phase evaporation, injection method, more preferably pressurization extrusion molding, film dispersion method.These preparation methoies can
With reference to relevant speciality books and document, to be completed by professional and technical personnel's design and operation.If preparing fat using film dispersion method
Plastid, can jointly be dissolved in organic solvent by membrane materials such as andrographolide and phospholipid, and in containing flask, reduce pressure rotary evaporation, obtains
To thin film, water or appropriate buffer are subsequently adding, are vibrated and ultrasound, until forming uniform suspension.If super
Sound time lengthening, it is also possible to obtain nanoscale disperse system.Liposome turbid liquor is also an option that appropriate prescription and in felicity condition
Under carry out lyophilization or spray drying, form solid powdery, so can ensure that the stability of preparation, water is added before use
Solution shaking is obtained liposome turbid liquor.Andrographolide nonionic surfactant capsule can be obtained with same technology
Bubble.
The particle diameter of the andrographolide liposome in the present invention be 1～1000 nanometer, preferably 10～600 nanometers, more preferably
Be 20～300 nanometers.The amount of andrographolide, the amount of adjuvant are not limited in andrographolide liposome, as long as meet wearing
The formulation requirements of heart lotus lactone nanometer inhalant and treatment are required just can be so that preferred Determination of Andrographolide is 0.1%～30% weight
Amount ratio, preferred Determination of Andrographolide is 0.3%～10% weight ratio, and further preferred Determination of Andrographolide is 1%～5%
Weight ratio.The adjuvant of andrographolide liposome inhalant, can also be containing other pharmaceutically in addition to emulsifying agent, co-emulsifier
Acceptable adjuvant, and live selected from adsorbent, solubilizing agent, cosolvent, preservative, stabilizer, freeze drying protectant, surface
One or more in property agent.
The lipid contained in andrographolide liposome is selected from lecithin, PHOSPHATIDYL ETHANOLAMINE, soybean phospholipid, cholesterol, brain phosphorus
Fat, cholesterol acetyl fat, cupreol, natrii tauroglycocholass, Yolk lecithin, DLPC, two Semen Myristicaes
Phosphatidyl choline, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, DPPG, distearyl
Acyl phosphatidyl glycerol, DPPA, Phosphatidylserine, phosphatidylinositols, sphingomyelin, sphingo, two
Cetyl Phosphate, stearmide, preferably are selected from lecithin, soybean phospholipid, cholesterol, DLPC, two lima bean
Dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, more preferably from lecithin, soybean phospholipid,
Cholesterol, dipalmitoyl phosphatidyl choline, most preferably from soybean phospholipid and cholesterol.When using soybean phospholipid and cholesterol preparation
During andrographolide liposome, the molar ratio of soybean phospholipid and cholesterol is selected from 100: 1～1: 2, preferably is selected from 20: 1～1: 1,
More preferably from 10: 1～2: 1.Other additives can also be added in andrographolide liposome, concrete kind is unrestricted,
Such as Vitamin E, 18-amine..
The preparation method of andrographolide nanoparticle has many kinds, different with requirement according to the material of nanoparticle, refers to related text
Offer and professional technique books.Andrographolide nanoparticle is selected from andrographolide polymer nanoparticle, andrographolide solid lipid
Nanoparticle, andrographolide inorganic nano-particle, preferably are selected from andrographolide solid lipid nanoparticle.Andrographolide polymer nano
The preparation method of the grain of rice is selected from polymerization, the sedimentation method, solvent evaporation method, salting out method.Andrographolide solid lipid nanoparticle
Preparation method is selected from film ultrasound, high-pressure stripping, the newborn even method of melting, the newborn even method of freezing, emulsification-evaporation method, nanometer
Newborn method.The preparation method of andrographolide inorganic nano-particle can adopt the sedimentation method.The method of andrographolide nanocapsule is selected from monomer
Interfacial polymerization and polymer interface nano-precipitation method.
In the preparation method of andrographolide solid lipid nanoparticle, usually, by the fat under andrographolide and room temperature for solid-state
Matter, such as phospholipid, fatty acid, glyceride, jointly plus heat fusing, are subsequently adding water or appropriate buffer, under heating state
Circulating emulsion repeatedly, forms the emulsion droplet of nano-dispersed on high pressure dispersing emulsification machine, and rapid cooling is allowed to solidify, that is, obtains in Herba Andrographis
Ester solid lipid nanoparticle.Andrographolide solid lipid nanoparticle can be also obtained with microemulsion method.
