CN101062020A - Tiotropium bromide capsule type dry powder inhalations and the preparing method thereof - Google Patents
Tiotropium bromide capsule type dry powder inhalations and the preparing method thereof Download PDFInfo
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- CN101062020A CN101062020A CN 200610050481 CN200610050481A CN101062020A CN 101062020 A CN101062020 A CN 101062020A CN 200610050481 CN200610050481 CN 200610050481 CN 200610050481 A CN200610050481 A CN 200610050481A CN 101062020 A CN101062020 A CN 101062020A
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- tiotropium bromide
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- lactose
- micropowder
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Abstract
The invention discloses a tipetropium bromine ammonium capsule type sucking powder cloud agent and preparing craft, which is characterized by the following: comprising capsule shell and capsule content; allocating the capsule content with 0. 1-10% tipetropium bromine ammonium load medicine super fine and 90%-99. 9% shaped agent; setting the average grain size less than 10mum and 80% grain size less than 5mum; setting the shaped grain size between 75mum and 180mum range; setting the shaped agent as the mixture of crystallisation milk sugar or crystallisation milk sugar and spray drying milk sugar.
Description
Technical field
The present invention relates to a kind of medicine for the treatment of chronic obstructive pulmonary disease, relate in particular to a kind of capsule type tiotropium bromide inhalation powder and preparation technology thereof.
Background technology
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) being the generally popular and increasing PD of industrialized country, is the general term that comprises a series of symptoms such as chronic cough, expectoration, exertional dyspnea and tangible reversible or irreversible carrying out property of air-flow minimizing.At present the whole world causes that COPD arranges the 4th in the dead disease, and the year two thousand twenty is arrived in the World Bank and WHO prediction in the world, because of the financial burden that COPD caused will be discharged to the 5th.
Tiotropium bromide (Tiotropium Bromide) is a kind of new COPD medicine, is effective m receptor antagonist, and calendar year 2001, JIUYUE was first at Holland listing (Spiriva
), in JIUYUE, 2002 obtains drugs approved by FDA, and dosage form is that capsule-type sucks powder.Single dose is very little, is 18 micrograms.
Suck powder spray (Inhalation Powder) and be also referred to as dry powder inhalant (Dry PowerInhalers, DPI), usually will contain the medicine powder encapsulating in single dose hard capsule or multiple dose storage storehouse, with certain simple and easy DPI suction apparatus administration, do not contain propellant, the air-flow that produces by patient's autonomous respiration makes the medicine powder atomization, and then drug powder is transported to pulmonary synchronously, the dyssynergia when having avoided dosage forms such as aerosol to use.Have and use advantages such as convenient, that dosage is controlled easily and zest is little, enjoy people to pay close attention in recent years, exploitation and clinical practice kind day by day increase.
Summary of the invention
The object of the present invention is to provide a kind of capsule type tiotropium bromide inhalation powder, this sucks powder spray and is made up of tiotropium bromide medicine carrying micropowder and excipient lactose.
Another object of the present invention also is to provide the preparation method of this capsule type tiotropium bromide inhalation powder.
A kind of capsule type tiotropium bromide inhalation powder of the present invention comprises capsule shells and capsule 's content, and capsule 's content is made up of the component of following weight ratio:
Tiotropium bromide medicine carrying micropowder 0.1%-10%
Excipient 90%-99.9%
Wherein the mean diameter of tiotropium bromide medicine carrying micropowder is less than 10 μ m, and wherein 80% particle diameter is less than 5 μ m; The excipient particle diameter is in the scope of 75 μ m-180 μ m, and described excipient is the mixture of crystallization lactose or crystallization lactose and spray-dried lactose.。
Described tiotropium bromide medicine carrying micropowder is made up of the component of following weight ratio:
Tiotropium bromide 9.09%-66.67%
Crystallization lactose 33.33%-90.91%
The preferred weight ratio of tiotropium bromide is 14.29%, and the weight ratio of crystallization lactose is 85.71%.
Described excipient is the mixture of crystallization lactose and spray-dried lactose, and its composition weight ratio is:
Crystallization lactose 30%-80%
Spray-dried lactose 20%-70%
The preferred weight ratio of crystallization lactose is 64.31%, and the preferred weight ratio of spray-dried lactose is 35.69%.
Capsule 's content weight is 5-35mg, and the capsule 's content preferred weight is 20mg.
