CN107569474A - A kind of preparation method of carrier used in the pharmaceutical composition of inhalable dry powder form - Google Patents
A kind of preparation method of carrier used in the pharmaceutical composition of inhalable dry powder form Download PDFInfo
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention belongs to pharmaceutical technology field, it is related to a kind of preparation method of the carrier used in pharmaceutical composition of inhalable dry powder form.The preparation method of the present invention; by the way that magnesium stearate and lactose granule are carried out being mixed with carrier in ball mill; resulting vehicle is not in the broken phenomenon of particulate abrasive; with directly using magnesium stearate compared with the carrier obtained after lactose granule mixing; and compared with the carrier with being prepared by the hybrid granulator of high shear force; effective deposition of the medicine in lung of inhalation powder spray can not only be significantly improved, but also the degraded of some drugses can be substantially reduced, improves the stability of medicine.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of carrier used in pharmaceutical composition of inhalable dry powder form
Preparation method, in particular to a kind of preparation method of the carrier used in inhalation powder spray.
Background technology
Inhalation powder spray is also known as Foradil Aerolizer formoterol fumarate (DPI), is the comprehensive powder technology on the basis of metered dose inhalation aerosol
Knowledge and the novel form that grows up, it is after micronized medicine individually or with carrier mix, through special administration dress
Put, it is medicinal atomized into respiratory tract is entered after aerosol by the active inspiration of patient, play one kind for locally or systemically acting on to
Medicine body system.
The physiological structure of lung determines that the size into the drug particle of lung needs strict control, according to 2015 editions
《Chinese Pharmacopoeia》" raw material drug particle size size should be generally controlled 10 in suction preparation for the requirement of four suction preparations of general rules 0111
Below μm, wherein most of should be below 5 μm ", therefore in the formulation study of inhalation powder spray, the micronizing of medicine and medicine
Thing particle size range should be strict with.After drug micronization, there is higher surface free energy, particle easily assemble it is agglomerating,
Adhesiveness is big, poor fluidity, can not effective inhalation.Therefore in the Formulation of inhalation powder spray, some loads are commonly incorporated into
Body, diluent can be used as, adsorb drug microparticles, improve the dry jet mixing pile of dry powder.The most frequently used carrier is lactose, mannitol etc.
Carbohydrate, wherein lactose are the only approved Foradil Aerolizer formoterol fumarate carriers used of FDA.When the patient inhales, air turbulence produces
Raw shearing force is detached from the carrier medicine, and the particulate less than 5 μm can enter people's lower respiratory tract, and bulky grain carrier or medicine then fall
In oral cavity and throat.
Lactose is combined by Van der Waals force, electrostatic adsorption force, capillary force with drug microparticles, and these active forces directly affect
Shadow is produced to medicine and the difficulty or ease of the desorption ability of lactose, and then to active component deposition distribution of the medicine in respiratory tract
Ring, select suitable carrier, make medicine be easier in atomization process with carrier desorption, then can effectively improve medicine in intrapulmonary
Effective deposition, the step for be very important, crucial.In addition, stability is most important for inhalation powder spray,
It is one of those skilled in the art's primary goal to develop the good inhalation powder spray of stability.
CN102858326A, which discloses magnesium stearate, can change the surface nature of carrier granular, using based on friction behavior
High shear force hybrid granulator magnesium stearate be subjected to coating to lactose granule prepare carrier.The key of the present invention is to use
Ball mill prepares carrier, is beneficial in terms of effective deposition of the medicine in intrapulmonary is improved and in terms of improving medicine stability
, significantly improve the performance of pharmaceutical preparation.
The content of the invention
On the one hand, the invention provides a kind of preparation side of the carrier used in pharmaceutical composition of inhalable dry powder form
Method, methods described include：Magnesium stearate is mixed in ball mill with lactose granule.
The wherein d (v0.5) of lactose granule is 5-800 microns, preferably 20-500 microns, more preferably 30-200 microns,
Most preferably 35-150 microns；In some embodiments of the present invention, the d (v0.5) of lactose granule is 50-100 microns.
Wherein the d (v0.9) of lactose granule is 10-1000 microns, preferably in 30-600 microns, more preferably 80-300
Micron, most preferably 100-180 microns；In some embodiments of the present invention, the d (v0.9) of lactose granule is 120-160
Micron.
In some specific embodiments of the present invention, the size distribution of lactose granule is as follows：D (v0.1) is that 5-15 is micro-
Rice, d (v0.5) is 50-100 microns, and d (v0.9) is 120-160 microns.
Wherein described lactose is selected from alpha-lactose or beta lactose or its solvate, preferably alpha-lactose or its solvate,
Most preferably alpha-lactose monohydrate.
