CN1593414A - Powder inhalation of tiotropium bromide capsule type and its preparation method - Google Patents
Powder inhalation of tiotropium bromide capsule type and its preparation method Download PDFInfo
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- CN1593414A CN1593414A CN 200410025716 CN200410025716A CN1593414A CN 1593414 A CN1593414 A CN 1593414A CN 200410025716 CN200410025716 CN 200410025716 CN 200410025716 A CN200410025716 A CN 200410025716A CN 1593414 A CN1593414 A CN 1593414A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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Abstract
The invention relates to a powder inhalation of tiotropium bromide capsule type and its preparation method, wherein the powder inhalation is prepared from tiotropium bromide drug carrying ultra-fine powder and excipient, through the method of spray-drying. The invention realizes fine pouring properties and and low moisture leading property.
Description
Technical field
The present invention relates to medical suction powder spray, more specifically relating to a kind of is the capsule type tiotropium bromide inhalation powder that is used for the treatment of obstructive pulmonary disease of principal agent with the made micropowder of the compositions that contains tiotropium bromide, carrier and additives.
The invention still further relates to the preparation method of this capsule type inhalation aerosol powder.
Background technology
Tiotropium bromide (Tiotropium Bromide), its chemical name is: oxygen base (1 α, 2 β, 4, β, 5 α, 7 β)-7-[(hydroxyl-2-thiophene acetyl)]-9,9-dimethyl-3-oxa--9-nitrogen oxonium ion three ring [3.3.3.02,4] nonane Bromides.Its chemical structural formula is as follows:
Tiotropium bromide is the competitive antagonist of cholinergic M-receptor, and the kinetics selectivity of M3 and M1 receptor is far surpassed the M2 receptor.Therefore strong to the lax selectively acting of bronchial smooth muscle, long action time is effective to chronic obstructive pulmonary disease (COPD) patient's the treatment of keeping.Studies show that one day be administered once (sucking 18 μ g/ days) can significantly improve the respiratory function of patients with chronic obstructive pulmonary diseases, act on sustainable keep (Drugs of the Future, 2000.25 (7): 693-699) more than 24 hours.Tiotropium bromide is a quaternary ammonium salt, and oral absorption is poor, is fit to inhalation.And the general cholinolytic effect is not remarkable behind the inhalation, so side effect is little, and toxicity also very low (Drugs of the Future, 2000.25 (7): 693-699).
Powder spray is a kind of inspiratory airflow by the patient, use special-purpose suction apparatus, with medicine or (with) the carrier micropowder sucks respiratory tract through aerodynamic atomization, make medicine enter therapentic part or human lung and play a class preparation of therapeutical effect, have big, the easy characteristics such as collaborative, bioavailability height of institute's lotus dosage.With medicine or (with) the carrier micropowder is filled in becomes unit formulation in the hard capsule, being loaded into the powder spray that sucks in the utensil then is capsule type inhalation aerosol powder.Its content is made up of principal agent, carrier and additives.It is generally acknowledged that particle diameter is the drug microparticles of 0.5-7 μ m, could arrive pulmonary.The effect of carrier mostly is the absorption drug microparticles, and additives have comprised surfactant, dispersant, lubricant, antistatic additive etc., and it mainly acts on is to improve the favourable physical property of powder spray, as improves flowability, reduce draw moist etc.
The characteristics of the at present used method for preparing capsule type tiotropium bromide inhalation powder be with behind the independent micronization of active component tiotropium bromide again with mixed with excipients.Be filled in the method for making (Chinese patent CN1392799A) of hard capsule after for example adopting excipient such as the sugar of two kinds of particle diameters of thickness and sugar alcohol and micronized tiotropium bromide mixing; The employing glycine is an excipient, with the method for making (Chinese patent CN1439362A) that is filled in hard capsule after micronized tiotropium bromide mixes.The amount of tiotropium bromide is about 20 micrograms in the unit formulation of suitable clinical treatment dosage, and excipient then needs to add to more than 20 milligrams, and both differ nearly thousand times.And existing method has been ignored the ratio that exists great disparity between the consumption of tiotropium bromide and excipient, and the problem of bringing thus is that the tiotropium bromide micropowder of mobile extreme difference is difficult to mix even with a large amount of excipient.In addition, utilize prior art for preparing the tiotropium bromide micropowder flowability and draw moist relatively poor, thereby influenced workmanship and the storage stability that sucks powder spray.
