CN101889993B - Surface-modified salbutamol suspension type non-Freon inhalation aerosol and preparation method thereof - Google Patents
Surface-modified salbutamol suspension type non-Freon inhalation aerosol and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a surface-modified salbutamol suspension type non-Freon inhalation aerosol and a preparation method thereof. The surface-modified salbutamol suspension type non-Freon inhalation aerosol contains 0.001%-3% of salbutamol with surface modified by using phospholipid by total weight of the aerosol. The surface-modified salbutamol suspension type non-Freon inhalation aerosol has the advantages of convenient use, safety and nonirritant because natural nontoxic phospholipid is used as a surface active agent has great low content, and higher clinical application value.
Description
Technical field
The present invention relates to technical field of medicine, specifically be albuterol inhalation aerosol and preparation method thereof.
Background technology
Since the Charles Thiel of Riker Laboratories in 1956 invention pressure metered dose inhalation aerosol (pressurized metered dose inhaler first, pMDI) since, in five more than ten years in the past, owing to have quick-acting, locate and avoid gastrointestinal tract first pass effect and volume little, convenient drug administration, price is low, the patient is easy to use, need not be such as Foradil Aerolizer formoterol fumarate drug loading or former thereby cause advantages such as the powder moisture absorption in the device because of environment etc. before use, treatment pulmonary disease such as asthma always, the main dosage form of chronic obstructive pulmonary disease has the irreplaceable advantage of other preparations.
Along with the enhancing of people to environmental consciousness, 40 countries had signed Montreal Protocol on Substances that Deplete the Ozone Layer at Montreal, CAN in 1987, propellant-freon (Chlorofluorocarbon among the pMDI, CFC), because it is greenhouse gases, and the stronger depletion of the ozone layer effect of tool, and face alternative.China has worked out " Chinese ODS is progressively eliminated national scheme " in January, 1993, and State Food and Drug Administration made an announcement in 2006, will stop to produce and using the pressure metered dose inhalation aerosol that contains freon in 2010 comprehensively.In alternative material, two kinds of hydrofluoroalkanes (hydrofluoroalkane, HFA) are that HFA-134a (tetrafluoroethane) and HFA-227 (heptafluoro-propane) have got permission to be used for pMDI as medicinal propellant.Nineteen ninety-five, European Union ratified the exploitation that HFA134a and HFA 227 CFC alternative are used for medicinal aerosol, and U.S. FDA had also been ratified HFA 134a in the application that sucks preparation in 1996.
Chinese patent [patent No.: ZL93100476.4, Granted publication number: CN1063321C] discloses a kind of medicinal aerosol formulations, and it is mainly by the granulated drug that is selected from salmaterol, salbutamol, FLUTICASONE PROPIONATE and physiologically acceptable salt and solvate, and as 1,1,1 of propellant, 2-tetrafluoroethane, 1,1,1,2,3,3,3-, seven fluorine n-propanes or its mixture form, do not contain cosolvent, contain hardly surfactant (＜0.0001%w/w);
Chinese patent [the patent No.: ZL93100477.2, Granted publication number: CN1048627C] a kind of medicinal aerosol formulations disclosed, its principal agent is anti-allergic drug, bronchodilator or anti-inflammatory type sterol compounds, it comprises granulated drug, as 1,1,1 of propellant, 2-tetrafluoroethane, 1,1,1,2,3,3,3-, seven fluorine n-propanes or its mixture, and take the polar co-solvent of propellant as benchmark 0.01-5%w/w, said polar co-solvent is C2-6 aliphatic alcohol or polyhydric alcohol or its mixture, and said preparation is substantially free of surfactant;
Chinese patent [the patent No.: ZL96194411.0, Granted publication number: CN1217654C] disclose the meter that a kind of inhaler surface scribbles polymer and decided the dosage inhalation aerosol, its principal agent is salbutamol or its physiology acceptable salt and a kind of anti-inflammatory agent or antiallergic agent combination.This aerosol composition comprises principal agent, polar latent solvent, propellant can not add surfactant;
Chinese patent [the patent No.: ZL00120072.0, Granted publication number: CN1152669C] a kind of aerosol preparations for inhalation disclosed, the granulated drug that it is mainly combined by FLUTICASONE PROPIONATE and salmaterol or its physiologically acceptable salt, and as 1 of propellant, 1,1,2-tetrafluoroethane forms, and said preparation randomly contains by the surfactant of drug weight less than 0.0001%w/w.This patent is a claim wherein, and described granulated drug is surface modification, but not mentioned how modification; And summary of the invention is pointed out, so-called " medicine of surface modification " refers to basically nonpolar non-solvent liquid mixing, removes liquid and by the drug particles of surface modification again;
Albuterol is classical beta 2 receptor agonist, it is the indispensable medicine of relieving asthma acute attack, because the active component of albuterol and the technology of above-mentioned patent disclosure is different, and the alternative of CFC is not the simple replacement that a preparation prescription forms in the medicinal aerosol, therefore, the technology of above-mentioned patent disclosure can't be simply for the preparation of the salbutamol suspension type inhalation aerosol.
