CN109745565A - A kind of dry powder composite and preparation method thereof for sucking - Google Patents
A kind of dry powder composite and preparation method thereof for sucking Download PDFInfo
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- CN109745565A CN109745565A CN201910080287.6A CN201910080287A CN109745565A CN 109745565 A CN109745565 A CN 109745565A CN 201910080287 A CN201910080287 A CN 201910080287A CN 109745565 A CN109745565 A CN 109745565A
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Abstract
The dry powder composite and preparation method thereof that the present invention relates to a kind of for sucking, the dry powder composite contains long-acting cholinergic antagonist, long acting beta agonists, stabilizer and pharmaceutical carrier, wherein, a part and the long acting beta agonists in the stabilizer form coating, which is so that the dosage that the long acting beta agonists are wrapped up completely.Dry powder composite of the invention has good chemical stability, and can target pulmonary administration by powder inhaler.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of for the dry powder composite of sucking and its preparation side
Method.
Background technique
Long-acting cholinergic antagonist and long acting beta agonists are to be commonly used in treatment Chronic Obstructive Pulmonary Disease
The drug of disease.Long-acting cholinergic antagonist can be in conjunction with acetylcholinergic receptor and beta receptor, to inhibit choline mediator institute
The bronchus tonicity of mediation, moreover it is possible to the bronchoconstriction reflection for blocking vagus nerve to be mediated.Long acting beta agonists can be with
In conjunction with beta receptor, adenosine cyclophosphate (cAMP) level is increased, makes tracheal smooth muscle diastole, it is also possible to reduce labrocyte medium
Release inhibits the response of neutrophil cell, eosinophil and lymphocyte, increases mucociliary conveying.The two combination
It can be relieved the dyspnea symptom of Patients with Chronic Obstructive Pulmonary Disease, drug effect, which is better than, to be administered alone.Foradil Aerolizer formoterol fumarate is made in the two
Drug can be deposited on pulmonary absorption after delivery device is atomized afterwards, and target-oriented drug further enhances, and toxic side effect is substantially reduced, and rise
Effect speed also obviously becomes faster, and has good safety and tolerance through clinical test verifying.
Long-acting cholinergic antagonist belongs to tropane class drug, majority be amino alcohol derived from tropane etc. from it is different
Organic acid is condensed into the alkaloid of ester formation, and molecular structure is because susceptible to hydrolysis more unstable containing ester bond.Long-acting beta receptor agonism
With the basic structure of phenyl ethylamine in agent (adrenomimetic drug drug) molecular structure, and there is phenolic hydroxyl group on phenyl ring, it is sensitive to alkali,
Light is encountered in air or heat is oxidizable.Dry powder drug inhalant belongs to solid pharmaceutical preparation, powder granule (comprising effective component and other
Auxiliary material), the moisture of particle surface, particulate interspaces air constitute the system of solid, liquid, gas three-phase coexistence.Since dry powder sucks
Agent targeting is stronger, and two kinds of active pharmaceutical ingredient dosages are usually lower, the accounting in prescription usually 0.05~5.0%,
It even will be lower than the content of the either impurity of the moisture in major auxiliary burden (such as lactose).In order to enable Foradil Aerolizer formoterol fumarate effective component
Lung is enough arrived at, micronization processes first often are done to effective component, partial size is usually less than 5 μm, not only greatly improves powder
The specific surface area of body also makes it be easier to contact with the moisture of the biggish filler adsorption of particle and impurity anti-to occur
It answers.Also there is potential compatibility risk between two kinds of effective components of compound dry powder inhalation.These factors make long-acting choline
After energy receptor blocking pharmacon and long acting beta agonists and filler appropriate and additive are mixed to form compound preparation, chemistry is steady
Qualitative poor, effective component is easily degraded in placement process, influences Drug safety and validity.
