CN101342155B - (R,R)-formoterol inhalation dust cloud agent and preparation method thereof - Google Patents
(R,R)-formoterol inhalation dust cloud agent and preparation method thereof Download PDFInfo
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- CN101342155B CN101342155B CN2007100578933A CN200710057893A CN101342155B CN 101342155 B CN101342155 B CN 101342155B CN 2007100578933 A CN2007100578933 A CN 2007100578933A CN 200710057893 A CN200710057893 A CN 200710057893A CN 101342155 B CN101342155 B CN 101342155B
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- Prior art keywords
- formoterol
- micropowder
- carrier
- preparation
- medicine carrying
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- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical class O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 235000008521 threonine Nutrition 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000002374 tyrosine Nutrition 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses (R,R)-formoterol powder inhalation which is composed of carrier powders and (R,R)-formoterol medicine carrier powders; wherein, the content of the medicine carrier powders is 5 percent to 80 percent (w/w), and the particulate diameter of at least 90 percent (w/w) of powder particulate is smaller than 10Mum; the content of the carrier powders is 20 percent to 95 percent (w/w), and the particulate diameter of at least 80 percent (w/w) of powder particulate is smaller than 40Mum to 100Mum. The powder inhalation of the invention is prepared by the follower steps: 1) preparing the carrier powders with a solvent crystallization method; 2) preparing the medicine carrier powders with a spray drying method; 3) mixing the medicine carrier powders and the carrier powders to obtain the preparation. The power inhalation of the invention has favorable fluidity and lower moisture-absorptivity; the preparation method is easy to operate, the cost is low, and the invention solves the problem of great disparity between main drug and auxiliary material.
Description
Technical field
The present invention relates to a kind of suction powder spray, be specifically related to a kind of formoterol inhalation dust cloud agent, also relate to its preparation method.
Background technology
Asthma is one of common chronic disease in the whole world, and at present, the drug kinds of treatment asthma has: 1. adrenoreceptor agonists; 2. Claritin; 3. theophylline class medicine; 4. glucocorticoid.Formoterol (Fomoterol) is a kind of Betz 2-adrenoceptor agonists of the later development success eighties, and the strong and length of holding time of its effect has been widely used in asthma and other OADs, main at present its fumarate of using.There are two asymmetric carbon atoms in the raceme formoterol structure, thus four kinds of different spatial configurations are arranged, promptly (R, R)-type, (S, S)-type (enantiomer), (R, S) type, (S, R) type (diastereomer).Be widely used at present clinical be formoterol (R, R) with (S, S) type equal amount of mixture, and (S, S)-isomer with (R, R)-isomer compares almost non-activity.So the employing active isomer (R, R)-formoterol, can reduce the dosage of administration, thereby reduce the incidence rate of toxic and side effects.
Suck powder spray (aerosol of micropowders for inspiration) mainly refer to micronized medicine or with carrier with capsule, vesicle or multiple dose reservoir type; Adopt special powder inhaler; Initiatively suck atomization medicine to pulmonary by the patient, a kind of drug-supplying system of performance whole body or local action.Sucking powder spray can effectively be used for the suction of low dosage and high dose medicament or spray into administration.Compare with aerosol, when the powder spray biggest advantage was to use, patient's air-flow was that powder gets into intravital unique power, so there is not dyssynergia; Reduced the incidence rate of drug side effect, especially be fit to the old man and use with the child, and during the aerosol inhalation, even through guidance; Also have 30% patient correctly not use approximately, powder spray initiatively sucks medicated powder by the patient, does not have administration dyssynergia; Pollution and respiratory tract to atmospheric environment can be avoided in no propellant fluorine Lyons, and medicine is with capsule or form of vesicles administration; Dosage is accurate, the danger of no overdose administration, and dosage is big.
The conventional method for preparing that sucks powder spray is: (1) with medicine through mechanical lapping to 10 μ m; (2) carrier is crossed 100 mesh sieves, obtaining particle diameter is the carrier about 150 μ m; (3) medicine after will pulverizing and carrier mix.