The water content of tiotropium crystal of the present invention is 1-6%, and ft-ir characteristic absorption peak is positioned at wavelength 3416cm
-1, 3095cm
-1, 1730cm
-1, 1254cm
-1, 1037cm
-1And 712cm
-1
The present invention also discloses a kind of preparation method of capsule type tiotropium bromide inhalation powder, comprises the steps:
(1) formula proportion by the tiotropium bromide micropowder takes by weighing each component, by equivalent incremental method mixing;
(2) material behind the mix homogeneously is carried out the particle diameter of comminution by gas stream to regulation;
(3) take by weighing each component by the excipient formula proportion, get crystallization lactose wherein, grind mixing by equivalent incremental method and tiotropium bromide micropowder, again with excipient in spray-dried lactose press equivalent incremental method mixing;
(4) by prescription design, the powder of getting behind the mixing is filled in suitable common hard capsule, promptly.
The present invention adopts common comminution by gas stream to prepare tiotropium bromide medicine carrying micropowder, adopts common equivalent to increase progressively mode of averaging again and is prepared into and can sucks powder, fills common hard capsule, promptly gets capsule type tiotropium bromide inhalation powder.Preparation is simple for the present invention's employing, and technical equipment is not had too much specific (special) requirements, is suitable for the industrialized great production of domestic general pharmacy corporation.The capsule type tiotropium bromide inhalation powder that adopts the present invention to make can satisfy every specification requirement of the suction powder spray of Chinese Pharmacopoeia regulation.
Capsule type inhalation aerosol powder be with medicine carrying micropowder and suitable excipient with capsule form, through suitable suction apparatus, can initiatively suck the preparation that atomizes to pulmonary.Drug microparticles that it is generally acknowledged particle diameter 0.5-7 μ m could arrive pulmonary's performance drug effect, therefore the particle diameter of the suction powder drug particles that makes should be controlled at below the 10 μ m, wherein great majority should be below 5 μ m, both just like this, also only there is the medicine of 1%-20% to deposit and onset, carries out external simulation test so reply sucks powder spray in effective site.Chinese Pharmacopoeia version (two ones) in 2000 appendix XH regulation deposition ratio in the effective position should be greater than 10%.
The effect that sucks excipient in the powder spray mostly is the absorption drug microparticles.The absorption of excipient and drug microparticles can not too closely can not be too loose, too closely then drug microparticles can't effectively separate in sucking flow perturbation with excipient, pastille excipient major part is deposited on upper respiratory tract, causes medicine can't arrive lung deep performance drug effect; Too loosely then may in suction process, be adsorbed on capsule shells or the suction apparatus, cause dosage to reduce with the excipient premature disengagement, particularly evident for drug influence so low dose of among the present invention.
The particle diameter that sucks the powder spray excipient should be 30-200 μ m, and the particle diameter increase then increases the zest of respiratory tract, reduces patient and uses compliance; Particle diameter reduces then mobile variation, and Emptying Rate descends, and influences drug effect.The present invention controls the excipient particle diameter in the scope of 75 μ m-180 μ m, and zest is little and Emptying Rate is high.
Lactose is powder spray excipient commonly used, and good water solubility is lower to respiratory tract.Examine under a microscope, spray-dried lactose is sphaerocrystal, thus mobile fine, and general crystallization lactose is irregular crystal, mobile relatively poor.But the absorption between crystallization lactose and drug microparticles is comparatively suitable, and drug microparticles is adsorbed in crystallization lactose surface, and simple is the powder spray that excipient makes with the crystallization lactose, and Emptying Rate is low, and deposition ratio in the effective position is still higher.Simple is the powder spray that excipient makes with the spray-dried lactose, though Emptying Rate improves and deposition ratio in the effective position slightly decline on the contrary greatly.This may be because the spray-dried lactose crystal has cellular surface, the surface energy height, and adsorb reason too closely between the drug microparticles.The present invention combines the advantage of two kinds of lactose, at first fully adsorb drug microparticles with the crystallization lactose, improve the flowability of whole powder body again with spray-dried lactose, lactose small-particle in the medicine carrying micropowder has occupied the high energy surface of part excipient simultaneously, prevent the adsorbed close of medicine and excipient, under suitable ratio, can make Emptying Rate and all qualified suction powder spray of deposition ratio in the effective position.