The physicochemical property of HFA has been compared larger difference with CFC.Compare with CFC, HFA polarity is larger, and dissolubility is bad.Kauri-Butanol Value (kauri-butanol value, K.B. value) is a kind of test value of reading that represents organic liquid or organic solvent dissolution ability quality.Kauri is the title of a kind of natural gum (Gum), is soluble in butanols and is insoluble to other hydrocarbon cosolvent.Treat as a kind of standard solution if will be dissolved with the butanols of examining vertical glue, and constantly a small amount of adding of the solvent that other is unknown, until become turbid (Yin Kaoli glue is insoluble to other solvent and muddiness) namely gets the KB value.20 ℃ CFC-12KB value is 18, and the KB value of HFA-134a only is 9.2.Than CFC, HFA has better hydrophilic simultaneously, thereby causes easily the flocculation of suspension aerosol principal agent or caking, and this also just has higher requirement to the production environment of aerosol and the manufacturing process of tank body and valve.
Because of the special physiological structure of pulmonary, suck drug particle in the preparation and need the site of action of being allowed for access less than 5 μ m.Research worker is found, diameter of aspirin particle can change in suction process, should represent with dynamic particle diameter, its numerical value is different from initial size (being static particle diameter) in the prescription, this changes relevant with the character of other composition in suction air-flow, doser, suction, the preparation prescription, even diameter of aspirin particle 100%, also may only have the dynamic particle diameter of 20-30% less than 5 μ m less than 5 μ m, and the amount that can arrive pulmonary may only have 5～30% (even lower).Therefore, fine particle dosage in the inhalant (Fine Particle Dose, FPD) mensuration is compared with other preparation the research of suction preparation and the foundation of quality control guarantee system, even more important and difficult.
Summary of the invention
First purpose of the present invention provides a kind of surface and adopts phospholipid modified albuterol and preparation method thereof, the defects that exists to overcome prior art;
Further object of the present invention provides a kind of salbutamol suspension type inhalation aerosol of finishing, to satisfy the needs of clinical practice.
Phospholipid modified albuterol is adopted on surface of the present invention, it is characterized in that the shared weight of phospholipid is the 0.0001-0.3% of albuterol weight;
Preferably, described albuterol is salbutamol sulfate or albuterol hydrochloride;
Preferred described phospholipid comprises one or more in natural phospholipid, synthetic phospholipid or the hydrogenated phospholipid;
The preparation method of phospholipid modified albuterol is adopted on described surface, comprises the steps:
Albuterol is added in the phospholipid alcoholic solution, disperse, obtaining suspendible has the phospholipid alcoholic solution of albuterol, collect the surface and adopt phospholipid modified albuterol granule, dry, then the albuterol granule micronization processes after effects on surface is modified can obtain the surface and adopt phospholipid modified albuterol;
Perhaps comprise the steps: the albuterol of mean diameter less than 10 microns added in the phospholipid alcoholic solution, disperse, obtaining suspendible has the phospholipid alcoholic solution of albuterol, collect the surface and adopt phospholipid modified albuterol granule, drying can obtain the surface and adopt phospholipid modified albuterol;
Described suspendible has in the phospholipid alcoholic solution of albuterol, and the weight percent content of phospholipid is 0.0001-4%, and the weight percent content of albuterol is 1-40%.