(R, R)-the formoterol powder spray in, (R R)-the formoterol consumption is very little, is merely Gamma Magnitude, differs greatly with supplementary product consumption; The suction powder spray of processing by conventional method draws moist strong, mobile poor; And because (R, R)-formoterol costs an arm and a leg, and sucks powder spray by the conventional method preparation, the loss of medicine is big, cost is too high, thus in actual fabrication process, be difficult to obtain ideal (R, R)-formoterol inhalation dust cloud agent.
Nanchang Hongyi Science Co., Ltd discloses " Ammonium suction powder dose and its preparation method " (open day 2003.9.3; Publication number CN1439362A); Medicine and carrier processed earlier meet the medicine carrying micropowder that sucks particle diameter; Mix with the carrier micropowder again, solved the problem that medicine and supplementary product consumption differ greatly to a certain extent.But the wherein preparation of medicine carrying micropowder only is to adopt the fluid bed supersonic jet mill, and mechanical crushing methods such as ball milling or vibromill grinding prepare the micropowder of particle diameter at 1-5 μ m, or supercritical solvent recrystallization method prepares micropowder.Wherein the crystal that obtains of mechanical crushing method is irregular, and electrostatic attraction is big, and powder body is sticking, and is mobile bad, in the process of powder spray preparation, is difficult for mixing the mobile bad fill capsule that is difficult for.And when pulverizing, be prone to produce a large amount of heat, influence stability of drug.Adopt supercritical solvent recrystallization method, then high to the requirement of equipment, production cost is big, is difficult for accomplishing scale production.
Shanghai Huatuo Medicine Sci-Tech Development Co., Ltd discloses " a kind of capsule type tiotropium bromide inhalation powder and preparation method thereof " (open day 2005.3.16; Publication number CN1593414A); Pharmaceutical lactose is crossed 100 mesh sieves; The micropowder that sieve is got is about 150 μ m and the direct mixing filling of medicine carrying micropowder.Because the particle diameter of pharmaceutical lactose micropowder and the particle diameter difference of medicine carrying micropowder are bigger, in mixing, the pouring process, are difficult for mixing, and layering easily; And it is also bigger to prepare carrier micropowder loss by this method.It is very high to meet the carrier micropowder commodity price that sucks powder spray requirement particle diameter, and the production cost is improved.
Relevant (R, R)-report that the suction powder spray of formoterol is not also succeeded in developing at present.
Summary of the invention
The object of the present invention is to provide a kind of (R, R)-formoterol inhalation dust cloud agent and preparation method thereof.Provided by the invention (R, R)-the formoterol inhalation dust cloud agent good fluidity, draw moist low; And method for preparing is simple to operate, is easy to mix, and cost reduces, and has solved the problem of principal agent and supplementary product consumption great disparity.
(R of the present invention; R)-formoterol inhalation dust cloud agent, by (R, R)-the medicine carrying micropowder of formoterol and carrier micropowder form; R wherein; The medicine carrying powder content of R-formoterol is 5%-80% (w/w), and the diameter of particle of its at least 90% (w/w) is preferably at least 70% (w/w) v in the 0.5-7 mu m range less than 10 μ m; The carrier micropowder is selected from one or more in the acceptable sugar of physiology, polyhydric alcohol, the aminoacid, and content is 20%-95% (w/w), and the microgranule particle diameter of its at least 80% (w/w) is 40 μ m-100 μ m.
In the described carrier micropowder, the acceptable sugar of physiology is one or more in lactose, sucrose, glucose, fructose, maltose, trehalose preferably; Further preferably one or more in mannitol, xylitol, sorbitol of polyhydric alcohol; Further preferably one or more in leucine, alanine, valine, isoleucine, glycine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, glutamic acid, threonine, aspartic acid, glutamine, lysine, arginine, histidine and agedoite of aminoacid.Described carrier micropowder further preferably one or more in lactose, mannitol or xylitol, most preferably lactose.
