CN107157964A - Coordinate the Foradil Aerolizer formoterol fumarate and its preparation and application of pollen shape carbohydrate carrier - Google Patents
Coordinate the Foradil Aerolizer formoterol fumarate and its preparation and application of pollen shape carbohydrate carrier Download PDFInfo
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- CN107157964A CN107157964A CN201710358207.XA CN201710358207A CN107157964A CN 107157964 A CN107157964 A CN 107157964A CN 201710358207 A CN201710358207 A CN 201710358207A CN 107157964 A CN107157964 A CN 107157964A
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- carbohydrate
- carrier
- fine powder
- formoterol fumarate
- foradil aerolizer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- 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
Abstract
The invention provides the Foradil Aerolizer formoterol fumarate and its preparation and application, the Foradil Aerolizer formoterol fumarate blending ingredients containing ternary for coordinating pollen shape carbohydrate carrier, include 0.01 2 parts of active drug composition（Gas-kinetic diameter intermediate value is preferably 0.5 5 μm）, 0 20 parts of carbohydrate coarse powder carrier（Gas-kinetic diameter intermediate value is preferably 10 100 μm）With 0 20 parts of carbohydrate fine powder carrier（Gas-kinetic diameter intermediate value is preferably 1 10 μm）, wherein carbohydrate coarse powder carrier and/or carbohydrate fine powder carrier are using the pollen shape carbohydrate carrier particulate prepared（Rough, internal porous, BET aperture surface areas are 10 60m2/g）, and the density of carbohydrate coarse powder carrier is preferably 13 times of carbohydrate fine powder support density, the particle diameter of carbohydrate coarse powder carrier is preferably 5 10 times of carbohydrate fine powder diameter of carrier；The fine powder distribution proportion of the Foradil Aerolizer formoterol fumarate（FPF）For 10 50%.By the preparation and application of the present invention, suction medicine higher drug carrier amount, respiratory tract transfer ability and stability are realized, with more preferably suction medication effect.
Description
Technical field
The present invention relates to field of medicine preparations, and in particular to a kind of Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier and its
Preparation and application.
Background technology
In recent years, due to the influence that atmosphere pollution and smoking are caused, COPD（COPD）, lung cancer and asthma suffers from
Person is more and more, Foradil Aerolizer formoterol fumarate（DPI）It is the best approach for treating these diseases.But due to Foradil Aerolizer formoterol fumarate technical threshold
Height, imitation difficulty is larger, and domestic Foradil Aerolizer formoterol fumarate market is greatly occupied by foreign brand name, and it is complete that further technology is badly in need of in the country
Kind and innovation.
Foradil Aerolizer formoterol fumarate, preparation method and use are described in the prior art（Application number CN200810151281.5）,
Inhalable drug powder containing low-density is prepared for by foaming technique, antineoplastic is improved from the preparation of bulk drug
Lung's transmission effect, but the most important technical parameter of Foradil Aerolizer formoterol fumarate also includes the design and proportioning of carrier, this method practicality
It is not enough.
Scopolamine hydrobromide dry powder inhalant for nose and preparation method are described in the prior art（Application number
CN200510033328.4）, this method is prepared for the auxiliary material carrier of drug containing composition, stability and practicality by adsorption technology
It is higher, but limited by carrier technique, this method is only used for nasal mucosa medicine administration, it is impossible to for pulmonary administration（Dry powder in the narrow sense
Inhalant field）.
In order to effectively utilize vehicle delivery medicine, prior art describes a kind of Foradil Aerolizer formoterol fumarate pharmaceutical composition and its system
Preparation Method（Application number CN201610147903.1）, after Foradil Aerolizer formoterol fumarate medicine is prepared, by medicine and the water for meeting size
Lactose carrier is mixed, and Foradil Aerolizer formoterol fumarate medicine is delivered using lactose particles, improves the ratio that Foradil Aerolizer formoterol fumarate effectively transports to lung
Rate, but because lactose monohydrate granule surface area is limited, grind, granulate anyway, all there is low drug carrier amount.
Therefore, by the preparation technology of highly effective, seek new, drug carrier amount it is big, respiratory tract transfer ability
Good, the carbohydrate carrier particulate that stability is strong, and use simple and convenient application method, come improve Foradil Aerolizer formoterol fumarate lung to
Passing on medicine releases efficiency, 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 for coordinating pollen shape carbohydrate carrier to inhale
Enter agent and its preparation and application, by producing pollen shape carbohydrate carrier, with composite medicine, micro mist realize the ternary of inhalant to
Medicine system, realizes high drug carrier amount, respiratory tract transfer ability and stability, to obtain more preferably suction medication effect.
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 of cooperation pollen shape carbohydrate carrier, it is characterised in that：It is described dry
Powders for inhalation blending ingredients containing ternary, include 0.01-2 parts of active drug composition（Gas-kinetic diameter intermediate value is preferably
0.5-5µm）, 0-20 parts of carbohydrate coarse powder carrier（Gas-kinetic diameter intermediate value is preferably 10-100 μm）With 0-20 parts of carbohydrate
Fine powder carrier（Gas-kinetic diameter intermediate value is preferably 1-10 μm）, wherein carbohydrate coarse powder carrier and/or carbohydrate fine powder carrier adopt
With the pollen shape carbohydrate carrier particulate of preparation（Rough, internal porous, BET aperture surface areas are 10-60m2/g）, and sugar
The density of class coarse powder carrier is preferably 1-3 times of carbohydrate fine powder support density, and the particle diameter of carbohydrate coarse powder carrier is preferably that carbohydrate is thin
5-10 times of powder carrier particle diameter；The fine powder distribution proportion of the Foradil Aerolizer formoterol fumarate（FPF）For 10-50%.
It should be noted that it is to improve Foradil Aerolizer formoterol fumarate to pass the side for releasing efficiency that ternary blending ingredients, which prepare Foradil Aerolizer formoterol fumarate,
Method, i.e., mix active drug composition, coarse powder carrier and fine powder carrier, and the high energy position on coarse powder carrier is occupied by fine powder carrier
Point（The strong position of absorption affinity）, the bond strength of active drug composition and coarse powder carrier is reduced, active drug composition is easier
It is released in respiratory tract.