Summary of the invention
The object of the invention is to provide a kind of capsule type tiotropium bromide inhalation powder, the made micropowder of compositions that the principal agent of this powder spray is served as reasons and contained tiotropium bromide, carrier and additives, tiotropium bromide medicine carrying micropowder good fluidity provided by the invention draws moist low.
Another object of the present invention is to provide the preparation method of this capsule type tiotropium bromide inhalation powder, to overcome the deficiencies in the prior art.
The present invention utilizes spray drying technology, will make good fluidity in the small dose drug (as tiotropium bromide) of tens of micrograms, draw moist low medicine carrying micropowder by adding carrier and hydrophobic amino acid (additives) in using.This medicine carrying micropowder can be even with mixed with excipients, thereby prepare the powder spray that has excellent storage stability, is fit to suction.The use of hydrophobic amino acid makes moist reducing of drawing of powder spray, and stability increases.
Capsule type inhalation aerosol powder of the present invention is filled in the hard capsule after evenly by principal agent tiotropium bromide medicine carrying micropowder and mixed with excipients and makes.The purpose of using excipient is when filling the dust cloud agent capsules, improves the flowability of micropowder, increases the grain to 20-50mg/ of measuring of content, and capsule filling machine easy to use is filled.
Capsule type inhalation aerosol powder of the present invention is made up of hard capsule and content, and the composition of its capsule 's content (by weight) is as follows:
Tiotropium bromide medicine carrying micropowder 5%-50%
Excipient 50%-95%
In the above-mentioned prescription, excipient is selected the acceptable sugar of physiology, sugar alcohol, aminoacid etc., preferred lactose monohydrate (pharmaceutical lactose) or glycine (L or DL type) or mannitol, pharmaceutical lactose (meet " two 410 pages of requirements of recording of Chinese pharmacopoeia version in 2000) most preferably wherein, drawing of these excipient is moist little, good biocompatibility is to the respiratory tract nonirritant.The preferred amount ranges of pharmaceutical lactose is 60%-90% (w/w), according to the consumption of medicine carrying micropowder and wherein tiotropium bromide content and decide, make that the content total amount of unit formulation is 20~50mg.The granularity requirements of excipient is: the percent of pass of 100 mesh sieves is 100%, and the percent of pass of 120 mesh sieves is no less than 95%.
The composition (by weight) of tiotropium bromide medicine carrying micropowder is as follows:
Tiotropium bromide 0.1%-5%
Hydrophobic amino acid 10%-70%
Water-solubility carrier 25%-89.9%
The preferred amount ranges 0.5%-1% of tiotropium bromide (w/w) wherein, its reason is: the amount of (1) micropowder in the powder spray unit formulation needs between 5%-50%, and the content total amount can be fit to automatization and fill between 20-50mg; (2) according to clinical dosage, tiotropium bromide content in unit formulation is about 20g, and carrier dilutes more than 100 times so need to use.
Hydrophobic amino acid is mobile and draw moist grade to help the character of capsule type inhalation aerosol powder preparation most important for changing micropowder that spray drying makes.Hydrophobic amino acid can be selected from one or both in leucine, isoleucine, tyrosine, phenylalanine, the tryptophan, L type or DL all can, preferred L-leucine.More than several hydrophobic amino acids do not draw moistly, have good lubricity simultaneously, the micropowder that makes is had reduce static, reduce to draw moist, increase mobile effect; When the consumption of hydrophobic amino acid during less than 10% (w/w), improve the mobile and hygroscopic DeGrain of reduction of micropowder, when consumption surpasses 70% (w/w), the micropowder flowability is not good enough (quality kicks the beam), its preferred amount ranges is 30%-70% (w/w), and optimum range is 30%-50% (w/w).
Water-solubility carrier is glycine (L or DL type all can) or mannitol or lactose, all size that meets medicinal standard all can because water-solubility carrier will be dissolved in the water earlier in use, spray drying then, originally physical aspect has not existed.The water-solubility carrier consumption is 25%-89.9% (w/w), and preferable range is 50%-70% (w/w).