Described (R, R)-formoterol medicine carrying micropowder in, preferred (R, R)-formoterol is 0.1%-10% (w/w), water-solubility carrier is 90%-99.9% (w/w); Further preferred (R, R)-formoterol is 0.2%-2% (w/w), water-solubility carrier 99.8%-98% (w/w).
Water-solubility carrier be selected from the acceptable sugar of physiology, polyhydric alcohol or amino acid whose one or more, be preferably in lactose, mannitol or the leucine one or more.
The method for preparing that the present invention adopts can be summarized as follows:
1) solvent crystallization is adopted in the preparation of carrier micropowder: the speed of control solution concentration, peristaltic pump, the size of nozzle diameter, atomizing pressure etc., and make and separate out crystalline particle diameter about 40 μ m-100 μ m, promptly get after the drying;
2) spray drying technology is adopted in the preparation of medicine carrying micropowder.
It is when filling that the present invention uses the purpose of carrier micropowder, improves the flowability of medicine carrying micropowder powder; Because (R, R)-the formoterol consumption is very little, just principal agent shared ratio very little (being merely some thousandths of) in preparation uses the carrier micropowder to increase the weight and volume of content, is convenient to fill.
Adopt spray drying technology to prepare the medicine carrying micropowder, (R R)-after formoterol employing The suitable solvent is dissolved, make it common drying through spray drying, processes good fluidity, draws moist low medicine carrying micropowder with carrier and low dose.This medicine carrying micropowder can with the adjuvant mix homogeneously, thereby prepare the powder spray that has excellent storage stability, be fit to suck.
Of the present invention (R, R)-method for preparing of formoterol inhalation dust cloud agent can further describe as follows:
1) preparation of carrier micropowder may further comprise the steps:
(1) in the acceptable sugar of physiology, polyhydric alcohol, the aminoacid one or more being mixed with concentration is that 0.1g/100ml is to saturated aqueous solution;
(2) solution mist is changed into tiny drop;
(3) spray in the organic solvent;
(4) drying;
2) preparation of medicine carrying micropowder can be adopted spray drying technology, may further comprise the steps:
(1) will (R, R)-formoterol and water-solubility carrier be dissolved in the water, the content of solute is 1-10g/100ml in the solution, further is preferably 2-7g/100ml,
(2) solution is carried out spray drying, promptly get;
3) carrier micropowder and medicine carrying micropowder are mixed.
Preferred one or more in ethanol, isopropyl alcohol, acetone, n-butyl alcohol, sec-butyl alcohol, ethyl acetate, butyl acetate, t-butyl methyl ether, Ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, butanone, methyl iso-butyl ketone (MIBK), isobutanol, pentane, n-amyl alcohol, normal propyl alcohol, petroleum ether of (3) described organic solvent most preferably are isopropyl alcohol or ethanol in the described step 1).
Sucking powder spray is through respiratory tract, and powder is sucked, directly absorb through alveolar, brings into play drug effect then.The physiological structure of lung requires the particle of medicine very trickle, and porous it is generally acknowledged ideal diameter of aspirin particle need less than 10 μ m to the periphery of lung, can not get in the bronchioles greater than the particle of this scope.So drug powder what of the deposition of pulmonary, directly influences the curative effect of medicine.And the deposition of the size of particle diameter and effective site is closely related.In order to reach best particle size range, need to confirm optimum experiment parameter.After application of the present invention is adopted principal agent and micronized carrier is combined; Suck the preparation of powder spray; Therefore according to the regulation of Chinese Pharmacopoeia in 2005; Utilize the droplet (grain) of effective site to distribute (Chinese Pharmacopoeia in 2000 is the effective site deposition), in order to estimate the reasonability of technological parameter as the index of screening.