The Pharmaceutical composition that Tiotropium Bromide and Formoterol are disclosed in CN105125542 patent can treat respiratory tract and lung
Portion's diseases associated with inflammation is directed to the powder spray dosage form of Tiotropium Bromide and Formoterol, but powder spray prescription only includes thiophene support
Bromine ammonium, Formoterol and lactose, and preparation process uses co-blended form, the product stability prepared is lower, places one section
The impurity content of time product improves, and shelf life reduces.
Requirement when being limited to drug delivery to atomization, supplementary material are difficult to using coating or form stable inclusion compound
Method.On the other hand common stabilizer, antioxidant can not be added from the security consideration of inhalation, dry powder inhaler formulations
Deng, and since moisture is too low easy to produce static electricity or the property of packaging system (such as capsule or plastic material) is caused to change, it is dry
The use of agent is also frequently subjected to certain limitation.Therefore it is highly desirable to develop in sucking preparation and promotes product chemical stability
Means.
Summary of the invention
In order to overcome product stability problems existing in the prior art, the present invention provides a kind of dry powder group for sucking
Object and preparation method thereof is closed, prepared dry powder composite has good chemical stability, and can pass through powder inhaler
Target pulmonary administration.
The present invention adopts the following technical scheme that solve.
On the one hand, the present invention provides a kind of dry powder composite for sucking, which contains long-acting cholinergic
Receptor blocking pharmacon, long acting beta agonists, stabilizer and pharmaceutical carrier, wherein a part and the length in the stabilizer
It imitates beta receptor agonist and forms coating, which is so that the long acting beta agonists are wrapped up completely
Dosage.
Preferably, it is pharmaceutically acceptable to be selected from tiotropium, glycopyrronium, aclidinium, Wumei ammonium for the long-acting cholinergic antagonist
Bromide, chloride, iodide or its monohydrate form, preferably Tiotropium Bromide or its monohydrate.
Preferably, the D of the long-acting cholinergic antagonist50Less than 5 μm.
Preferably, the stabilizer is selected from one of stearate, amino acid and its derivative, polyethylene glycol or more
Kind, preferably magnesium stearate or leucine.
Preferably, the long acting beta agonists are selected from datro, Formoterol, Vilantro, salmeterol, Austria
The dihydrate of Da Teluo and its officinal salt, preferably Formoterol, its fumarate or its fumarate.
Preferably, the D of the long acting beta agonists50Less than 5 μm.
Preferably, the pharmaceutical carrier is selected from one of carbohydrate, sugar alcohol or a variety of, preferably lactose monohydrate, anhydrous lactitol
Or mixtures thereof sugar.
In the present invention, in the dry powder composite of the sucking pharmaceutical carrier mean serve as in the formulation filler at
Point.Active constituent or the compound containing active constituent can be incorporated into carrier surface in formulation process, to meet dispersion, mix
The processing request of the processes such as conjunction and Quantitative charging.In order to achieve the goal above, pharmaceutical carrier is in the dry powder composite of sucking
Proportion usually requires the compound of significantly greater than active constituent or active constituent.
Active constituent or its compound containing active constituent can be from loads under the action of during inhalation in air-flow
Body surface dissociation arrives at lung, to play therapeutic effect.
Preferably, the weight ratio of the long-acting cholinergic antagonist and the pharmaceutical carrier is 1:20~1:2000.
Preferably, the weight ratio of the long acting beta agonists and the pharmaceutical carrier is 1:20~1:2000.
Preferably, the weight ratio of the stabilizer and the pharmaceutical carrier is 1:20~1:2000.
Preferably, the stabilizer and the long acting beta agonists of coating are formed with the long acting beta agonists
Weight ratio is 1:10~10:1.
On the other hand, the present invention also provides a kind of method for preparing the above-mentioned dry powder composite for sucking, this method packets
It includes following steps: a) be co-mulled and made into being mixed to form compound with partially stabilized dose by long acting beta agonists；B) by step a)
The compound of middle formation carries out high-speed stirred with long-acting cholinergic antagonist, remaining stabilizer, pharmaceutical carrier and mixes i.e.
