CN107028922A - A kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier - Google Patents
A kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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Abstract
The present invention relates to a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier, include 0.5 ~ 20% inhalant fine drug powder（Median diameter is 1 ~ 5 μm）, 10 ~ 70% contain micro-, mesoporous lactose fine powder（Median diameter is 5 ~ 50 μm）With 10 ~ 70% containing micro-, mesoporous lactose coarse powder（Median diameter is 50 ~ 200 μm）；It is described containing micro-, mesoporous lactose fine powder and it is described containing micro-, mesoporous lactose coarse powder be the particle with loose structure, aperture surface area is 10 ~ 80m2/ g, pore volume is 0.15 ~ 0.99cc/g, and containing diameter be less than 2nm micropore and a diameter of 2 ~ 50nm it is mesoporous.Micro Nano material technology of preparing, nano-pore absorption medicine restriction technologies and ternary system inhalant technology have been used in present invention fusion first, the new Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier prepared, the drug delivery ability of Foradil Aerolizer formoterol fumarate is improved, practicality is higher.
Description
Technical field
The present invention relates to pharmaceutical formulating art, and in particular to a kind of Foradil Aerolizer formoterol fumarate three based on micro-, mesoporous lactose carrier
First delivery system.
Background technology
Recently as environmental pollution, asthma, pneumonia, lung cancer and other PUD Ds are multiple, pulmonary delivery system development
Comparatively fast.Wherein Foradil Aerolizer formoterol fumarate delivery system is that, using the best pulmonary administration mode of most wide, effect, it uses micro mist carrier（1
~ 5 microns）Drug particles are transferred to deep lung by intratracheal, administration effect is played.
" albumen and polypeptide drugs Foradil Aerolizer formoterol fumarate New research progress " described in prior art（《Acta Pharmaceutica Sinica》2015
814-823 pages of the phase of volume 50 7）, the advantage of ternary delivery system is discussed, i.e., using coarse powder carrier, fine powder carrier and pastille fine powder
Mixing composition ternary delivery system, is conducive to transmission of the fine drug powder in pulmonary delivery system, drug effect has been lifted.
" FLUTICASONE PROPIONATE and salmeterol xinafoate compound dry powder inhalation and its system are described in the prior art
Standby technique "（Application number CN200810204741.6）, using FLUTICASONE PROPIONATE and salmeterol xinafoate medicine, fine powder
Lactose and coarse powder lactose carrier constitute ternary delivery system, realize the transmission capacity and inhalant of preferable medicine to drug effect
Really；But the water solubility of drug particles, which does not have, to get a promotion, and human absorptivity is low, lactose fine powder and coarse powder size are larger, medicine
Adsorption capacity is poor.
Describe in the prior art " a kind of Foradil Aerolizer formoterol fumarate and preparation method thereof "（Application number CN201310581101.8）,
Using salbutamol sulfate（Medicine）, particle additive（Lactose fine powder）And carrier（Lactose coarse powder）The ternary administration system of composition
System, realizes preferable inhalant administering effect；But got a promotion likewise, the water solubility of drug particles does not have, lactose is thin
Powder and coarse powder are lactose monohydrate crystal, and water-soluble, Drug absorbability ability is all poor.
In order to improve the Drug absorbability ability of lactose carrier, " Foradil Aerolizer formoterol fumarate, its preparation method are described in the prior art
And purposes "（Application number CN200810151281.5）, using ammonium carbonate or/and ammonium hydrogen carbonate as foaming agent, it is added to spraying
Dry during preparing carbohydrate micro mist carrier, prepared the less carbohydrate micro mist carrier of density, improved carbohydrate carrier
Drug delivery ability；But prepared carbohydrate carrier does not possess nano-pore structure, the adsorption capacity to medicine does not obtain excellent
Change.
Therefore, seek highly efficient Foradil Aerolizer formoterol fumarate pulmonary administration process, be administered by using the ternary more optimized
System, improves the drug delivery ability of ternary delivery system, lifts the water solubility, curative effect, human absorptivity of water-insoluble medicine,
It is the problem of being currently needed for solving.
