Summary of the invention
At the existing quantitatively micron existing drug particles bad dispersibility of inhalation aerosol and low this problem of lung transmission efficiency, the invention provides the nano-particle of a kind of chemicals and biomolecule, utilize the quantitative nano aerosol of this preparation of nanoparticles and their preparation method.
One of purpose of the present invention provides the nano-particle of a kind of chemicals or biomolecule.
Another object of the present invention provides the quantitative nano aerosol of a kind of chemicals or biomolecule, and the chemicals in this aerosol or the nano-particle of biomolecule can disperse in propellant uniformly and stably, and in pulmonary high transmission efficiency are arranged.
Another object of the present invention provides the manufacture method of the nano-particle of a kind of chemicals and biomolecule, and this method can obtain the nano-particle of chemicals and biomolecule in conjunction with micro-emulsion technology and quick drying technology.
Another object of the present invention provides the preparation method of the quantitative nano aerosol of a kind of chemicals or biomolecule, this method adds propellant again and can obtain quantitative nano aerosol or directly this nanoparticulate dispersed be obtained quantitative nano aerosol in propellant by being dissolved in the cosolvent in conjunction with the chemicals and the biomolecule nano-particle of microemulsified and quick drying technology acquisition.
Goal of the invention of the present invention is realized by the following technical programs:
The nano-particle of chemicals of the present invention or biomolecule is prepared through microemulsified and quick drying technology combination, and this nano-particle stable state equably is dispersed in the mixture of propellant or propellant and cosolvent.
The even particle size of the nano-particle of this chemicals or biomolecule, particle diameter (particle diameter) is less than 300nm, preferably less than 100nm; Its mean diameter is 1-90nm, preferred 5-50nm.
Wherein, described chemicals and biomolecule comprise various chemicalses, protein, polypeptide, nucleic acid or various active composition and the mixture of depositing or contain the mixture of active component.
Described nano-particle is spherical particle and/or other particle shape;
Described quick drying technology can be spray drying, supersonic jet spray drying, vacuum microwave rapid draing, quick drying tunnel, expansion drying, other quick drying technology or their combination drying technology.
Described microemulsified can be the microemulsion technology of preparing of any routine, with the liquid (water or oil phase) of soluble chemistry medicine or biomolecule at surfactant or contain under the effect of surfactant solution of cosurfactant to be dispersed in and carry out the microemulsion preparation in another immiscible solvent (oil phase or water) with drop form less than 100nm.
Described surfactant comprises anion surfactant such as carboxylic acid type, cationic surfactant such as quaternary, non-ionic surface active agent such as polyglycols type and zwitterionic surfactant such as betaine type or their mixture.
Specifically, described surfactant can be fatty glyceride such as single glyceride, fatty acid cane sugar ester, fatty acid sorbitan ester, fatty acid propylene glycol ester, soybean phospholipid, Radix Acaciae senegalis, alginic acid, sodium caseinate, gelatin and egg yolk etc., other surfactant types also comprises and contains the amino acids ester surfactant, in conjunction with polysaccharide or proteinic high molecular surfactant and granule surface activity agent etc. or their mixture.
Described cosurfactant is generally alcohol, alcohol ether or the carboxylic acid of medium carbochain C3-C8.
Described immiscible solvent can be the alkane of medium carbochain C5-C8, aromatic hydrocarbons, cycloalkane during as oil phase.
The preparation method of the nano-particle of chemicals of the present invention or biomolecule, comprise microemulsified and rapid draing step, wherein microemulsified can be the microemulsion technology of preparing of any routine, and with the liquid (water or oil phase) of soluble chemistry medicine or biomolecule at surfactant or contain under the effect of surfactant solution of cosurfactant to be dispersed in and carry out the microemulsion preparation in another immiscible solvent (oil phase or water) with drop form less than 100nm.
Wherein, the even particle size of the nano-particle of described chemicals or biomolecule, particle diameter (particle diameter) is less than 300nm, preferably less than 100nm; Its mean diameter is 1-90nm, preferred 5-50nm.
Described chemicals and biomolecule comprise various chemicalses, protein, polypeptide, nucleic acid or various active composition and the mixture of depositing or contain the mixture of active component.