?.
Preferably, in step a), it is described be co-mulled and made into the milling apparatus that is used in mixed way be selected from ball milling instrument, disc type beveller,
Planetary type ball-milling instrument, mechanical fusion machine or airslide disintegrating mill.
Preferably, in step a), the stabilizer and the long-acting beta receptor of coating are formed with long acting beta agonists
The weight ratio of agonist is 1:10~10:1.
It is co-mulled and made into mixing and refers to long acting beta agonists first with stabilizer by suitable equipment, under the promotion of external force
The local mixing of progress.The severity of grind of these equipment is generally significantly higher than high-speed stirred mixing.Common milling apparatus includes
Ball milling instrument, disc type beveller, mechanical fusion machine, airslide disintegrating mill etc., these equipment can by air-flow, agitating paddle, grinding rod,
Mill ball, chamber wall etc. drive particle mutual extrusion in container, shock, friction by loose active constituent and stabilizer group
The particle for dividing break-up agglomerates to be suitble at partial size, and keep stabilizer and active constituent evenly dispersed, then pass through interparticle force
Form loose powder aggregates.Long acting beta agonists effective component crystal grain has with stabilizer agent particle in powder
Large specific surface area, mutual binding force is stronger, can effectively reduce length during preparation processing and storage later
Imitate beta receptor agonist effective component crystal grain and long-acting cholinergic antagonist either other pharmaceutical carriers (and its table
The moisture or impurity in face) contact area, promoted medicine stability.
For carrying out total micronization, the general crushing pressure for using 0.2MPa or more using airslide disintegrating mill；For using
High speed ball milling instrument is co-mulled and made into, the general revolving speed for using 300r/min or more；For being ground altogether using planetary type ball-milling instrument
Mill, sun wheel speed is generally in 30r/min or more；For disc type beveller, generally turned using 700r/min or more vibrating chassis
Speed.
High-speed stirred mixing refers to the particle in material group by from outer masterpieces such as cutter, agitating paddle or sieves
With, inside powder because flowing generate mixing effect, cause material to mix.The equipment being stirred includes high-speed mixer, high speed
Mixing machine etc., besides the flow can also be by the high speed rotation of cutter or agitating paddle by loose active constituent or activity
The loose break-up agglomerates that ingredient and stabilizer are formed at lesser agglomerate, and make its it is evenly dispersed be incorporated on carrier, these
The mixing intensity of equipment generally below be co-mulled and made into equipment, in order not to elementary particle generate crushing effect and not destabilizer with
The combination of active constituent, the linear velocity of agitating paddle (or cutter) are 1-100m/s, preferably 10-60m/s.
It can be otherwise appropriately mixed in technical process to promote stabilizer and active constituent and disperse in the carrier
Uniformity coefficient, the mixing apparatus includes V-Mixer, three-dimensional mixer, wet mixing pelletizer, Universal mixing machine
Deng.
Manufactured composition powder can be quantitative in advance be loaded in single dose or multi-dose container, can be by appropriate
Packaging chemically and physically protected with providing, by actively or passively formula suction apparatus be administered, the container can be capsule or bubble-cap,
It is preferred that capsule.
The invention has the benefit that
Stabilizer is added in one aspect of the present invention on the basis of the prescription of existing compound dry powder inhalation, and by the way that part is steady
Determine agent and long acting beta agonists be co-mulled and made into and are mixed to get compound, significantly reduces long acting beta agonists and long-acting gallbladder
Contact between alkali energy receptor blocking pharmacon, pharmaceutical carrier particle so that in composition long acting beta agonists and long-acting cholinergic by
The improved chemical stability of body blocking agent.