Andrographolide administration nano-drug administration system directly as andrographolide nanometer inhalant, or can be processed by being adapted to technical process
After prepare andrographolide nanometer inhalant.Andrographolide administration nano-drug administration system, can be with when carrying out technical process and processing
Andrographolide nanometer inhalant is directly obtained without adjuvant；Can also as needed with the difference of dosage form, addition adjuvant obtain
Andrographolide nanometer inhalant.
The dosage form of andrographolide nanometer inhalant is selected from aerosol, water smoke agent, powder spray.Aerosol is by medicine and propellant
Mixing, pressurization is poured in pressure vessel, and when valve is opened, propellant carries medicine and gasifies rapidly into respiratory tract and lung.Water
Mist agent is that the solution or suspension of medicine are atomized into into superfine droplet by ultrasound or high pressure draught, is then drawn into respiratory tract and lung.
Powder spray is, by Diskuses, to be actively drawn into the powder of drug containing in respiratory tract and lung.Therefore, correspondence different dosage form,
Andrographolide nanometer inhalant is received selected from andrographolide nano aerosol, andrographolide nanometer water smoke agent, andrographolide
Rice powder spray.
Andrographolide administration nano-drug administration system can directly be prepared into andrographolide nano aerosol, be chosen in particular from andrographolide and receive
Rice milk aerosol, andrographolide microemulsion aerosol, andrographolide liposome aerosols, andrographolide non-ionic surface are lived
Property agent vesicle aerosol, andrographolide nanoparticle aerosol, andrographolide nanocapsule aerosol.Andrographolide nanometer gas
The preparation process of mist agent can mix andrographolide administration nano-drug administration system with propellant, and pressurization is poured in pressure vessel just can be with
Obtain.Propellant is selected from dichlorodifluoromethane, Dichloromonofluoromethane, F-22, dichlorotetra-fluoroethane, the fluorine of a chlorine five
Ethane, chlorodifluoroethane, Difluoroethane, trichorotrifluoroethane, Perfluorocyclobutane, isceon.
Andrographolide administration nano-drug administration system can directly be prepared into andrographolide nanometer water smoke agent, be chosen in particular from andrographolide and receive
Rice milk water smoke agent, andrographolide microemulsion water smoke agent, andrographolide liposome water smoke agent, andrographolide non-ionic surface are lived
Property agent vesicle water smoke agent, andrographolide nanoparticle water smoke agent, andrographolide nanocapsule water smoke agent.
Andrographolide nanometer powder spray is selected from andrographolide nano-emulsion powder spray, andrographolide microemulsion powder spray, Herba Andrographis
Interior ester liposome powder spray, andrographolide nonionic surfactant vesicle powder spray, andrographolide nanoparticle powder spray,
Andrographolide nanocapsule powder spray.The preparation process of andrographolide nanometer powder spray is not limited, as long as being worn accordingly
Heart lotus lactone administration nano-drug administration system, and prepare andrographolide nanometer powder spray can meet the present invention requirement.Usually,
The preparation of andrographolide nanometer powder spray can adopt following steps：
(1) andrographolide administration nano-drug administration system is prepared；
(2) andrographolide administration nano-drug administration system is dried to into powder；
(3) andrographolide administration nano-drug administration system powder is mixed with carrier；
Above-mentioned steps (2), according to the property of andrographolide administration nano-drug administration system, can add or without suitable when being dried
Adjuvant, for the purpose of obtaining the powder of the thin good fluidity of granule；Dry method is selected from lyophilization and spray drying.
In some cases, it is not necessary to which carrier is participated in, independent andrographolide administration nano-drug administration system powder can serve as Herba Andrographis
Lactone nanometer powder spray.Therefore, the preparation of andrographolide nanometer powder spray can also adopt following steps：
(1) andrographolide administration nano-drug administration system is prepared；
(2) andrographolide administration nano-drug administration system is dried to into powder.
The explanation of above-mentioned steps (2) is identical with aforesaid preparation process with requirement.