Described nano-particle is spherical particle and/or other particle shape.
Described quick drying technology can be spray drying, supersonic jet spray drying, vacuum microwave rapid draing, quick drying tunnel, expansion drying, other quick drying technology or their combination drying technology.
Described surfactant comprises anion surfactant such as carboxylic acid type, cationic surfactant such as quaternary, non-ionic surface active agent such as polyglycols type and zwitterionic surfactant such as betaine type or their mixture.
Specifically, described surfactant can be fatty glyceride such as single glyceride, fatty acid cane sugar ester, fatty acid sorbitan ester, fatty acid propylene glycol ester, soybean phospholipid, Radix Acaciae senegalis, alginic acid, sodium caseinate, gelatin and egg yolk etc., other surfactant types also comprises and contains the amino acids ester surfactant, in conjunction with polysaccharide or proteinic high molecular surfactant and granule surface activity agent etc. or their mixture.
Described cosurfactant is generally alcohol, alcohol ether or the carboxylic acid of medium carbochain C3-C8.
Described immiscible solvent can be the alkane of medium carbochain C5-C8, aromatic hydrocarbons, cycloalkane during as oil phase.
The quantitative nano aerosol of chemicals of the present invention or biomolecule, this aerosol by will through microemulsified and quick drying technology in conjunction with the nanoparticulate dispersed of chemicals that is prepared or biomolecule in propellant or be dispersed in the mixture of cosolvent and propellant and make.
The even particle size of the nano-particle of described chemicals or biomolecule, particle diameter (particle diameter) is less than 300nm, preferably less than 100nm; Its mean diameter is 1-90nm, preferred 5-50nm.
Described chemicals and biomolecule comprise various chemicalses, protein, polypeptide, nucleic acid or various active composition and the mixture of depositing or contain the mixture of active component.
Described nano-particle is spherical particle and/or other particle shape.
Wherein, the amount of chemicals in the every spray of described aerosol or biomolecule is selected according to its corresponding treatment requirement and medicament categories.For example, the amount of chemicals that contains in every spray or biomolecule is 0.01mg-2mg.
Described quick drying technology can be spray drying, supersonic jet spray drying, vacuum microwave rapid draing, quick drying tunnel, expansion drying, other quick drying technology or their Aassociation drying.
Described microemulsified can be the microemulsion technology of preparing of any routine, with the liquid (water or oil phase) of soluble chemistry medicine or biomolecule at surfactant or contain under the effect of surfactant solution of cosurfactant to be dispersed in and carry out the microemulsion preparation in another immiscible solvent (oil phase or water) with drop form less than 100nm.
Described surfactant comprises anion surfactant such as carboxylic acid type, cationic surfactant such as quaternary, non-ionic surface active agent such as polyglycols type and zwitterionic surfactant such as betaine type or their mixture.
Specifically, described surfactant can be fatty glyceride such as single glyceride, fatty acid cane sugar ester, fatty acid sorbitan ester, fatty acid propylene glycol ester, soybean phospholipid, Radix Acaciae senegalis, alginic acid, sodium caseinate, gelatin and egg yolk etc., other surfactant types also comprises and contains the amino acids ester surfactant, in conjunction with polysaccharide or proteinic high molecular surfactant and granule surface activity agent etc. or their mixture.
Described immiscible solvent can be the alkane of medium carbochain C5-C8, aromatic hydrocarbons, cycloalkane during as oil phase.
Described propellant is can produce enough vapour pressures and produce ether, alkane, fluorohydrocarbon, chlorohydrocarbon, chloro fluorohydrocarbon of impelling effect and composition thereof.Preferred propellant is insoluble for the Nano medication granule.Suitable propellant comprises ether, as dimethyl ether; Alkane such as propane, normal butane, iso-butane, isopentane; Fluoric ether, as Difluoroethane (HFC152a), tetrafluoroethane (HFC134a), heptafluoro-propane (HFC227); The chloro fluoric ether, as isceon (CFC11), dichlorodifluoromethane (CFC12), dichlorotetra-fluoroethane (CFC114), dichloro one fluoroethane (HCFC141b), chlorodifluoroethane (HCFC142b), or their mixture propellant.
Described cosolvent can be alkane, aromatic hydrocarbons or the cycloalkane of medium chain C5-C8.