Described process for dispersing comprises and shears dispersion, grinding distribution, ball milling dispersion or conventional dispersed with stirring;
Described micronization processes method is method well known in the art, adopts as the disclosed jet mill pulverizing of " New research progress of Technology of Ultrafine Airflow Smashing " [Hunan is metallurgical, the 34th volume, the 6th phase, 42-46] document.
Can obtain the albuterol mean diameter less than 10 microns micronised powder, preferably 2～3 microns;
The albuterol of the phospholipid finishing that obtains, behind its micronization, the phospholipid proportion is the 0.0001-0.3% of albuterol weight;
The salbutamol suspension type inhalation aerosol of finishing of the present invention, in described aerosol gross weight, phospholipid modified albuterol is adopted on the described surface of containing the 0.001-3% percentage by weight;
Preferably, the component that comprises following percentage by weight:
Phospholipid modified albuterol 0.001-3% is adopted on the surface
Ethanol 0-40%
Propellant 57-99.999%.
Described propellant is selected from more than one in tetrafluoroethane (HFA-134a) or the HFA-227ea (HFA-227ea).
Further preferably, comprise the component of following percentage by weight:
Phospholipid modified albuterol 0.01-1% is adopted on the surface
Ethanol 1-15%
The propellant surplus.
Described propellant is selected from more than one in tetrafluoroethane (HFA-134a) or the HFA-227ea (HFA-227ea).
Further preferably, comprise the component of following percentage by weight:
Phospholipid modified salbutamol sulfate 0.001% is adopted on the surface
HFA-227 99.999％。
Further preferably, comprise the component of following percentage by weight:
Phospholipid modified salbutamol sulfate 0.15% is adopted on the surface
Ethanol 4.94%
The HFA-134a surplus.
Further preferably, comprise the component of following percentage by weight:
Phospholipid modified albuterol hydrochloride 0.99% is adopted on the surface
Ethanol 19.80%
The HFA-134a surplus.
Further preferably, comprise the component of following percentage by weight:
Phospholipid modified albuterol hydrochloride 3.0% is adopted on the surface
Ethanol 40.0%
HFA-134a 33.33％
HFA-227 23.67％。
Further preferred, in the salbutamol suspension type inhalation aerosol of described finishing, it is 1～10 micron that the granule mean diameter of phospholipid modified albuterol is adopted on the surface.
The preparation method of the salbutamol suspension type inhalation aerosol of finishing of the present invention comprises the steps:
Adopt phospholipid modified albuterol, ethanol and propellant to adopt document " development of aerosol and suitability for industrialized production " [Hou Shuguang on the surface, 2008 suck the preparation international Conference, 104-116] disclosed one-step method, two step method or cold tank legal system standby, can obtain described aerosol, be a kind of suspension aerosol.
The salbutamol suspension type inhalation aerosol of finishing of the present invention, can be used for the treatment of asthma and chronic obstructive pulmonary disease, can put on the patient who needs treatment by oral cavity inhalation route, administration metering is generally and 3～6 presses/day, specifically can be determined by the doctor according to age of patient, the state of an illness etc.
The salbutamol suspension type inhalation aerosol of finishing of the present invention, content of phospholipid is extremely low after modifying, and in vitro tests proves, and aerosol of the present invention have significant therapeutic effect for treatment asthma and chronic obstructive pulmonary disease, and toxic and side effects is less.
By above-mentioned disclosed technical scheme as seen, the salbutamol suspension type inhalation aerosol of finishing of the present invention, easy to use, the employing surfactant is that phospholipid and the content of Nantural non-toxic is extremely low, safe and non-stimulating property has larger clinical value.
Description of drawings
Fig. 1 is the particle size distribution figure that the ACI of embodiment 6 records.
Fig. 2 is the particle size distribution figure that the NGI of embodiment 6 measures.
The specific embodiment
Embodiment 1
Get 0.15mg lecithin in the 150g dehydrated alcohol, after the dissolving, add 100g granule mean diameter less than 10 microns salbutamol sulfates, dispersed with stirring 10 minutes is filtered the phospholipid of removing solvent and not adsorbing, 50 ℃ of dryings,, acquisition 100.0001g mean diameter is 10 microns granule.Wherein, the shared weight of phospholipid is 0.0001% of salbutamol sulfate weight.
