CN1292748C - Timepidium bromide inhalant powders and their preparing process - Google Patents
Timepidium bromide inhalant powders and their preparing process Download PDFInfo
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- CN1292748C CN1292748C CNB031051227A CN03105122A CN1292748C CN 1292748 C CN1292748 C CN 1292748C CN B031051227 A CNB031051227 A CN B031051227A CN 03105122 A CN03105122 A CN 03105122A CN 1292748 C CN1292748 C CN 1292748C
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- tiotropium bromide
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Abstract
The present invention relates to a tiotropium bromide inhalant powder medicament and preparation technology thereof. The medicament is a mucosa absorption medicament for entering respiratory tracts in a dry powder form by a special medicament administration device after the medicament is taken and prepared from 10 micrograms to 30 micrograms of tiotropium bromide anhydride super-micropowder and 10 mg to 30 mg of amino acid class medicinal carrier miropowder by being filled in capsules after being fully and uniformly mixed, comprising glycine. In addition, the particle diameter of the tiotropium bromide anhydride super-micropowder is from 1 micrometer to 5 micrometers, and the average particle diameter of the amino acid class medicinal carrier miropowder is from 30 micrometers to 80 micrometers. Moreover, the medicament exerts the treatment action of target properties, high efficiency, high speed and high safety. Meanwhile, the medicament has the advantages of convenient use, portability, good following properties, exact dosage, no danger of overdosage medicament administration, no stimulation on mucosa, no preservatives or organic solvents, no gastrointestinal tract degradation action, no liver first pass effect, etc.
Description
Technical field
The present invention relates to a kind of pharmaceutical product and preparation technology, specifically, is a kind of Ammonium suction powder dose and its preparation method for the treatment of chronic obstructive disease of lung.
Technical background
Chronic obstructive disease of lung (Chronic Obstructive Pulmonary Disease, COPD) be a kind of common, chronic gradual chronic bronchitis or emophysematous respiratory tract disease with airflow obstruction feature, often cause the severe exacerbation of pulmonary function, finally cause deformity and death, the serious harm human health, be the 4th cause of death in the world, be only second to heart disease, cerebrovascular and acute pulmonary infection.
According to Lancet in 1997, COPD is the 6th cause of the death in the world, according to Inpharma in 1998, COPD is the 5th cause of death in the world, in the U.S. is the 4th cause of death (having every year 11.2 ten thousand people to die from this disease), 30 years from now on global mortality rates of The World Health Organization (WHO) prediction can double many, anticipate that the year two thousand twenty will become the 3rd cause of death in the whole world.Show that according to Decision Resources (DR) company current research the COPD sickness rate of 7 countries in the world (U.S., method, moral, meaning, west, English, day) more than 45 years old in the population is about 4%～6% (patient's COPD number will increase to from 1999 3500 ten thousand 2009 more than 3,800 ten thousand).The sickness rate of the present COPD of China is 3.3%～5.1%, because of the mortality rate of concurrent other diseases of COPD very high.
Result of study shows, the whole world is suffered from the asthma number and grown with each passing day, and its annual morbidity is with 5% speed increment, and asthma prevalence is 4%～32%.The whole world has 1.53 hundred million people to be suffered from asthma by diagnosis approximately.In western countries, there are 5% adult and child to suffer from asthma approximately.For example in Britain, asthmatic patient accounts for 13% among the child, accounts for 6% among the adult.U.S.'s asthmatic patient number was turned over some from 1980 to 1996, nearly 1,500 ten thousand people.Particularly the child's sickness rate below 5 years old is the highest, increases by 160% from 1980～1994, has at least 2 to suffer from asthma in per 30 school age populations.According to the WHO statistics, die from asthma more than annual 180000 people.U.S.'s asthma death toll in 1998 is 140,000 people.Confirm that according to China's latest survey the asthma patient has 2,500 ten thousand approximately at present, wherein child and old people's sickness rate is respectively 2%～3% and 1%.Along with living condition's " modernization ", " westization ", " industrialization ", China's pathogenesis of asthma rate will further increase.Asthma has become the public health problem that people are concerned about, and its control worldwide causes extensive concern.
Tiotropium bromide (Tiotropium Bromide) is the anticholinergic agents of developing after ipratropium bromide of new generation, and it is that first optionally acts on M by sucking once a day
1, M
3Receptor makes patient's COPD bronchiectasis reach 24 hours, effectively brings into play the therapeutical effect of medicine, and improves pulmonary function and dyspnea symptom significantly enduringly.Therefore, make tiotropium bromide performance targeting, efficient, quick-acting, safe therapeutical effect, particularly instant the use is purpose of the present invention when the first aid of pulmonary's occlusive disease.