Earlier carried out a large amount of screening experiment with single factor investigation method, the major influence factors of having confirmed solvent crystallization is the speed of solution concentration, peristaltic pump, the size of nozzle particle diameter.High-pressure fog makes the particle diameter of droplet reach very little; Re-use organic solvent the carrier in the drop is separated out, realize the method for preparing of application of the present invention through the speed (1-8ml/min) of variable concentrations (0.1g/100ml is to saturated aqueous solution) and peristaltic pump, the control of nozzle particle diameter conditions such as (0.7-2.0mm); Concentration further is preferably 30g/100ml-50g/100ml, and peristaltic pump speed further is preferably 2-5ml/min.
Prepare the carrier micropowder by solvent crystallization.Particle diameter through discovering the carrier micropowder meets the particle diameter requirement that sucks powder spray most when 40 μ m-100 μ m.The particle diameter of carrier micropowder is during greater than 100 μ m, and medicine carrying micropowder and carrier micropowder mix difficulty, and layering easily; During less than 40 μ m, the suction powder spray then processed is mobile poor, draw moist by force, and poor at the assimilation effect again of pulmonary.
The powder body of processing with method provided by the invention is the basis, can process the suction powder spray of forms such as capsule-type, vesicle type and reservoir devices, and the suction powder spray of these Different Package forms all drops within protection scope of the present invention.
When the actual use of patient suction powder spray of the present invention, adopt special powder inhaler, initiatively be sucked into pulmonary by the patient.
Will (R, R)-formoterol processes powder spray after pulmonary absorbs, directly onset and can avoid the shortcoming of aerosol improves patient's compliance, better brings into play curative effect.
Method for preparing provided by the invention has adopted high-pressure fog to make the particle diameter of droplet reach very little; Re-using organic solvent separates out the carrier in the drop; The control of conditions such as the speed through variable concentrations and peristaltic pump, nozzle particle diameter, the combination of this Several Factors can be easily control to the particle diameter of microgranule between the 40 μ m-100 μ m.Method is simple, and equipment requirements is not high, is easy to accomplish scale production.The powder fluidity that makes is good, draws moist low; Be easy to mixing, solved problem owing to principal agent and the greatly different uniformity of dosage units that produces of supplementary product consumption.Whole preparation method is simple to operate, and cost is low, easy realization of industrialization.
The specific embodiment
As follows concrete excessively embodiment is further described the present invention, but not as limitation of the present invention.
Spray dryer adopts the BUCHI Mini Spray DryerB-290 type spray dryer that Bu Qi company produces among the embodiment; Sem photograph adopts the JSM-6700F type scanning electron microscope appearance of the GEOL of company of NEC.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 granularity of carrier micropowder and medicine carrying micropowder adopts microscopic, accurately measures and adopts the scanning electron microscope appearance.
The preparation of embodiment 1 carrier micropowder
Take by weighing the 0.5g lactose, be dissolved in the 500ml deionized water.This solution is sprayed with spray dryer, drop is sprayed in the isopropyl alcohol, stir constantly.After spraying finishes, filter, again filter cake is carried out drying, pulverize, promptly get.When spraying, control atomization air flow speed 30ml/h, peristaltic pump speed 8ml/min.
The assay of powder body: the granularity of carrier micropowder be 80% diameter of particle in 40 μ m-100 mu m ranges, angle of repose be 35.6 the degree
The preparation of embodiment 2 carrier micropowders
Take by weighing the 50g lactose, add water and be mixed with saturated solution.This solution is sprayed with spray dryer, drop is sprayed in the isopropyl alcohol, stir constantly.After spraying finishes, filter, again filter cake is carried out drying, pulverize, promptly get.When spraying, control atomization air flow speed 30ml/h, peristaltic pump speed 1ml/min.