The content of the invention
For defect of the prior art, present invention aims at provide a kind of dry powder based on micro-, mesoporous lactose carrier
Inhalant ternary delivery system, medicine restriction technologies and three are adsorbed by merging with micro Nano material technology of preparing, nano-pore
Metasystem inhalant technology, prepares ternary delivery system new, for Foradil Aerolizer formoterol fumarate, realizes high drug delivery ability
It is water-soluble with medicine, to obtain more preferably curative effect of medication.
To achieve the above object, the technical scheme that provides of the present invention is：
In a first aspect, the invention provides a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier, it is special
Levy and be：The Foradil Aerolizer formoterol fumarate ternary delivery system includes 0.5 ~ 20% inhalant fine drug powder（Median diameter is 1 ~ 5 μ
m）, 10 ~ 70% contain micro-, mesoporous lactose fine powder（Median diameter is 5 ~ 50 μm）With 10 ~ 70% containing micro-, mesoporous lactose coarse powder
（Median diameter is 50 ~ 200 μm）；It is described containing micro-, mesoporous lactose fine powder and it is described containing micro-, mesoporous lactose coarse powder be to have
The particle of loose structure, aperture surface area is 10 ~ 80m2/ g, pore volume is 0.15 ~ 0.99cc/g, and is less than containing diameter
2nm micropore and a diameter of 2 ~ 50nm's is mesoporous.
It should be noted that ternary delivery system includes drug moiety and thick, fine powder carrier two parts, due to drug moiety
Release efficiency is easily influenceed by carrier adsorbed close, so first being combined using fine powder carrier with coarse powder carrier, fine powder is occupied
High-energy face on coarse powder carrier, then after being mixed again with drug moiety, the bond strength of medicine and coarse powder carrier has declined, medicine
The release efficiency of thing also just gets a promotion；The releasing effect of medicine receives the burden control of ternary delivery system simultaneously, and fine powder is carried
Body used at most adsorption capacity of the fine drug powder on coarse powder carrier then weaker, it is easier to be released, but load medicine adsorbance has
Declined, it is on the contrary then be difficult to be released, Drug absorbability amount increases.
It is described containing micro-, mesoporous lactose fine powder and it is described containing micro-, mesoporous lactose coarse powder be with loose structure
Grain, then surface area greatly, porosity it is higher, the adsorption capacity to drug ingedient is larger；And during using solution adsorption method, medicine point
Son can be adsorbed to it is micro-, mesoporous in, play a nanometer restriction effect, there is more preferable Drug absorbability, transmission capacity.
That is, a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier that the present invention is provided,
By design vector high porosity nanopore system and ternary delivery system, improve Foradil Aerolizer formoterol fumarate carrier drug delivery,
The ability of medicine is discharged, it is more practical.
On the other hand, the invention provides a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier
Preparation process, including：Crystallized out in organic solution containing micro-, mesoporous lactose fine powder；Crystallized out in organic solution containing it is micro-,
Mesoporous lactose coarse powder；Mixed after the lactose fine powder and the lactose coarse powder are separately dried；By mixture and inhalant medicine
Thing fine powder is mixed, and obtains product.
In the further embodiment of the present invention, the solvent of the organic solution is preferably hypotoxicity, volatile had
Machine solvent, using ethanol as most preferably.It should be noted that in crystallization preparation process, first by lactose aqueous solution or unsetting
Solid is added in organic solvent, because lactose does not dissolve in organic solvent, and the over-saturation phase of lactose, knot are produced in organic solution
Brilliant process occurs immediately；As crystallization, available organic solvent includes alcohol, ether, acid, ester, ketone, chloroform etc., but in view of having
Machine thing remains and dries problem, preferably wherein hypotoxicity, volatile organic solvent, therefore preferred with ethanol.
In the further embodiment of the present invention, the crystallization is crystallizes out lactose crystal under over-saturation state, when super
The median diameter of the lactose size crystallized out when lactose concn is 15 ~ 100g/L in saturated solution is 5 ~ 50 μm, i.e., described
Containing micro-, mesoporous lactose fine powder；The intermediate value of the lactose size crystallized out when lactose concn is 1 ~ 15g/L in supersaturated solution
A diameter of 50 ~ 200 μm, i.e., described contains micro-, mesoporous lactose coarse powder.It should be noted that over-saturation crystallization rate, degree by
In solution solute over-saturation degree control, wherein concentration be control over-saturation degree the biggest factor, in addition temperature, space, stir
Mix the factor such as suspended particulate in speed, concussion, solution thermodynamically influences super by influenceing into nuclear concentration, growth, indirectly
Saturation degree.Because over-saturation degree is higher, then nucleation is faster, and then nucleus quantity is more soon for nucleation, because concentration is certain, therefore formed
Crystalline size is smaller, therefore, and the median diameter of the lactose size crystallized out when lactose concn is high in supersaturated solution is smaller,
Contain micro-, mesoporous lactose fine powder described in being formed；The lactose size crystallized out when lactose concn is low in supersaturated solution
Median diameter it is larger, that is, formed and described contain micro-, mesoporous lactose coarse powder.