On the other hand by the screening design to process and parameter, by partially stabilized dose and long acting beta agonists
It is mixed by high-speed stirred with long-acting cholinergic antagonist and pharmaceutical carrier again be co-mulled and made into the compound being mixed to get
It closes, avoids the decline of active constituent stability caused by the over-mixed of long-acting cholinergic antagonist and stabilizer, obtain
Chemical stability is preferable and finely dispersed compound dry powder preparation, can be loaded on single dose or multi-dose dry powder is inhaled by quantitative
Enter device to pulmonary administration.Overcome long-acting cholinergic antagonist, long acting beta agonists and filling in the prior art
The poor technical problem of chemical compatibility, greatly prolongs the shelf life of product between agent particle three.
Detailed description of the invention
Fig. 1 is Tiotropium Bromide total impurities growth trend in section Example in 16 stability study of the embodiment of the present invention
Figure；And
Fig. 2 is Formoterol total impurities growth trend in section Example in 16 stability study of the embodiment of the present invention
Figure.
Specific embodiment
Embodiment 1: the preparation of micronised Tiotropium bromide
Tiotropium bromide monohydrate, thiatro bromoaminium anhydrous compound are micronized in airslide disintegrating mill respectively, crush pressure
Power is 0.6Mpa, resulting particle size D50Reach 5 μm or less.
Embodiment 2: the preparation of micronized formoterol
Formoterol fumarate dihydrate, formoterol fumarate are micronized respectively in airslide disintegrating mill,
Crushing pressure is 0.6Mpa, resulting particle size D50Reach 5 μm or less.
Embodiment 3: using lactose monohydrate as carrier, magnesium stearate is stabilizer, the Tiotropium Bromide Formoterol for sucking
Dry powder preparation
According to the form below weighs micronized formoterol dihydrate obtained in the magnesium stearate and embodiment 2 of recipe quantity 1/10
It is stirred 2min, is transferred in planetary ball mill, sun wheel speed 500r/min mixing 10min is set, appropriate to stand, system
Standby powdered compound (D50=2.23 μm), the micronised Tiotropium bromide monohydrate (D prepared in embodiment 1 is then added50=
2.65 μm), lactose monohydrate and the remaining magnesium stearate of recipe quantity, 2min, agitating paddle linear velocity are mixed in high-speed mixer
10m/s。
Embodiment 4: using mannitol as carrier, leucine is stabilizer, the Tiotropium Bromide dry powder formoterol for sucking
Preparation
According to the form below weighs the leucine of recipe quantity 1/10 and micronized formoterol obtained in embodiment 2 is stirred
2min is transferred in planetary ball mill, sets sun wheel speed 500r/min mixing 10min, appropriate to stand, and it is multiple to prepare powder
Close object (D50=2.4 μm), the micronised Tiotropium bromide (D prepared in embodiment 1 is then added50=2.7 μm), mannitol and
Recipe quantity is remainingLeucine, 2min, agitating paddle linear velocity 60m/s, finally then at three-dimensional hybrid are mixed in high-speed mixer
10-20min is mixed in machine.
Embodiment 5: using lactose monohydrate as carrier, magnesium stearate is stabilizer, the Tiotropium Bromide Formoterol for sucking
Dry powder preparation
According to the form below weighs 0.5g magnesium stearate and 0.5g formoterol fumarate dihydrate is stirred 2min, is transferred to
In airslide disintegrating mill, pressure is crushed with 0.4MPa and is micronized altogether, powdered compound (D is prepared50=2.3 μm, formoterol fumarate
Content of dihydrate 48.2%), take powdered compound appropriate, wherein Formoterol is suitable with recipe quantity, and embodiment 1 is then added
Micronised Tiotropium bromide monohydrate (the D of middle preparation50=2.65 μm), lactose monohydrate and the remaining magnesium stearate of recipe quantity,
2min is mixed in high-speed mixer, agitating paddle linear velocity 100m/s finally mixes 10-20min in three-dimensional mixer.