Adjuvant described in step prepared above selected from saccharide, alcohols, amino acidses, phospholipid, pulmonary surfactant,
Cyclodextrin, polymer substance, fluidizer, antioxidant, citric acid and its salt, phosphate.Saccharide selected from Lactose, galactose,
Glucose, sucrose, trehalose.Alcohols is selected from Mannitol, xylitol, maltose alcohol, Sorbitol.Aminoacid recited above
Class, selected from glycine, Aspartic Acid, alanine, tryptophan, threonine, glutamic acid, Phenylalanine, leucine, different bright
Propylhomoserin, cystine, lysine, proline, arginine.Phospholipid is selected from soybean phospholipid, lecithin, phosphatidylcholine, phospholipid
Acyl ethanolamine, synthetic phospholipid.Pulmonary surfactant selected from dipalmitoyl phosphatidyl choline, DLPC,
Cholesterol.Cyclodextrin spreads out selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, large cyclodextrin, the alpha-cyclodextrin of various substitution values
The beta-cyclodextrin derivative of biological, various substitution values, the gamma-cyclodextrin derivant of various substitution values, HP-β-CD, sulphur
Butyl ether-beta-schardinger dextrin-, branched cyclodextrin, methylated cyclodextrin, dimethyl-β-cyclodextrin, hydroxyethyl cyclodextrin, low-molecular-weight
Beta cyclo dextrin polymer (molecular weight is 3000-6000), ethyl cyclodextrin, acetyl cyclodextrin, ionic cyclodextrin derivative,
Carboxymethyl cyclodextrin, sulfuric ester cyclodextrin.Polymer substance selected from biodegradable polymer substance for example albumin, dextrin,
Polyvinylpyrrolidone, cellulose derivative, starch derivatives, polylactic acid, poly lactic-co-glycolic acid, Polyethylene Glycol, pool Lip river
Sha Mu, hyaluronic acid, hyaluronate sodium, sodium alginate.Fluidizer is selected from micropowder silica gel, Pulvis Talci, hard magnesium, Hard Fat
Sour, hard ester fumaric acid sodium.Antioxidant is selected from vitamin C, sodium L-ascorbate-2-phosphate, each analog derivative of vitamin C, coenzyme
The each analog derivative of Q10, Vitamin E, polyethylene glycol 1000 vitamin E succinic acid ester, Vitamin E.
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 Mannitol.Andrographolide administration nano-drug administration system powder does not have with the weight ratio of carrier
There are strict requirements, as long as meeting good fluidity, pulmonary deposition effect higher position can be with.Usually, andrographolide nanometer administration system
System powder is 1: 50～50: 1, preferably 1: 20～10: 1, most preferably 1: 10～5: 1 with the part by weight of carrier.
Andrographolide nanometer powder spray is packaged in capsule or bubble-cap or Diskuses, it is possible to easily carry and make
With.
Andrographolide nanometer inhalant is used to treat bacterial pneumonia.The strain of antibacterial is unrestricted, may be selected from golden yellow Fructus Vitis viniferae
Coccus, streptococcus pneumoniae, hemophilus influenza, Pseudomonas aeruginosa, acinetobacter calcoaceticus, Enterobacter, proteus vulgaris,
Bacillus subtilises, Streptococcus sobrinus, Branhamella catarrhalis, streptococcus pyogeness, Actinomycesviscosus, Streptococcus mutans, pneumonia
Klebsiella, escherichia coli, Acinetobacter bauamnnii, Fusobacterium nucleatum, lactobacilluss, Methicillin-resistant Staphylococcus aureus.
The pharmacodynamicss experiment results proved on animal bacteria pulmonary inflammation model, andrographolide nanometer inhalant disclosed by the invention,
There are antibacterial and antiphlogistic effects, bacterial pneumonia is treated by synergism.
Description of the drawings
Fig. 1. the transmission electron microscope photo of andrographolide liposome
Fig. 2. andrographolide liposomal particle size measurement result
Fig. 3. the Zeta potential measurement result of andrographolide liposome
Fig. 4. andrographolide liposome powder spray stereoscan photograph
Fig. 5. andrographolide liposome powder spray particle size determination result
Fig. 6. andrographolide liposome powder spray is to lung tissue HE dyeing disease after the treatment of the rat of infection of staphylococcus aureus
Reason section photo (200 ×) (A. normal group, B. model group, C. andrographolide crude drug treatment group, in D. Herba Andrographis
Ester liposome powder spray treatment group, E. penicillins treatment group)
Fig. 7. andrographolide liposome powder spray is to lung tissue P-IKB- α eggs after the treatment of the rat of infection of staphylococcus aureus
White immunofluorescence photograph (400 ×) (A. normal group, B. model group, C. andrographolide crude drug treatment group, D. punchings
Ester liposome powder spray treatment group, E. penicillins treatment group in lotus)
Specific embodiment
The andrographolide nano-emulsion of embodiment 1.
