CN105476961A - Beclomethasone aerosol and preparation method thereof - Google Patents
Beclomethasone aerosol and preparation method thereof Download PDFInfo
- Publication number
- CN105476961A CN105476961A CN201510942974.6A CN201510942974A CN105476961A CN 105476961 A CN105476961 A CN 105476961A CN 201510942974 A CN201510942974 A CN 201510942974A CN 105476961 A CN105476961 A CN 105476961A
- Authority
- CN
- China
- Prior art keywords
- aerosol
- beclometasone
- propionic acid
- beclomethasone
- propellant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a beclomethasone aerosol and a preparation method of the beclomethasone aerosol. The preparation method of the beclomethasone aerosol comprises the following steps: weighing the main medicine beclomethasone, the auxiliary material medicinal absolute ethyl alcohol and menthol according to the formulated amounts; adding beclomethasone, the menthol and the like into the medicinal absolute ethyl alcohol, and starting the stirring operation till the components are completely dissolved; carrying out the on-line sampling operation by a sampling person for detecting a middle product; filtering, filling, rolling a valve, and filling 1,1,1,2-tetrafluoroethane; and detecting leakage, packaging, inspecting the finished product, and delivering the finished product from storage. According to the beclomethasone aerosol and the preparation method of the beclomethasone aerosol, HFA134a (tetrafluoroethane) replaces CFC, many kinds of beclomethasone aerosols containing no CFC appear on the market at home and abroad, and the representative types are QVAR, IVAX and the like; a propellant used by all the beclomethasone aerosols containing no CFC is HFA134a, the beclomethasone aerosol belongs to a solution type aerosol, and medicines are dissolved in the propellant, so that a uniform solution is formed, and after the solution is sprayed out, the propellant volatilizes, and then the medicines arrive at the applied parts in the state of solid or liquid particles, so that the treatment effects are achieved.
Description
Technical field
The invention belongs to valve aerosol spray technique field, particularly relate to a kind of propionic acid beclometasone aerosol and preparation method thereof.
Background technology
At present conventional metered dose inhalation aerosol refers to and jointly fills in the pressure vessel being encapsulated in and having special valve system containing drug solns or suspension with the propellant be suitable for, be vaporific ejection by the pressure of propellant by content during use, suck for pulmonary or be directly sprayed onto tract mucosa, skin and space, the formulation C FC (chlorofluoro-alkane, freon) of sterilization is the propellant the most often used in the past aerosol.Chloride ion contained by CFC, very huge to the destruction of ozone layer, environmental protection is affected.
Summary of the invention
The object of the present invention is to provide a kind of propionic acid beclometasone aerosol and preparation method thereof, the formulation C FC being intended to sterilize in solution metered dose inhalation aerosol conventional is at present as propellant institute chloride ion-containing, very huge to the destruction of ozone layer, on the problem of environmental protection impact.
The present invention is achieved in that a kind of preparation method of propionic acid beclometasone aerosol, and the preparation method of described propionic acid beclometasone aerosol comprises:
Sampling: operate in clean area, take the principal agent beclometasone of recipe quantity, adjuvant anhydrous alcohol for medical use and Mentholum etc., for subsequent use;
Preparating liquid: operate in clean area, adds in anhydrous alcohol for medical use by beclometasone, Mentholum, is constantly circulated by medicinal liquid through stirring and circulating pump, through sufficient circulation stirring, makes medicinal liquid disperse suspendible even;
Intermediate products detect: get the molten medicinal liquid prepared, detect assay item, drug content controls at 92%-108%;
Filter: operate in clean area, use filtering with microporous membrane medicinal liquid;
Wash bottle: aluminium pot hot-water soak 15 minutes afterflush of more than 60 DEG C, then use deionized water rinsing, drying in oven put into by aluminium pot, temperature 70-80 DEG C, and the time is greater than 10 hours;
Fill: according to measured intermediates content, adjusts theoretical fill amount, and according to fill amount quantitative perfusion liquid on quantitative filling machine, detect content uniformity, controlling deviation of weight is ± 5%;
Roll valve: to be rolled by proportional valve with inhalator jar sealing machine and be encapsulated in tank mouth;
Fill propellant: on quantitative propellant can packing machine, quantitatively press-fit HFA 134a by recipe quantity, the weighing products press-fited, check fill weight differential, control to fill difference in ± 5% scope, reject underproof product;
Leak detection: by inhalator jar complete for filling, through leak detection in 5 minutes in 50 DEG C of water-baths, bubble-free is overflowed; Moisture content is dried up fast after taking-up;
Stamp labeling: inhalator jar label print the date of manufacture, lot number, valid until content, paste label;
Packaging: capsule print the date of manufacture, lot number, valid until content, by inhalator jar, together with actuator, description, load capsule;
Product inspection: let pass after the assay was approved;
Load corrugated case, stamp is put in storage.