Meanwhile, the gas-kinetic diameter intermediate value of active drug composition is preferably 0.5-5 μm, is then easily spread less than the value
Deposition, then easily hits or settles deposition in lung higher than the value, influence drug effect；The aerodynamics of carbohydrate coarse powder carrier is straight
Footpath intermediate value is preferably 10-100 μm, and less than the carrying efficiencies that the value does not reach coarse carrier then, higher than the value, then particle is too big, easily
Deposition is hit or settles in throat；During as regulation and control coarse powder carrier energy point position, the gas-kinetic diameter of carbohydrate fine powder carrier
Intermediate value is preferably 1-10 μm, and preferred gas-kinetic diameter intermediate value is 5-10 μm, and the density of carbohydrate coarse powder carrier is preferably
1-3 times of carbohydrate fine powder support density, the particle diameter of carbohydrate coarse powder carrier is preferably 5-10 times of carbohydrate fine powder diameter of carrier, other
The uniform in effect influence that scope is mixed on ternary, is in particular in the effect for not reaching and occupying the highenergy sites on coarse powder carrier；
In addition, carbohydrate fine powder carrier is alternatively arranged as adsorbing a part for the carrier, i.e. bulk drug of drug molecule in the solution, according to lung
Respiratory tract size, its gas-kinetic diameter intermediate value is preferably 1-5 μm, similarly, and being more or less than the value can be by hitting, depositing
Or diffusion causes particle to deposit, and affects the treatment.
Carbohydrate coarse powder carrier and/or carbohydrate fine powder carrier are using the pollen shape carbohydrate carrier particulate prepared, the pollen shape
Carbohydrate carrier particulate is prepared by solution recrystallization process, and size can be controlled in 1-100 μm, in the corresponding BET holes table of this scope
Area is 10-60m2/ g, rough surface, outer appearnce floweriness powder shape（Or be described as spherical flower-shape, bouquet shape, matte, ball top shape,
Flank of tooth particle etc.）, cut particle and observe that inside has loose structure.
Further, since only less than 5 μm of fine powder can just arrive at alveolar, the fine powder distribution proportion of Foradil Aerolizer formoterol fumarate（FPF）Say
Understand medicine effect, curative effect and carrying capacity that up to 50% FPF can guarantee that, less than 10% unsatisfactory curative effect.
That is, the Foradil Aerolizer formoterol fumarate for the cooperation pollen shape carbohydrate carrier that the present invention is provided, by designing and optimizing three
First blending ingredients system, improves the respiratory tract laser propagation effect of medicine, drug effect is more preferably.
Second aspect, the invention provides the preparation process of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier：It is logical
Cross solution recrystallization process and prepare pollen shape carbohydrate carrier particulate；It is adsorbed with carbohydrate fine powder carrier physical mixed or solution
Imitate drug ingedient；Uniformly mixed with carbohydrate coarse powder carrier with extra carbohydrate fine powder carrier；By above-mentioned active drug composition, carbohydrate
Slightly, fine powder carrier ternary is mixed.
In the further embodiment of the present invention, the solvent that solution recrystallization process is used is ethanol（Alcohol）, crystallization
The powder particle of precipitation（1-100µm）After filtration by blow air-dry, then sub-elected with flow separator different-shape and
The powder particle of grain size specification, obtains pollen shape carbohydrate carrier particulate.It should be noted that solution recrystallization is i.e. by amorphous state
（Preparation is separated out or is spray-dried by over-saturation moment）Glucide recrystallized in organic solvent, can select it is a variety of
The organic solvent of insoluble glucide, it is contemplated that hypotoxicity and price, preferred alcohol（Alcohol）, after stablizing（More than 15 minutes）
Separation obtains powder particle, according to《Hydrothermal crystallization》（Shi Er fears etc. write, and Science Press publishes for 2004）Record, powder is micro-
The size of grain is by factor controllings such as the concentration, temperature, mixing speed of crystallization process, and actual conditions parameter illustrates in embodiment,
And in view of suction agent carrier design, as it was previously stated, the size of carbohydrate coarse powder carrier is 10-100 μm, the chi of carbohydrate fine powder carrier
Very little is 1-10 μm.To prevent hot method is dried from causing pattern to change at high temperature, preferred blow of dried powder particulate air-dries, meanwhile,
It is different with the inertia of gas motion for the particle of different-shape and grain size specification, and flow separator is used for isolated required flower
Powder shape carbohydrate carrier particulate.
In the further embodiment of the present invention, first, 0-20 parts of carbohydrate fine powder carrier, active drug composition are used
0.01-2 parts, mixing or adsorption time are 5-60 minutes；Then, using 0-20 parts of carbohydrate coarse powder carrier, carbohydrate fine powder carrier 0-
20 parts, mixing or adsorption time are 5-60 minutes；By above-mentioned active drug composition, carbohydrate be thick, when fine powder carrier ternary is mixed
Between be 5-60 minutes.It should be noted that carbohydrate fine powder carrier can be only as the Auto-regulator of ternary hybrid system, also can conduct
The adsorbent of drug molecule, the incorporation time often walked is at 5-60 minutes, and shorter time mixing can cause undercompounding, aggregation
Effect is bad, and incorporation time is long, can cause the depolymerization of medicine and carrier, is also not necessarily to.