The quantitative nano aerosol of described chemicals or biomolecule can be used as the application that lung transmission, mouth or nose transmit medicine.
The preparation method of the quantitative nano aerosol of chemicals of the present invention or biomolecule, comprise the nano-particle of the chemicals that will obtain after microemulsified and the rapid draing or biomolecule or nano-particle and surfactant mixtures be dispersed in the propellant or be dispersed in cosolvent and the mixture of propellant in step.
In this preparation method, can also comprise a separating step after a microemulsified and the rapid draing, so that the nano-particle of chemicals or biomolecule separates with surfactant.
Described separating step can adopt absorption, ion exchange, chromatography, membrance separation, infiltration, nanofiltration, ultrafiltration, microfiltration, dialysis, separation method such as centrifugal, or their combination separation method.
The even particle size of the nano-particle of described chemicals or biomolecule, particle diameter (particle diameter) is less than 300nm, preferably less than 100nm; Its mean diameter is 1-90nm, preferred 5-50nm.
Described chemicals and biomolecule comprise various chemicalses, protein, polypeptide, nucleic acid or various active composition and the mixture of depositing or contain the mixture of active component.
Described nano-particle is spherical particle and/or other particle shape.
Described quick drying technology can be spray drying, supersonic jet spray drying, vacuum microwave rapid draing, quick drying tunnel, expansion drying, other quick drying technology or their combination drying technology.
Described microemulsified can be the microemulsion technology of preparing of any routine, with the liquid (water or oil phase) of soluble chemistry medicine or biomolecule at surfactant or contain under the effect of surfactant solution of cosurfactant to be dispersed in and carry out the microemulsion preparation in another immiscible solvent (oil phase or water) with drop form less than 100nm.
Described surfactant comprises anion surfactant such as carboxylic acid type, cationic surfactant such as quaternary, non-ionic surface active agent such as polyglycols type and zwitterionic surfactant such as betaine type or their mixture.
Specifically, described surfactant can be fatty glyceride such as single glyceride, fatty acid cane sugar ester, fatty acid sorbitan ester, fatty acid propylene glycol ester, soybean phospholipid, Radix Acaciae senegalis, alginic acid, sodium caseinate, gelatin and egg yolk etc., other surfactant types also comprises and contains the amino acids ester surfactant, in conjunction with polysaccharide or proteinic high molecular surfactant and granule surface activity agent etc. or their mixture.
Described immiscible solvent can be the alkane of medium carbochain C5-C8, aromatic hydrocarbons, cycloalkane during as oil phase.
Described propellant is can produce enough vapour pressures and produce ether, Hydrocarbon, fluoric ether, chloro fluoric ether of impelling effect and composition thereof.Preferred propellant is insoluble for the Nano medication granule.Suitable propellant comprises ether, as dimethyl ether; Alkane such as propane, normal butane, iso-butane, isopentane; Fluoric ether, as Difluoroethane (HFC152a), tetrafluoroethane (HFC134a), heptafluoro-propane (HFC227); The chloro fluoric ether, as isceon (CFC11), dichlorodifluoromethane (CFC12), dichlorotetra-fluoroethane (CFC114), dichloro one fluoroethane (HCFC141b), chlorodifluoroethane (HCFC142b), or their mixture propellant.
Described cosolvent can be alkane, aromatic hydrocarbons or the cycloalkane of medium chain C5-C8.
The present invention combines with quick drying technology by the micro-emulsion technology of routine, successfully develop a kind of preparation method and come the nano-particle of manufacturing chemistry medicine or biomolecule, can disperse uniformly and stably in propellant thereby develop a kind of Nano medication granule, and the quantitative nano aerosol of high transmission efficiency is arranged in pulmonary.Simultaneously, this integrated technology also provides a platform, and it can make nanoparticle with numerous chemicalses and biomolecule, thereby the sucked nanometer formulation that obtains them is realized intravital transmission and treated the disease of locality and general.