Goal of the invention
The present invention is exactly the method that sucks powder spray (respiratory mucosa absorbable preparation) by preparing, make tiotropium bromide after special-purpose doser administration, enter respiratory tract, absorb by the down abundant blood capillary of respiratory mucosa and reach targeting, efficient, quick-acting, safe therapeutic purposes with dry powder form.
Because sucking powder spray is on the basis of aerosol, for overcoming the shortcoming of aerosol, and use a kind of novel form that achievement in research that comprehensive powder technology learns grows up.Because it is easy to use, does not contain propellant, medicine is powdery, good stability, and interference factor is few, and is subject to people's attention day by day.When the great advantage of powder spray was to use, patient's inspiratory airflow was that powder enters intravital unique power, so there is not dyssynergia, has reduced the incidence rate of drug side effect, especially was fit to old man and child and used; And during the aerosol inhalation,, also have 30% patient correctly not use approximately even through instructing.Compare with aerosol and spray, powder spray has following characteristics: (1) patient initiatively sucks medicated powder, does not have administration coordinated difficulty; (2) pollution and respiratory tract to atmospheric environment can be avoided in no propellant fluorine Lyons.(3) medicine can capsule or vesicle form administration, and dosage is accurate, no overdose administration danger; (4) do not contain solvents such as antiseptic and ethanol, to pathological changes mucosa nonirritant.(5) no gastrointestinal tract Degradation; (6) no liver first-pass effect; (7) drug absorption is rapid, and is rapid-action after the administration; (8) directly enter the body circulation after the drug absorption, reach the purpose of whole body therapeutic; (9) patient's compliance is good, is specially adapted to carry out the patient of long-term treatment; (10) play the medicine of local action, dosage obviously reduces, and toxic and side effects is little, and safety is good.
Summary of the invention
For achieving the above object, the present invention adopts following technical scheme: can the suction form be dry powder, active ingredient be a thiatro bromoaminium anhydrous compound, and its structural formula is
The present invention is with the superfine powder of active component and the mixed uniformly dry powder form of pharmaceutically useful carrier micropowder, preferably contain pharmaceutically suitable carrier, and described pharmaceutically suitable carrier is selected from the known material that can be used as the carrier of dry powder inhalation composition, for example aminoacid comprises glycine, Aspartic Acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, proline, tyrosine, valine etc.Particularly preferred carrier is a glycine.Dry powder can place with the form of single dose in the gelatin of powder inhaler or the plastic capsule or in the bubble-cap, preferred 10 μ g to 30 μ g tiotropium bromide unit dose.Perhaps, dry powder can be included in the form of bank in the multiple dose powder inhaler.
Active component tiotropium bromide in the dry powder can have the mean diameter of the most about 10 μ m, 0.1 μ m to 5 μ m for example, preferred 1 μ m to 5 μ m.Carrier in the dry powder has the maximum particle diameter of the highest 200 μ m usually, preferably the highest 150 μ m particle diameters, and have 10 μ m to 100 μ m particle diameters, the mean diameter of preferred 30 μ m to 80 μ m usually.
When medicine of the present invention is the compositions that contains unit dose tiotropium bromide and carrier in the capsule, when for example being used for from pharmaceutical composition dry powder that single capsule inhaler sucks, capsule can contain 10 μ g to 30 μ g tiotropium bromides, preferred 15 μ g～20 μ g, the particularly tiotropium bromide of 18 μ g and above-mentioned pharmaceutically suitable carrier, the amount of pharmaceutically suitable carrier is for can make the gross weight of dry powder in every capsules reach 10mg to 30mg, for example 10mg, 13mg, 15mg, 20mg, 25mg or 30mg, preferred especially 13mg.
The present invention reduces to desired level by methods such as grinding or supercritical solvent recrystallization in the pulverizing of fluid bed supersonic airstream, high speed grinding, ball mill or the vibromill with the granularity of tiotropium bromide and carrier, the preferred especially fluid bed supersonic airstream comminuting method of tiotropium bromide, the preferred especially high speed polishing of carrier.
The preparation technology of described inhaled tiotropium bromide powder preparation gets tiotropium bromide 1 weight portion porphyrize to cross carrier that No. 9 sieve backs and 30 to 100 weight portion porphyrizes cross No. 9 sieves with behind the dilution method mixing progressively, the granularity that micronizing obtains is reduced to the ultra micro dry powder of desired level and is reduced to the carrier micropowder of desired level equivalent incremental method mixing through grinding the granularity that obtains at a high speed, fill No. 3 capsule, promptly.