In the further embodiment of the present invention, described active drug composition is to include M- receptor antagonists（It is preferred that
For Tiotropium Bromide, ipratropium bromide）, broxaterol（Preferably salmeterol, salbutamol）, glucocorticosteroid agent（It is excellent
Elect budesonide, fluticasone as）, polypeptide and protein drug（It is preferred that hyperglycemic factor, insulin, calcitonin, polymyxins,
Interleukin, protease inhibitors, LSF, deoxyribonuclease, albumin）, amino acid, Fu meter Te Luo, hydroxypropyl
Theophylline, flunisolide, antineoplastic, diprophylline, beclomethasone, Terbutaline, aminophylline, theophylline, fenoterol, third
One or more hybrid medicines including Quattro, Acetospan and its derivative.It should be noted that above medicine is dry
As the material of active drug composition in powders for inhalation, active drug composition of the present invention includes but is not limited to above act
Example, above drug ingedient is mixed by physics mode with carrier, the technique that particular/special requirement is not related to, wherein, M- receptor antagonists
（Preferably Tiotropium Bromide, ipratropium bromide）, broxaterol（Preferably salmeterol, salbutamol）, cortin
Agent（Preferably budesonide, fluticasone）, amino acid, Fu meter Te Luo, brontyl, flunisolide, antineoplastic, dihydroxy
Third theophylline, beclomethasone, Terbutaline, aminophylline, theophylline, fenoterol, Procaterol, Acetospan and its derivative can lead to
The physisorphtion in organic solution is crossed directly to mix by fine powder carrier adsorption, or after physical grinding, and polypeptide and protein drug
（It is preferred that hyperglycemic factor, insulin, calcitonin, polymyxins, interleukin, protease inhibitors, LSF, deoxidation
Ribalgilase, albumin）, can only be by the way of directly being mixed after physical grinding due to organic solvent solvent can not be used.
In the further embodiment of the present invention, the carbohydrate fine powder carrier, the carbohydrate coarse powder carrier and the flower
The material of powder shape carbohydrate carrier is including but not limited to lactose, gossypose, trehalose, glucose, sucrose, antierythrite, sweet dew
One or more edible materials including alcohol, xylitol, sorbierite, dextran, cyclodextrin.It should be noted that more than
Glucide be Foradil Aerolizer formoterol fumarate in as carrier or the material of Drug absorbability carrier, recrystallized by solution of the present invention
Process prepares corresponding pollen shape carbohydrate carrier particulate, and lactose is current FDA exclusive authorities safety barrier, it is preferred to use
Lactose is as carrier, and other materials is due to being also glucide, and being also can be as pharmaceutical carrier, but without related certification
Put into effect.
The preparation method of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier provided using the present invention, is tied again by solution
Brilliant process prepares pollen shape carbohydrate carrier particulate, using the stable drug delivery ability of ternary hybrid system, prepares
Foradil Aerolizer formoterol fumarate its gas fluidity, stability, drug effect, practicality are more preferably.
The third aspect, a kind of application method of the Foradil Aerolizer formoterol fumarate for cooperation pollen shape carbohydrate carrier that the present invention is provided, its
It is characterised by：The Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier of preparation is fitted into inhalator or inhalator capsule,
In further embodiment, during using inhalator inhalation, often inhale or the unit administration metering per capsule is preferably 10-
50mg, can multiple dosing.It should be noted that according to the design of Diskus, there is bottled type inhalator and capsule-type suction
The kinds such as device, the dosage of bottled type inhalator is pressed spray amount control, and the dosage of capsule-type inhalator is by unit capsule
The amount of powder control of middle loading, unit administration metering preferably is 10-50mg, and single-dose amount is then administered very little less than 10mg,
Curative effect is too low, it is necessary to multiple dosing；Single-dose amount then often inhales amount of powder too much higher than 50mg, easily causes waste and breathes not
It is suitable.
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 be the embodiment of the present invention in cooperation pollen shape carbohydrate carrier Foradil Aerolizer formoterol fumarate preparation method flow
Figure.
Fig. 2 is the ternary blending ingredients of the Foradil Aerolizer formoterol fumarate prepared in the embodiment of the present invention two（Active drug composition, carbohydrate
Carefully, coarse powder carrier）Laser particle scanning figure.
Fig. 3 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention three
Mirror figure.
Fig. 4 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention four
Mirror figure.
Fig. 5 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention five
Mirror figure.
Fig. 6 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention six
Mirror figure.
Fig. 7 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention seven
Mirror figure.
Fig. 8 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention eight
Mirror figure.
Fig. 9 is the SEM scanning electron microscope (SEM) photographs of the pollen shape carbohydrate carrier for preparing after lancing in the embodiment of the present invention nine.
Figure 10 is micro-, the mesoporous knot of the pollen shape carbohydrate carrier for preparing after absorption drug molecule in the embodiment of the present invention ten
Structure variation diagram.
Figure 11 is the Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier in the embodiment of the present invention 11, and contrast coordinates conventional one
The Foradil Aerolizer formoterol fumarate of water and milk sugar carrier, the pellet transportation test chart in respiratory tract simulation model.
Figure 12 is the Foradil Aerolizer formoterol fumarate of the conventional lactose monohydrate carrier of cooperation in the embodiment of the present invention 12 and coordinates thick, fine powder
Drug deposition test comparison chart of the Foradil Aerolizer formoterol fumarate of pollen shape carbohydrate carrier in lung's simulation model, and coordinate a conventional water
The SEM scanning electron microscope (SEM) photographs of the Foradil Aerolizer formoterol fumarate of lactose carrier or pollen shape 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.Based on this
Embodiment in invention, the every other reality that those of ordinary skill in the art are obtained under the premise of creative work is not made
Example is applied, the scope of protection of the invention is belonged to.
Embodiment one
Present embodiments provide a kind of Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier, blending ingredients containing ternary, including 0.01-
2 parts of active drug composition（Gas-kinetic diameter intermediate value is preferably 0.5-5 μm）, 0-20 parts of carbohydrate coarse powder carrier（Gas
Kinetic diameter intermediate value is preferably 10-100 μm）With 0-20 parts of carbohydrate fine powder carrier（Gas-kinetic diameter intermediate value is preferably
1-10µm）, wherein carbohydrate coarse powder carrier and/or carbohydrate fine powder carrier are using the pollen shape carbohydrate carrier particulate prepared（Particle table
Face is coarse, internal porous, and BET aperture surface areas are 10-60m2/g）, and the density of carbohydrate coarse powder carrier is preferably that carbohydrate fine powder is carried
1-3 times of volume density, the particle diameter of carbohydrate coarse powder carrier is preferably 5-10 times of carbohydrate fine powder diameter of carrier；The Foradil Aerolizer formoterol fumarate
Fine powder distribution proportion（FPF）For 10-50%.