Wherein the weight of magnesium stearate is the 0.05%-1.5%, preferably 0.1-1.0% of carrier；In some of the present invention
In embodiment, the weight of magnesium stearate can be 0.1-0.5%, 0.1-0.3%, 0.3-1.0%, 0.3-0.5% of carrier
Or 0.5-1.0%；In some specific embodiments of the present invention, the weight of the magnesium stearate for carrier 0.1%,
0.3%th, 0.5% or 1%.
Wherein the rotation rotating speed of the container of ball mill is 15-960rpm, preferably 60-600rpm, more preferably 120-
530rpm, most preferably 240-500rpm；In some specific embodiments of the present invention, the rotation rotating speed of the container of ball mill
For 480rpm.
Wherein ball mill can select suitable abrasive media as needed, the material of the abrasive media include metal and
Nonmetallic, preferably nonmetallic, the shape of abrasive media can be spherical or spherical, in some specific implementations of the present invention
In scheme, abrasive media is agate ball.
Wherein abrasive media can select suitably sized as needed, such as when abrasive media is spherical, grinding medium
The diameter of matter is not more than 2cm, preferably no greater than 1cm.
Preferably, the ball mill is planetary ball mill；In some specific embodiments of the present invention, planetary ball
Grinding machine is QM-3SP4 planetary ball mills or QM-1SP4 planetary ball mills.
Wherein the rotation rotating speed of the container of planetary ball mill is 30-600rpm, preferably 120-530rpm, is more preferably
240-500rpm, in some specific embodiments of the present invention, the rotation rotating speed of planetary ball mill is 480rpm.
Wherein the revolution rotating speed of the container of planetary ball mill is 15-240rpm, preferably 60-265rpm, is more preferably
120-250rpm, in some specific embodiments of the present invention, the revolution rotating speed of planetary ball mill is 240rpm.
In other specific embodiments of the present invention, the rotating ratio of rotation and the revolution of planetary ball mill is 2：1.
Wherein incorporation time is not more than 360 minutes, preferably 5-120 minutes, more preferably 30-90 minutes, in the present invention
Some specific embodiments in, incorporation time be 60 minutes.
Wherein described pharmaceutical composition includes carrier and one or more than one kinds of active components.
After wherein described carrier causes carrier and active component mixing, the pulmonary deposition ratio of active component is not less than 30%.
Wherein active component is at least one is selected from β 2- activators, muscarinic antagonist or corticosteroid, it is preferred that living
Property composition is at least one is selected from β 2- activators；In some embodiments of the present invention, described pharmaceutical composition include carrier and
More than one active component, wherein active component at least one are selected from β 2- activators, and at least another kind is selected from muscarine
Antagonist or corticosteroid.
It should be appreciated that the active component can also be other pharmaceutical compositions for being adapted to be prepared into inhalable dry powder form
Medicine, such as some anti-inflammatory drugs or treatment chronic obstructive pulmonary disease, chronic bronchitis, the medicine of pulmonary emphysema or asthma
Deng.
Wherein β 2- activators are selected from Terbutaline, dimension Lactel sieve (vilanterol), Reproterol, salbutamol, Sha Mei
Special sieve, Formoterol, carmoterol, meter Wei Teluo, QAB-149, Ao Dateluo, fenoterol, clenbuterol, bambuterol,
Broxaterol, adrenaline, isoprel or Hexoprenaline or their salt and/or solvate forms, are preferably tieed up
Lactel sieve or its salt and/or solvate forms, most preferably three phenylacetic acids tie up Lactel sieve or its solvate forms.
Wherein muscarinic antagonist is selected from Tiotropium Bromide, Wumei bromine ammonium (umeclidinium bromide), isopropyl support bromine
Ammonium, oxitropine, oxybutynin, aclidinium, trospium or glycopyrronium or their salt and/or solvate
Form, preferably Wumei bromine ammonium or its salt and/or solvate forms.
Wherein corticosteroid is selected from rofleponide, flunisolide budesonide, ciclesonide, Mometasone and its ester
(i.e. furoate), fluticasone and its ester (i.e. propionic ester and furoate), beclomethasone and its ester (i.e. propionic ester), chlorine replace
Sprinkle promise or Triamcinolone acetonide or their salt and/or solvate forms, preferably fluticasone furoate.
The pharmaceutical composition of wherein described inhalable dry powder form is inhalation powder spray.
On the other hand, the invention provides a kind of pharmaceutical composition of inhalable dry powder form used in carrier, the load
Body includes magnesium stearate and lactose granule, the drug regimen that the carrier passes through inhalable dry powder form as described above of the invention
It is prepared by the preparation method of the carrier used in thing.
Wherein described pharmaceutical composition includes carrier and one or more kinds of active components.