The specific embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
The preparation of tiotropium bromide medicine carrying micropowder
Get tiotropium bromide and crystallization lactose, by weight 1: 6 ratio mixing, comminution by gas stream to mean diameter less than 10 μ m, wherein 80% particle diameter is less than 5 μ m.
The preparation of inhaled tiotropium bromide powder preparation
Tiotropium bromide medicine carrying micropowder 157.5mg
Crystallization lactose 12.85g
Spray-dried lactose 7.13g
Make 1000 altogether
Press recipe quantity tiotropium bromide medicine carrying micropowder is mixed by the equivalent incremental method with the crystallization lactose of crossing 100 mesh sieves in advance, be ground to repeatedly evenly, again with particle diameter 200-80 purpose spray-dried lactose mixing, survey content, after qualified,, adorn capsule No. 3 according to the cubage loading amount.
Embodiment 2
The preparation of tiotropium bromide medicine carrying micropowder
Get tiotropium bromide and crystallization lactose, by weight 1: 5 ratio mixing, comminution by gas stream to mean diameter less than 10 μ m, wherein 80% particle diameter is less than 5 μ m.
The preparation of inhaled tiotropium bromide powder preparation
Tiotropium bromide medicine carrying micropowder 135mg
Crystallization lactose 12.85g
Spray-dried lactose 7.13g
Make 1000 altogether
Press recipe quantity tiotropium bromide medicine carrying micropowder is mixed by the equivalent incremental method with the crystallization lactose of crossing 100 mesh sieves in advance, be ground to repeatedly evenly, again with particle diameter 200-80 purpose spray-dried lactose mixing, survey content, after qualified,, adorn capsule No. 3 according to the cubage loading amount.
Embodiment 3
The preparation of tiotropium bromide medicine carrying micropowder
Get tiotropium bromide and crystallization lactose, by weight 1: 6 ratio mixing, comminution by gas stream to mean diameter less than 10 μ m, wherein 80% particle diameter is less than 5 μ m.
The preparation of inhaled tiotropium bromide powder preparation
Tiotropium bromide medicine carrying micropowder 157.5mg
Crystallization lactose 13g
Spray-dried lactose 7g
Make 1000 altogether
Press recipe quantity tiotropium bromide medicine carrying micropowder is mixed by the equivalent incremental method with the crystallization lactose of crossing 100 mesh sieves in advance, be ground to repeatedly evenly, again with particle diameter 200-80 purpose spray-dried lactose mixing, survey content, after qualified,, adorn capsule No. 3 according to the cubage loading amount.
Embodiment 4
The preparation of tiotropium bromide medicine carrying micropowder
Get tiotropium bromide and crystallization lactose, by weight 1: 6 ratio mixing, comminution by gas stream to mean diameter less than 10 μ m, wherein 80% particle diameter is less than 5 μ m.
The preparation of inhaled tiotropium bromide powder preparation
Tiotropium bromide medicine carrying micropowder 157.5mg
Crystallization lactose 11g
Spray-dried lactose 9g
Make 1000 altogether
Press recipe quantity tiotropium bromide medicine carrying micropowder is mixed by the equivalent incremental method with the crystallization lactose of crossing 100 mesh sieves in advance, be ground to repeatedly evenly, again with particle diameter 200-80 purpose spray-dried lactose mixing, survey content, after qualified,, adorn capsule No. 3 according to the cubage loading amount.
Claims (9)
1, a kind of capsule type tiotropium bromide inhalation powder comprises capsule shells and capsule 's content, it is characterized in that capsule 's content is made up of the component of following weight ratio:
Tiotropium bromide medicine carrying micropowder 0.1%-10%
Excipient 90%-99.9%
Wherein the mean diameter of tiotropium bromide medicine carrying micropowder is less than 10 μ m, and wherein 80% particle diameter is less than 5 μ m; The excipient particle diameter is in the scope of 75 μ m-180 μ m, and described excipient is the mixture of crystallization lactose or crystallization lactose and spray-dried lactose.
2, capsule type tiotropium bromide inhalation powder according to claim 1 is characterized in that described tiotropium bromide medicine carrying micropowder is made up of the component of following weight ratio:
Tiotropium bromide 9.09%-66.67%
Crystallization lactose 33.33%-90.91%
3, tiotropium bromide medicine carrying micropowder according to claim 2, the weight ratio that it is characterized in that tiotropium bromide is 14.29%, the weight ratio of crystallization lactose is 85.71%.