In the further embodiment of the present invention, the mode of the drying process is that drying or low pressure are evaporated, and temperature is excellent
Elect 30 ~ 50 degree as, the drying i.e. using gas blasting's organic solvent after dehumidifying, the low pressure is evaporated i.e. using 0.01 ~
Organic solvent is evaporated off under 0.5atm air pressure.It should be noted that the drying or low pressure are evaporated process, to be easily caused product hardened,
In drying process should more dispersed arrangement product to be dried, or be aided with machinery or wind-force concussion dispersed waits to do
Dry product；And the drying temperature should not be heated more than 50 degree, otherwise in the case of residual organic solvent, lactose crystal can be sent out
Raw deformation, causes porosity to decline.
The present invention further embodiment in, the inhalant fine drug powder be by directly grind medicine be made 1 ~
The inhalant fine drug powder particulate of 5 microns of sizes, or following existed by size at 5 microns and containing micro-, mesoporous lactose fine powder
Adsorb after drug molecule and obtain in organic solvent.It should be noted that the size of commercially available inhalant medicine crude product is larger, using straight
The mode for connecing grinding flour is more conventional in rough thin mode, and the suction of 1 ~ 5 micron of size can be obtained by mechanical lapping
Enter agent fine drug powder particulate, in crystalline state；Preferred method is selected for commercially available inhalant medicine crude product is dissolved in into organic solvent
The size of preparation at 5 microns and it is following described in containing micro-, mesoporous lactose fine powder as medicinal porous adsorption carrier, organic molten
Drug absorbability is carried out in liquid, due to micro-, mesoporous Drug absorbability ability preferably, it is 0.5 ~ 20% to test the adsorbance measured（w/
w）, and adsorbed drug molecule with nano particle it is uniform in size be distributed in it is described contain in micro-, mesoporous lactose fine powder, with carrying
The water solubility and medicine stability risen.
A kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier that the present invention is provided, first will be micro-
Nano material preparation technology, nano-pore absorption medicine restriction technologies and the technological incorporation of ternary system inhalant are used, and are prepared
Ternary delivery system new, for Foradil Aerolizer formoterol fumarate, realizes that high drug delivery ability, medicine be water-soluble and stability
Medicine physicochemical property, obtain more preferably curative effect of medication.
The additional aspect and advantage of the present invention will be set forth in part in the description, and will partly become from the following description
Obtain substantially, or recognized by the practice of the present invention.
Brief description of the drawings
Fig. 1 is the Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier in the embodiment of the present invention
Preparation method flow chart.
Fig. 2 be in the embodiment of the present invention two the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier for preparing to
The SEM scanning electron microscope (SEM) photographs of medicine system.
Fig. 3 be in the embodiment of the present invention three the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier for preparing to
The SEM scanning electron microscope (SEM) photographs of medicine system.
Fig. 4 be in the embodiment of the present invention four the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier for preparing to
The SEM scanning electron microscope (SEM) photographs of medicine system.
Fig. 5 is adsorbing medicine respectively for micro-, mesoporous lactose carrier coarse powder, the fine powder prepared in the embodiment of the present invention five
Graph of pore diameter distribution before and after composition.
Fig. 6 is micro-, the mesoporous lactose carrier coarse powder, the laser particle size measurement of fine powder that prepare in the embodiment of the present invention five
Figure.
Fig. 7 be in the embodiment of the present invention six the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier for preparing to
The photo of medicine system.
Fig. 8 be in the embodiment of the present invention six the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier for preparing to
Medicine system contrasts the water solubility rate figure of the Foradil Aerolizer formoterol fumarate ternary delivery system based on conventional lactose monohydrate carrier.
Embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete
Site preparation is described, it is clear that described embodiment is only a part of embodiment of the invention, rather than whole embodiments.It is based on
Embodiment in the present invention, it is every other that those of ordinary skill in the art are obtained under the premise of creative work is not made
Embodiment, belongs to the scope of protection of the invention.
Embodiment one
The present embodiment provides a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier, it is characterised in that：Institute
Stating Foradil Aerolizer formoterol fumarate ternary delivery system includes 0.5 ~ 20% inhalant fine drug powder（Median diameter is 1 ~ 5 μm）, 10 ~ 70%
Containing micro-, mesoporous lactose fine powder（Median diameter is 5 ~ 50 μm）With 10 ~ 70% containing micro-, mesoporous lactose coarse powder（Median diameter is
50~200µm）；It is described containing micro-, mesoporous lactose fine powder and it is described containing micro-, mesoporous lactose coarse powder be with loose structure
Particle, aperture surface area is 10 ~ 80m2/ g, pore volume is 0.15 ~ 0.99cc/g, and containing diameter be less than 2nm micropore and
A diameter of 2 ~ 50nm's is mesoporous.
For the Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier of the present invention, the present invention is devised
The preparation method of the Foradil Aerolizer formoterol fumarate ternary delivery system.
Fig. 1 is the Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier in the embodiment of the present invention
Preparation method flow chart, as shown in figure 1, the preparation method of Foradil Aerolizer formoterol fumarate ternary delivery system that the present invention is provided, including
Following steps：
S1：Crystallized out in organic solution containing micro-, mesoporous lactose fine powder；
S2：Crystallized out in organic solution containing micro-, mesoporous lactose coarse powder；
S3：Mixed after the lactose fine powder and the lactose coarse powder are separately dried；
S4：Mixture is mixed with inhalant fine drug powder, product is obtained.
With reference to specific embodiment to the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier that provides of the present invention to
The preparation method of medicine system is described further.
Embodiment two
A kind of preparation method of the Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier is present embodiments provided,
Comprise the following steps：
S1：At normal temperatures and pressures, the unsetting lactose of 40kg is added into 400L ethanol solutions, stirred crystallization goes out containing micro-, mesoporous
Lactose fine powder；
S2：At normal temperatures and pressures, the unsetting lactose of 1kg is added into 400L ethanol solutions, stirred crystallization goes out containing micro-, mesoporous breast
Sugared coarse powder；
S3：Mixed after the lactose fine powder and the lactose coarse powder are separately dried；The mode of the drying process is drying（Remove
Compressed air after wet blows down organic solvent）, temperature is 30 degree；
S4：Configure 1M budesonide ethanol solution, from median diameter for 5 microns containing micro-, mesoporous lactose fine powder in second
Adsorbed in alcohol after budesonide molecule, by the inhalant fine drug powder being dried to obtain and lactose slightly, fine powder mixture mix, obtain
Product.
Embodiment three
A kind of preparation method of the Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier is present embodiments provided,
Comprise the following steps：
S1：At normal temperatures and pressures, 5kg lactose aqueous solutions are added into 100L ethanol solutions（Lactose mass fraction is 50%）, stirring
Crystallize out containing micro-, mesoporous lactose fine powder；
S2：At normal temperatures and pressures, 0.6kg lactose aqueous solutions are added into 50L ethanol solutions（Lactose mass fraction is 50%）, stir
Mix and crystallize out containing micro-, mesoporous lactose coarse powder；
S3：Mixed after the lactose fine powder and the lactose coarse powder are separately dried；The mode of the drying process is steamed for low pressure
Dry, using ethanol is evaporated off under 0.01atm air pressure, temperature is 40 degree；
S4：Configure 5M Tiotropium Bromide acetone soln, from median diameter for 3 microns containing micro-, mesoporous lactose fine powder in second
Adsorbed in alcohol after Tiotropium Bromide molecule, by the inhalant fine drug powder being dried to obtain and lactose slightly, fine powder mixture mix, obtain
Product.