Result of study shows that the present invention is a kind of a kind of N-quaternary ammonium compound with low gastrointestinal bioavailability, is similar to ipratropium.The pharmacological research of inhaled tiotropium bromide powder preparation shows that it is a kind of special, and efficiently, competitive (reversible) muscarine antagonist demonstrates slow separation especially from M
3On-the M-ChR, this slow separation from M-ChR is considered to its long and very stable pharmacological action of acting duration that shows several external and body inner models is responsible for.The pharmacology profile of inhaled tiotropium bromide powder preparation shows as prolongation in the chronic obstructive disease of lung patient and stable anticholinergic dilating effect.It is a quite long lasting anticholinergic agents, is suitable for administration once-a-day, has unique kinetics selectivity, from M
1-and M
3Separate ratio on the-receptor from M
2More slow on the receptor.It is an impressive progress that inhaled tiotropium bromide powder preparation is once-a-day treated chronic obstructive disease of lung, and this medicine may become the anticholinergic of standard and keep Therapeutic Method, will become treatment chronic obstructive disease of lung patient's the most widely used bronchiectasis medicine in future.
Below through detecting explanation beneficial effect of the present invention
Detect index and method
1. the particle diameter of dry powder detects: get dry powder of the present invention, mix well with a small amount of dehydrated alcohol, be applied on the microscope slide, add coverslip, put under the Electronic Speculum and detect.
2. dry powder mobility-detected: the flowability of dry powder is to represent angle of repose, assay method adopts the fixed funnel method, be about to funnel and be fixed on suitable height (H), dry powder of the present invention is put in the funnel, naturally it is in heaps to leak down, till the tip of cone will touch the outlet of funnel, measure the radius r of circular cone bottom surface then, angle of repose=arctg (H/r).
3. the dry powder hygroscopicity detects: precision takes by weighing each 3 parts in dry powder of the present invention, places 20 ℃, relative humidity to be respectively 92.5% hermetic container and detects the relative weight gain after 24 hours.
4. uniformity of dosage units detects: get 1 of this product, in content impouring 5ml measuring bottle, use the mobile phase ultrasonic dissolution, add mobile phase and be diluted to scale, shake up, filter (filter membrane is 0.45 μ m), get filtrate, measure according to the method under the assay item, limit is ± 25%, should (two appendix XE of Chinese Pharmacopoeia version in 2000) up to specification.
5. Emptying Rate detects: get 10 of this product, check that according to Emptying Rate algoscopy (two appendix IL of Chinese Pharmacopoeia version in 2000) every Emptying Rate should be not less than 90%.
6. deposition of drug in effective site detects: checking according to effective fraction medicine quantitative determination method (two appendix XH of Chinese Pharmacopoeia version in 2000), is acceptable solution with mobile phase.Get 1 of this product capsule, put in the suction apparatus,, the capsule two ends are punctured, open vacuum pump with finger pressing device both sides button; Suction apparatus is horizontal close proximity through suitable rubber interface with simulation throat, takes off inhaler after 10 seconds, settles 1 capsules again.Aspirate 10 capsules so altogether, close pump, detaching device.Clean the inside and outside wall of conduit of importing lower taper bottle and the surface of pad ridge with blank acceptable solution, washing liquid and lower floor's acceptable solution merge, be settled in the 50ml measuring bottle, shake up, filter (filter membrane is 0.45 μ m), get filtrate, measure according to the method under the assay item, and calculate content, the gained result is divided by 10, and compare with indicating content, be the drug deposition amount of effective site.The drug deposition amount should be no less than 10% of labelled amount.
Tiotropium bromide assay: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are filler, phosphoric acid solution (phosphoric acid 5.5ml, add water to 1000ml, triethylamine is regulated pH to 3.2)-acetonitrile (80: 20) is a mobile phase, detect wavelength 238nm, number of theoretical plate calculates by the tiotropium bromide peak should be not less than 2000, and the separating degree of main peak and each impurity peaks should meet the requirements.
Algoscopy is got 20 of this product, inclining content, and accurate the title decides, and tries to achieve average loading amount, precision takes by weighing above-mentioned mixed content an amount of (being equivalent to contain tiotropium bromide 112.5 μ g approximately) and puts in the 25ml measuring bottle, add an amount of ultrasonic dissolving that makes of mobile phase, add mobile phase and be diluted to scale, shake up, filter (filter membrane is 0.45 μ m), discard filtrate just, get subsequent filtrate 20 μ l and inject chromatograph of liquid, the record chromatogram.Precision takes by weighing the about 22.5mg of tiotropium bromide reference substance in addition, puts in the 100ml measuring bottle, adds the mobile phase dissolving and is diluted to scale, shakes up, and the accurate 2ml that draws puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale, measures with method.Press external standard method with calculated by peak area, promptly.