The assay of powder body: the granularity of carrier micropowder be 80% diameter of particle in 40 μ m-100 mu m ranges, angle of repose be 36.7 the degree
The preparation of embodiment 3 carrier micropowders
Take by weighing the 45g lactose, be dissolved in the 150ml deionized water.This solution is sprayed with spray dryer, drop is sprayed in the ethanol, stir constantly.After spraying finishes, filter, again filter cake is carried out drying, pulverize, promptly get.When spraying, control atomization air flow speed 30ml/h, peristaltic pump speed 5ml/min.
The assay of powder body: the granularity of carrier micropowder be 80% diameter of particle in 40 μ m-100 mu m ranges, angle of repose be 38.2 the degree
The preparation of embodiment 4 carrier micropowders
Take by weighing the 75g lactose, be dissolved in the 150ml deionized water.This solution is sprayed with spray dryer, drop is sprayed in the isopropyl alcohol, stir constantly.After spraying finishes, filter, again filter cake is carried out drying, pulverize, promptly get.When spraying, control atomization air flow speed 30ml/h, peristaltic pump speed 2ml/min.
The assay of powder body: the granularity of carrier micropowder be 80% diameter of particle in 40 μ m-100 mu m ranges, angle of repose be 36.1 the degree
The preparation of embodiment 5 carrier micropowders
Take by weighing the 50g lactose, be dissolved in the 150ml deionized water.This solution is sprayed with spray dryer, drop is sprayed in the isopropyl alcohol, stir constantly.After spraying finishes, filter, again filter cake is carried out drying, pulverize, promptly get.When spraying, control atomization air flow speed 30ml/h, peristaltic pump speed 3ml/min.
The assay of powder body: the granularity of carrier micropowder be 80% diameter of particle in 40 μ m-100 mu m ranges, angle of repose be 35.6 the degree.
The preparation of embodiment 6 carrier micropowders
Take by weighing 50g mannitol, be dissolved in the 150ml deionized water.This solution is sprayed with spray dryer, drop is sprayed in the dehydrated alcohol, stir constantly.After spraying finishes, filter, again filter cake is carried out drying, pulverize, promptly get.When spraying, control atomization air flow speed 30ml/h, peristaltic pump speed 3ml/min.
The assay of powder body: the granularity of carrier micropowder be 80% diameter of particle in 40 μ m-100 mu m ranges, angle of repose be 36.4 the degree.
The preparation of embodiment 7 carrier micropowders
Take by weighing the 50g xylitol, be dissolved in the 200ml deionized water.This solution is sprayed with spray dryer, drop is sprayed in the dehydrated alcohol, stir constantly.After spraying finishes, filter, again filter cake is carried out drying, pulverize, promptly get.When spraying, control atomization air flow speed 30ml/h, peristaltic pump speed 4ml/min.
The assay of powder body: the granularity of carrier micropowder be 80% diameter of particle in 40 μ m-100 mu m ranges, angle of repose be 37.5 the degree.
Embodiment 8 (R, R)-preparation of formoterol medicine carrying micropowder
(R, R)-formoterol 0.01g
Lactose 5g
Take by weighing each component by the prescription proportioning, be dissolved in the 500ml deionized water.With this solution with spray dryer carry out spray drying obtain (R, R)-formoterol medicine carrying micropowder.When carrying out spray drying, 110 ℃ of control EATs, 60 ℃ of leaving air temps, atomization air flow speed 30ml/h, peristaltic pump speed 3ml/min.
The assay of powder body: (R, R)-granularity of formoterol 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; Be 43.4 degree angle of repose.
Embodiment 9 (R, R)-preparation of formoterol medicine carrying micropowder
(R, R)-formoterol 0.05g
Lactose 25g
Take by weighing each component by the prescription proportioning, be dissolved in the 250ml deionized water.With this solution with spray dryer carry out spray drying obtain (R, R)-formoterol medicine carrying micropowder.When carrying out spray drying, 110 ℃ of control EATs, 60 ℃ of leaving air temps, atomization air flow speed 30ml/h, peristaltic pump speed 5ml/min.
The assay of powder body: (R, R)-granularity of formoterol 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; Be 41.8 degree angle of repose.