The specific embodiment
Microemulsified, promptly preparation of microemulsion is a known technology.Microemulsion is thermodynamically stable, isotropism, appearance transparent or the translucent dispersion that is formed under Action of Surfactant by two kinds of immiscible liquid, wherein a kind of liquid is continuous phase, and another liquid is scattered in wherein with the drop of particle diameter less than 100nm.One of them of two kinds of immiscible liquid is called water (W), and another is oil phase (O) mutually.Common microemulsion is two types of Water-In-Oil (W/O) and oil-in-waters (O/W).
Microemulsion system generally is made up of organic solvent, aqueous solution, surfactant and cosurfactant.Organic solvent commonly used mostly is medium carbochain such as C5~C8 alkane, aromatic hydrocarbons or cycloalkane; Usually have hydrophilic group (hydroxyl etc.) and lipophilic group (alkyl) in the surfactant molecule, easily on the interface of water and oil phase, form adsorption layer, form microemulsion thereby immiscible one in biphase is dispersed in another continuous phase mutually.Surfactant generally comprises anion surfactant such as carboxylic acid type, cationic surfactant such as quaternary, non-ionic surface active agent such as polyglycols type and zwitterionic surfactant such as betaine type or their mixture.Cosurfactant is generally the fatty alcohol and carboxylic acid of medium carbochain C3~C8.Because the particularity of medicine industry, surfactant must be to the people nontoxic or low toxicity and can being absorbed by the body and metabolism, surfactant commonly used with good biocompatibility has fatty glyceride (being mainly single glyceride), fatty acid cane sugar ester, fatty acid sorbitan ester, fatty acid propylene glycol ester, soybean phospholipid, Radix Acaciae senegalis, alginic acid, sodium caseinate, gelatin and egg yolk etc., also comprising of other contains the amino acids ester, in conjunction with polysaccharide/proteinic high molecular surfactant and granule surface activity agent etc. or their mixture.
Utilize microemulsion system to prepare the important research direction that nano material is nanotechnology.In microemulsion system, the nano-liquid droplet of decentralized photo provides the place of a nanoscale in fact, can carry out chemical reaction here, can carry out processing modifiedly to material, can also be based on this comprehensive other technology preparation have the new form and the nano material of performance.The microemulsion system that the present invention promptly makes up based on the surfactant by good biocompatibility is aided with special dry technology and prepares the nano-particle of medicine to improve their lung suction transmission efficiency.
Dry technology of the present invention is a quick drying technology.Because the biphase volatility difference of profit in the microemulsion system adopts general evaporation technology microemulsion system to be damaged because of the two-phase solvent evaporation rate differs.Quick drying technology then can before microemulsion system might change, steam all solvents in the extremely short time simultaneously fast, thereby obtains nano-particle.Quick drying technology commonly used has spray drying technology, supersonic jet spray drying technology, vacuum microwave quick drying technology, quick drying tunnel technology, expansion drying, other quick drying technology or their combination drying technology.
Comprehensive micro-emulsion technology of the present invention and quick drying technology have been formulated a platform.Under this platform technology, numerous chemicalses and biomolecule can be prepared into nano-particle, improve the transmission efficiency that they suck through lung.Specifically, under the effect of surfactant, be dispersed in another immiscible solvent by the liquid of micro-emulsion technology dissolved substance.The liquid that contains medicine is discontinuous phase, and it is scattered in the middle of the immiscible solvent with the drop form less than 100nm.Adopt special dry technology evaporation to remove all liquid then, promptly obtain the nano-particle of medicine.The medicament nano granule can be dispersed in the middle of the fluid that contains propellant, thereby makes the nanometer dosage form of metered dose inhalation aerosol.This nanometer inhalable formulations has highly stable medicine efficiently pulmonary transmission capacity.
The present invention also may adopt isolation technics, and nano-particle is separated with surfactant.Possible isolation technics comprises absorption, ion exchange, chromatography, membrance separation, infiltration, nanofiltration, ultrafiltration, microfiltration, dialysis, separation method such as centrifugal, or their combination separation method.