Wherein active component is at least one is selected from β 2- activators, muscarinic antagonist or corticosteroid, it is preferred that living
Property composition is at least one is selected from β 2- activators；In some embodiments of the present invention, described pharmaceutical composition include carrier and
More than one active component, wherein active component at least one are selected from β 2- activators, and at least another kind is selected from muscarine
Antagonist or corticosteroid.
Wherein β 2- activators are selected from Terbutaline, dimension Lactel sieve (vilanterol), Reproterol, salbutamol, Sha Mei
Special sieve, Formoterol, carmoterol, meter Wei Teluo, QAB-149, Ao Dateluo, fenoterol, clenbuterol, bambuterol,
Broxaterol, adrenaline, isoprel or Hexoprenaline or their salt and/or solvate forms, are preferably tieed up
Lactel sieve or its salt and/or solvate forms, most preferably three phenylacetic acids tie up Lactel sieve or its solvate forms.
Wherein muscarinic antagonist is selected from Tiotropium Bromide, Wumei bromine ammonium (umeclidinium bromide), isopropyl support bromine
Ammonium, oxitropine, oxybutynin, aclidinium, trospium or glycopyrronium or their salt and/or solvate
Form, preferably Wumei bromine ammonium or its salt and/or solvate forms.
Wherein corticosteroid is selected from rofleponide, flunisolide budesonide, ciclesonide, Mometasone and its ester
(i.e. furoate), fluticasone and its ester (i.e. propionic ester and furoate), beclomethasone and its ester (i.e. propionic ester), chlorine replace
Sprinkle promise or Triamcinolone acetonide or their salt and/or solvate forms, preferably fluticasone furoate.
After wherein described carrier causes carrier and active component mixing, the pulmonary deposition ratio of active component is not less than 30%.
The pharmaceutical composition of wherein described inhalable dry powder form is inhalation powder spray.
Another further aspect, the invention provides a kind of pharmaceutical composition of inhalable dry powder form, described pharmaceutical composition bag
Containing carrier and one or more kinds of active components, wherein the carrier passes through dry powder shape inhalable as described above of the invention
It is prepared by the preparation method of the carrier used in the pharmaceutical composition of formula.
Wherein active component is at least one is selected from β 2- activators, muscarinic antagonist or corticosteroid, it is preferred that living
Property composition is at least one is selected from β 2- activators；In some embodiments of the present invention, described pharmaceutical composition include carrier and
More than one active component, wherein active component at least one are selected from β 2- activators, and at least another kind is selected from muscarine
Antagonist or corticosteroid.
Wherein β 2- activators are selected from Terbutaline, dimension Lactel sieve (vilanterol), Reproterol, salbutamol, Sha Mei
Special sieve, Formoterol, carmoterol, meter Wei Teluo, QAB-149, Ao Dateluo, fenoterol, clenbuterol, bambuterol,
Broxaterol, adrenaline, isoprel or Hexoprenaline or their salt and/or solvate forms, are preferably tieed up
Lactel sieve or its salt and/or solvate forms, most preferably three phenylacetic acids tie up Lactel sieve or its solvate forms.
Wherein muscarinic antagonist is selected from Tiotropium Bromide, Wumei bromine ammonium (umeclidinium bromide), isopropyl support bromine
Ammonium, oxitropine, oxybutynin, aclidinium, trospium or glycopyrronium or their salt and/or solvate
Form, preferably Wumei bromine ammonium or its salt and/or solvate forms.
Wherein corticosteroid is selected from rofleponide, flunisolide budesonide, ciclesonide, Mometasone and its ester
(i.e. furoate), fluticasone and its ester (i.e. propionic ester and furoate), beclomethasone and its ester (i.e. propionic ester), chlorine replace
Sprinkle promise or Triamcinolone acetonide or their salt and/or solvate forms, preferably fluticasone furoate.
Wherein described pharmaceutical composition may be inhaled used in the pharmaceutical composition of dry powder form as described above with the present invention
Carrier preparation method described in pharmaceutical composition it is identical.
After wherein described carrier causes carrier and active component mixing, the pulmonary deposition ratio of active component is not less than 30%.
The pharmaceutical composition of wherein described inhalable dry powder form is inhalation powder spray.
Another aspect, the invention provides a kind of preparation method of the pharmaceutical composition of inhalable dry powder form, the side
Method includes mixing carrier with the active component of one or more, and the carrier passes through of the invention as described above inhalable
It is prepared by the preparation method of the carrier used in the pharmaceutical composition of dry powder form.