Embodiment 10 (R, R)-preparation of formoterol medicine carrying micropowder
(R, R)-formoterol 0.022g
Lactose 11g
Take by weighing each component by the prescription proportioning, be dissolved in the 250ml deionized water.With this solution with spray dryer carry out spray drying obtain (R, R)-formoterol medicine carrying micropowder.When carrying out spray drying, 110 ℃ of control EATs, 60 ℃ of leaving air temps, atomization air flow speed 30ml/h, peristaltic pump speed 4ml/min.
The assay of powder body: (R, R)-granularity of formoterol 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; Be 42.6 degree angle of repose.
Embodiment 11 (R, R)-preparation of formoterol medicine carrying micropowder
(R, R)-formoterol 0.022g
Mannitol 11g
Take by weighing each component by the prescription proportioning, be dissolved in the 250ml deionized water.With this solution with spray dryer carry out spray drying obtain (R, R)-formoterol medicine carrying micropowder.When carrying out spray drying, 110 ℃ of control EATs, 60 ℃ of leaving air temps, atomization air flow speed 30ml/h, peristaltic pump speed 2ml/min.
The assay of powder body: (R, R)-granularity of formoterol medicine carrying micropowder is that 90% diameter of particle is less than 10 μ m in the 0.5 μ m-5 mu m range; Be 41.2 degree angle of repose.
Embodiment 12 (R, R)-preparation of formoterol medicine carrying micropowder
(R, R)-formoterol 0.022g
Leucine 11g
Take by weighing each component by the prescription proportioning, be dissolved in the 250ml deionized water, this solution is carried out spray drying with spray dryer obtain (R; R)-formoterol medicine carrying micropowder; When carrying out spray drying, 110 ℃ of control EATs, 60 ℃ of leaving air temps; Atomization air flow speed 30ml/h, peristaltic pump speed 4ml/min.
The assay of powder body: (R, R)-granularity of formoterol 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; Be 40.2 degree angle of repose.Embodiment 13 (R, R)-preparation of formoterol capsule type inhalation aerosol powder
(R, R)-formoterol medicine carrying micropowder (contain (R, R)-formoterol 0.022g) 11.4g
Carrier micropowder (particle diameter is between 40-140 μ m) 14g
Get the carrier grain size of micropowder after crossing 100 mesh sieves between the 40-140 μ m, progressively increase behind the method mixing with equivalent with the medicine carrying micropowder, fill No. 4 Capsules, every loading is 30mg.
According to the assay method of Chinese Pharmacopoeia 2005 editions, detect, capsular Emptying Rate is 99.1%, and capsular droplet (grain) measure of spread is 17.2%, and other each item indexs all meet the requirement of Chinese Pharmacopoeia version suction in 2005 powder spray.
Claims (6)
1. one kind (R, R)-formoterol inhalation dust cloud agent, by the carrier micropowder with (R, R)-the medicine carrying micropowder of formoterol forms, R wherein, the medicine carrying powder content of R-formoterol is 5%-80% (w/w), the diameter of particle of its at least 90% (w/w) is less than 10 μ m; The carrier micropowder is selected from one or more in the acceptable sugar of physiology, polyhydric alcohol, the aminoacid; Content is 20%-95% (w/w), and the microgranule particle diameter of its at least 80% (w/w) is 40 μ m-100 μ m, it is characterized in that described (R; R)-formoterol medicine carrying micropowder in; (R, R)-formoterol accounts for 0.1%-10% (w/w), and water-solubility carrier accounts for 90%-99.9% (w/w); Water-solubility carrier be the acceptable sugar of physiology, polyhydric alcohol or amino acid whose one or more.
Claim 1 described (R, R)-formoterol inhalation dust cloud agent, wherein said (R, R)-formoterol medicine carrying micropowder in, (R, R)-formoterol accounts for 0.2%-2% (w/w), water-solubility carrier accounts for 99.8%-98% (w/w); Water-solubility carrier is one or more in lactose, mannitol or the leucine.