Take andrographolide 0.5g, isopropyl myristate 2g, CREMOPHORE EL 4g, water 30ml be placed in beaker mix
Close uniform, make to form colostrum by 1000rpm mechanical agitation, homogenizing 3 times, obtains punching under Jing high pressure homogenizer 15000psi
Lotus lactone nano-emulsion.
The andrographolide liposome of embodiment 2.
Andrographolide liposome is prepared using alcohol injection.Weigh in soybean phospholipid 1.57g, cholesterol 0.157g, Herba Andrographis
Ester 0.28g, Vitamin E 0.098g, add 40ml ethanol, ultrasound to be completely dissolved them；100ml is taken by Chinese Pharmacopoeia system
The phosphate buffer of standby pH6.5, is placed on magnetic stirring apparatuss, injects above-mentioned ethanol with 1ml speed per minute with needle tubing molten
To in buffer, after injection is finished, suspension is transferred in round-bottomed flask liquid, magnetic agitation 30min, then in 40 DEG C of water-baths
Solvent flashing 60 minutes on Rotary Evaporators, to without ethanol flavor, remaining suspension is andrographolide liposome.In Herba Andrographis
The outward appearance of ester liposome is the clear transparent solutions for having light blue opalescence.The distribution of andrographolide liposome is observed under transmission electron microscope
Uniformly, great majority are in spherical (Fig. 1).The particle diameter peak value for measuring andrographolide liposome with Malvern laser particle analyzer is
120.5nm (Fig. 2), mean diameter is about 117.5nm, and polydispersity coefficient (PDI) is 0.275, and particle size range is in 100～150nm
Between.The Zeta potential of andrographolide liposome is -11.8mV (Fig. 3).
Using other method for preparing lipidosome, such as film dispersion method can equally prepare qualified andrographolide liposome.
The andrographolide solid lipid nanoparticle of embodiment 3.
Take Vitamin E 0.1g, cetyl palmitate 2.0g, caprylic/capric glyceride 0.4g and melting be heated in 53 DEG C of water-baths,
Mix as oil phase with andrographolide 1.0g；By injection fabaceous lecithin 1.5g, Polyethylene oxide 660-12 hydroxy stearic acid ester 1.8g
Plus water for injection 100ml stirring and dissolving, 53 DEG C are heated to, as water phase；Under stirring and logical condition of nitrogen gas, by water phase Deca
To in synthermal oil phase, continue to stir certain hour and form colostrum, Probe Ultrasonic Searching 5 minutes, 0～2 DEG C it is closed stir 2h, 0.22 μm
Microporous filter, obtains andrographolide solid lipid nanoparticle.Observe under transmission electron microscope, mostly below 100nm's
Particle.
The andrographolide microemulsion of embodiment 4.
Take andrographolide 50mg to be dissolved in 5ml tetrahydrofurans, add appropriate polyoxyethylene castor oil and monoglyceride, heated and stirred
Into solution, under the conditions of high-speed stirred, about 4ml water is added, persistently stirred, obtain transparence dispersing liquid, obtain Herba Andrographis
Lactone microemulsion.Granulometry result shows most of particle in below 100nm.
The andrographolide liposome water smoke agent of embodiment 5.
Andrographolide liposome is prepared using alcohol injection.Weigh in soybean phospholipid 1.57g, cholesterol 0.157g, Herba Andrographis
In 40ml ethanol, ultrasound is completely dissolved them for ester 0.28g, Vitamin E 0.098g, on eddy mixer with syringe with
1ml speed per minute is injected in the pH6.5 phosphate buffers by Chinese Pharmacopoeia preparation of the 100ml containing 2% Mannitol, magnetic
Power is stirred 30 minutes, is evaporated 30 minutes in 40 DEG C of water-baths and Rotary Evaporators, is prepared into andrographolide liposome；To wear
Ester liposome is fitted in the special nebulizer used for lung suction in heart lotus, obtains andrographolide nano-emulsion water smoke agent.
The andrographolide liposome aerosols of embodiment 6.
Method preparation according to embodiment 5 prepares andrographolide liposome, and embedding is oily to the sorbester p37 and 0.5g dissolved with 0.5g
In the dichlorodifluoromethane 20g of acetoacetic ester, mix, obtain andrographolide liposome aerosols.
The andrographolide liposome powder spray of embodiment 7.