Wherein active component is at least one is selected from β 2- activators, muscarinic antagonist or corticosteroid, it is preferred that living
Property composition is at least one is selected from β 2- activators；In some embodiments of the present invention, described pharmaceutical composition include carrier and
More than one active component, wherein active component at least one are selected from β 2- activators, and at least another kind is selected from muscarine
Antagonist or corticosteroid.
When active component is more than one, after the carrier can mix respectively with each active component, then carry out
Mixing.
Wherein β 2- activators are selected from Terbutaline, dimension Lactel sieve (vilanterol), Reproterol, salbutamol, Sha Mei
Special sieve, Formoterol, carmoterol, meter Wei Teluo, QAB-149, Ao Dateluo, fenoterol, clenbuterol, bambuterol,
Broxaterol, adrenaline, isoprel or Hexoprenaline or their salt and/or solvate forms, are preferably tieed up
Lactel sieve or its salt and/or solvate forms, most preferably three phenylacetic acids tie up Lactel sieve or its solvate forms.
Wherein muscarinic antagonist is selected from Tiotropium Bromide, Wumei bromine ammonium (umeclidinium bromide), isopropyl support bromine
Ammonium, oxitropine, oxybutynin, aclidinium, trospium or glycopyrronium or their salt and/or solvate
Form, preferably Wumei bromine ammonium or its salt and/or solvate forms.
Wherein corticosteroid is selected from rofleponide, flunisolide budesonide, ciclesonide, Mometasone and its ester
(i.e. furoate), fluticasone and its ester (i.e. propionic ester and furoate), beclomethasone and its ester (i.e. propionic ester), chlorine replace
Sprinkle promise or Triamcinolone acetonide or their salt and/or solvate forms, preferably fluticasone furoate.
Wherein described pharmaceutical composition may be inhaled used in the pharmaceutical composition of dry powder form as described above with the present invention
Carrier preparation method described in pharmaceutical composition it is identical.
After wherein described carrier causes carrier and active component mixing, the pulmonary deposition ratio of active component is not less than 30%.
The pharmaceutical composition of wherein described inhalable dry powder form is inhalation powder spray.
Another aspect, the invention provides the carrier used in a kind of pharmaceutical composition of inhalable dry powder form of the invention
For the purposes for the pharmaceutical composition for preparing inhalable dry powder form.
Another further aspect, the invention provides a kind of pharmaceutical composition of inhalable dry powder form of the invention to prepare treatment
And/or the purposes in the medicine of prevention respiratory disease, wherein respiratory disease include but is not limited to chronic obstructive pulmonary
Disease, chronic bronchitis, pulmonary emphysema or asthma.
Further aspect, the invention provides the method for treating and/or preventing mammal (such as people) disease, this method bag
Include the pharmaceutical composition for the inhalable dry powder form of the invention that therapeutically effective amount is given to mammal (such as people), wherein institute
State disease and be selected from respiratory disease, including but not limited to chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema or asthma.
The carrier that the present invention is prepared, be not in the broken phenomenon of particulate abrasive, with directly use magnesium stearate and
The carrier obtained after lactose granule mixing is compared, and compared with the carrier with being prepared by the hybrid granulator of high shear force, no
Effective deposition of the medicine in lung of inhalation powder spray can be only significantly improved, but also some drugses can be substantially reduced
The degraded of (such as dimension Lactel sieve), improve the chemical stability of medicine；The carrier of the present invention also has good fluidity, compressibility
Small, hygroscopicity is small and the advantages that good permeability, and prepare it is simple to operation, particularly useful for making inhalation powder spray.
Definition
Unless otherwise noted, term " medicine ", " active component ", " active matter " and " active material " is synonym.
Term " ball mill " refers to the device with abrasive media and rotatable container, including but not limited to planetary ball
Grinding machine, among abrasive media and carrier are collectively disposed at into container before ball mill operation, when container rotates, abrasive media is in container
In carrier is collided and ground and be sufficiently mixed carrier." abrasive media " as described herein refers in a reservoir to carrying
Body is collided and ground and makes the well-mixed energy carrier of carrier, and it is separated with container, the abrasive media typical shape
Including spherical, spherical (such as oval) but it is also possible to be other shapes (such as bar-shaped, round platform, post ball, short pole), institute
Stating the material of abrasive media includes metal (such as steel, iron, alloy etc.) and nonmetallic (such as glass, plastics, agate, zircon, rock
Stone, ceramics etc.), the example of abrasive media has glass marble, plastic bead, steel ball, agate ball, zirconium oxide bead, zirconium silicate pearl etc.；It can turn
The material of dynamic container include metal (such as stainless steel) and it is nonmetallic (such as agate, ceramic, nylon, polyurethane, polytetrafluoroethylene (PTFE),
Zirconium oxide, hard alloy etc.).