Example IV
A kind of preparation method of the Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier is present embodiments provided,
Comprise the following steps：
S1：At normal temperatures and pressures, the unsetting lactose of 5kg is added into 50L acetone solns, stirred crystallization goes out containing micro-, mesoporous breast
Sugared fine powder；
S2：At normal temperatures and pressures, the unsetting lactose of 0.1kg is added into 50L acetone solns, stirred crystallization goes out containing micro-, mesoporous
Lactose coarse powder；
S3：Mixed after the lactose fine powder and the lactose coarse powder are separately dried；The mode of the drying process is steamed for low pressure
Dry, using acetone is evaporated off under 0.5atm air pressure, temperature is 50 degree；
S4：Directly the inhalant fine drug powder particulate of 1 ~ 5 micron of size is made in grinding fluticasone medicine, and thick, thin with lactose
Powder mixture is mixed, and obtains product.
The Foradil Aerolizer formoterol fumarate ternary delivery system prepared according to above-described embodiment two, embodiment three, example IV
Pattern is determined：
System is administered for the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier prepared in the embodiment of the present invention two in Fig. 2
The SEM scanning electron microscope (SEM) photographs of system；
System is administered for the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier prepared in the embodiment of the present invention three in Fig. 3
The SEM scanning electron microscope (SEM) photographs of system；
System is administered for the Foradil Aerolizer formoterol fumarate ternary based on micro-, mesoporous lactose carrier prepared in the embodiment of the present invention four in Fig. 4
The SEM scanning electron microscope (SEM) photographs of system.
Determined by SEM scanning electron microscope (SEM) photographs, the form of the lactose carrier material is in small porous particle, ternary delivery system compared with
For uniform distribution, the drug design of pulmonary administration is met.It should be noted that ternary delivery system comprising drug moiety and
Slightly, fine powder carrier two parts, because drug moiety easily influences release efficiency by carrier adsorbed close, so being carried using fine powder
Body first and coarse powder carrier combine, fine powder occupies the high-energy face on coarse powder carrier, then after mix again with drug moiety, medicine and
The bond strength of coarse powder carrier has declined, and the release efficiency of medicine also just gets a promotion；The releasing effect of medicine is received simultaneously
The burden control of ternary delivery system, fine powder carrier used at most adsorption capacity of the fine drug powder on coarse powder carrier then compared with
It is weak, it is easier to be released, but carry medicine adsorbance and declined, it is on the contrary then be difficult to be released, Drug absorbability amount increases.
Meanwhile, it is described containing micro-, mesoporous lactose fine powder and it is described containing micro-, mesoporous lactose coarse powder be with loose structure
Particle, and part have flower-shape appearance, then surface area greatly, porosity it is higher, the adsorption capacity to drug ingedient is larger；And
During using solution adsorption method, drug molecule can be adsorbed to it is micro-, mesoporous in, play a nanometer restriction effect, there is more preferable medicine to inhale
Attached, transmission capacity.
During the Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier is prepared, it should say
It is bright, in crystallization preparation process, lactose aqueous solution or unsetting solid are added in organic solvent first, due to lactose not
Organic solvent is dissolved in, the over-saturation phase of lactose is produced in organic solution, crystallization process occurs immediately；It is optional as crystallization
Organic solvent includes alcohol, ether, acid, ester, ketone, chloroform etc., but in view of organic substance residues and dries problem, low toxicity preferably
The species of property, such as methanol, ethanol, normal propyl alcohol, n-butanol, n-amyl alcohol, n-hexyl alcohol, n-heptanol, fatty alcohol, n-nonyl alcohol, Decanol,
N-undecane alcohol, n-dodecane alcohol, n-tetradecanol, cetyl alcohol, n-octadecane alcohol, n-eicosane alcohol, positive docosanol,
N-octacosanol, triacontanol, 2- propyl alcohol, 2- butanol, 2- hexanols, cyclohexanol, the tert-butyl alcohol, triphenylcarbinol, 2- methyl -2- fourths
Alcohol, 2- methyl isophthalic acids-propyl alcohol, 3- methyl-1-butanols, pentane, formic acid, acetic acid, ether, acetone, methyl phenyl ethers anisole, butyl acetate, three fourths
Methyl ether, isopropyl acetate, MEK, dimethyl sulfoxide, cumene, ethyl acetate, Ethyl formate, isobutyl acetate, second
Sour methyl esters, methylisobutylketone, propyl acetate, 1,1- di ethyl propyl ethers, 1,1- dimethoxymethane, 2,2- dimethoxys third
In alkane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid and chloroform etc.