For the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier of the present invention, the present invention devises the Foradil Aerolizer formoterol fumarate
Preparation method.
Fig. 1 be the embodiment of the present invention in cooperation pollen shape carbohydrate carrier Foradil Aerolizer formoterol fumarate preparation method flow
Figure, as shown in figure 1, the preparation method of the Foradil Aerolizer formoterol fumarate for the cooperation pollen shape carbohydrate carrier that the present invention is provided is：
S1：Pollen shape carbohydrate carrier particulate is prepared by solution recrystallization process；
S2：Effective drug ingedient is adsorbed with carbohydrate fine powder carrier physical mixed or solution；
S3：Uniformly mixed with carbohydrate coarse powder carrier with extra carbohydrate fine powder carrier；
S4：By above-mentioned active drug composition, carbohydrate be thick, fine powder carrier ternary is mixed.
The Foradil Aerolizer formoterol fumarate carrier of the cooperation pollen shape carbohydrate carrier provided with reference to specific embodiment the present invention
Preparation method is described further.
Embodiment two
A kind of preparation method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
S1：Unsetting lactose particles prepared by 50 grams of spray drying are mixed with 500mL ethanol, and stirring is filtered after 30 minutes and removed
Supernatant, air-dried precipitation particle by flow separator sub-elect flower-shape carbohydrate fine powder carrier that median particle diameter is 7 microns and
Median particle diameter is 20 microns of flower-shape carbohydrate coarse powder carrier；
S2：Commercially available budesonide micro mist is subjected to smooth grinding, the active drug composition that median diameter is 1.5 microns is obtained, presses
Ratio is by 2 parts of carbohydrate fine powder carriers and 0.05 part of active drug composition physical mixed 5 minutes；
S3：Extra, in proportion by 5 parts of carbohydrate fine powder carriers and 13 parts of 5 points of carbohydrate fine powder carrier physical mixeds
Clock；
S4：By above-mentioned active drug composition, carbohydrate be thick, fine powder carrier physical mixed, incorporation time is 5 minutes.
To verify the accuracy of preparation method, product is test with laser particle size measurement instrument, and Fig. 2 is implemented for the present invention
The ternary blending ingredients of the Foradil Aerolizer formoterol fumarate prepared in example two（Active drug composition, carbohydrate are thin, coarse powder carrier）Laser particle
Scanning figure, as shown in Fig. 2 above-mentioned active drug composition, carbohydrate are thick, to obtain particle size be in normal distribution substantially to fine powder carrier, has
The median diameter for imitating drug ingedient is 1.5 microns, and the median diameter of flower-shape carbohydrate fine powder carrier is 7 microns, flower-shape carbohydrate coarse powder
The median diameter of carrier is 20 microns, meets the requirement of ternary blending ingredients Foradil Aerolizer formoterol fumarate proposed by the present invention.It should illustrate
, the size of ternary blending ingredients influences larger to drug effect, after active drug composition, coarse powder carrier and the mixing of fine powder carrier,
Fine powder carrier is by occupying the highenergy sites on coarse powder carrier（The strong position of absorption affinity）, reduction active drug composition and coarse powder are carried
The bond strength of body, makes active drug composition be easier to be released in respiratory tract.
Embodiment three
A kind of preparation method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
S1：10 grams of supersaturated solutions are separated out to the unsetting lactose particles prepared to mix with 100mL ethanol, mistake after stirring 15 minutes
Filter off and remove supernatant, air-dried precipitation particle sub-elects the flower-shape carbohydrate fine powder that median particle diameter is 8 microns by flow separator
Carrier and the flower-shape carbohydrate coarse powder carrier that median particle diameter is 30 microns；
S2：Commercially available Tiotropium Bromide micro mist is subjected to smooth grinding, the active drug composition that median diameter is 2 microns is obtained；
S3：In proportion by 5 parts of carbohydrate fine powder carriers and 15 parts of carbohydrate fine powder carrier physical mixeds 60 minutes；
S4：By above-mentioned active drug composition, carbohydrate be thick, fine powder carrier physical mixed, incorporation time is 60 minutes.
Example IV
A kind of preparation method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
S1：100 grams of supersaturated solutions are separated out to the unsetting lactose particles prepared to mix with 1L alcohol, stirring is filtered after 30 minutes
Supernatant is removed, air-dried precipitation particle sub-elects the flower-shape carbohydrate fine powder that median particle diameter is 2 microns by flow separator and carried
Body and the flower-shape carbohydrate coarse powder carrier that median particle diameter is 5 microns；
S2：Tiotropium Bromide is dissolved in ethanol, 0.1M Tiotropium Bromide ethanol solution is mixed with the flower-shape carbohydrate fine powder carrier
Absorption 30 minutes, filtering removes supernatant, air-dries precipitation particle；
S3/S4：In proportion by 19 parts of carbohydrate fine powder carriers and 1 part of carbohydrate fine powder carrier physical mixed 5 minutes.
Embodiment five
A kind of preparation method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
S1：Unsetting antierythrite particulate prepared by 10 grams of spray drying is mixed with 100mL methanol, and stirring is filtered after 30 minutes
Supernatant is removed, air-dried precipitation particle sub-elects the flower-shape carbohydrate fine powder that median particle diameter is 5 microns by flow separator and carried
Body and the flower-shape carbohydrate coarse powder carrier that median particle diameter is 100 microns；
S2：Commercially available brontyl is subjected to smooth grinding, the active drug composition that median diameter is 0.5 micron is obtained, in proportion
By 0.01 part of active drug composition and 20 parts of carbohydrate fine powder carrier physical mixeds 15 minutes；
S3/S4：This Foradil Aerolizer formoterol fumarate does not use carbohydrate coarse powder carrier.