4, capsule type tiotropium bromide inhalation powder according to claim 1, the described excipient of its feature is the mixture of crystallization lactose and spray-dried lactose, its composition weight ratio is:
Crystallization lactose 30%-80%
Spray-dried lactose 20%-70%
5, capsule type tiotropium bromide inhalation powder according to claim 4, the weight ratio that it is characterized in that the crystallization lactose is 64.31%, the weight ratio of spray-dried lactose is 35.69%.
6, capsule type tiotropium bromide inhalation powder according to claim 1 is characterized in that capsule 's content weight is 5-35mg.
7, capsule type tiotropium bromide inhalation powder according to claim 6 is characterized in that capsule 's content weight is 20mg.
8, according to the described capsule type tiotropium bromide inhalation powder of claim 1～7, the water content that it is characterized in that tiotropium crystal is 1-6%, and ft-ir characteristic absorption peak is positioned at wavelength 3416cm
-1, 3095cm
-1, 1730cm
-1, 1254cm
-1, 1037cm
-1And 712cm
-1
9, according to the preparation technology of any one described capsule type tiotropium bromide inhalation powder of claim 1～8, its feature comprises the steps:
(1) formula proportion by the tiotropium bromide micropowder takes by weighing each component, by equivalent incremental method mixing;
(2) material behind the mix homogeneously is carried out the particle diameter of comminution by gas stream to regulation;
(3) take by weighing each component by the excipient formula proportion, get crystallization lactose wherein, grind mixing by equivalent incremental method and tiotropium bromide micropowder, again with excipient in spray-dried lactose press equivalent incremental method mixing;
(4) by prescription design, the powder of getting behind the mixing is filled in suitable common hard capsule, promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610050481 CN101062020A (en) | 2006-04-24 | 2006-04-24 | Tiotropium bromide capsule type dry powder inhalations and the preparing method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610050481 CN101062020A (en) | 2006-04-24 | 2006-04-24 | Tiotropium bromide capsule type dry powder inhalations and the preparing method thereof |
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| CN101062020A true CN101062020A (en) | 2007-10-31 |
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| CN 200610050481 Pending CN101062020A (en) | 2006-04-24 | 2006-04-24 | Tiotropium bromide capsule type dry powder inhalations and the preparing method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102451173A (en) * | 2010-10-22 | 2012-05-16 | 山东新时代药业有限公司 | Tiotropium bromide capsule-type inhalation aerosol powder |
| CN102614154A (en) * | 2012-03-31 | 2012-08-01 | 中山大学 | Asarone dry powder inhalant and method for preparing same |
| CN107823193A (en) * | 2017-11-16 | 2018-03-23 | 广州迈达康医药科技有限公司 | A kind of aclidinium bromide induction type powder spray and preparation method thereof |
| CN111374995A (en) * | 2020-03-30 | 2020-07-07 | 常州道宁医药科技有限公司 | α/β mixed crystal anhydrous lactose blumea balsamifera oil-loaded respiratory system antiviral dry powder inhalant and preparation method thereof |
-
2006
- 2006-04-24 CN CN 200610050481 patent/CN101062020A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102451173A (en) * | 2010-10-22 | 2012-05-16 | 山东新时代药业有限公司 | Tiotropium bromide capsule-type inhalation aerosol powder |
| CN102451173B (en) * | 2010-10-22 | 2015-02-18 | 山东新时代药业有限公司 | Tiotropium bromide capsule-type inhalation aerosol powder |
| CN102614154A (en) * | 2012-03-31 | 2012-08-01 | 中山大学 | Asarone dry powder inhalant and method for preparing same |
| CN107823193A (en) * | 2017-11-16 | 2018-03-23 | 广州迈达康医药科技有限公司 | A kind of aclidinium bromide induction type powder spray and preparation method thereof |
| CN107823193B (en) * | 2017-11-16 | 2021-02-05 | 广州迈达康医药科技有限公司 | Aclidinium bromide inhalation type powder aerosol and preparation method thereof |
| CN111374995A (en) * | 2020-03-30 | 2020-07-07 | 常州道宁医药科技有限公司 | α/β mixed crystal anhydrous lactose blumea balsamifera oil-loaded respiratory system antiviral dry powder inhalant and preparation method thereof |
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Open date: 20071031 |