Claim 1-2 any one described (R R)-method for preparing of formoterol inhalation dust cloud agent, is characterized in that may further comprise the steps:
1) preparation of carrier micropowder may further comprise the steps:
(1) with in the acceptable sugar of physiology, polyhydric alcohol, the aminoacid one or more be mixed with concentration be 0.1g/100ml to saturated aqueous solution,
(2) solution mist is changed into tiny drop,
(3) spray in the organic solvent,
(4) drying;
2) preparation of medicine carrying micropowder may further comprise the steps:
(1) will (R, R)-formoterol and water-solubility carrier be dissolved in the water, the content of solute is 1-10g/100ml in the solution,
(2) solution is carried out spray drying;
3) with carrier micropowder and medicine carrying micropowder with the equivalent method mix homogeneously that progressively increases, process preparation.
4. in the claim 3 described (R R)-method for preparing of formoterol inhalation dust cloud agent, is characterized in that step 2) (1), the content of solute is 2-7g/100ml in the said solution.
5. described (the R of claim 3; R)-and the method for preparing of formoterol inhalation dust cloud agent, it is characterized in that (3) described organic solvent in the step 1) is selected from one or more in ethanol, isopropyl alcohol, acetone, n-butyl alcohol, sec-butyl alcohol, ethyl acetate, butyl acetate, t-butyl methyl ether, Ethyl formate, normal heptane, isobutyl acetate, isopropyl acetate, methyl acetate, butanone, methyl iso-butyl ketone (MIBK), isobutanol, pentane, n-amyl alcohol, normal propyl alcohol, the petroleum ether.
6. described (R R)-method for preparing of formoterol inhalation dust cloud agent, is characterised in that described organic solvent is isopropyl alcohol or ethanol to claim 5.
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| JOP20120023B1 (en) * | 2011-02-04 | 2022-03-14 | Novartis Ag | Dry powder formulations of particles that contain two or more active ingredients for treating obstructive or inflammatory airways diseases |
| GB201609940D0 (en) * | 2016-06-07 | 2016-07-20 | Novabiotics Ltd | Microparticles |
| CN106509972B (en) * | 2016-11-25 | 2018-08-03 | 福建中烟工业有限责任公司 | A kind of composition and the method for preparing tobacco extract using the composition |
| CN112043687A (en) * | 2020-09-24 | 2020-12-08 | 珠海瑞思普利生物制药有限公司 | Inhalation powder inhalation for treating asthma and preparation method thereof |
| CN112451509B (en) * | 2020-12-19 | 2023-03-07 | 沈阳药科大学 | A kind of trabutanterol inhalation powder mist and preparation method thereof |
| CN116165319B (en) * | 2022-05-30 | 2023-11-17 | 上海奥科达医药科技股份有限公司 | Method for detecting diastereoisomers in formoterol fumarate inhalation solution |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1399540A (en) * | 1999-11-30 | 2003-02-26 | 诺瓦提斯公司 | Aerosol composition comprising formoterol |
| CN1429103A (en) * | 2000-05-19 | 2003-07-09 | 阿斯特拉曾尼卡有限公司 | Novel process |
| CN1593414A (en) * | 2004-07-02 | 2005-03-16 | 上海华拓医药科技发展有限公司 | Powder inhalation of tiotropium bromide capsule type and its preparation method |
-
2007
- 2007-07-11 CN CN2007100578933A patent/CN101342155B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1399540A (en) * | 1999-11-30 | 2003-02-26 | 诺瓦提斯公司 | Aerosol composition comprising formoterol |
| CN1429103A (en) * | 2000-05-19 | 2003-07-09 | 阿斯特拉曾尼卡有限公司 | Novel process |
| CN1593414A (en) * | 2004-07-02 | 2005-03-16 | 上海华拓医药科技发展有限公司 | Powder inhalation of tiotropium bromide capsule type and its preparation method |
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