Because tiotropium bromide is a kind of carboxylate, and is unsettled in alkaline solution, when therefore carrying out spray drying, tiotropium bromide should be dissolved in the aqueous solution of pH4.0-7.0, preferred pH scope is 4.5-6.5.Optimum range 5.0-6.0.PH is lower than at 4.0 o'clock, resulting tiotropium bromide medicine carrying micropowder can stimulate throat to cause cough, and pH is higher than 7.0 o'clock tiotropium bromides and can decomposes when being heated, and therefore need use the pH regulator agent when preparation tiotropium bromide medicine carrying micropowder, so that the pH value of solution reaches 4.0-7.0.The acceptable acid-base reagent of the optional various physiology of used pH regulator agent, as the sulphuric acid in the mineral acid and salt, hydrochloric acid and salt thereof, phosphoric acid and salt thereof, acetic acid in the organic acid and sodium salt thereof or potassium salt, citric acid and sodium thereof or potassium salt, fumaric acid and sodium salt thereof or potassium salt, lactic acid and sodium salt or potassium salt etc., can also be acidic amino acid such as aspartic acid and glutamic acid and sodium salt thereof or potassium salt, wherein preferably citric acid and sodium hydroxide be acid-base reagent.The consumption of pH regulator agent is the required minimum amount of practical adjustments.
The water content of tiotropium bromide medicine carrying micropowder is less than 3%.80% diameter of particle is in 0.5 μ m-5 mu m range, and 90% diameter of particle is less than 10 μ m.The angle of repose of micropowder is less than 45 degree.
The characteristics of the preparation method of capsule type inhalation aerosol powder of the present invention specifically comprise the steps: for adopting spray drying method for preparation tiotropium bromide medicine carrying micropowder
(1) formula proportion by tiotropium bromide medicine carrying micropowder takes by weighing each component, tiotropium bromide, hydrophobic amino acid and water-solubility carrier are dissolved in the water, make the solids content of solution reach 1%-10% (w/v), adjust the solution pH value with the pH regulator agent and reach 4.0-7.0.
(2) with spray dryer solution is carried out spray drying, the tiotropium bromide medicine carrying micropowder that makes is standby.
(3) the capsule 's content prescription by capsule type inhalation aerosol powder takes by weighing tiotropium bromide medicine carrying micropowder and excipient, mixes, and is filled in hard capsule promptly, the processing of should sieving before the excipient weighing.
The key of the inventive method is to control the solid content and the pH value of solution, and when the solution solid content surpassed 10% (w/v), the powder diameter that makes obviously increased, the requirement that is not suitable for sucking.In the inventive method, the solid content of control is preferably 2%-5% (w/v), and the optimum controling range of pH is 5.0-6.0.
Spray drying adopts conventional method, its control of process condition is decided on the spray dryer of concrete power, the TWG-120 type spray dryer of producing with Tianli Drying Equipment Co., Ltd., Shandong is an example, the process conditions of being controlled are: inlet temperature 110-150 ℃, leaving air temp 70-90 ℃, atomization air flow speed 0.5-1.0m
3/ h, sample introduction speed 50-200mL/h.
Beneficial effect:
1, the tiotropium bromide medicine carrying micropowder that makes of the inventive method has solved active component and adjuvant ratio great disparity, is difficult to the uniform difficult problem of mechanical mixture, and tiotropium bromide powder spray of the present invention has stability for storage and flowability.
2, the present invention uses hydrophobic amino acid, utilizes the prepared tiotropium bromide medicine carrying of spray drying micropowder, has good fluidity, draws moist little advantage.The angle of repose of tiotropium bromide medicine carrying micropowder of the present invention is less than 45 degree.
3, the present invention makes tiotropium bromide not decompose at spray-drying process by the pH value of control solution.
The specific embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
Spray dryer adopts the TWG-120 type spray dryer that Tianli Drying Equipment Co., Ltd., Shandong produces among the embodiment 1-3; The granularity of tiotropium bromide medicine carrying micropowder adopts measurement microscope; Moisture content adopts Ka Feishi moisture content titration method to measure; The assay method of angle of repose is the fixed funnel method, is about to funnel and is fixed on suitable height H, and powder is put in the funnel, makes under the spontaneous current in heapsly, till the top of cone rigidly connects when contacting hopper outlet, measures the radius r of circular cone bottom surface, calculates angle of repose.Angle of repose=tan
-1(H/r).