Embodiment 6: using Lactis Anhydrous as carrier, magnesium stearate is stabilizer, the Tiotropium Bromide Formoterol for sucking
Dry powder preparation
According to the form below weighs 0.5g magnesium stearate and 0.5g formoterol fumarate dihydrate is stirred 2min, is transferred to
In airslide disintegrating mill, pressure is crushed with 0.4MPa and is micronized altogether, powdered compound (D is prepared50=2.3 μm, formoterol fumarate
Content of dihydrate 48.2%), take powdered compound appropriate, wherein Formoterol is suitable with recipe quantity, and embodiment 1 is then added
Micronised Tiotropium bromide monohydrate (the D of middle preparation50=2.65 μm), Lactis Anhydrous and the remaining magnesium stearate of recipe quantity,
2min is mixed in high-speed mixer, agitating paddle linear velocity 10m/s finally mixes 10-20min in three-dimensional mixer.
Embodiment 7: using lactose monohydrate as carrier, Macrogol 6000 is stabilizer, and the Tiotropium Bromide good fortune for sucking is not
Special Luo Gan's powder preparation
According to the form below weighs 0.05g Macrogol 6000 and 0.2g formoterol fumarate dihydrate is stirred 2min,
It is transferred in airslide disintegrating mill, pressure is crushed with 0.4MPa and is micronized altogether, powdered compound (D is prepared50=2.3 μm, fumaric acid good fortune
Mo Teluo content of dihydrate 82.4%), take powdered compound appropriate, wherein Formoterol is suitable with recipe quantity, is then added
Micronised Tiotropium bromide monohydrate (the D prepared in embodiment 150=2.65 μm), lactose monohydrate and recipe quantity it is remaining poly-
Ethylene glycol 6000, mixes 2min in high-speed mixer, and agitating paddle linear velocity 50m/s is finally mixed in three-dimensional mixer
5-10min。
Embodiment 8: the preparation of micronization Wumei bromine ammonium
Wumei bromine ammonium is micronized in airslide disintegrating mill, crushing pressure is 0.8Mpa, resulting particle size D50
Reach 5 μm or less.
Embodiment 9: it is micronized the preparation of aclidinium bromide
It willAclidinium bromideIt is micronized in airslide disintegrating mill, crushing pressure is 1.2Mpa, resulting particle size D50
Reach 5 μm or less.
Embodiment 10: the preparation of micronised glycopyrrolate
It willGlycopyrronium bromideIt is micronized in airslide disintegrating mill, crushing pressure is 0.6Mpa, resulting particle size D50
Reach 5 μm or less.
Embodiment 11: using lactose monohydrate as carrier, magnesium stearate is stabilizer, the Wumei bromine ammonium Vilantro for sucking
Dry powder preparation
According to the form below weighs 0.2g magnesium stearate and 0.2g trifluoromethanesulfonic acid Vilantro is stirred 2min, is transferred to air-flow
In pulverizer, pressure is crushed with 0.4MPa and is micronized altogether, preparing powdered compound, (D50=1.88 μm, trifluoromethanesulfonic acid ties up Lactel
Luo Hanliang 50.5%), take powdered compound appropriate, wherein Vilantro is suitable with recipe quantity, is then added in embodiment 8 and prepares
Micronization Wumei bromine ammonium (D50=2.05 μm), lactose monohydrate and the remaining magnesium stearate of recipe quantity, in high-speed mixer
2min is mixed, agitating paddle linear velocity 50m/s finally mixes 5-10min in three-dimensional mixer.