Embodiment six
A kind of preparation method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
S1：Unsetting gossypose particulate prepared by 50 grams of spray drying is mixed with 500mL acetone, and stirring is crossed after 5 minutes and filtered off
Except supernatant, air-dried precipitation particle sub-elects the flower-shape carbohydrate fine powder carrier that median particle diameter is 1 micron by flow separator
With the flower-shape carbohydrate coarse powder carrier that median particle diameter is 20 microns；
S2：Commercially available hyperglycemic factor micro mist is subjected to smooth grinding, the active drug composition that median diameter is 1 micron is obtained, presses
Ratio is by 1 part of carbohydrate fine powder carrier and 2 parts of active drug composition physical mixeds 10 minutes；
S3：Extra, in proportion by 2 parts of carbohydrate fine powder carriers and 15 parts of 20 points of carbohydrate fine powder carrier physical mixeds
Clock；
S4：By above-mentioned active drug composition, carbohydrate be thick, fine powder carrier physical mixed, incorporation time is 15 minutes.
Embodiment seven
A kind of preparation method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
S1：Unsetting glucose particulate prepared by 30 grams of spray drying is mixed with 500mL ethyl acetate, mistake after stirring 10 minutes
Filter off and remove supernatant, air-dried precipitation particle sub-elects the flower-shape carbohydrate fine powder that median particle diameter is 10 microns by flow separator
Carrier and the flower-shape carbohydrate coarse powder carrier that median particle diameter is 15 microns；
S2：Commercially available salmeterol micro mist is subjected to smooth grinding, the active drug composition that median diameter is 0.5 micron is obtained, presses
Ratio is by 5 parts of carbohydrate fine powder carriers and 1 part of active drug composition physical mixed 5 minutes；
S3：Extra, in proportion by 4 parts of carbohydrate fine powder carriers and 10 parts of 30 points of carbohydrate fine powder carrier physical mixeds
Clock；
S4：By above-mentioned active drug composition, carbohydrate be thick, fine powder carrier physical mixed, incorporation time is 60 minutes.
Embodiment eight
A kind of preparation method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
S1：Unsetting mannitol particulate prepared by 30 grams of spray drying is mixed with 300mL ethanol, and stirring is crossed after 15 minutes and filtered off
Except supernatant, air-dried precipitation particle sub-elects the flower-shape carbohydrate fine powder carrier that median particle diameter is 2 microns by flow separator
With the flower-shape carbohydrate coarse powder carrier that median particle diameter is 10 microns；
S2：Commercially available flunisolide micro mist is subjected to smooth grinding, the active drug composition that median diameter is 1 micron is obtained, by than
Example is by 2 parts of carbohydrate fine powder carriers and 0.5 part of active drug composition physical mixed 10 minutes；
S3：Extra, in proportion by 7.5 parts of carbohydrate fine powder carriers and 10 parts of 10 points of carbohydrate fine powder carrier physical mixeds
Clock；
S4：By above-mentioned active drug composition, carbohydrate be thick, fine powder carrier physical mixed, incorporation time is 10 minutes.
In order to observe the microscopic appearance of obtained Foradil Aerolizer formoterol fumarate in embodiment, by above-described embodiment three, example IV, reality
The Foradil Aerolizer formoterol fumarate for the cooperation pollen shape carbohydrate carrier that example five, embodiment six, embodiment seven and embodiment eight are prepared is applied, is entered
The micro- scanning of Electronic Speculum of having gone（SEM）Pattern determine.
Fig. 3 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention three
Mirror figure, as shown in figure 3, the microscopic dimensions of active drug composition are about 2 microns, the microscopic dimensions of carbohydrate fine powder carrier are about 8 micro-
Rice, the microscopic dimensions of carbohydrate coarse powder carrier are about 30 microns, and ternary blending ingredients are more uniformly mixed；And Foradil Aerolizer formoterol fumarate is thin
Powder distribution proportion is 30%.
Fig. 4 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention four
Mirror figure, as shown in figure 4, not observing active drug composition（Carbohydrate fine powder carrier particles are adsorbed to suffer）, carbohydrate fine powder load
The microscopic dimensions of body are about 2 microns, and the microscopic dimensions of carbohydrate coarse powder carrier are about 5 microns, and ternary blending ingredients are more uniformly mixed
Close；And the fine powder distribution proportion of Foradil Aerolizer formoterol fumarate is 50%.
Fig. 5 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention five
Mirror figure, as shown in figure 5, the microscopic dimensions of active drug composition are about 0.5 micron, the microscopic dimensions of carbohydrate fine powder carrier are about 2
Micron, the microscopic dimensions of carbohydrate coarse powder carrier are about 100 microns, and ternary blending ingredients are more uniformly mixed；Due to embodiment five
Coarse powder carrier is not used, therefore the fine powder distribution proportion of Foradil Aerolizer formoterol fumarate is 100%.
Fig. 6 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention six
Mirror figure, as shown in fig. 6, the microscopic dimensions of active drug composition are about 1 micron, the microscopic dimensions of carbohydrate fine powder carrier are about 1 micro-
Rice, the microscopic dimensions of carbohydrate coarse powder carrier are about 20 microns, and ternary blending ingredients are more uniformly mixed；And Foradil Aerolizer formoterol fumarate is thin
Powder distribution proportion is 15%.
Fig. 7 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention seven
Mirror figure, as shown in fig. 7, due to solvent effect, carbohydrate carrier can not form pollen shape, but form porous strip, effective medicine
The microscopic dimensions of thing composition are about 0.5 micron, and the size of carbohydrate carrier is about 10-15 microns, the adjoining dimensions of thick, thin carrier；
And the fine powder distribution proportion of Foradil Aerolizer formoterol fumarate is 10%.
Fig. 8 is electric for the SEM scannings of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier prepared in the embodiment of the present invention eight
Mirror figure, as shown in figure 8, the microscopic dimensions of active drug composition are about 1 micron, the microscopic dimensions of carbohydrate fine powder carrier are about 2 micro-
Rice, the microscopic dimensions of carbohydrate coarse powder carrier are about 10 microns, and ternary blending ingredients are more uniformly mixed；And Foradil Aerolizer formoterol fumarate is thin
Powder distribution proportion is 40%.