With respect to tablet and injection, utilizing lung suction preparation to carry out drug delivery is an emerging technology.Lung sucks preparation and is mainly used to treat pulmonary disease such as asthma, chronic obstructive pulmonary disease, cyst cystic fibrosis, pneumonia etc. traditionally.Because pulmonary's absorption area is big, rich blood vessel is easy to drug absorption.People recognize the effective ways of still treating systemic disease through the lung drug delivery, it have no gastrointestinal tract Degradation, no liver first-pass effect, drug absorption rapidly, directly enter advantages such as body circulation, good patient compliance, dosage reduce, toxic and side effects is little after the drug absorption.Metered dose inhalation aerosol is present the most frequently used inhalable formulations.Wherein propellant is those ether, Hydrocarbon, fluoric ether, chloro fluoric ether or its mixture that can produce enough vapour pressures and produce the impelling effect.Preferred propellant is insoluble for the Nano medication granule.Suitable propellant comprises ether, as dimethyl ether; Alkane such as propane, normal butane, iso-butane, isopentane; Fluoric ether, as Difluoroethane (HFC152a), tetrafluoroethane (HFC134a), heptafluoro-propane (HFC227); The chloro fluoric ether, as isceon (CFC11), dichlorodifluoromethane (CFC12), dichlorotetra-fluoroethane (CFC114), dichloro one fluoroethane (HCFC141b), chlorodifluoroethane (HCFC142b), or their mixture propellant.This metered dose inhalation aerosol also may contain a spot of cosolvent, and cosolvent can be alkane, aromatic hydrocarbons or the cycloalkane of medium chain C5-C8.
Be surfactant below with lecithin, with the isopropyl alcohol is that cosurfactant is the preparation method that example illustrates microemulsified and rapid draing technology and aerosol, at this only as example, be not difficult to find out, any chemicals can adopt identical preparation technology and method to carry out the preparation of nanoparticles and the aerosol preparation of chemicals and biomolecule with biomolecule, wherein, the surfactant of employing, cosurfactant, water, oil phase etc. can adopt respective substance known in the art to replace and can not change invention effect of the present invention.
The structure of microemulsion system
Lecithin is dissolved in isopropyl alcohol and makes surfactant solution (its mass ratio is a lecithin: isopropyl alcohol=1: 3), oil phase is an isobutyltrimethylmethane., and water is 15% (mass percent concentration) albuterol aqueous solution.Surfactant solution and oil phase isobutyltrimethylmethane. are mixed with a series of mixed liquor, and both mass ratioes were from 5: 95 to 95: 5 in the mixed liquor, and the mass percent of surfactant solution in mixed liquor risen progressively with 5%.Then the albuterol aqueous solution is dripped in mixed liquor, and vibration, up to its muddiness, and calculating water, oil phase and surfactant phase three's mass ratio is drawn on and promptly gets its phasor among the DeltaGraph, as shown in Figure 1.In scope shown in the phasor, all can form water-in-oil microemulsion.
The drying of microemulsion
The drying of microemulsion can be selected spray drying for use, only needs single stepping can obtain the nano-particle of medicine fast.Obviously, according to spirit of the present invention, the drying of microemulsion can adopt any quickly drying method, for example can be supersonic jet spray drying technology, vacuum microwave quick drying technology, quick drying tunnel technology, expansion drying, other quick drying technology or their combination drying technology.At this is the drying of Nanometer Particles technology that example illustrates chemicals or biomolecule with the spray drying only, and other dry technology is enumerated no longer one by one, but can know those skilled in the art with other the exploitativeness of dry technology.
The particulate Standard Operating Procedure of preparation Nano medication is summarized as follows.During spray drying, the standard operation state of spray dryer is 120 ℃ for the gas access temperature, and the Compressed Gas flow velocity is 580L/ hour, and outlet temperature transfers to temperature and be stabilized in 80 ℃ by the flow velocity of regulating pump.Keep this jet velocity, microemulsion is carried out spray drying.Finish, use cosolvent, reclaim the dry thing that is deposited in spray chamber, whirlwind centrifuge and the catcher as low alkane (normal heptane) dissolving.Natural drying under the room temperature is removed cosolvent, as low alkane (normal heptane), obtains nanometer albuterol granule and surfactant mixtures.
Show that through transmission electron microscope observing the Nano medication particle grain size that is generated by the microemulsion drying is obviously less than 100nm, mean diameter is between 5-50nm, and the granular size homogeneous is spherical more, also can comprise differential mode granule (Fig. 2).Measure nano particle diameter with the photon correlation spectrometry and distribute, its granule mean diameter is 18nm (Fig. 3).