Further, the beclometasone taking recipe quantity described in is 34.5mg, anhydrous alcohol for medical use is 3kg and for Mentholum 45mg.
Another object of the present invention is to the propionic acid beclometasone aerosol providing a kind of preparation method of described propionic acid beclometasone aerosol to prepare, described propionic acid beclometasone aerosol is 85.0% ~ 120.0% of labelled amount containing beclometasone.
Further, the medicinal liquid of described propionic acid beclometasone aerosol in pressure vessel should be colourless to micro-yellow liquid; Pressing valve, the i.e. ejection in droplet of medicinal liquid.
Further, described propionic acid beclometasone aerosol is every bottle 200 and presses, and often presses containing beclometasone 50 μ g.
Another object of the present invention is the using method providing a kind of propionic acid beclometasone aerosol, this using method comprises: open and jointly fill containing drug solns or suspension and suitable propellant the pressure vessel being encapsulated in and having special valve system, pressing valve, be vaporific ejection by the pressure of propellant by content, vaporific ejecta is sucked by pulmonary or is directly sprayed onto tract mucosa, skin and space.
The selection of correctives of the present invention: better accept this product for allowing user, improve mouthfeel and the comfort level of this product, experimentation has been carried out to the correctives in prescription, with the subjective feeling of experimenter for inspection target, determine the impact of correctives on this product, Mentholum consumption 0.085%, cool taste, has joyful sense; Consumption 0.1%, refrigerant sense is too heavy, uncomfortable; Consumption 0, generally, without special impression; Aromatic oil consumption 0, generally, without special impression; Consumption 0.1%, mouthfeel is too fragrant, and abnormal flavour sense is obvious; Consumption 0.01%, abnormal flavour sense is slightly light, but inharmonious with product; Experimental result shows, when the consumption of Mentholum or aromatic oil is excessive, can makes the mouthfeel of product that serious change occurs, affect the mouthfeel of product, and also can clash with this product when the consumption of aromatic oil is very little, illustrate that this product should not use this type of adjuvant; But when the consumption in Mentholum system is 0.085% time, active influence can be produced to this product, contribute to experimenter and accept this product, therefore the Mentholum of choice for use 0.085% is as the correctives of this product.
Beclometasone is that one synthesizes adrenocortical hormone efficiently, and be the dipropionate of beclometasone, its chemical name is: 16 Beta-methyl-11 β, the pregnant steroid of 17 α, 21-trihydroxy-9 α-chlorine-Isosorbide-5-Nitrae-diene-3,20-diketone-17,21-dipropionate.This medical instrument has antiinflammatory, antiallergic and the effect such as antipruritic, can suppress bronchus exudate, eliminates bronchial mucosa swelling, removes bronchospasm.Pharmacological research shows, this medicine local contraction blood capillary act as 5000 times of hydrocortisone, and local anti-inflammatory effect is 5 times of fluocinolone acetonide and omcilon.