The preparation of embodiment 1 tiotropium bromide medicine carrying micropowder
[prescription proportioning]:
Component sequence number component title consumption percentage composition %w/w
1 tiotropium bromide 0.022g 0.2
2 L-leucine 4g 36.3
3 lactose 7g 63.5
Method for making: take by weighing each component by the prescription proportioning, each components dissolved in the 250ml deionized water, is measured the pH value of solution, adjust the solution pH value between the 5.0-6.0 with 1mol/L citric acid or 1mol/L NaOH.The solution that makes thus carries out spray drying with spray dryer and obtains tiotropium bromide medicine carrying micropowder, when carrying out spray drying, and 130 ℃ of control inlet temperature, 75 ℃ of leaving air temps, atomization air flow speed 0.8m
3/ h, sample introduction speed 100mL/h.
Quality control index is measured: the granularity of tiotropium bromide medicine carrying micropowder be 80% diameter of particle in 0.5 μ m-5 mu m range, 90% diameter of particle is less than 10 μ m; Moisture content is 2.51%; Be 42.2 degree angle of repose.
The preparation of embodiment 2 tiotropium bromide medicine carrying micropowders
[prescription proportioning]:
Component sequence number component title consumption percentage composition %w/w
1 tiotropium bromide 0.022g 0.2
2 L-leucine 4g 36.3
3 glycine 7g 63.5
Method for making: with embodiment 1.
Quality control index is measured: the granularity of tiotropium bromide medicine carrying micropowder be 80% diameter of particle in 0.5 μ m-5 mu m range, 90% diameter of particle is less than 10 μ m; Moisture content is 1.73%; Be 41.4 degree angle of repose.
The preparation of embodiment 3 tiotropium bromide medicine carrying micropowders
[prescription proportioning]:
Component sequence number component title consumption percentage composition %w/w
1 tiotropium bromide 0.022g 0.2
2 L-leucine 2g 18.1
3 mannitol 9g 81.7
Method for making: with embodiment 1.
Quality control index is measured: the granularity of tiotropium bromide medicine carrying micropowder be 80% diameter of particle in 0.5 μ m-5 mu m range, 90% diameter of particle is less than 10 μ m; Moisture content is 2.73%; Angle of repose: 44.4 degree.
Tiotropium bromide content in the embodiment 4 liquid chromatography for measuring tiotropium bromide medicine carrying micropowders
1, liquid-phase condition:
Chromatographic column: the C18 post is filler (Alltima Platinum C18100A, 5 μ, 150 * 4.6mm) with octadecylsilane chemically bonded silica.
Mobile phase: methanol-potassium phosphate buffer (volume ratio is 57: 43), flow velocity is 1.0ml/min.The collocation method of potassium phosphate buffer adds water 1000ml and makes dissolving for getting potassium dihydrogen phosphate 2.7g and octyl sodium sulfate 0.2g, adds triethylamine 10ml, shakes up, and regulates pH value to 6.0 with phosphoric acid.
Detector: Waters 2487 dual wavelength detectors detect wavelength 237nm.
The appearance time of tiotropium bromide is 4.4 minutes.
2, test specimen:
The tiotropium bromide medicine carrying micropowder of embodiment 1-3 preparation; Reference substance is tiotropium bromide (The National Center for Drug Screening, a purity 99.6%).
3, test method:
Take by weighing sample 0.05g, put in the 50ml measuring bottle, add methanol-phosphate buffer solution and (get potassium dihydrogen phosphate 2.72g, add water 1000ml and make dissolving, add triethylamine 10ml, with phosphoric acid regulating ph value to 3.0) (volume ratio is 50: 50) dissolve and be diluted to scale, shake up, 0.8 the micron filter membrane filters, and gets filtrate as need testing solution; Precision is measured 20 μ l and is injected chromatograph of liquid, writes down chromatogram, measures the peak area at tiotropium bromide peak.It is an amount of that precision takes by weighing the tiotropium bromide reference substance in addition, adds above-mentioned solution dissolving and quantitative dilution and make the tiotropium bromide solution that concentration is 2.0 μ g/1ml, solution in contrast; With the method operation, use external standard method with calculated by peak area, promptly.