Embodiment 2
Get the 5g soybean phospholipid in the 790g dehydrated alcohol, after the dissolving, add 100g granule mean diameter less than 10 microns salbutamol sulfates, adopting cutter to shear disperseed 5 minutes, filter the phospholipid of removing solvent and not adsorbing, 50 ℃ of dryings, comminution by gas stream, acquisition 100.03g mean diameter is 5 microns granule.Wherein, the shared weight of phospholipid is 0.03% of salbutamol sulfate weight.
Embodiment 3
Get the 0.4g soybean phospholipid in the 400g dehydrated alcohol, after the dissolving, add the 100g albuterol hydrochloride, ball milling 20 minutes, the other the same as in Example 2, acquisition 100.001g mean diameter are 2 microns granule.Wherein, the shared weight of phospholipid is 0.001% of albuterol hydrochloride weight.
Embodiment 4
Get the 412.5g hydrogenated soya phosphatide in the 9900g dehydrated alcohol; After the dissolving, add the albuterol hydrochloride of 100g, ground 30 minutes, the other the same as in Example 2, acquisition 100.3g mean diameter are 3 microns granule.Wherein, the shared weight of phospholipid is 0.3% of albuterol hydrochloride weight.
Embodiment 5
Get the salbutamol sulfate of embodiment 1 finishing, by following weight, the two-step method fill of adopting " development of aerosol and suitability for industrialized production " [Hou Shuguang, 2008 suck preparation international Conference, 104-116] document to provide, and get final product:
The salbutamol sulfate 0.15mg of finishing
HFA-227 15.0g。
Embodiment 6
Get the salbutamol sulfate of embodiment 2 finishinges, the one-step method fill of adopting " development of aerosol and suitability for industrialized production " [Hou Shuguang, 2008 suck preparation international Conference, 104-116] document to provide, and get final product;
Prescription:
The salbutamol sulfate 24mg of finishing
Dehydrated alcohol 0.78g
HFA-134a 15.0g。
Embodiment 7
Get the albuterol hydrochloride of embodiment 3 finishinges, the cold tank method fill of adopting " development of aerosol and suitability for industrialized production " [Hou Shuguang, 2008 suck preparation international Conference, 104-116] document to provide, and get final product;
Prescription:
The albuterol hydrochloride 150mg of finishing
Dehydrated alcohol 3.0g
HFA-134a 12.0g。
Embodiment 8
Get the albuterol hydrochloride of embodiment 4 finishinges, adopt that " development of aerosol and suitability for industrialized production " [Hou Shuguang, 2008 suck preparation international Conference, 104-116] document provides than one-step method fill, and get final product;
Prescription:
Composition weight (%)
The albuterol hydrochloride 450mg 3.0 of finishing
Dehydrated alcohol 6.0g 40.0
HFA-134a 5.0g 33.33
HFA-227 3.55g 23.67
The mensuration of embodiment 9 TI particle size distribution
Fine particle dosage (Fine Particle Fraction, FPF) is as weigh sucking important parameter in the quality of the pharmaceutical preparations control, with the curative effect of preparation very large dependency arranged.After embodiment sample 5～8 preparation is finished, select respectively 10～20 bottles of samples, with reference to Chinese Pharmacopoeia 2005 editions, inhalation aerosol droplet (grain) the measure of spread method and the instrument that record among two appendix X H carry out.
With following chromatographic condition, the albuterol content in the working sample.
Mobile phase: sodium dihydrogen phosphate [get sodium dihydrogen phosphate 11.04g, be dissolved in water and be diluted to 1000ml, with phosphorus acid for adjusting pH to 3.10 ± 0.05], wavelength: 276nm, flow velocity: 1ml/min, sample size: 20 μ l;
The reference substance solution preparation: it is an amount of that precision takes by weighing the albuterol reference substance, is dissolved in water, and makes every 1mL and contain approximately 6ug albuterol solution, in contrast product solution.