Term " planetary ball mill " refer to have rotatable disk, rotatable container (such as 2 or 4 containers) and
The device of abrasive media, among abrasive media and carrier are collectively disposed at into container before ball mill operation, container it is orderly be placed in disk
On, when the disk makees revolution motion, container makees spinning motion on its revolution orbit, and container and disk rotate simultaneously, and rotation turns
Speed is more than the rotating speed of revolution, such as the rotating ratio of rotation and revolution is 2：1.
Term " the hybrid granulator of high shear force " refers to the device for being provided with oar shape hybrid element, and wherein carrier is added by oar
Speed, and be sufficiently mixed by the friction with chamber wall, for example, the hybrid granulator of high shear force that the present invention uses is
Heysun process equipment (Shanghai Hui Shen engineering equipments Co., Ltd), model M1.
Term " rpm " refers to the unit of rotating speed, and rpm is revolutions per minute abbreviation, is represented per minute
Rotating speed, such as 480rpm refers to that per minute is 480 turns.
Term " pulmonary deposition ratio of active component " refers to the active component for sucking the lung depths that preparation can reach patient
The percentage of particle.
Term " droplet distribution ", i.e. minuteness particle dosage, it is the important parameter of the evaluation suction quality of the pharmaceutical preparations, refers to suction dust cloud
The fine medicine particle dose of agent accounts for the percentage of labelled amount, can be measured and (can refer to by device outside《The Chinese people are total to
With state's pharmacopeia》" the 0951 suction preparation minuteness particle air dynamic behaviour determination method " of version the 4th in 2015 is measured),
Its numerical value can reflect deposition of the active component in lung, such as when gas flow reaches 60L/min, droplet is distributed in 2-7 levels
Ratio it is suitable with the pulmonary deposition ratio of active component.
Term " w/w " refers to weight ratio, such as in the carrier containing magnesium stearate, 0.3%w/w magnesium stearate refers to
The weight of magnesium stearate is the 0.3% of carrier.
In general, by the equivalent sphere diameter (being referred to as volume diameter) of laser diffraction measurement characteristic, so as to quantitative
The granularity of grain, such as determined by laser particle analyzer.
The present invention represents size distribution (particle size distribution) with volume diameter (VD).
Term " d (v0.5) " refers to that cumulative particle sizes percentile reaches particle diameter corresponding when 50%, referred to as in volume
Position diameter (volum median diameter), its physical significance is that particle diameter accounts for 50% more than its particle, less than its
Grain also accounts for 50%.
Term " d (v0.1) " refers to that cumulative particle sizes percentile reaches particle diameter corresponding when 10%, its physics meaning
Justice is that particle diameter accounts for 90% more than its particle, and the particle less than it accounts for 10%.
Term " d (v0.9) " refers to that cumulative particle sizes percentile reaches particle diameter corresponding when 90%, its physics meaning
Justice is that particle diameter accounts for 10% more than its particle, and the particle less than it accounts for 90%.
Embodiment
Following specific embodiment, the purpose is to those skilled in the art is more clearly understood that and implement this hair
It is bright.They should not be construed as limiting the scope of the present invention, and the simply exemplary illustration and Typical Representative of the present invention.
The planetary ball mill of embodiment 1 prepares carrier
Commercially available alpha-lactose monohydrate, model：200, specification：D (v0.1) is 5-15 microns, d
(v0.5) it is 50-100 microns, d (v0.9) is 120-160 microns.
1st, carrier a1 preparation
Alpha-lactose monohydrate 1.2kg, magnesium stearate 1.2g (0.1%w/w) and agate ball (diameter is not more than 1cm) is suitable
Amount, 4 parts are equally divided into after well mixed, is placed in 4 rotatable agate jars, passes through QM-3SP4 planetary type ball-millings
Machine (Nanjing Univ. Instrument Factory's production) is processed, and machined parameters are：Rotating speed (rotational velocity)：480rpm, continue 60 minutes, carried
Body a1.
2nd, carrier a2 preparation
According to above-mentioned carrier a1 preparation method, 0.1%w/w magnesium stearate is replaced with to 0.3%w/w stearic acid
Magnesium, obtain carrier a2.
3rd, carrier a3 preparation
According to above-mentioned carrier a1 preparation method, 0.1%w/w magnesium stearate is replaced with to 0.5%w/w stearic acid
Magnesium, obtain carrier a3.
4th, carrier a4 preparation
According to above-mentioned carrier a1 preparation method, 0.1%w/w magnesium stearate is replaced with to 1.0%w/w stearic acid
Magnesium, obtain carrier a4.