7. dry powder detects the respiratory mucosa zest:
1. single-dose respiratory mucosa irritation test
Get 8 of experimental rabbits, body weight is 2.0-3.0Kg, during test inhaled tiotropium bromide powder preparation is sprayed into animal oral cavity and pharyngeal, every rabbit spray 2mg makes and is tried thing and contact at least 4 hours with its mucosa, then in 24 hours execution animals, taking-up local mucous membrane tissue, observation has or not phenomenons such as hyperemia, redness.
2. repeat multiple dosing respiratory mucosa irritation test
Get 8 of experimental rabbits, body weight is 2.0-3.0Kg, during test inhaled tiotropium bromide powder preparation is sprayed into animal oral cavity and pharyngeal, once a day, each every rabbit spray 2mg, continuous seven days, make and tried thing and contact at least 4 hours, put to death animal in 24 hours after the last administration, take out the local mucous membrane tissue with its mucosa, observation has or not hyperemia, phenomenons such as redness.
8. hypersensitive test: in both sides, the preceding 24 hours backs of administration unhairing, the every side in unhairing district is about 3 * 3cm, wipes clean with warm water to be for experiment, and does not want injured skin during unhairing.Sensitization contact: inhaled tiotropium bromide powder preparation (0.2g), positive control 0.1%2,4-dinitrochlorobenzene (0.2ml), pharmaceutical carrier (0.2g) are evenly smeared respectively on the Cavia porcellus one side skin of unhairing, cover with one deck oilpaper and two-layer gauze, fixing or the dressing of reuse nonirritant adhesive plaster sealing, make test sample can contact 6 hours well with skin, the next day sensitization once, totally 3 times.Excite sensitization: contact back the 14th day in last, on the one side skin of unhairing of back, evenly smear and be subjected to reagent thing (0.1g), positive control (0.1ml), pharmaceutical carrier (0.1g), remove test sample after 6 hours, observe immediately, and after administration, observed the anaphylactoid situation that has or not again in 24,48,72 hours, divide the order of reaction.
Testing result
One, example 1 sample detection result
1. the particle diameter of dry powder: the particle diameter of tiotropium bromide is 2.07 μ m ± 0.89 μ m.The maximum particle diameter of carrier glycine is 80 μ m, and mean diameter is 50 μ m to 75 μ m.
2. the flowability of dry powder: be 58 ° angle of repose.
3. the hygroscopicity of dry powder: the relative weight gain 7.5%.
4. uniformity of dosage units: ± 12.3%.
5. Emptying Rate: 98.6%.
6. deposition of drug in effective site: 20.6%.
7. to the zest of respiratory mucosa: do not see the obvious stimulation effect.
8. hypersensitive test: do not see obvious anaphylaxis.
Two, example 2 sample detection results
1. the particle diameter of dry powder: the particle diameter of tiotropium bromide is 3.12 μ m ± 0.75 μ m.The maximum particle diameter of carrier glycine is 150 μ m, and mean diameter is 70 μ m to 135 μ m.
2. the flowability of dry powder: be 52 ° angle of repose.
3. the hygroscopicity of dry powder: the relative weight gain 6.5%.
4. uniformity of dosage units: ± 15.3%.
5. Emptying Rate: 96.2%.
6. deposition of drug in effective site: 17.5%.
7. to the zest of respiratory mucosa: do not see the obvious stimulation effect.
8. hypersensitive test: do not see obvious anaphylaxis.
Three, example 3 sample detection results
1. the particle diameter of dry powder: the particle diameter of tiotropium bromide is 2.62 μ m ± 0.56 μ m.The maximum particle diameter of carrier glycine is 200 μ m, and mean diameter is 100 μ m to 190 μ m.
2. the flowability of dry powder: be 49 ° angle of repose.
3. the hygroscopicity of dry powder: the relative weight gain 7.8%.
4. uniformity of dosage units: ± 16.5%.
5. Emptying Rate: 95.7%.
6. deposition of drug in effective site: 14.3%.
7. to the zest of respiratory mucosa: do not see the obvious stimulation effect.
8. hypersensitive test: do not see obvious anaphylaxis.
Above testing result shows, the present invention has targeting, efficient, quick-acting, safe advantage.