Determined by SEM, be in pollen shape small porous particle the form of the carbohydrate microparticles carrier, diameter is in 1-100 more
Between micron, pattern is by saccharide material and solvent effect.It should be noted that the gas-kinetic diameter intermediate value of active drug composition
Preferably 0.5-5 μm, less than the value then easy diffusional deposition, then easily deposition, equal shadow are hit or settle in lung higher than the value
Ring drug effect；The gas-kinetic diameter intermediate value of carbohydrate coarse powder carrier is preferably 10-100 μm, does not reach coarse carrier then less than the value
Carrying efficiencies, higher than the value, then particle is too big, easily throat hit or settle deposition；It is used as regulation and control coarse powder carrier energy point
During position, the gas-kinetic diameter intermediate value of carbohydrate fine powder carrier is preferably 1-10 μm, preferred gas-kinetic diameter intermediate value
For 5-10 μm, the density of carbohydrate coarse powder carrier is preferably 1-3 times of carbohydrate fine powder support density, and the particle diameter of carbohydrate coarse powder carrier is excellent
Elect carbohydrate fine powder diameter of carrier as 5-10 times, the uniform in effect influence that other scopes are mixed on ternary, is in particular in up to not
To the effect for occupying the highenergy sites on coarse powder carrier；In addition, carbohydrate fine powder carrier is alternatively arranged as adsorbing medicine point in the solution
A part for the carrier, i.e. bulk drug of son, according to lung airways size, its gas-kinetic diameter intermediate value is preferably 1-5 μm,
Similarly, be more or less than the value can cause particle to deposit by hitting, depositing or spread, and affect the treatment.Due to only less than 5 μm
Fine powder can just arrive at alveolar, the fine powder distribution proportion of Foradil Aerolizer formoterol fumarate（FPF）Medicine effect is illustrated, up to 50% FPF can be protected
The curative effect and carrying capacity demonstrate,proved, less than 10% unsatisfactory curative effect.
Embodiment nine
A kind of method for preparing and observing flower-shape carrier granular internal pore structure is present embodiments provided, is comprised the following steps：Will
Unsetting lactose particles prepared by 50 grams of supersaturated solution methods are mixed with 600mL ethanol, and stirring is filtered after 8 minutes and removes supernatant
Liquid, air-dried precipitation particle sub-elects the flower-shape carbohydrate carrier that median particle diameter is 10 microns by flow separator；It is burnt with copolymerization
Ion is cut after the carrier granular, is observed in the secure execution mode (sem.
Fig. 9 is the SEM scanning electron microscope (SEM) photographs of the pollen shape carbohydrate carrier for preparing after lancing in the embodiment of the present invention nine, is such as schemed
Shown in 9, mesoporous and macropore, which can be observed directly, to be obtained, wherein less hole includes the mesoporous of 18nm and 32nm, demonstrates the flower
The porous of powder shape carbohydrate carrier.
Embodiment ten
A kind of method for preparing and measuring flower-shape carrier granular absorption drug molecule front and rear gaps structure change is present embodiments provided,
Comprise the following steps：Unsetting mannitol particulate prepared by 50 grams of spray drying is mixed with 800mL ethanol, after stirring 15 minutes
Filtering removes supernatant, and it is thin for 3 microns of flower-shape carbohydrate that air-dried precipitation particle sub-elects median particle diameter by flow separator
Powder carrier；Then, commercially available salbutamol is dissolved in acetone, the solution carried out with 10 parts of flower-shape carbohydrate fine powder carriers 60 minutes is inhaled
It is attached, air-dried after centrifugation；The flower-shape carbohydrate fine powder carrier adsorbed with unadsorbed salbutamol is measured with gas absorption instrument, obtained
Structure change of portalling characterize data.
Figure 10 is micro-, the mesoporous knot of the pollen shape carbohydrate carrier for preparing after absorption drug molecule in the embodiment of the present invention ten
Structure variation diagram, as shown in Figure 10, after absorption drug molecule, the micropore and mesoporous number of pollen shape carbohydrate carrier have declined, and
BET aperture surface areas are from 60m2/ g have decreased to 10m2/ g, illustrates that drug molecule is attracted to nano-pore structure and suffered.
What deserves to be explained is, carbohydrate coarse powder carrier and/or carbohydrate the fine powder carrier is carried using the pollen shape carbohydrate prepared
Body particulate, the pollen shape carbohydrate carrier particulate is prepared by solution recrystallization process, and size can be controlled in 1-100 μm, herein
The corresponding BET aperture surface areas of scope are 10-60m2/ g, rough surface, outer appearnce floweriness powder shape（Or be described as flower-shape, bouquet shape,
Matte is spherical, ball top shape, flank of tooth particle etc.）, cut particle and observe that inside has loose structure.
Embodiment describe solution recrystallization process in, it is preferred to use solvent be ethanol（Alcohol）, what crystallization was separated out
Powder particle size is 1-100 μm, is air-dried after filtration by blowing, then sub-elects different-shape and grain with flow separator
The powder particle of footpath specification, obtains pollen shape carbohydrate carrier particulate.It should be noted that solution recrystallization is i.e. by amorphous state
（Preparation is separated out or is spray-dried by over-saturation moment）Glucide recrystallized in organic solvent, can select it is a variety of
The organic solvent of insoluble glucide, it is contemplated that hypotoxicity and price, preferred alcohol（Alcohol）, after stablizing（More than 15 minutes）
Separation obtains powder particle, according to《Hydrothermal crystallization》（Shi Er fears etc. write, and Science Press publishes for 2004）Record, powder is micro-
The size of grain is by factor controllings such as the concentration, temperature, mixing speed of crystallization process, and actual conditions parameter illustrates in embodiment,
And in view of suction agent carrier design, as it was previously stated, the size of carbohydrate coarse powder carrier is 10-100 μm, the chi of carbohydrate fine powder carrier
Very little is 1-10 μm.To prevent overheat from causing pattern to change, preferred blow of dried powder particulate air-dries, meanwhile, different-shape and grain
It is different with the inertia of gas motion for the particle of footpath specification, and flow separator is used for isolated required pollen shape carbohydrate carrier
Particulate.