With HELOS-OASIS types laser granulometry (Sympatec GmbH) comparative study200 and
Carrier a1, a2, a3, a4 size distribution.Method of testing is as follows：Take testing sample appropriate, make sample detection optical concentration 2%
~15% scope, using dry method, RODOS decentralized systems, (0.5-350 μm) test of R4 camera lenses, scattered pressure is 3.0bar, sample
Time of measuring is 5s, gathers volume/Mass Distribution granularity, as a result such as table 1.
The granularity distribution result of table 1
| Bearer number | Sample | d(v0.1) | d(v0.5) | d(v0.9) |
| LH200 | 10.93 | 70.70 | 129.49 | |
| a1 | LH200+0.1%MS | 9.48 | 70.86 | 127.53 |
| a2 | LH200+0.3%MS | 10.07 | 71.53 | 127.56 |
| a3 | LH200+0.5%MS | 10.54 | 72.60 | 128.93 |
| a4 | LH200+1.0%MS | 10.99 | 73.85 | 129.58 |
The physical mixed of embodiment 2 prepares carrier
Commercially available alpha-lactose monohydrate, model：200, specification：D (v0.1) is 5-15 microns, d
(v0.5) it is 50-100 microns, d (v0.9) is 120-160 microns.
1st, carrier b1 preparation
Common 80 mesh sieves of mistake of alpha-lactose monohydrate 50g and magnesium stearate 0.05g (0.1%w/w) are mixed for 5 times,
Obtain carrier b1.
2nd, carrier b2 preparation
According to above-mentioned carrier b1 preparation method, 0.1%w/w magnesium stearate is replaced with to 0.3%w/w stearic acid
Magnesium, obtain carrier b2.
3rd, carrier b3 preparation
According to above-mentioned carrier b1 preparation method, 0.1%w/w magnesium stearate is replaced with to 0.5%w/w stearic acid
Magnesium, obtain carrier b3.
4th, carrier b4 preparation
According to above-mentioned carrier b1 preparation method, 0.1%w/w magnesium stearate is replaced with to 1.0%w/w stearic acid
Magnesium, obtain carrier b4.
The hybrid granulator of the high shear force of embodiment 3 prepares carrier
Commercially available alpha-lactose monohydrate, model：200, specification：D (v0.1) is 5-15 microns, d
(v0.5) it is 50-100 microns, d (v0.9) is 120-160 microns.
1st, carrier c1 preparation
Alpha-lactose monohydrate (400g) and magnesium stearate 0.4g (0.1%w/w) are placed in the hybrid granulation of high shear force
Processed in machine (heysun process equipment, Shanghai Hui Shen engineering equipments Co., Ltd, model M1), machined parameters
For：Rotating speed 1000rpm, continue 10min, obtain carrier c1.
2nd, carrier c2 preparation
According to above-mentioned carrier c1 preparation method, 0.1%w/w magnesium stearate is replaced with to 0.3%w/w stearic acid
Magnesium, obtain carrier c2.
3rd, carrier c3 preparation
According to above-mentioned carrier c1 preparation method, 0.1%w/w magnesium stearate is replaced with to 0.5%w/w stearic acid
Magnesium, obtain carrier c3.
4th, carrier c4 preparation
According to above-mentioned carrier c1 preparation method, 0.1%w/w magnesium stearate is replaced with to 1.0%w/w stearic acid
Magnesium, obtain carrier c4.
Embodiment 4 ties up the preparation of Lactel sieve inhalation powder spray
By three phenylacetic acids dimension Lactel sieve after 0.16g air-flow crushings, (laser particle instrument detects：D (v0.5)≤5 μm, d
(v0.9)≤9 μm) mixed 5 times with the common mesh sieves of mistake 80 of 50g carriers a1, obtained three phenylacetic acids dimension Lactel sieve inhalation powder spray 1-
A1。
By above-mentioned same process, carrier a1 is replaced respectively with carrier a2, a3, a4, b1, b2, b3, b4, c1, c2, c3 and c4,
It is corresponding to respectively obtain three phenylacetic acids dimension Lactel sieve inhalation powder spray 1-A2,1-A3,1-A4,1-B1,1-B2,1-B3,1-B4,1-
C1,1-C2,1-C3 and 1-C4.
Three phenylacetic acids dimension Lactel sieve inhalation powder spray 1-A1,1-A2,1-A3,1-A4,1-B1,1-B2,1-B3,1-B4,1-
C1,1-C2,1-C3 and 1-C4 preparation prescription composition such as table 2：
The phenylacetic acid of table 2 three ties up Lactel sieve inhalation powder spray prescription
The Wumei bromine ammonium of embodiment 5 ties up the preparation of Lactel sieve inhalation powder spray
By three phenylacetic acids dimension Lactel sieve after 0.16g air-flow crushings, (laser particle instrument detects：D (v0.5)≤5 μm, d
(v0.9)≤9 μm) mixed 5 times with the common mesh sieves of mistake 80 of 25g carriers a1, obtained three phenylacetic acids dimension Lactel sieve moiety intermediate X.