The specific embodiment
One, example 1
Tiotropium bromide (C
19H
22BrNO
4S
2) 18mg
Glycine 13g
Fill becomes 1000 No. 3 capsules
Two, example 2
Tiotropium bromide (C
19H
22BrNO
4S
2) 18mg
Glycine 10g
Fill becomes 1000 No. 3 capsules
Three, example 3
Tiotropium bromide (C
19H
22BrNO
4S
2) 18mg
Glycine 20g
Fill becomes 1000 No. 3 capsules
Suck the preparation technology of powder spray in the above-mentioned example
Get 1 weight portion tiotropium bromide porphyrize and cross glycine that No. 9 sieve backs and 75 weight portion porphyrizes cross No. 9 sieves with behind the dilution method mixing progressively, the ultra micro dry powder of putting pulverizing obtains in the fluid bed supersonic jet mill particle diameter and be 1 μ m to 5 μ m with through grind at a high speed the maximum particle diameter that obtains less than the glycine carrier of 200 μ m with equivalent incremental method mixing, fill No. 3 capsule, promptly.
Claims (5)
1. inhaled tiotropium bromide powder preparation is characterized in that: it is to be the powder spray for inhalation that filled capsules is prepared from behind the tiotropium bromide superfine powder of 1 μ m to 5 μ m and the abundant mixing of glycine pharmaceutical carrier that 10mg to 30mg, particle diameter are 30 μ m to 80 μ m with single agent 10 μ g to 30 μ g, particle diameter.
2. the described inhaled tiotropium bromide powder preparation of claim 1, it is characterized in that: tiotropium bromide is an anhydride, and its structural formula is
3. the described inhaled tiotropium bromide powder preparation of claim 1 is characterized in that: adopt the method for fluid bed supersonic airstream pulverizing to be prepared into the tiotropium bromide superfine powder that particle diameter is 1 μ m to 5 μ m.
4. the described inhaled tiotropium bromide powder preparation of claim 1 is characterized in that: adopt pulverizing of fluid bed supersonic airstream and high speed abrasive method to be prepared into the glycine pharmaceutical carrier micropowder that particle diameter is 30 μ m to 80 μ m.
5. the preparation method of the described tiotropium bromide powder spray of claim 1, it is characterized in that: get 1 weight portion tiotropium bromide porphyrize cross glycine pharmaceutical carrier that No. 9 sieve backs and 76 weight portion porphyrizes cross No. 9 sieves with to pulverize the particle diameter that obtains in the rearmounted fluid bed supersonic speed of the dilution method mixing pulverizer progressively be 1 μ m to 5 μ m superfine powder with through grind at a high speed the particle diameter that obtains be the glycine pharmaceutical carrier micropowder of 30 μ m to 80 μ m with the abundant mixing of equivalent incremental method after, fill No. 3 capsule, promptly.
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| SE0303269L (en) * | 2003-12-03 | 2005-06-04 | Microdrug Ag | Medical product |
| 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 |
| CN101889994A (en) * | 2010-06-01 | 2010-11-24 | 中国药科大学 | Salbutamol sulfate sustained-release aerosol of micropowder for inspiration and preparation method thereof |
| CN103110584A (en) * | 2013-01-29 | 2013-05-22 | 青岛大学 | Tiotropium bromide powder inhalation and preparation method thereof |
| CN108451936A (en) * | 2018-06-19 | 2018-08-28 | 杭州勃锐思莫生物医药科技有限责任公司 | A kind of Tiotropium Bromide sucking preparation prepare treat lung-cancer medicament in apply |
| CN111751454B (en) * | 2019-03-29 | 2023-12-08 | 天津药业研究院股份有限公司 | Method for detecting content of ipratropium bromide intermediate I and related substances |
| CN111407747A (en) * | 2020-05-14 | 2020-07-14 | 王兆霖 | Multi-dose blister type tiotropium bromide powder aerosol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315852A (en) * | 1998-08-04 | 2001-10-03 | 杰格研究股份公司 | Medicinal aerosol formulations |
| CN1328473A (en) * | 1998-09-22 | 2001-12-26 | 气体药品技术公司 | Medicinal aerosol formulation |
| WO2002036104A2 (en) * | 2000-10-31 | 2002-05-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Inhalative solution formulation containing a tiotropium salt |
-
2003
- 2003-03-05 CN CNB031051227A patent/CN1292748C/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315852A (en) * | 1998-08-04 | 2001-10-03 | 杰格研究股份公司 | Medicinal aerosol formulations |
| CN1328473A (en) * | 1998-09-22 | 2001-12-26 | 气体药品技术公司 | Medicinal aerosol formulation |
| WO2002036104A2 (en) * | 2000-10-31 | 2002-05-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Inhalative solution formulation containing a tiotropium salt |
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