One or more, wherein ethanol（Alcohol）For most preferably.
Further, the crystallization is crystallizes out lactose crystal under over-saturation state, when lactose concn is in supersaturated solution
The median diameter of the lactose size crystallized out during 15 ~ 100g/L is 5 ~ 50 μm, i.e., described contains micro-, mesoporous lactose fine powder；
The median diameter of the lactose size crystallized out when lactose concn is 1 ~ 15g/L in supersaturated solution is 50 ~ 200 μm, i.e. institute
That states contains micro-, mesoporous lactose coarse powder.It should be noted that the over-saturation of over-saturation crystallization rate, degree by solute in solution
Degree control, wherein concentration are the biggest factors for controlling over-saturation degree, in addition in temperature, space, mixing speed, concussion, solution
The factors such as suspended particulate thermodynamically by influenceing into nuclear concentration, growth, influence over-saturation degree indirectly.Due to over-saturation degree
Higher, then nucleation is faster, and then nucleus quantity is more soon for nucleation, and because concentration is certain, therefore the crystalline size formed is smaller, therefore,
The median diameter of the lactose size crystallized out when lactose concn is high in supersaturated solution is smaller, that is, formed it is described containing it is micro-,
Mesoporous lactose fine powder；The median diameter of the lactose size crystallized out when lactose concn is low in supersaturated solution is larger, i.e.,
Contain micro-, mesoporous lactose coarse powder described in being formed.
Further, the mode of the drying process is that drying or low pressure are evaporated, and temperature is preferably 30 ~ 50 degree, the drying
I.e. using gas blasting's organic solvent after dehumidifying, the low pressure is evaporated i.e. organic molten using being evaporated off under 0.01 ~ 0.5atm air pressure
Agent.It should be noted that the drying or low pressure are evaporated process, to be easily caused product hardened, more should uniformly divide in drying process
Scattered arrangement product to be dried, or it is aided with machinery or the next dispersed product to be dried of wind-force concussion；And the drying temperature
It should not heat more than 50 degree, otherwise in the case of residual organic solvent, lactose crystal can be deformed upon, and be caused under porosity
Drop.
Further, the drug ingedient is to include broxaterol（Preferably salbutamol, salmeterol）, M- by
Body antagonist（Preferably ipratropium bromide, Tiotropium Bromide）, glucocorticosteroid agent（Preferably budesonide, fluticasone）, it is anti-
Tumour medicine, Terbutaline, fenoterol, Fu meter Te Luo, Procaterol, aminophylline, theophylline, brontyl, diprophylline,
One or more hybrid medicines including dipropionic acid beclometasone, flunisolide, Acetospan and its derivative；The inhalant
Fine drug powder is the inhalant fine drug powder particulate that 1 ~ 5 micron of size is made by directly grinding medicine, or micro- 5 by size
Rice and following being adsorbed in organic solvent containing micro-, mesoporous lactose fine powder are obtained after drug molecule.It should be noted that commercially available
The size of inhalant medicine crude product is larger, and the mode for using direct grinding flour is more conventional in rough thin mode, is led to
The inhalant fine drug powder particulate of 1 ~ 5 micron of size can be obtained by crossing mechanical lapping, in crystalline state；Preferred method is will be commercially available
Inhalant medicine crude product is dissolved in organic solvent, from preparation size at 5 microns and it is following described in it is thin containing micro-, mesoporous lactose
Powder carries out Drug absorbability as medicinal porous adsorption carrier in organic solution, due to micro-, mesoporous Drug absorbability ability compared with
Good, it is 0.5 ~ 20% to test the adsorbance measured（w/w）, and adsorbed drug molecule is distributed in so that nano particle is uniform in size
It is described to contain in micro-, mesoporous lactose fine powder, water solubility and medicine stability with lifting.
With reference to specific embodiment being inhaled in medicine to the Foradil Aerolizer formoterol fumarate ternary delivery system of the invention provided
Echo and be described further in water-soluble test.