Beclometasone is the potent external adrenal cortex hormones drug of synthetic, propionic acid beclometasone aerosol external has: 1. antiinflammatory, antiallergic, antipruritic and minimizing transudation, bronchus exudate can be suppressed, eliminate a gas mucosa swelling, remove bronchospasm; 2. can alleviate and prevent tissue to the reaction of inflammation, the heating that local non-infectious inflammation causes, rubescent and swelling can be eliminated, thus the performance reduced inflammation; 3. immunosuppressive action: prevent or the immunoreation of T suppression cell intermediary, retardance anaphylaxis, and alleviate and formerly send out expansion immunoreactive; 4. this product topical application, to sodium retention and gluconeogenesis function of liver very weak, also without effect that is male, female and protein anabolic hormone sample, to body temperature and urine also have no significant effect, the curative effect that inhalation is panted to bronchus is more effective than oral.
Lipotropy of the present invention is comparatively strong, easily permeates.Can absorb from lung rapidly after this medicine aerosol sucks, its bioavailability is 10%-25%.After 75% of remainder is swallowed, in gastrointestinal absorption.Human body is distributed in rapidly the effect such as antiinflammatory, antiallergic that plays powerful 17-hydroxy-11-dehydrocorticosterone in bronchus, alveolar and is distributed in nasal cavity and reaches resisting allergic rhinitis effect after sucking this medicine, also can be distributed in the tissue such as liver, Placenta Hominis, based on liver in viscera tissue, Vd is 0.3L/kg.Swallow part in liver deactivation, some are hydrolyzed by tissue esterases.Half-life is 15 hours.Can extend during hepatic disease.Its metabolite 70% through bile, 10%-15% through homaluria.
At present conventional metered dose inhalation aerosol refers to and jointly fills in the pressure vessel being encapsulated in and having special valve system containing drug solns or suspension with the propellant be suitable for, and is vaporific ejection by the pressure of propellant by content during use; CFC (chlorofluoro-alkane, freon) be the propellant the most often used in the past aerosol, the chloride ion contained by CFC is very huge to the destruction of ozone layer, from the angle of environmental protection, the present invention uses HFA134a (tetrafluoroethane) CFC alternative.
Existing a lot of not going on the market containing the propionic acid beclometasone aerosol of CFC both at home and abroad at present, representational kind has QVAR, the kinds such as IVAX.The propellant used is HFA134a, and solution aerosol, basic demand be medicine dissolution in propellant, form homogeneous solution, propellant volatilization after ejection, medicine reaches site of action with solid or liquid particle state, and its product gross weight is about 18g.
Accompanying drawing explanation
Fig. 1 is the preparation method flow chart of the propionic acid beclometasone aerosol that the embodiment of the present invention provides.
Detailed description of the invention
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Below in conjunction with drawings and the specific embodiments, application principle of the present invention is further described.
The present invention is containing beclometasone (C
28h
37clO
7) should be 85.0% ~ 120.0% of labelled amount.The medicinal liquid of the present invention in pressure vessel should be colourless to micro-yellow liquid; Pressing valve, the i.e. ejection in droplet of medicinal liquid.The present invention is every bottle 200 and presses, and often presses containing beclometasone 50 μ g.