The preparation of aerosol
According to the requirement of conventional therapy and the kind of medicine, the chemicals that contains in general every jet stream cloud agent or the amount of biomolecule are 0.01mg-2mg, and for example the each dosage of albuterol is 100~200 μ g.Get certain amount of nano drug particles and surfactant mixtures, place aerosol container.Add a spot of low alkane such as normal heptane dissolving surfactant and dispersing nanometer drug particles, use quantitative valve (100 μ l) sealing then.Then inject fluoric ether HFC134a, can make and all disperse and extremely stable supernatant liquid (Fig. 4 A).Place after four months, deposit-free produces, and does not also have floating thing and (Fig. 4 B) occur.So utilize the Nano medication granule can successfully prepare highly stable aerosol, good dispersity has shown that they have excellent ability in the pulmonary drug transmission.
The test that pulmonary drug is transmitted
Aerosol to preparation has carried out pulmonary drug transmission test respectively, and the pulmonary drug transmission test of aerosol is to adopt lung model-carry out under the gas flow rate 28.3L/min of standard.This is the detection method of a standard, and quilt many countries in the world closes in its pharmacopeia.Be deposited on second rank and following granule, its aerodynamics diameter is referred to as and can sucks granule less than 5.8.Tested the pulmonary deposition of nanometer formulation in this research, and breathed heavily happy peaceful (Ventolin) work one relatively (Fig. 5) with suction micron preparation commonly used.
By testing result, the nanometer medicament the deposition of bottleneck throat be starkly lower than commercially available medicine breathe heavily happy peaceful, show the atomizing of nanometer formulation after bulky grain few, the good flowing properties of particle.After entering branch stepwise particle diameter sampler, Nano medication mostly is deposited on Lower Half, the 6th rank especially, the 7th rank and filter course, be higher than far away breathe heavily happy rather in the drug delivery amount of this position, and this some exactly corresponding the alveolar in the human body.So the nanometer medicament can improve targeting (alveolar) the drug delivery efficient of medicine greatly, its microparticle ratio can reach 60%, rather has only 35% and breathe heavily to find pleasure in.In addition, also can modify to control its release the Nano medication granule.So nanometer formulation has the incomparable advantage of present metered dose inhalation aerosol micron dosage form, therefore will become the strong competitor of inhalable formulations.
Following example only is to illustrate for example; and should not explain or be interpreted as protection scope of the present invention is done any restriction; because method of the present invention is a kind of preparation method of blanket nano-particle; so; can not carry out exhaustive examples to all medicines and biomolecule or their compositions, mixture, only enumerate some representational medicines and biological example to be illustrated more clearly in the present invention at this.
Embodiment 1
Lecithin is dissolved in isopropyl alcohol and makes surfactant solution (mass ratio is a lecithin: isopropyl alcohol=1: 3).56.3mL surfactant solution joins in the 43.5mL isobutyltrimethylmethane., vibration was evenly left standstill 30 minutes.15% (mass percent) albuterol aqueous solution that adds 23.8mL then, thermal agitation, mix homogeneously makes it to become microemulsion.
The Standard Operating Procedure of albuterol preparation of nanoparticles is as follows.Spray dryer under the duty of standard with above-mentioned microemulsion spray drying.Finish, reclaim the dry thing that is deposited in spray chamber, whirlwind centrifuge and the catcher with the normal heptane dissolving.Natural drying under the room temperature is removed normal heptane, the exsiccant particulate mixture of nanometer albuterol that contains that obtains, and the mean diameter of nano-particle is near 20nm.
Get 30mg mixture (containing medicine 7.5mg) and insert in the aerosol container, add the 1mL normal heptane Nano medication uniform particles is scattered in wherein.With the sealing of 100 μ L metering valves, inject 6.5mL propellant HFC134a then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 100 μ g/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 58%.
Embodiment 2
In embodiment 1, take by weighing 30mg (containing medicine 7.5mg) insert in the aerosol container above-mentioned spray-dried prepared containing in the particulate mixture of Nano medication, inject the 1mL pentane Nano medication uniform particles is scattered in wherein.With the sealing of 100 μ L metering valves, and then inject 6.5mL propellant HFC134a, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 100 μ g/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 61%.