Embodiment five
Present embodiments provide containing micro-, mesoporous lactose is thick, the preparation method of fine powder carrier, comprise the following steps：
S1：At normal temperatures and pressures, the unsetting lactose of 1kg is added into 40L ethanol solutions, stirred crystallization goes out containing micro-, mesoporous breast
Sugared fine powder；
S2：At normal temperatures and pressures, the unsetting lactose of 0.1kg is added into 40L acetone solns, stirred crystallization goes out containing micro-, mesoporous
Lactose coarse powder.
The present embodiment is measured containing micro-, mesoporous lactose is thin, the coarse powder carrier porosity change before and after Drug absorbability, figure
5 be the embodiment of the present invention five in prepare micro-, mesoporous lactose carrier coarse powder, fine powder respectively absorption drug ingedient before and after
Graph of pore diameter distribution, Fig. 5 upper lefts, top right plot show respectively fine powder absorption medicine after pore volume, aperture surface area change, Fig. 5
Lower-left, bottom-right graph show respectively coarse powder absorption medicine after pore volume, aperture surface area change.
As shown in figure 5, the lactose carrier fine powder absorption drug molecule after be mainly shown as it is mesoporous（2 ~ 50 microns）'s
Pore volume is reduced and micropore（<5 microns）Aperture surface area reduction, illustrate drug molecule be adsorbed to the carrier it is micro-, be situated between
Kong Zhong；The lactose carrier coarse powder is mainly shown as mesoporous after absorption drug molecule（2 ~ 50 microns）Pore volume reduction, say
Clear drug molecule be mainly adsorbed to the carrier it is mesoporous in.
In order to verify grain size accuracy that SEM scanning figures are provided, the present embodiment is also surveyed using Mastersizer instruments
Measure containing micro-, mesoporous lactose is thick, the Laser particle-size distribution figure of fine powder carrier.
Fig. 6 is that micro-, the mesoporous lactose prepared in the embodiment of the present invention five is thin, the laser particle size measurement of coarse powder carrier
Figure, the upper and lower figures of Fig. 6 are respectively that the lactose is thin, the particle diameter distribution of coarse powder carrier, in the range of description of the invention, i.e., carefully
Powder median diameter is 5 ~ 50 μm, and coarse powder median diameter is 50 ~ 200 μm.
Embodiment six
A kind of preparation method of the Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier is present embodiments provided,
Comprise the following steps：
S1：At normal temperatures and pressures, the unsetting lactose of 5kg is added into the mixed solution of 30L ethanol, stirred crystallization goes out containing micro-, Jie
The lactose fine powder in hole；
S2：At normal temperatures and pressures, the unsetting lactose of 0.1kg is added into 30L ethanol solutions, stirred crystallization goes out containing micro-, mesoporous
Lactose coarse powder；
S3：Mixed after the lactose fine powder and the lactose coarse powder are separately dried；The mode of the drying process is steamed for low pressure
Dry, using ethanol is evaporated off under 0.1atm air pressure, temperature is 40 degree；
S4：Directly the inhalant fine drug powder particulate of 1 ~ 5 micron of size, and and lactose is made in grinding ipratropium bromide medicine
Slightly, fine powder mixture is mixed, and obtains product.
In order to illustrate the product pattern of the Foradil Aerolizer formoterol fumarate ternary delivery system, Fig. 7 is system in the embodiment of the present invention six
The photo of the standby Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier, is white powder.
In order to illustrate the water solubility of the Foradil Aerolizer formoterol fumarate ternary delivery system, Fig. 8 is preparation in the embodiment of the present invention six
The Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier contrast dry based on conventional lactose monohydrate carrier
The water solubility rate figure of powders for inhalation ternary delivery system, it is described based on micro-, mesoporous lactose carrier that the contrast surface present invention is provided
Foradil Aerolizer formoterol fumarate ternary delivery system have preferable water solubility.
It should be noted that because the porous lactose carrier has coarse surface, and internal porous, therefore connect with the external world
Contacting surface product is larger, soluble in water；It is water-soluble poor and conventional lactose carrier is the lactose monohydrate crystal of grinding.Then as dry powder
During the carrier of inhalant ternary delivery system, the water-soluble speed of porous lactose carrier group is very fast, can reach 80% after 6 minutes
Insoluble drug release efficiency；And the water-soluble speed of conventional lactose carrier group is slower, the insoluble drug release efficiency only 50% after water-soluble 10 minutes.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changed, replacing and modification, and the essence of appropriate technical solution is departed from various embodiments of the present invention skill
The scope of art scheme, it all should cover among the claim of the present invention and the scope of specification.