Embodiment 12: using lactose monohydrate as carrier, magnesium stearate is stabilizer, the aclidinium bromide Ao Dateluo for sucking
Dry powder preparation
According to the form below weighs 0.2g magnesium stearate and 0.2g hydrochloric acid Ao Dateluo is stirred 2min, is transferred to airslide disintegrating mill
In, with 0.4MPa crush pressure be micronized altogether, prepare powdered compound (D50=2.28 μm, hydrochloric acid Ao Dateluo content
51.9%), take powdered compound appropriate, wherein Ao Dateluo is suitable with recipe quantity, and the micro mist prepared in embodiment 9 is then added
Change aclidinium bromide (D50=2.02 μm), lactose monohydrate and the remaining magnesium stearate of recipe quantity, mixed in high-speed mixer
2min, agitating paddle linear velocity 50m/s, finally mixes 5-10min in three-dimensional mixer.
Embodiment 13: using lactose monohydrate as carrier, magnesium stearate is stabilizer, the glycopyrronium bromide datro for sucking
Dry powder preparation
According to the form below weighs 0.4g magnesium stearate and 4g maleic acid datro is stirred 2min, is transferred to airslide disintegrating mill
In, with 0.4MPa crush pressure be micronized altogether, prepare powdered compound (D50=1.81 μm, maleic acid datro content
91.5%), take powdered compound appropriate, wherein datro is suitable with recipe quantity, then prepares in addition embodiment 10 micro-
Dusting glycopyrronium bromide (D50=1.76 μm), lactose monohydrate and the remaining magnesium stearate of recipe quantity, mixed in high-speed mixer
2min, agitating paddle linear velocity 50m/s, finally mixes 5-10min in three-dimensional mixer.
Embodiment 14: using lactose monohydrate as carrier, magnesium stearate is stabilizer, the Tiotropium Bromide salmeterol for sucking
Dry powder preparation
According to the form below weighs 0.2g magnesium stearate and 2.0g SALMETEROL XINAFOATE is stirred 2min, is transferred to air-flow crushing
In machine, pressure is crushed with 0.4MPa and is micronized altogether, preparing powdered compound, (particle size is 1.81 μm, SALMETEROL XINAFOATE
Content 91.5%), take powdered compound appropriate, wherein salmeterol is suitable with recipe quantity, then prepares in addition embodiment 1
Micronised Tiotropium bromide (D50=2.65 μm), lactose monohydrate and the remaining magnesium stearate of recipe quantity, mixed in high-speed mixer
2min is closed, agitating paddle linear velocity 50m/s finally mixes 5-10min in three-dimensional mixer.
Embodiment 15: using lactose monohydrate as carrier, acetylcysteine is stabilizer, the husky beauty of the Tiotropium Bromide for sucking
Special Luo Gan's powder preparation
According to the form below weighs 0.2g acetylcysteine and 2.0g SALMETEROL XINAFOATE is stirred 2min, is transferred to air-flow
In pulverizer, pressure is crushed with 0.4MPa and is micronized altogether, preparing powdered compound, (particle size is 1.99 μm, the husky beauty of former times naphthoic acid
Special Luo Hanliang 91.5%), take powdered compound appropriate, wherein salmeterol is suitable with recipe quantity, is then added in embodiment 1 and makes
Standby micronised Tiotropium bromide (D50=2.65 μm), lactose monohydrate and the remaining acetylcysteine of recipe quantity, in high-speed stirring
It mixes and mixes 2min in machine, agitating paddle linear velocity 50m/s finally mixes 5-10min in three-dimensional mixer.
Comparative example 1
According to the form below weigh weighed according to the ratio of 200:1 the micronised Tiotropium bromide monohydrate prepared in embodiment 1 and
Magnesium Stearate proper quantity is transferred in airslide disintegrating mill after mixing thoroughly, and crushing pressure with 0.4MPa, micronization prepares powdered compound altogether
(particle size is 2.11 μm, tiotropium bromide monohydrate content 99.1%) according to the form below weighs, and takes powdered compound appropriate, in addition
Micronized formoterol dihydrate, the remaining magnesium stearate of recipe quantity, lactose monohydrate prepared by embodiment 2 is added,
3min is mixed in high-speed mixer, agitating paddle linear velocity 50m/s is finally transferred in three-dimensional mixer and mixes 5-10min.