Embodiment 3
In embodiment 1, adopt the chromatography technology to remove the above-mentioned spray-dried prepared surfactant that contains in the particulate mixture of Nano medication, heptane is as mobile phase.Collection contains the mobile phase of drug particles, the dry nanometer albuterol granule that gets.Taking by weighing the 13mg drug particles inserts in the aerosol container, seal with 100 μ L metering valves, inject 2mL propellant normal butane earlier the Nano medication uniform particles is scattered in wherein, inject 4.5mL propellant HFC227 then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 200 μ g/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 64%.
Embodiment 4
Lecithin is dissolved in isopropyl alcohol and makes surfactant solution (mass ratio is a lecithin: isopropyl alcohol=1: 3).56.3mL surfactant solution join in the 43.5mL isobutyltrimethylmethane., vibration was evenly left standstill 30 minutes.10mg/mL (mass percent) the ipratropium bromide solution that adds 23.8mL then, thermal agitation, mix homogeneously makes it to become microemulsion.According to the Standard Operating Procedure of preparation of nanoparticles, make and contain the particulate mixture of nanometer ipratropium bromide.The mean diameter of nano-particle is near 47nm.
Adopt the chromatography technology to remove surfactant, heptane is as mobile phase.Collection contains the mobile phase of drug particles, the dry nanometer ipratropium bromide granule that gets.Get 1.5mg nanometer ipratropium bromide granule and insert in the aerosol container, add the 0.2mL normal heptane Nano medication uniform particles is scattered in wherein.With the sealing of 100 μ L metering valves, inject 7.3mL propellant HFC134a then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 20 μ g/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 62%.
Embodiment 5
In embodiment 4, above-mentioned spray-dried preparation takes by weighing 1.5mg in the isolated Nano medication granule of chromatographic technique and inserts in the aerosol container, adds the 0.2mL normal hexane Nano medication uniform particles is scattered in wherein.With the sealing of 100 μ L metering valves, inject 7.3mL propellant HFC134a then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 20 μ g/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 61%.
Embodiment 6
In embodiment 4, above-mentioned spray-dried preparation, taking by weighing 0.75mg in the isolated Nano medication granule of chromatographic technique inserts in the aerosol container, seal with 100 μ L metering valves, injecting 2mL propellant iso-butane earlier is scattered in wherein the Nano medication uniform particles, inject 5.5mL propellant HFC134a then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 10 μ g/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 69%.
Embodiment 7
In embodiment 4, above-mentioned spray-dried preparation, taking by weighing 3mg in the isolated Nano medication granule of chromatographic technique inserts in the aerosol container, seal with 100 μ L metering valves, injecting 1mL propellant propane earlier is scattered in wherein the Nano medication uniform particles, inject 5.5mL propellant HFC134a then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 40 μ g/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 68%.
Embodiment 8
Lecithin is dissolved in isopropyl alcohol and makes surfactant solution (mass ratio is a lecithin: isopropyl alcohol=1: 3).11.3mL surfactant solution joins in the 8.7mL isobutyltrimethylmethane., vibration was evenly left standstill 30 minutes.30mg/mL (mass percent) insulin solutions that adds 4.9mL then, thermal agitation, mix homogeneously makes it to become microemulsion.According to the Standard Operating Procedure of preparation of nanoparticles, make and contain the particulate mixture of nanometer insulin.The mean diameter of nano-particle is near 39nm.
Adopt chromatography to remove surfactant, normal heptane is as mobile phase.Collect the particulate mobile phase of insulin, natural drying obtains nanometer insulin granule.Get 60mg nanometer insulin granule and insert in the aerosol container, add 400 μ L normal heptane the Nano medication uniform particles is scattered in wherein.With the sealing of 100 μ L metering valves, inject 5.6mL propellant HFC134a then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 1mg/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 65%.
Embodiment 9
In embodiment 8, above-mentioned spray-dried preparation is got 120mg in the isolated nanometer insulin of the chromatographic technique granule and is inserted in the aerosol container, with the sealing of 100 μ L metering valves, injects 1.5mL propane the Nano medication uniform particles is scattered in wherein.Inject 4.5mL HFC134a then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 2mg/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 68%.