The sample solution preparation steps is as follows: take water as acceptable solution, get aerosol 1 tank, placed at least 1 hour shake well in test temperature, after discarding the number spray, driver is inserted in the rubber interface, opened vacuum pump, 5 seconds of jolting aluminium pot, aluminium pot is inserted on the driver, spray immediately 1 time, timing waited for for 10 seconds; After taking off aluminium pot, reinsert driver in 5 seconds of jolting aluminium pot, spray the 2nd time; Repeat this process, until finish 10 or 20 times.After spraying the last time, take off driver and aluminium pot, timing waited for for 5 seconds, detaching device.Wash driver with water; Rubber running-on and throat; Trunnion and one-level distribution bottle; The conduit inside and outside wall of filter, F interface and importing lower taper bottle and surface and the second level distribution bottle (conical flask) of pad ridge, the each several part washing liquid is settled to scale, shake up, precision is measured 20 μ l injection liquid chromatographies, the record chromatogram, with calculated by peak area, the conduit inside and outside wall of filter, F interface and importing lower taper bottle and the surface of pad ridge and the collected medication amount of second level distribution bottle namely get the FPF value of sample divided by the summation of each several part collection medicine by external standard method.The data obtained is table 1 as a result:
Table 1
| Sample | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 |
| FPF(％) | 43.27 | 50.43 | 55.12 | 30.85 |
Embodiment 10
After 5～8 preparations of embodiment sample are finished, select respectively 10～20 bottles of samples, with reference to the fine particle mark (Fine Particle Fraction) of the U.S. and British Pharmacopoeia employing Andersen Cascade Impactor working sample
Chromatographic process is with embodiment 9
The experimental enviroment relative humidity should be 45% to 55%.Regulate flow velocity to 28 liter/min.Get respectively 2 bottles of this product, placed at least 1 hour at 22 ± 2 ℃; Behind the shake well, discard 4 sprays, water flushing valve and driver are dried, discard again 2 sprays, open vacuum pump, 5 seconds of jolting, this product is inserted the special (purpose) rubber interface, sprays immediately 1 time, take off aluminium pot and driver after, 5 seconds of jolting reinsert the rubber interface, spray the 2nd time, repeat this process, until finish 5 times, after last the injection, wait for 1 minute, take off aluminium pot, powered-down.Wash rubber interface and conduit, each layer of ram, filter paper with water, the each several part washing liquid is settled to scale, shake up, precision is measured 20 μ l injection liquid chromatographies, the record chromatogram, with calculated by peak area, from the 3rd layer of summation of collecting medicine divided by each several part to the collected medication amount of filter paper of ram, namely get the FPF value of sample by external standard method.The data obtained as a result particle size distribution figure of table 2, embodiment 6 is seen Fig. 1.
Table 2
| Sample | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 |
| FPF(％) | 44.13 | 50.68 | 56.21 | 30.32 |
Embodiment 11
After embodiment sample 5～8 preparation is finished, select respectively 10～20 bottles of samples, adopt the fine particle mark (Fine ParticleFraction) of the working sample of New Generation Impactor working sample with reference to the U.S. and British Pharmacopoeia.
Chromatographic process is with embodiment 9.
The experimental enviroment relative humidity should be 45% to 55%.Regulate flow velocity to 30 liter/min.Get respectively 2 bottles of this product, placed at least 1 hour at 22 ± 2 ℃; Behind the shake well, discard 4 sprays, water flushing valve and driver are dried, discard again 2 sprays, open vacuum pump, 5 seconds of jolting, this product is inserted the special (purpose) rubber interface, sprays immediately 1 time, take off aluminium pot and driver after, 5 seconds of jolting reinsert the rubber interface, spray the 2nd time, repeat this process, until finish 5 times, after last the injection, wait for 1 minute, take off aluminium pot, powered-down.Wash rubber interface and conduit with water; Each sedimentation glass of ram; Filter paper, the each several part washing liquid is settled to scale, shakes up, precision is measured 20 μ l injection liquid chromatographies, and the record chromatogram is pressed external standard method with calculated by peak area, collect the summation of medicine from ram the 4th sedimentation glass to the collected medication amount of MOC divided by each several part, namely get the FPF value of sample.The data obtained as a result table 3, embodiment 6 particle size distribution figure is seen Fig. 2.