4, result of the test:
The content (by weight) of tiotropium bromide is respectively 0.193%, 0.196% and 0.192% in the tiotropium bromide medicine carrying micropowder that embodiment 1-3 makes.
The preparation of embodiment 5 capsule type tiotropium bromide inhalation powders
[prescription proportioning]:
Component sequence number component title consumption percentage composition %w/w
The thiophene holder 11.4g of embodiment 1 preparation
1 44.9
Bromine ammonium medicine carrying micropowder (containing tiotropium bromide 0.022g)
2 pharmaceutical lactose 14g 55.1
Method for making: the fine powder of getting it filled and getting through 100 mesh sieves sieve with lactose, directly mix with the medicine carrying micropowder, fill No. 3 Capsules, every loading is 25.4mg.
The accelerated stability test of embodiment 6 capsule type tiotropium bromide inhalation powders
1, test specimen: according to the prepared capsule type tiotropium bromide inhalation powder of embodiment 5 described methods;
2, test index: character, content, Emptying Rate, related substance;
3, test method: with reference to " two appendix XIX of Chinese pharmacopoeia version in 2000 C;
4, result of the test:
(1) stability test result: tested 10 days through high light (4500lx) exposure experiment and high temperature (60 ℃), every investigation index and zero-time sample are not relatively seen significant change.Under the environment of relative humidity 75%, do not see the content adhesion in 10 days; HPLC checks that do not detect new catabolite peak, the peak area ratio of original impurity peaks is not seen obvious change.
(2) accelerated test result: powder spray is put in the aluminium-plastic bubble plate packing, puts into climatic chamber, is controlled under the condition of 40 ℃ and relative humidity 75%, observes by the investigation project and measures.Show that through six months result of the tests physical and chemical indexs such as outward appearance and content color and luster, content, Emptying Rate relatively there is no significant change with the zero-time result, show to have good stability that specifically experimental result sees Table 1.
Table 1 capsule type tiotropium bromide inhalation powder accelerated stability test result
(relative humidity 75%, 40 ℃ of temperature)
Time is investigated project
Lot number
(moon) outward appearance Emptying Rate (%) related substance (%) content (%)
0 includes off-white powder>90 0.33 102.12
1 includes off-white powder>90 0.39 108.32
010,901 2 include off-white powder>90 0.41 107.58
3 include off-white powder>90 0.40 109.72
6 include off-white powder>90 0.40 107.58
0 includes off-white powder>90 0.35 99.81
1 includes off-white powder>90 0.40 106.60
010,902 2 include off-white powder>90 0.40 105.60
3 include off-white powder>90 0.37 104.03
6 include off-white powder>90 0.39 107.33
0 includes off-white powder>90 0.36 100.21
1 includes off-white powder>90 0.41 106.46
010,903 2 include off-white powder>90 0.38 108.69
3 include off-white powder>90 0.40 109.91
6 include off-white powder>90 0.40 108.61
Claims (11)
1. capsule type tiotropium bromide inhalation powder, its capsule 's content are formed (by weight) and are:
Tiotropium bromide medicine carrying micropowder 5%-50%
Excipient 50%-95%
Wherein the particle diameter of tiotropium bromide medicine carrying micropowder be 80% diameter of particle in 0.5 μ m-5 mu m range, 90% diameter of particle is less than 10 μ m; Excipient is the acceptable sugar of physiology or sugar alcohol or aminoacid, and its granularity is that the percent of pass of 100 mesh sieves is 100%, and the percent of pass of 120 mesh sieves is no less than 95%.
2. capsule type tiotropium bromide inhalation powder according to claim 1 is characterized in that the composition (by weight) of tiotropium bromide medicine carrying micropowder is:
Tiotropium bromide 0.1%-5%
Hydrophobic amino acid 10%-70%
Water-solubility carrier 25%-89.9%.
3. tiotropium bromide medicine carrying micropowder according to claim 2, the consumption (by weight) that it is characterized in that tiotropium bromide is 0.5%-1%.