As shown in Figure 1, the preparation method of the propionic acid beclometasone aerosol of the embodiment of the present invention comprises the following steps:
S101: sampling: operate in clean area, take the principal agent beclometasone of recipe quantity, adjuvant anhydrous alcohol for medical use and Mentholum etc., for subsequent use;
S102: preparating liquid: operate in clean area, adds in anhydrous alcohol for medical use by beclometasone, Mentholum, is constantly circulated by medicinal liquid through stirring and circulating pump, through sufficient circulation stirring, makes medicinal liquid disperse suspendible even;
S103: intermediate products detect: get the molten medicinal liquid prepared, detect assay item, drug content controls at 92%-108%;
S104: filter: operate in clean area, use filtering with microporous membrane medicinal liquid;
S105: wash bottle: aluminium pot hot-water soak 15 minutes afterflush of more than 60 DEG C, then use deionized water rinsing, drying in oven put into by aluminium pot, temperature 70-80 DEG C, and the time is greater than 10 hours;
S106: fill: according to measured intermediates content, adjusts theoretical fill amount, and according to fill amount quantitative perfusion liquid on quantitative filling machine, detect content uniformity, controlling deviation of weight is ± 5%;
S107: roll valve: with inhalator jar sealing machine proportional valve rolled and be encapsulated in tank mouth;
S108: fill propellant: quantitatively press-fit HFA 134a by recipe quantity on quantitative propellant can packing machine, the weighing products press-fited, checks fill weight differential, controls to fill difference in ± 5% scope, rejects underproof product;
S109: leak detection: by inhalator jar complete for filling, through leak detection in 5 minutes in 50 DEG C of water-baths, bubble-free is overflowed; Moisture content is dried up fast after taking-up;
S1010: stamp labeling: inhalator jar label print the date of manufacture, lot number, valid until content, paste label;
S1011: packaging: capsule print the date of manufacture, lot number, valid until content, by inhalator jar, together with actuator, description, load capsule;
S1012: product inspection: let pass after the assay was approved;
S1013: load corrugated case, stamp is put in storage.
The described beclometasone taking recipe quantity is 34.5mg, anhydrous alcohol for medical use is 3kg and for Mentholum 45mg.
According to impact and the controlled grade of Technical Parameters on Product Quality in the preparation method of propionic acid beclometasone aerosol, in conjunction with the probability that deviation occurs, critical process step and controling parameters all should in the scopes that suitability for industrialized production is controlled.In conjunction with the practical situation of production technology, dosing of the present invention and filling propellant operation, have considerable influence to product quality, therefore, be defined as committed step.In intermediate control, strict incoming test standard is formulated to raw material beclometasone crude drug of the present invention, and controlled the quality of raw material in conjunction with the means such as exfactory inspection of manufacturer.
A propionic acid beclometasone aerosol prepared by the preparation method of described propionic acid beclometasone aerosol, described propionic acid beclometasone aerosol is 85.0% ~ 120.0% of labelled amount containing beclometasone.
The medicinal liquid of described propionic acid beclometasone aerosol in pressure vessel should be colourless to micro-yellow liquid; Pressing valve, the i.e. ejection in droplet of medicinal liquid.
Described propionic acid beclometasone aerosol is every bottle 200 and presses, and often presses containing beclometasone 50 μ g.
A kind of using method of propionic acid beclometasone aerosol, this using method comprises: open and jointly fill containing drug solns or suspension and suitable propellant the pressure vessel being encapsulated in and having special valve system, pressing valve, be vaporific ejection by the pressure of propellant by content, vaporific ejecta is sucked by pulmonary or is directly sprayed onto tract mucosa, skin and space.
Below in conjunction with concrete experiment, effect of the present invention is further described.
Experiment 1: differentiate
(1) this product 1 bottle is got, aluminium lid bores an aperture, insert the entry needle (not contacting with liquid level) being connected with dry rubber tube, one end of rubber tube passes in water exits, treat that propellant gasification is waved to the greatest extent, removing aluminium lid, put in water-bath and eliminate propellant residual in bottle, add cyclohexane extraction 3ml and wash content, filter after leaving standstill.Wash 3 times altogether, filter with same filter paper, residue in bottle and on filter paper is with after hot blast removing thiacyclohexane, add ethanol 50ml and make dissolving, filter, precision measures subsequent filtrate appropriate (being about equivalent to beclometasone 1mg), with ethanol dilution to 50ml, measure according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version general rule 0401 in 2015), have absorption maximum at the wavelength place of 239nm.
(2), in the chromatogram recorded under assay item, the retention time of need testing solution main peak should be consistent with the retention time of reference substance solution main peak.