Table 3
| Sample | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 |
| FPF(％) | 43.49 | 51.18 | 54.29 | 29.53 |
Embodiment 12
It is as follows that Proventil Inhaler of the present invention has been carried out irritation test:
A test specimen: embodiment 6
Under the rabbit waking state, directly with albuterol MDI or with the adjuvant (same volume) of method preparation medicine is directly sprayed into the rabbit air flue, need synchronous with the rabbit breathing process when spraying into.Every rabbit gives albuterol MDI or adjuvant, and once a day, each 4 press, continuous 7 days.Be 0d after the administration observing time, 1d, and 2d, 3d, 4d, 5d, 6d, 7d, and at d0, d3, d7 weighs.Behind last administration 24h, dissect rabbit; When dissected takes out lung and the trachea of every group every rabbit, and perusal is respectively organized the lung tissue surface and had or not petechia, struvite pus to swell; Tunica mucosa tracheae has or not the phenomenons such as hyperemia, redness.After taking out lungs and trachea, the formalin 15ml injection trachea with 10%, ligation, and with the fixing 5-7d of 10% formalin solution.Paraffin embedding, section 5 μ m, through dewaxing, dehydration of alcohol step by step, HE dyeing; Upper sem observation histopathology changes and photography.
Result of the test:
1 overview
Respiratory system: have no cough, sneeze, sialorrhea, rhinorrhea after the administration, shed tears, breathe steadily.
Nervous system: the no abnormality seens such as behavior, action.
Gastronintestinal system: have no diarrhoea after the administration, just secrete, abdominal part flatulence.Stool is shaped.
Fur: have no perpendicular hair, erythra after the administration, fur is rubescent, relaxing has gauffer etc.
Mucosa: have no conjunctiva, oral mucosa after the administration secretions, hyperemia are arranged, bleed, cyanosis, jaundice.
Eye: have no eye blepharoptosis on the face after the administration, exophthalmos, tremble and muddy.
Body weight: see Table 3, multiple dosing, before the administration with administration after albuterol MDI group compare there was no significant difference with the adjuvant group.
The body weight observation of table 3, multiple dosing (n=5, x ± SD)
The t-test check is compared P＞0.05 with the adjuvant group
2 dissect the naked eyes pathological observation
Put to death animal behind last administration 24h, take out trachea and lung and observe, each organizes the lung tissue surface there are no obviously petechia, struvite pus swell; Also have no tunica mucosa tracheae the phenomenons such as hyperemia, redness are arranged.
3 pathological section results show: have no significantly and the medicine associated change.
Conclusion (of pressure testing):
Many local inhalations of albuterol MDI have no the local irritation reaction.Compare no significant difference between albuterol MDI and adjuvant group.
B test specimen: embodiment 7
Under the rat waking state, the adjuvant (same volume) of directly using albuterol MDI or preparing with method directly sprays into rat airway with medicine, needs synchronous with the rat breathing process when spraying into.Every rat gives albuterol MDI or adjuvant, and once a day, each 2 press, continuous 7 days.Be 0d after the administration observing time, 1d, and 2d, 3d, 4d, 5d, 6d, 7d, and at d0, d3, d7 weighs.
The multiple dosing group is dissected rat behind last administration 24h; When dissected takes out lung and the trachea of every group every rat, and perusal is respectively organized the lung tissue surface and had or not petechia, struvite pus to swell; Tunica mucosa tracheae has or not the phenomenons such as hyperemia, redness.The formalin 2ml of the lungs gentle effective 10% that the multiple dosing group is taken out injects trachea, and the ligation trachea is with the fixing 5-7d of 10% formalin solution.Paraffin embedding, section 5 μ m, through dewaxing, dehydration of alcohol step by step, HE dyeing; Upper sem observation histopathology changes and photography.
Result of the test:
1 overview:
Respiratory system: have no cough, sneeze, sialorrhea, rhinorrhea after the administration, shed tears, breathe steadily.
Nervous system: the no abnormality seens such as behavior, action.
Gastronintestinal system: have no diarrhoea after the administration, just secrete, abdominal part flatulence.Stool is shaped.
Fur: have no perpendicular hair, erythra after the administration, fur is rubescent, relaxing has gauffer etc.
Mucosa: sham operated rats, before each group of albuterol MDI group and adjuvant group has the administration of fraction rat, because the stimulation of atrium and operator's proficiency level causes nasal membrane that blood is arranged.Have no oral mucosa secretions, hyperemia arranged, bleed, cyanosis, jaundice.
Eye: have no eye blepharoptosis on the face after the administration, exophthalmos, tremble and muddy.
Body weight: see Table 4, multiple dosing, before the administration with administration after albuterol MDI group compare there was no significant difference (P＞0.05) with the adjuvant group.