In the ternary mixed process that embodiment is described, first, 0-20 parts of carbohydrate fine powder carrier, active drug composition are used
0.01-2 parts, mixing or adsorption time are 5-60 minutes；Then, using 0-20 parts of carbohydrate coarse powder carrier, carbohydrate fine powder carrier 0-
20 parts, mixing or adsorption time are 5-60 minutes；By above-mentioned active drug composition, carbohydrate be thick, when fine powder carrier ternary is mixed
Between be 5-60 minutes.It should be noted that carbohydrate fine powder carrier can be only as the Auto-regulator of ternary hybrid system, also can conduct
The adsorbent of drug molecule, the incorporation time often walked is at 5-60 minutes, and shorter time mixing can cause undercompounding, aggregation
Effect is bad, and incorporation time is long, can cause the depolymerization of medicine and carrier, is also not necessarily to.
For the medicine and carrier used in embodiment：On the one hand, described active drug composition is that to include M- acceptors short of money
Anti-agent（Preferably Tiotropium Bromide, ipratropium bromide）, broxaterol（Preferably salmeterol, salbutamol）, cortex
Hormone preparation（Preferably budesonide, fluticasone）, polypeptide and protein drug（It is preferred that hyperglycemic factor, insulin, calcitonin,
Polymyxins, interleukin, protease inhibitors, LSF, deoxyribonuclease, albumin）, amino acid, good fortune rice
Special sieve, brontyl, flunisolide, antineoplastic, diprophylline, beclomethasone, Terbutaline, aminophylline, theophylline, phenol
Third breathes heavily one or more hybrid medicines including peaceful, Procaterol, Acetospan and its derivative.It should be noted that more than
Medicine is the material as active drug composition in Foradil Aerolizer formoterol fumarate, and active drug composition of the present invention includes but do not limited
Illustrated more than, above drug ingedient mixed by physics mode with carrier, the technique that particular/special requirement is not related to, wherein, M- by
Body antagonist（Preferably Tiotropium Bromide, ipratropium bromide）, broxaterol（Preferably salmeterol, salbutamol）、
Glucocorticosteroid agent（Preferably budesonide, fluticasone）, it is amino acid, Fu meter Te Luo, brontyl, flunisolide, antitumor
Medicine, diprophylline, beclomethasone, Terbutaline, aminophylline, theophylline, fenoterol, Procaterol, Acetospan and its
Derivative can by organic solution physisorphtion directly mixed by fine powder carrier adsorption, or after physical grinding, and polypeptide
And protein drug（It is preferred that hyperglycemic factor, insulin, calcitonin, polymyxins, interleukin, protease inhibitors, cytositimulation
The factor, deoxyribonuclease, albumin）Due to organic solvent solvent can not be used, directly mixed after physical grinding can only being used
Mode.On the other hand, the material of the carbohydrate fine powder carrier, the carbohydrate coarse powder carrier and the pollen shape carbohydrate carrier is
Including but not limited to lactose, gossypose, trehalose, glucose, sucrose, antierythrite, mannitol, xylitol, sorbierite, dextrorotation
One or more edible materials including glucosides, cyclodextrin.It should be noted that above glucide is in Foradil Aerolizer formoterol fumarate
As carrier or the material of Drug absorbability carrier, corresponding pollen is prepared by solution recrystallization process of the present invention
Shape carbohydrate carrier particulate, and lactose is current FDA exclusive authorities safety barrier, it is preferred to use lactose is used as carrier, other materials
It is also that can be put into effect as pharmaceutical carrier but without related certification due to being also glucide.
To sum up, the preparation method of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier provided using embodiment, by molten
Liquid recrystallization process prepares pollen shape carbohydrate carrier particulate, using the stable drug delivery ability of ternary hybrid system, prepares
Obtained Foradil Aerolizer formoterol fumarate its gas fluidity, stability, drug effect, practicality are more preferably.
The use of the Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier provided with reference to specific embodiment the present invention
Method is described further.
Embodiment 11
A kind of application method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
The Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is fitted into inhalator, in further embodiment, inhaled using inhalator
When entering to be administered, the unit administration metering often inhaled is 10mg, is administered 3 times.
For the effect for the Foradil Aerolizer formoterol fumarate for verifying the cooperation pollen shape carbohydrate carrier that the embodiment of medication is provided, Figure 11
To coordinate the Foradil Aerolizer formoterol fumarate of pollen shape carbohydrate carrier in the embodiment of the present invention 11, contrast coordinates conventional lactose monohydrate carrier
Foradil Aerolizer formoterol fumarate, the pellet transportation test chart in respiratory tract simulation model.
As shown in figure 11, under 30L/min suction velocity, coordinate the Foradil Aerolizer formoterol fumarate of pollen shape carbohydrate carrier more can be with
Gas by bend, at this moment due to pollen shape appearance and big contact area make its close to respiratory tract wall when, by bigger
Crosswind pressure, so as to change direct of travel；And then inertia is larger for the Foradil Aerolizer formoterol fumarate of the conventional lactose monohydrate carrier of cooperation, easily
Directly it is flushed on respiratory tract wall, causes to hit deposition, so as to influence drug effect.
Embodiment 12
A kind of application method for the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier is present embodiments provided, is comprised the following steps：
The Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier of preparation is fitted into inhalator capsule, in further embodiment,
During using inhalator inhalation, the unit administration metering per capsule is 50mg, is administered once.