Embodiment 10
Lecithin is dissolved in isopropyl alcohol and makes surfactant solution (mass ratio is a lecithin: isopropyl alcohol=1: 3).11.3mL surfactant solution joins in the 8.7mL isobutyltrimethylmethane., vibration was evenly left standstill 30 minutes.20mg/mL (mass percent) fentanyl citrate that adds 4.8mL then, thermal agitation, mix homogeneously makes it to become microemulsion.According to the Standard Operating Procedure of preparation of nanoparticles, make and contain the particulate mixture of nanometer fentanyl citrate.The mean diameter of nano-particle is near 45nm.
Adopt chromatography to remove surfactant, heptane is as mobile phase.Collect the particulate mobile phase of fentanyl citrate, drying obtains nanometer fentanyl citrate granule.Get 6mg nanometer fentanyl citrate granule and insert in the aerosol container,, inject 1mL propellant iso-butane the Nano medication uniform particles is scattered in wherein with the sealing of 100 μ L metering valves.Inject 5mL propellant HFC134a then, promptly obtain the aerosol in the dispersive fluid of Nano medication uniform particles.The nano aerosol of this 0.1mg/ spray can keep highly stable dispersity.Measuring its microparticle ratio (particle diameter<5.8 μ m) with lung model is 69%.
In above-mentioned all embodiment, its quickly drying method can also be supersonic jet spray drying technology, vacuum microwave quick drying technology, quick drying tunnel technology, expansion drying, other drying means or their Aassociation drying.
Isolation technics in embodiment 3-10 can also adopt absorption, ion exchange, chromatography, membrance separation, infiltration, nanofiltration, ultrafiltration, microfiltration, dialysis, separation method such as centrifugal, or their combination separation method.
It should be noted that term " propellant " among the application can adopt comprises ether, as dimethyl ether; Alkane such as propane, normal butane, iso-butane, isopentane; Fluoric ether, as Difluoroethane (HFC152a), tetrafluoroethane (HFC134a), heptafluoro-propane (HFC227); The chloro fluoric ether, as isceon (CFC11), dichlorodifluoromethane (CFC12), dichlorotetra-fluoroethane (CFC114), dichloro one fluoroethane (HCFC141b), chlorodifluoroethane (HCFC142b), or the propellant of a lot of types of their mixture propellant or the like, the selection of this propellant type is all expected to those skilled in the art easily, enumerates no longer one by one here.Term among the application " cosolvent " can adopt alkane, aromatic hydrocarbons or the cycloalkane of medium chain C5-C8, and the cosolvent type that provides in embodiment, other cosolvent type is no longer enumerated here.The preparation process of " microemulsion " among the application has been very perfect technology, the any chemicals and biomolecule that can be prepared to microemulsion can obtain its nano-particle and the aerosol that utilizes this nano-particle to make through preparation method of the present invention, clearly, preparation method of the present invention is a kind of method of generally using, chemicals and biomolecule are had no particular limits, as long as can prepare its microemulsion, can prepare its nano-particle in conjunction with rapid draing again, and make aerosol, therefore, chemicals and biomolecule are not done special restriction, this statement also can obtain the abundant support of description, here repeat no more the embodiment of various chemicalses and biomolecule, those of ordinary skills can know and know that this preparation method can obtain the aerosol of various chemicalses and biomolecule.In addition, it should be noted that, in the preparation of microemulsion process, there is no particular limitation for parameters such as the weight of its various compositions, it can do the variation of certain limit as required, equally, chemicals need make corresponding changes according to different medicine or biotype according to the demand of treatment with the dispersion amount of cosolvent at propellant or propellant with the biomolecule nano-particle, here do not limit its quantity especially yet, those skilled in the art can expect, because the universality of this method, so the medicament categories of preparation is various, the consumption of contained drug also has very big-difference in its aerosol, these have all depended on the purpose of treatment and the kind of medicine, therefore, the chemicals in every spray or the amount of biomolecule are not done special qualification at this, and the example is also enumerated no longer one by one.
Although above embodiments of the invention are described in detail and illustrate, should indicatedly be, we can carry out various changes and modification to the foregoing description, but these do not break away from the scope that spirit of the present invention and appended claim are put down in writing.