Andrographolide liposome is prepared using alcohol injection.Weigh in soybean phospholipid 1.57g, cholesterol 0.157g, Herba Andrographis
Ester 0.28g, Vitamin E 0.098g, in being dissolved in 40ml ethanol；Mannitol 2.958g is weighed, 100ml is dissolved according to middle traditional Chinese medicines
In the phosphate buffer of pH6.5 prepared by allusion quotation method, it is placed on magnetic stirring apparatuss, with syringe with 1ml per minute injection speed
To in phosphate buffer, injection is transferred in round-bottomed flask the above-mentioned ethanol solution of degree injection after finishing, magnetic agitation 30 minutes,
Revolving obtains andrographolide liposome in 60 minutes to without ethanol flavor in 40 DEG C of water-baths and on Rotary Evaporators；Continue freezing
Lyophilization in dry machine, obtains the white loose andrographolide liposome powder spray of good fluidity.Observe under scanning electron microscope and wear
Ester liposome powder spray in heart lotus, is irregular lump shaped crystalline (Fig. 4).The powder diameter D measured by laser particle analyzer50For
13.4 μm (Fig. 5), aerodynamic size～5 μm meet the requirement of powder spray for lung inhalation.
The andrographolide liposome powder spray of embodiment 8.
It is same as Example 7 to prepare andrographolide liposome, continue the lyophilization in freeze dryer, obtain good fluidity
White loose andrographolide liposome powder, be subsequently adding the inhalable lactose granule of liposome powder phase homogenous quantities, mix
After obtain andrographolide liposome powder spray.Aerodynamic size～5 μm of powder spray, meet the requirement of powder spray for lung inhalation.
Therapeutic effect of the andrographolide liposome powder spray of experimental example 1. to staphylococcal pneumonia rat
Material：(1) andrographolide (lot number 20140516, Sichuan Wen Long pharmaceutical factories)；(2) according to prepared by embodiment 7 wearing
Ester liposome powder spray in heart lotus；(3) penicillin (lot number F3127216, North China pharmaceutical Co. Ltd)；(4) normal saline
(lot number 1506043201, Shijiazhuang Siyao Co., Ltd)；(5) staphylococcus aureuses (ATCC29213, military medicine
Prevention and control of diseases institute of academy of science).
Method：30 healthy SD rats are randomly divided into into 5 groups, 6 per group, respectively normal group (healthy rat), model
Group (staphylococcal pneumonia rat, not to curative), andrographolide liposome powder spray treatment group, andrographolide
Raw material treatment group and positive drug (penicillin, 240mg/ml) treatment group.In addition to normal group, other 4 groups of rat transtracheals are once
Property spray into staphylococcus aureuses liquid make rat infection pneumonia.Normal group transtracheal sprays into normal saline.The 1st day after modeling success
Transtracheal sprays into administration, and dosage is converted with reference to the daily routine dose of adult.Blank group and model group rats lung feed life
Reason saline 0.2ml/ is only；Andrographolide raw material treatment group induced lung gives andrographolide 10mg/ only；Andrographolide liposome
Powder spray treatment group induced lung gives andrographolide liposome powder spray 20mg/ only (1mg containing andrographolide)；Positive drug is controlled
Treatment group induced lung gives penicillin 48mg/ only.Above-mentioned medicine lung gives that one time a day, successive administration 3 days.After administration 3 days,
Animal is put to death, breast is opened and lung is completely taken out and separated, left lung makees pathological section and Immunofluorescence test.
As a result：Active active, strong big and fleshy, the fur gloss of normal rats is shinny, breathing is steady, body weight gradually increases.Mould
Type group rat, appearance activity and enters drinking water and significantly reduces in 3 days, curls in cage corner, the messy tarnish of hair, and breathing is anxious
Promote and with sound of stridulating, body weight is decreased obviously, and has obvious bony, eye secretions increase.Remaining treatment group rat is upon administration
Also slightly rapid in breathing, fur owes gloss, and diet is general, and active state is slightly worse, but good than model group.The double lung of normal group is in
Pale pink, surface is smooth, and elasticity is good.Model group lung color is dark red, and lobe of the lung profile is unclear, and quality is hardened, and lung volume slightly reduces,
It can be seen that strip, rough pale stove, surface is visible bleeding profusely a little of differing in size.Andrographolide liposome dust cloud
Agent group and andrographolide crude drug group, lung color shows slightly dark, and surface is slightly coarse, and tactile elasticity is fair, and volume is without being obviously reduced.