4. tiotropium bromide medicine carrying micropowder according to claim 2, it is characterized in that hydrophobic amino acid is one or both in leucine, isoleucine, tyrosine, phenylalanine, the tryptophan, L type or DL all can, content (by weight) is 30%-70%.
5. tiotropium bromide medicine carrying micropowder according to claim 4 is characterized in that hydrophobic amino acid is the L-leucine.
6. tiotropium bromide medicine carrying micropowder according to claim 4, the consumption (by weight) that it is characterized in that hydrophobic amino acid is 30%-50%.
7. tiotropium bromide medicine carrying micropowder according to claim 2 is characterized in that water-solubility carrier is lactose or mannitol or glycine (L or DL type), and its consumption (by weight) is 50%-70%.
8. capsule type tiotropium bromide inhalation powder according to claim 1 is characterized in that excipient is pharmaceutical lactose or glycine or mannitol.
9. capsule type tiotropium bromide inhalation powder according to claim 8 is characterized in that excipient is a pharmaceutical lactose, and its consumption (by weight) is 60%-90%.
10. the preparation method of the described capsule type tiotropium bromide inhalation powder of claim 1 is characterized in that adopting spray drying method for preparation tiotropium bromide medicine carrying micropowder, may further comprise the steps:
(1) formula proportion by tiotropium bromide medicine carrying micropowder takes by weighing each component, tiotropium bromide, hydrophobic amino acid and water-solubility carrier are dissolved in the water, make the solids content of solution reach 1%-10% (w/v), adjust the solution pH value with the pH regulator agent and reach 4.0-7.0;
(2) with spray dryer solution is carried out spray drying, it is standby to make tiotropium bromide medicine carrying micropowder;
(3) the capsule 's content prescription by capsule type inhalation aerosol powder takes by weighing tiotropium bromide medicine carrying micropowder and excipient, mixes, and is filled in hard capsule promptly, the processing of should sieving before the excipient weighing.
11. the preparation method of capsule type tiotropium bromide inhalation powder according to claim 10, the solid content that it is characterized in that step (1) prepared solution is 2%-5% (w/v), and pH value is 5.0-6.0.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101422457B (en) * | 2007-10-31 | 2011-01-26 | 江苏正大天晴药业股份有限公司 | Tiotropium bromide respirable dry powder composition |
CN101342155B (en) * | 2007-07-11 | 2012-01-04 | 天津帝士力投资控股集团有限公司 | (R,R)-formoterol inhalation dust cloud agent and preparation method thereof |
CN101754749B (en) * | 2007-07-09 | 2016-04-13 | 诺顿·希尔思凯尔有限公司 | Inhalable drug |
WO2016057641A1 (en) * | 2014-10-08 | 2016-04-14 | Pulmatrix Operating Company, Inc. | Formulations containing tiotropium, amino acid and acid and methods thereof |
CN117233286A (en) * | 2023-09-19 | 2023-12-15 | 南京力成药业有限公司 | Quantitative detection method of tiotropium bromide |
-
2004
- 2004-07-02 CN CN 200410025716 patent/CN1593414A/en active Pending
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101754749B (en) * | 2007-07-09 | 2016-04-13 | 诺顿·希尔思凯尔有限公司 | Inhalable drug |
CN101342155B (en) * | 2007-07-11 | 2012-01-04 | 天津帝士力投资控股集团有限公司 | (R,R)-formoterol inhalation dust cloud agent and preparation method thereof |
CN101422457B (en) * | 2007-10-31 | 2011-01-26 | 江苏正大天晴药业股份有限公司 | Tiotropium bromide respirable dry powder composition |
WO2016057641A1 (en) * | 2014-10-08 | 2016-04-14 | Pulmatrix Operating Company, Inc. | Formulations containing tiotropium, amino acid and acid and methods thereof |
JP2017530988A (en) * | 2014-10-08 | 2017-10-19 | パルマトリックス オペレーティング カンパニー,インコーポレイテッド | Formulation containing tiotropium, amino acid and acid, and method thereof |
CN117233286A (en) * | 2023-09-19 | 2023-12-15 | 南京力成药业有限公司 | Quantitative detection method of tiotropium bromide |
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