Claims (6)
1. a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier, it is characterised in that：The dry powder suction
Agent ternary delivery system includes 0.5 ~ 20% inhalant fine drug powder（Median diameter is 1 ~ 5 μm）, 10 ~ 70% containing micro-, mesoporous
Lactose fine powder（Median diameter is 5 ~ 50 μm）With 10 ~ 70% containing micro-, mesoporous lactose coarse powder（Median diameter is 50 ~ 200 μ
m）；It is described containing micro-, mesoporous lactose fine powder and it is described containing micro-, mesoporous lactose coarse powder be the particle with loose structure, hole
Surface area is 10 ~ 80m2/ g, pore volume is 0.15 ~ 0.99cc/g, and containing diameter be less than 2nm micropore and it is a diameter of 2 ~
50nm's is mesoporous.
2. a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier according to claim 1, it is special
Levy and be, including following preparation process：
S1：Crystallized out in organic solution containing micro-, mesoporous lactose fine powder；
S2：Crystallized out in organic solution containing micro-, mesoporous lactose coarse powder；
S3：Mixed after the lactose fine powder and the lactose coarse powder are separately dried；
S4：Mixture is mixed with inhalant fine drug powder, product is obtained.
3. a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier according to claim 2, it is special
Levy and be：The solvent of the organic solution is preferably hypotoxicity, volatile organic solvent, using ethanol as most preferably.
4. a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier according to claim 2, it is special
Levy and be：The crystallization is crystallizes out lactose crystal under over-saturation state, when lactose concn is 15 ~ 100g/L in supersaturated solution
When the median diameter of lactose size that crystallizes out be 5 ~ 50 μm, i.e., it is described containing micro-, mesoporous lactose fine powder；When over-saturation is molten
The median diameter of the lactose size crystallized out when lactose concn is 1 ~ 15g/L in liquid is 50 ~ 200 μm, i.e., described containing is micro-, be situated between
The lactose coarse powder in hole.
5. a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier according to claim 2, it is special
Levy and be：The mode of the drying process is that drying or low pressure are evaporated, and temperature is preferably 30 ~ 50 degree, and the drying, which is used, to remove
Gas blasting's organic solvent after wet, the low pressure is evaporated to use is evaporated off organic solvent under 0.01 ~ 0.5atm air pressure.
6. a kind of Foradil Aerolizer formoterol fumarate ternary delivery system based on micro-, mesoporous lactose carrier according to claim 2, it is special
Levy and be：The inhalant fine drug powder is micro- by directly grinding the inhalant fine drug powder of obtained 1 ~ 5 micron of size of medicine
Grain, or by size at 5 microns and it is following adsorb drug molecule in organic solvent containing micro-, mesoporous lactose fine powder after obtain
.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109771397A (en) * | 2019-02-24 | 2019-05-21 | 谭淞文 | The integration of equipments and method of lung's inhaled medication are improved by lactose micropowder pre-deposition |
| CN111374995A (en) * | 2020-03-30 | 2020-07-07 | 常州道宁医药科技有限公司 | α/β mixed crystal anhydrous lactose blumea balsamifera oil-loaded respiratory system antiviral dry powder inhalant and preparation method thereof |
-
2017
- 2017-05-07 CN CN201710314829.2A patent/CN107028922A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109771397A (en) * | 2019-02-24 | 2019-05-21 | 谭淞文 | The integration of equipments and method of lung's inhaled medication are improved by lactose micropowder pre-deposition |
| CN109771397B (en) * | 2019-02-24 | 2021-09-28 | 谭淞文 | Equipment integration and method for improving pulmonary inhalation medication through lactose micropowder predeposition |
| CN111374995A (en) * | 2020-03-30 | 2020-07-07 | 常州道宁医药科技有限公司 | α/β mixed crystal anhydrous lactose blumea balsamifera oil-loaded respiratory system antiviral dry powder inhalant and preparation method thereof |
| CN111374995B (en) * | 2020-03-30 | 2021-12-21 | 常州道宁医药科技有限公司 | Alpha/beta mixed crystal anhydrous lactose blumea oil-loaded respiratory system antiviral dry powder inhalant and preparation method thereof |
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