The body weight observation of table 4, multiple dosing test (n=10, x ± SD)
The t-test check is compared with the A group
*P＜0.05,
*P＜0.01.
2 dissect the naked eyes pathological observation
Put to death animal behind last administration 24h, take out trachea and lung and observe, each organizes the lung tissue surface there are no obviously petechia, struvite pus swell; Also have no tunica mucosa tracheae the phenomenons such as hyperemia, redness are arranged.
3 pathological section results show: have no significantly and the medicine associated change.
Conclusion (of pressure testing):
Albuterol MDI has no the local irritation reaction for for many times the local inhalation of rat.Compare no significant difference between albuterol MDI and adjuvant group.
The test of embodiment 13 maximum dosage-feedings
It is as follows that Proventil Inhaler of the present invention has been carried out the maximum dosage-feeding test:
Sample: embodiment 6
Under the rat waking state, directly with albuterol MDI or with the adjuvant (same volume) of method preparation medicine is directly sprayed into rat airway, need synchronous with the rat breathing process when spraying into.Every rat gives in adjuvant and the albuterol MDI one day minute 4 times (each 3 press, every minor tick 2h), and in the Continuous Observation 7 days this product to untoward reaction and the mortality rate of rat.
Be 0d after the administration observing time, 1d, and 2d, 3d, 4d, 5d, 6d, 7d, 8d, and at d0, d4, d8 weighs.
Vehicle group and medicine group are put to death animal behind administration 8d, dissect rat, take out whole internal organs, observe the organs and tissues surface and have or not struvite abscess, hemorrhage and downright bad.The formalin 2ml of the lungs gentle effective 10% that take out injects trachea, and the ligation trachea is with the fixing 5-7d of 10% formalin solution.Every group of lung tissue paraffin embedding of getting 6 rats, section 5 μ m are through dewaxing, dehydration of alcohol step by step, HE dyeing; Upper sem observation histopathology changes and photography.
Result of the test
1 overview:
Respiratory system: have no cough, sneeze, sialorrhea, rhinorrhea after the administration, shed tears, breathe steadily.
Nervous system: the no abnormality seens such as behavior, action.
Gastronintestinal system: have no diarrhoea after the administration, just secrete, abdominal part flatulence.Stool is shaped.
Fur: have no perpendicular hair, erythra after the administration, fur is rubescent, relaxing has gauffer etc.
Mucosa: have no conjunctiva, oral mucosa secretions, hyperemia are arranged, bleed, cyanosis, jaundice.
Eye: have no eye blepharoptosis on the face after the administration, exophthalmos, tremble and muddy.
Body weight: see Table 5, multiple dosing, before the administration with administration after albuterol MDI group compare there was no significant difference (P＞0.05) with the adjuvant group.
The body weight observation of table 5, maximum medicine-feeding test (n=14, x ± SD)
The t-test check is compared P＞0.05 with the adjuvant group
2 dissect the naked eyes pathological observation
Put to death animal behind last administration 24h, take out trachea and lung and observe, each organizes the lung tissue surface there are no obviously petechia, struvite pus swell; Also have no tunica mucosa tracheae the phenomenons such as hyperemia, redness are arranged.
3 pathological section results show: have no significantly and the medicine associated change.
Conclusion (of pressure testing):
Albuterol MDI maximum dosage-feeding has no toxic reaction.Compare no significant difference between albuterol MDI and adjuvant group.
Claims (11)
1. phospholipid modified albuterol is adopted on a surface, it is characterized in that the shared weight of phospholipid is the 0.0001-0.3% of albuterol weight;
Preparation method comprises the steps:
The albuterol of mean diameter less than 10 microns added in the phospholipid dehydrated alcohol, shear dispersion, grinding distribution, ball milling dispersion or conventional dispersed with stirring, obtaining suspendible has the phospholipid alcoholic solution of albuterol, collect the surface and adopt phospholipid modified albuterol granule, drying can obtain the surface and adopt phospholipid modified albuterol;
Described suspendible has in the phospholipid alcoholic solution of albuterol, and the weight percent content of phospholipid is 0.0001-4%, and the weight percent content of albuterol is 1-40%;
Described albuterol is salbutamol sulfate or albuterol hydrochloride.