Comparative example 2
The micronization richness horse that according to the form below weighs the micronised Tiotropium bromide monohydrate of the preparation of embodiment 1, prepared by embodiment 2
Sour Formoterol dihydrate, magnesium stearate, are stirred 2min, are then transferred in planetary ball mill, set sun gear
Revolving speed 500r/min mixing 10min, it is appropriate to stand, powder mixing volume object is prepared, lactose monohydrate is then added, in high-speed mixer
Middle mixing 3min, agitating paddle linear velocity 50m/s, is finally transferred in three-dimensional mixer and mixes 5-10min.
Comparative example 3
The micronization richness horse that according to the form below weighs the micronised Tiotropium bromide monohydrate of the preparation of embodiment 1, prepared by embodiment 2
Sour Formoterol dihydrate is stirred 2min, is then transferred in planetary ball mill, sets sun wheel speed 500r/
Min mixing 10min, it is appropriate to stand, mixture of powders is prepared, lactose monohydrate is then added, 3min is mixed in high-speed mixer,
Agitating paddle linear velocity 50m/s, is finally transferred in three-dimensional mixer and mixes 5-10min.
Comparative example 4
Weigh Wumei bromine ammonium, trifluoromethanesulfonic acid Vilantro is stirred 2min, be transferred in airslide disintegrating mill, with
0.4MPa crushes pressure and is micronized altogether, prepares powdered compound, takes mixture of powders appropriate, wherein Wumei bromine ammonium, Vilantro
It is substantially suitable with recipe quantity, magnesium stearate, lactose monohydrate is then added, 2min, agitating paddle linear speed are mixed in high-speed mixer
50m/s is spent, 5-10min is finally mixed in three-dimensional mixer.
Comparative example 5
It weighs Tiotropium Bromide, SALMETEROL XINAFOATE, Magnesium Stearate proper quantity and distinguishes air-flow crushing to D50At 5 μm hereinafter, so
Respectively 0.4g is taken to be transferred in planetary ball mill in the ratio of 1:1:1 afterwards, sets sun wheel speed 500r/min mixing 10min,
It is appropriate to stand, prepare powdered compound.Take mixture of powders appropriate, wherein Tiotropium Bromide, SALMETEROL XINAFOATE and recipe quantity
Substantially quite, the remaining magnesium stearate that lactose monohydrate and recipe quantity are added according to recipe quantity is then added, in high-speed mixer
2min is mixed, agitating paddle linear velocity 50m/s finally mixes 5-10min in three-dimensional mixer.
Embodiment 16: long-acting cholinergic antagonist and long acting beta agonists stability study for sucking
The purpose of the research is to simulate product obtained stability change situation during storage.
The powder of Example 3-7 and comparative example 1-3, by 25mg/ filling capsules, preparation can be sucked by dry powder
Device sucks preparation to the Tiotropium Bromide dry powder formoterol of pulmonary administration；The powder of Example 11 and comparative example 4, is pressed
12.5mg/ filling capsule preparations, which can be sucked by powder inhaler to the Wumei bromine ammonium Vilantro dry powder of pulmonary administration, makes
Agent；The powder of embodiment 14 and comparative example 5, by 5.5mg/ filling capsules, preparation can be by powder inhaler to lung
The Tiotropium Bromide salmeterol dry powder inhaler formulations of portion's administration.Each group capsule is sealed using aluminium foil bag, is subsequently placed in 40 DEG C,
In RH75% environment, content and the variation of related substance are measured at regular intervals, as a result as follows,
1 Formoterol of table and Tiotropium Bromide impurity content change table
2 Vilantro of table and Wumei bromine ammonium impurity content change table
3 salmeterol of table and Tiotropium Bromide impurity content change table
Embodiment 3-7 and comparative example 1,2,3, embodiment 11 and comparative example 4, the stability number of embodiment 14 and comparative example 5
Studies show that, the addition of stabilizer and the stability of hybrid technique joint effect product, only stabilizer and long-acting beta receptor swash
Dynamic agent first carries out after being mixed to get compound, then the product stability being mixed to get with other formulation ingredients can just greatly improve.