By the Wumei bromine ammonium after 0.297g air-flow crushings, (laser particle instrument detects：D (v0.5)≤5 μm, d (v0.9)≤9 μm) carried with 25g
The common mesh sieves of mistake 80 of body a1 mix 5 times, obtained Wumei bromine ammonium moiety intermediate Y.X and Y are crossed into 80 mesh sieve 5 times together.Obtain
Wumei bromine ammonium dimension Lactel sieve inhalation powder spray 2-A1.
By above-mentioned same process, carrier a1 is replaced respectively with carrier a2, a3, a4, b1, b2, b3, b4, c1, c2, c3 and c4,
It is corresponding to respectively obtain Wumei bromine ammonium dimension Lactel sieve inhalation powder spray 2-A2,2-A3,2-A4,2-B1,2-B2,2-B3,2-B4,2-
C1,2-C2,2-C3 and 2-C4.
Wumei bromine ammonium dimension Lactel sieve inhalation powder spray 2-A1,2-A2,2-A3,2-A4,2-B1,2-B2,2-B3,2-B4,2-
C1,2-C2,2-C3 and 2-C4 preparation prescription composition such as table 3：
The Wumei bromine ammonium of table 3 ties up Lactel sieve inhalation powder spray prescription
The fluticasone furoate of embodiment 6 ties up the preparation of Lactel sieve inhalation powder spray
By three phenylacetic acids dimension Lactel sieve after 0.16g air-flow crushings, (laser particle instrument detects：D (v0.5)≤5 μm, d
(v0.9)≤9 μm) mixed 5 times with the common mesh sieves of mistake 80 of 25g carriers a1, obtained three phenylacetic acids dimension Lactel sieve moiety intermediate X.
By the fluticasone furoate after 0.4g air-flow crushings, (laser particle instrument detects：D (v0.5)≤5 μm, d (v0.9)≤9 μm) and 25g
The common mesh sieves of mistake 80 of carrier a1 mix 5 times, obtained fluticasone furoate moiety intermediate Y.X and Y are crossed into 80 mesh sieves 5 together
Time.Obtain fluticasone furoate dimension Lactel sieve inhalation powder spray 3-A1.
By above-mentioned same process, carrier a1 is replaced respectively with carrier a2, a3, a4, b1, b2, b3, b4, c1, c2, c3 and c4,
It is corresponding to respectively obtain fluticasone furoate dimension Lactel sieve inhalation powder spray 3-A2,3-A3,3-A4,3-B1,3-B2,3-B3,3-
B4,3-C1,3-C2,3-C3 and 3-C4.
Fluticasone furoate dimension Lactel sieve inhalation powder spray 3-A1,3-A2,3-A3,3-A4,3-B1,3-B2,3-B3,3-
B4,3-C1,3-C2,3-C3 and 3-C4 preparation prescription composition such as table 4：
The fluticasone furoate of table 4 ties up Lactel sieve inhalation powder spray prescription
The minuteness particle dosimetry of embodiment 7
Minuteness particle dosimetry：
According to the device 3 (next generation impactor, NGI) of four general rules of Chinese Pharmacopoeia version in 2015 0951, method 2
Attachment means.15ml acceptable solutions are added into preseparator central collection cup, tightening device detects air-tightness, and air-tightness is qualified
After adjust flow.Vavuum pump is opened, flowmeter is connected at L-type connecting tube, regulation flow control valve makes by the steady of system
Constant flow reaches 60 ± 5%L/min.In the case where testing flow, the pressure ratio (P before and after flow control valve3/P2) answer≤0.5.
Flowmeter is removed, starts to determine.This product is taken, keeps suction apparatus horizontal, opens vavuum pump, Drawing switch is once put
In Kai Chu, aspirate 4 ± 5% seconds, repeat aforesaid operations 10 times, close vavuum pump, remove device, 2-7 levels are washed with acceptable solution
Catch tray, merge washing lotion, constant volume, shake up, filter, take subsequent filtrate to be examined as need testing solution with high performance liquid chromatograph
Survey, sample segment test result is shown in Table 5-7.
Table 5 ties up the test result of Lactel sieve inhalation powder spray
The Wumei bromine ammonium of table 6 ties up the test result of Lactel sieve inhalation powder spray
The fluticasone furoate of table 7 ties up the test result of Lactel sieve inhalation powder spray
The phenylacetic acid of embodiment 8 three ties up Lactel sieve stability
Fluticasone furoate ties up Lactel sieve inhalation powder spray 3-A1 and 3-B4, reference《Pharmacopoeia of People's Republic of China》2010
Two annex XIX C bulk drugs of version are tested with pharmaceutical preparation stability experiment guideline, and following table lists 40 DEG C and places 10
After it, the purity of three phenylacetic acids dimension Lactel sieve and impurity detect situation of change result such as table 8 through HPLC in sample.