2. phospholipid modified albuterol is adopted on surface according to claim 1, it is characterized in that described phospholipid comprises more than one in natural phospholipid, synthetic phospholipid or the hydrogenated phospholipid.
3. the method for phospholipid modified albuterol is adopted on preparation claim 1 or 2 described surfaces, it is characterized in that, comprise the steps: the albuterol of mean diameter less than 10 microns added in the phospholipid dehydrated alcohol, shear dispersion, grinding distribution, ball milling dispersion or conventional dispersed with stirring, obtaining suspendible has the phospholipid alcoholic solution of albuterol, collect the surface and adopt phospholipid modified albuterol granule, drying can obtain the surface and adopt phospholipid modified albuterol;
Described suspendible has in the phospholipid dehydrated alcohol of albuterol, and the weight percent content of phospholipid is 0.0001-4%, and the weight percent content of albuterol is 1-40%.
4. the salbutamol suspension type inhalation aerosol of a finishing is characterized in that, in described aerosol gross weight, phospholipid modified albuterol is adopted on claim 1 or the 2 described surfaces of containing the 0.001-3% percentage by weight.
5. the salbutamol suspension type inhalation aerosol of finishing according to claim 4 is characterized in that,
Component by following percentage by weight forms:
Phospholipid modified albuterol 0.001-3% is adopted on the surface
Ethanol 0-40%
Propellant 57-99.999%
Each constituent content percentage ratio sum should equal 100%;
Described propellant is selected from more than one in tetrafluoroethane or the HFA-227ea.
6. the salbutamol suspension type inhalation aerosol of finishing according to claim 5 is characterized in that, comprises the component of following percentage by weight:
Phospholipid modified albuterol 0.01-1% is adopted on the surface
Ethanol 1-15%
The propellant surplus.
7. the salbutamol suspension type inhalation aerosol of finishing according to claim 4 is characterized in that, comprises the component of following percentage by weight:
Phospholipid modified salbutamol sulfate 0.001% is adopted on the surface
HFA-227 99.999％。
8. the salbutamol suspension type inhalation aerosol of finishing according to claim 4 is characterized in that, comprises the component of following percentage by weight:
Phospholipid modified salbutamol sulfate 0.15% is adopted on the surface
Ethanol 4.94%
The HFA-134a surplus.
9. the salbutamol suspension type inhalation aerosol of finishing according to claim 4 is characterized in that, comprises the component of following percentage by weight:
Phospholipid modified albuterol hydrochloride 0.99% is adopted on the surface
Ethanol 19.80%
The HFA-134a surplus.
10. the salbutamol suspension type inhalation aerosol of finishing according to claim 4 is characterized in that, comprises the component of following percentage by weight:
11. the salbutamol suspension type inhalation aerosol of finishing according to claim 4 is characterized in that, it is 1～10 micron that the granule mean diameter of phospholipid modified albuterol is adopted on described surface.
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| CN 200910051538 CN101889993B (en) | 2009-05-19 | 2009-05-19 | Surface-modified salbutamol suspension type non-Freon inhalation aerosol and preparation method thereof |
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| CN 200910051538 CN101889993B (en) | 2009-05-19 | 2009-05-19 | Surface-modified salbutamol suspension type non-Freon inhalation aerosol and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1353980A (en) * | 2001-11-14 | 2002-06-19 | 丛繁滋 | Quick-acting aerosol for relieving asthma and its preparation method |
| CN1389202A (en) * | 2002-04-24 | 2003-01-08 | 上海信谊药业有限公司 | Levo-salbutamol hydrochloride aerosol and its prepn. |
| CN1559389A (en) * | 2004-03-05 | 2005-01-05 | 山东京卫制药有限公司 | Levo-salbutamol sulfate inhaler, and its prepn. method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1353980A (en) * | 2001-11-14 | 2002-06-19 | 丛繁滋 | Quick-acting aerosol for relieving asthma and its preparation method |
| CN1389202A (en) * | 2002-04-24 | 2003-01-08 | 上海信谊药业有限公司 | Levo-salbutamol hydrochloride aerosol and its prepn. |
| CN1559389A (en) * | 2004-03-05 | 2005-01-05 | 山东京卫制药有限公司 | Levo-salbutamol sulfate inhaler, and its prepn. method |
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