To verify the Foradil Aerolizer formoterol fumarate for coordinating pollen shape carbohydrate carrier that the embodiment of the present embodiment medication is provided
Effect, Figure 12 be the Foradil Aerolizer formoterol fumarate of the conventional lactose monohydrate carrier of cooperation prepared in the embodiment of the present invention 12 and coordinate it is thick,
Drug deposition test comparison chart of the Foradil Aerolizer formoterol fumarate of fine powder pollen shape carbohydrate carrier in lung's simulation model, and coordinate conventional
The SEM scanning electron microscope (SEM) photographs of the Foradil Aerolizer formoterol fumarate of lactose monohydrate carrier or pollen shape carrier.
As shown in figure 12, coordinate fine powder pollen shape carbohydrate carrier Foradil Aerolizer formoterol fumarate can deeper into entrance lung, reach
Alveolar, next to that coordinating the Foradil Aerolizer formoterol fumarate of coarse powder pollen shape carbohydrate carrier, and coordinates the dry powder of conventional lactose monohydrate carrier to inhale
Enter agent due to the possibility with higher shock, sedimentation deposition, so as to be relatively inaccessible to deep lung；In addition, SEM ESEMs
Figure compared for coordinating the pattern of the Foradil Aerolizer formoterol fumarate of conventional lactose monohydrate carrier or flower-shape carrier, meet the outer of pollen shape of the present invention
Looks are set.
It should also be noted that, according to the design of Diskus, there is the product such as bottled type inhalator and capsule-type inhalator
Kind, the dosage of bottled type inhalator is pressed spray amount control, and the dosage of capsule-type inhalator is loaded by unit capsule
Amount of powder control, unit administration metering preferably is 10-50mg, and single-dose amount is then administered very little less than 10mg, and curative effect is too
It is low, it is necessary to multiple dosing；Single-dose amount then often inhales amount of powder too much higher than 50mg, easily causes waste and breathing is uncomfortable.
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 (8)
1. coordinate the Foradil Aerolizer formoterol fumarate of pollen shape carbohydrate carrier, it is characterised in that：The Foradil Aerolizer formoterol fumarate blending ingredients containing ternary,
Including 0.01-2 parts of active drug composition（Gas-kinetic diameter intermediate value is preferably 0.5-5 μm）, 0-20 parts of carbohydrate coarse powder
Carrier（Gas-kinetic diameter intermediate value is preferably 10-100 μm）With 0-20 parts of carbohydrate fine powder carrier（In gas-kinetic diameter
Value is preferably 1-10 μm）, wherein carbohydrate coarse powder carrier and/or carbohydrate fine powder carrier are using the pollen shape carbohydrate carrier particulate prepared
（Rough, internal porous, BET aperture surface areas are 10-60m2/g）, and the density of carbohydrate coarse powder carrier is preferably carbohydrate
1-3 times of fine powder support density, the particle diameter of carbohydrate coarse powder carrier is preferably 5-10 times of carbohydrate fine powder diameter of carrier；The dry powder
The fine powder distribution proportion of inhalant（FPF）For 10-50%.
2. the Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier according to claim 1, it is characterised in that including following system
Standby step：
S1：Pollen shape carbohydrate carrier particulate is prepared by solution recrystallization process；
S2：Effective drug ingedient is adsorbed with carbohydrate fine powder carrier physical mixed or solution；
S3：Uniformly mixed with carbohydrate coarse powder carrier with extra carbohydrate fine powder carrier；
S4：By above-mentioned active drug composition, carbohydrate be thick, fine powder carrier ternary is mixed.
3. the Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier according to claim 2, it is characterised in that：In S1 steps
In, the solvent that solution recrystallization process is used is ethanol（Alcohol）, crystallize the powder particle separated out（1-100µm）Lead to after filtration
Cross air blowing to air-dry, different-shape and the powder particle of grain size specification are then sub-elected with flow separator, pollen shape carbohydrate is obtained
Carrier particles.
4. the Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier according to claim 2, it is characterised in that：In S2 steps
In, the usage amount of carbohydrate fine powder carrier is 0-20 parts, and the usage amount of active drug composition is 0.01-2 parts, mixing or adsorption time
For 5-60 minutes；In S3 steps, the usage amount of carbohydrate coarse powder carrier is 0-20 parts, and the usage amount of carbohydrate fine powder carrier is 0-20
Part, mixing or adsorption time are 5-60 minutes；In S4 steps, by above-mentioned active drug composition, carbohydrate be thick, fine powder carrier ternary
The time of mixing is 5-60 minutes.
5. the Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier according to claim 1 or 2, it is characterised in that：Described
Active drug composition is to include M- receptor antagonists（Preferably Tiotropium Bromide, ipratropium bromide）, broxaterol（It is excellent
Elect salmeterol, salbutamol as）, glucocorticosteroid agent（Preferably budesonide, fluticasone）, polypeptide and protein drug（It is excellent
Select hyperglycemic factor, insulin, calcitonin, polymyxins, interleukin, protease inhibitors, LSF, deoxyribose
Nuclease, albumin）, amino acid, Fu meter Te Luo, brontyl, flunisolide, antineoplastic, diprophylline, times chlorine rice
One or more including pine, Terbutaline, aminophylline, theophylline, fenoterol, Procaterol, Acetospan and its derivative
Hybrid medicine.
6. the Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier according to claim 1 or 2, it is characterised in that：The sugar
The material of class fine powder carrier, the carbohydrate coarse powder carrier and the pollen shape carbohydrate carrier is to include lactose, gossypose, marine alga
One or more including sugar, glucose, sucrose, antierythrite, mannitol, xylitol, sorbierite, dextran, cyclodextrin
Edible material.
7. the application method of the Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier according to claim 1, it is characterised in that：
The Foradil Aerolizer formoterol fumarate of the cooperation pollen shape carbohydrate carrier of preparation is fitted into inhalator or inhalator capsule.
8. the application method of the Foradil Aerolizer formoterol fumarate of cooperation pollen shape carbohydrate carrier according to claim 7, it is characterised in that：
During using inhalator inhalation, often inhale or the unit administration metering per capsule is preferably 10-50mg, can multiple dosing.
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| CN113679690A (en) * | 2021-09-06 | 2021-11-23 | 复旦大学附属中山医院 | Theophylline dry powder preparation and preparation method and application thereof |
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