Lung tissue of rats pathological section (Fig. 6) shows andrographolide raw material group and model group local lung field is visible oozes out (alveolar intracavity
It can be seen that pink transudate), bleeding, and mononuclear phagocyte showed increased, with the performance of local pulmonary parenchyma；And andrographolide fat
Plastid powder spray group oozes out scope and degree is slightly light, the visible a small amount of transudate of positive drug penicillin group part alveolar intracavity.Therefore
Andrographolide liposome powder spray has more preferable therapeutic effect to staphylococcal pneumonia than positive drug penicillin.
P-I κ B- α under physiological statuss the overwhelming majority tissue do not express, under the pathological states such as inflammation, tumor by inflammatory stimulus thing,
After the pro-inflammatory mediator induction such as damage and carcinogen, in expression trend is increased, participate in various pathophysiological processes.We are by adding
Enter that P-I κ B- α mono- are anti-to be combined with P-I κ B- α protein-specifics, then by two anti-colour developings.Rat immunity fluorescence (Fig. 7) inspection,
And examine under a microscope, wherein blue is nucleus, red is the positive expression (how much being expressed with arrow) of the albumen.
P-I κ B- alpha expressions are more in model group.The protein expression is in endochylema, and red dye is more.Red dye is also more in penicillin group endochylema,
Represent that therapeutic effect is poor；And red dye is less in andrographolide liposome powder spray group, therapeutic effect is better than penicillin group and wears
Heart lotus lactone crude drug group.
Andrographolide dosage in the andrographolide liposome powder spray that every animal gives in experiment (1mg andrographolide/only
Rat) less, far below the penicillin concn (a 48mg penicillins/rat) of administration.Therefore can further judge in Herba Andrographis
The drug effect of ester is considerably beyond penicillin.
At present the general Resistant strain and multiple antibiotic resistant strain of staphylococcus aureuses are increasing, are mostly that heavy dose of antibacterials are abused
Cause, and natural broad-spectrum antibacterial andrographolide liposome powder spray has fine antibacterial in relatively low dosage, just and resists
Inflammation effect, be nearly free from drug resistance, thus the antibacterial feature of andrographolide liposome powder spray be little dosage, antimicrobial agent,
Antibacterial and antiinflammatory synergism.
Claims (10)
1. a kind of andrographolide nanometer inhalant.
2. andrographolide nanometer inhalant as claimed in claim 1, its preparation can adopt following steps：
(1) andrographolide administration nano-drug administration system is prepared；
(2) andrographolide administration nano-drug administration system is prepared into into andrographolide nanometer inhalant.
3. andrographolide nanometer inhalant as claimed in claim 2, wherein andrographolide administration nano-drug administration system are in Herba Andrographis
Ester nano-emulsion, andrographolide microemulsion, andrographolide liposome, andrographolide nonionic surfactant vesicle, punching
Ester nanoparticles, andrographolide nanocapsule in lotus.
4. andrographolide nanometer inhalant as claimed in claim 2, wherein andrographolide administration nano-drug administration system is andrographolide
Liposome.
5. andrographolide Foradil Aerolizer formoterol fumarate as claimed in claim 4, wherein Determination of Andrographolide is in andrographolide liposome
0.1%～30% weight ratio.
6. andrographolide nanometer inhalant as claimed in claim 1, dosage form is selected from aerosol, water smoke agent, powder spray.
7. andrographolide nanometer inhalant as claimed in claim 1, is andrographolide nanometer powder spray, and it prepares and adopts
Following steps：
(1) andrographolide administration nano-drug administration system is prepared；
(2) andrographolide administration nano-drug administration system is dried to into powder；
(3) andrographolide administration nano-drug administration system powder is mixed with carrier；
Above-mentioned steps (2), according to the property of andrographolide administration nano-drug administration system, can add or without suitable when being dried
Adjuvant, for the purpose of obtaining the powder of the thin good fluidity of granule；Dry method is selected from lyophilization and spray drying.
8. andrographolide nanometer inhalant as claimed in claim 7, the adjuvant used in step (2) selected from saccharide, alcohols,
Amino acidses, phospholipid, pulmonary surfactant, cyclodextrin, polymer substance, fluidizer, antioxidant, citric acid
And its salt, phosphate.
9. andrographolide inhalant as claimed in claim 7, the carrier used in step (3) selected from saccharide selected from Lactose,
Galactose, glucose, sucrose, trehalose.
10. andrographolide nanometer inhalant as claimed in claim 1, for treating bacterial pneumonia.
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| CN109125302A (en) * | 2018-10-09 | 2019-01-04 | 上海市杨浦区中心医院(同济大学附属杨浦医院) | Application of resveratrol in medicine for treating bacterial pneumonia |
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