The technique of the compound formed by ground and mixed and high-speed stirred can be same after stabilizer is added in the prescription that the present invention uses
The stability of two kinds of ingredients of Shi Tigao.Dedicated medicinal powder inhaler can be cooperated to carry out inhalation after gained powder packing capsule,
For Treatment of COPD.
Claims (10)
1. a kind of dry powder composite for sucking, which is characterized in that the dry powder composite contains long-acting cholinergic recepter resistance
Disconnected agent, long acting beta agonists, stabilizer and pharmaceutical carrier, wherein a part and the long-acting beta in the stabilizer by
Body agonist forms coating, which is so that the use that the long acting beta agonists are wrapped up completely
Amount.
2. dry powder composite according to claim 1, which is characterized in that the long-acting cholinergic antagonist is selected from thiophene
Ammonium, glycopyrronium, aclidinium, the pharmaceutical bromide of Wumei ammonium, chloride, iodide and its monohydrate form are held in the palm, preferably
Tiotropium Bromide or its monohydrate；
Preferably, the D of the long-acting cholinergic antagonist50Less than 5 μm.
3. dry powder composite according to claim 1 or 2, which is characterized in that the stabilizer is selected from stearate, amino
One of acid and its derivative, polyethylene glycol are a variety of, preferably magnesium stearate or leucine.
4. dry powder composite according to any one of claim 1 to 3, which is characterized in that the long acting beta agonists
Selected from datro, Formoterol, Vilantro, salmeterol, Ao Dateluo and its officinal salt, preferably Formoterol,
The dihydrate of its fumarate or its fumarate；
Preferably, the D50 of the long acting beta agonists is less than 5 μm.
5. dry powder composite according to any one of claim 1 to 4, which is characterized in that the pharmaceutical carrier is selected from sugar
One of class, sugar alcohol are a variety of, preferably or mixtures thereof lactose monohydrate, Lactis Anhydrous.
6. dry powder composite according to any one of claim 1 to 5, which is characterized in that the long-acting cholinergic by
The weight ratio of body blocking agent and pharmaceutical carrier is 1:20~1:2000；
Preferably, the weight ratio of the long acting beta agonists and the pharmaceutical carrier is 1:20~1:2000.
7. dry powder composite according to any one of claim 1 to 6, which is characterized in that the stabilizer and the medicine
It is 1:20~1:2000 with the weight ratio of carrier.
8. dry powder composite according to any one of claim 1 to 7, which is characterized in that with the long-acting beta receptor agonism
Dosage form is 1:10~10:1 at the stabilizer of coating and the weight ratio of the long acting beta agonists.
9. a kind of prepare the method such as dry powder composite described in any item of the claim 1 to 8, this method includes following step
It is rapid: a) be co-mulled and made into being mixed to form compound with partially stabilized dose by long acting beta agonists；B) by formation in step a)
Compound carries out high-speed stirred with long-acting cholinergic antagonist, remaining stabilizer, pharmaceutical carrier and mixes to obtain the final product.
10. described to be co-mulled and made into the grinding being used in mixed way according to the method described in claim 9, it is characterized in that, in step a)
Equipment is selected from ball milling instrument, disc type beveller, planetary type ball-milling instrument, mechanical fusion machine or airslide disintegrating mill；
In step b), the blender linear velocity of the high-speed stirred mixing is 1-100m/s, preferably 10-60m/s.
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| 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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| CN115364075A (en) * | 2022-09-16 | 2022-11-22 | 苏州易合医药有限公司 | Inhalation particle composition and preparation method thereof |
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| GB2614901A (en) * | 2022-01-21 | 2023-07-26 | Nanopharm Ltd | Inhalable formulations |
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