The phenylacetic acid of table 8 three ties up the purity and impurity situation of change result of Lactel sieve
Note 1：Total impurities content value added refers to relative 0 day increased value of total impurities content
Note 2：Total impurities and purity in upper table are the testing results individually for dimension Lactel sieve
As a result show, the carrier prepared using ball mill prepares inhalation powder spray, can significantly improve and Lactel is tieed up in product
The chemical stability of sieve.
Claims (10)
1. a kind of preparation method of the carrier used in pharmaceutical composition of inhalable dry powder form, including：By magnesium stearate and breast
Sugared particle is mixed in ball mill, and the wherein d (v0.5) of lactose granule is the weight of 5-800 microns, wherein magnesium stearate
For the 0.05%-1.5% of carrier.
2. the rotation rotating speed of the container of the preparation method of claim 1, wherein ball mill is 15-960rpm.
3. the material of the abrasive media of the preparation method of claim 1, wherein ball mill is metal and nonmetallic.
4. the preparation method of claim 1, wherein described pharmaceutical composition include carrier and one or more than one kinds of activity
Composition.
5. the preparation method of claim 4, wherein active component at least one are selected from β 2- activators, muscarinic antagonist or skin
Matter steroids.
6. the carrier used in a kind of pharmaceutical composition of inhalable dry powder form, the carrier includes magnesium stearate and lactose
Grain, the carrier are prepared by the preparation method described in claim any one of 1-5.
7. a kind of pharmaceutical composition of inhalable dry powder form, described pharmaceutical composition includes carrier and one or more
Active component, wherein the carrier is prepared by the preparation method described in claim any one of 1-5.
8. the pharmaceutical composition of claim 7, wherein active component it is at least one selected from β 2- activators, muscarinic antagonist or
Corticosteroid.
9. a kind of preparation method of the pharmaceutical composition of inhalable dry powder form, methods described is included carrier and a kind of or one kind
Active component mixing above, the carrier are prepared by the preparation method described in claim any one of 1-5.
10. purposes of the claim 7-8 pharmaceutical composition in the medicine for preparing treatment and/or prevention respiratory disease,
Wherein respiratory disease includes but is not limited to chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema or asthma.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109745565A (en) * | 2019-01-28 | 2019-05-14 | 上海方予健康医药科技有限公司 | A kind of dry powder composite and preparation method thereof for sucking |
| CN110251492A (en) * | 2019-07-04 | 2019-09-20 | 珠海瑞思普利生物制药有限公司 | A kind of SB 209509 inhalation powder spray and its preparation method and application |
| CN111297837A (en) * | 2020-03-26 | 2020-06-19 | 上海方予健康医药科技有限公司 | Preparation method of dry powder inhalant |
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| CN102858326A (en) * | 2010-04-01 | 2013-01-02 | 奇斯药制品公司 | Process for preparing carrier particles for dry powders for inhalation |
| CN102946868A (en) * | 2010-06-22 | 2013-02-27 | 奇斯药制品公司 | Dry powder formulation comprising an antimuscarinic drug |
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2016
- 2016-07-04 CN CN201610525589.6A patent/CN107569474A/en active Pending
- 2016-07-04 CN CN202210093510.2A patent/CN114425049A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102858326A (en) * | 2010-04-01 | 2013-01-02 | 奇斯药制品公司 | Process for preparing carrier particles for dry powders for inhalation |
| CN104257610A (en) * | 2010-04-01 | 2015-01-07 | 奇斯药制品公司 | Process For Preparing Carrier Particles For Dry Powders For Inhalation |
| CN102946868A (en) * | 2010-06-22 | 2013-02-27 | 奇斯药制品公司 | Dry powder formulation comprising an antimuscarinic drug |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109745565A (en) * | 2019-01-28 | 2019-05-14 | 上海方予健康医药科技有限公司 | A kind of dry powder composite and preparation method thereof for sucking |
| CN109745565B (en) * | 2019-01-28 | 2021-05-18 | 上海方予健康医药科技有限公司 | Dry powder composition for inhalation and preparation method thereof |
| CN110251492A (en) * | 2019-07-04 | 2019-09-20 | 珠海瑞思普利生物制药有限公司 | A kind of SB 209509 inhalation powder spray and its preparation method and application |
| CN111297837A (en) * | 2020-03-26 | 2020-06-19 | 上海方予健康医药科技有限公司 | Preparation method of dry powder inhalant |
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