Experiment 2: check related substance
Get this product 1 bottle, aluminium lid bores an aperture, insert the entry needle (not contacting with liquid level) being connected with dry rubber tube, treat that propellant gasification is waved to the greatest extent, removing aluminium lid, is all transferred to residue medicinal liquid in 10ml measuring bottle, dissolves with diluent (diluent: mobile phase A: Mobile phase B=45:55) and be diluted to scale, shake up, as need testing solution.Precision measures 1ml, puts in 100ml measuring bottle, is diluted to scale with diluent, in contrast solution a.5mg beclometasone system suitability reference substance (impure D) is dissolved in 3ml Mobile phase B, then is settled to 5ml by mobile phase A, solution b in contrast.By 5mg beclometasone peak identity reference substance (containing impurity A, B, C, L, M) be dissolved in 3ml Mobile phase B, then be settled to 5ml by mobile phase A, a bottle beclometasone impurity F and N reference substance is dissolved, in contrast solution c with this solution 1ml.Test according to high performance liquid chromatography (Chinese Pharmacopoeia version general rule 0512 in 2015), be filler (HubbleC18 with octadecylsilane chemically bonded silica, 4.6mm × 250mm, the chromatographic column of 5 μm or the suitable triple end group sealing difunctionals of performance); With the potassium dihydrogen phosphate phosphorus acid for adjusting pH to 2.35 of 2.72g/L for mobile phase A, oxolane: acetonitrile: methanol (5:23:25) is Mobile phase B, and according to the form below carries out gradient elution
Flow velocity is 1.4ml/min, and determined wavelength is 254nm, and number of theoretical plate calculates by beclometasone peak and is not less than 2500.Precision measures need testing solution, each 20ul of contrast solution a, b, c, respectively injection liquid chromatography.If any impurity peaks in the chromatogram of need testing solution, the calibration peak area of impurity L must not be greater than 60% (0.6%) of contrast solution a main peak area; Each calibration peak area of impurity B, F, M all must not be greater than 50% (0.5%) of contrast solution a main peak area; Each calibration peak area of impurity A, D, N all must not be greater than 30% (0.3%) of contrast solution a main peak area; The calibration peak area of impurity C must not be greater than 20% (0.2%) of contrast solution a main peak area; Other unknown impuritie peak areas must not be greater than 60% (0.6%) of contrast solution a main peak area; Total impurities peak area must not be greater than 200% (2.0%) of contrast solution a main peak area; (0.05%) is ignored at the peak being less than 5% of contrast solution a main peak area in need testing solution.(relative retention time and the correction factor of each impurity peaks see the following form)
Experiment 3: minuteness particle dosage
Measure according to suction preparation minuteness particle air dynamic behaviour algoscopy (Chinese Pharmacopoeia version general rule 0951 first method in 2015).Get test sample 1 tank, at least place 1 hour at 22 DEG C ± 2 DEG C, lower floor's conical flask mid-30ml ethanol acceptable solution, upper strata conical flask puts 7ml ethanol acceptable solution.Get this product, shake well, examination spray 5 times, pressing sprays 20 times (noting each injection interval 5 seconds and slowly jolting), predetermined member is cleaned with appropriate amount of ethanol, merge the acceptable solution in washing liquid and lower floor's conical flask (H), put in 50ml measuring bottle, with ethanol dilution to scale, shake well, filters, it is appropriate that precision measures subsequent filtrate, quantitatively dilute the solution made about containing 10 μ g in every 1ml with ethanol, according to the chromatographic condition under assay item, precision measures 50 μ l injection liquid chromatographies; Separately get beclometasone reference substance, accurately weighed, add dissolve with ethanol and quantitatively dilute the solution made containing 10 μ g in every 1ml, being measured in the same method.By external standard method with calculated by peak area, minuteness particle medication amount should be not less than often presses 20% of labelled amount.
Experiment 4: slip
Get this product 12 bottles, remove outer package, with ethanol, surface clean is clean, room temperature vertical (uprightly) is placed 24 hours, respectively accurately weighed weight (W
1), then place 72 hours (being accurate to 30 minutes) in room temperature, then distinguish accurately weighed weight (W
2), after putting 2 DEG C ~ 8 DEG C coolings, on valve, bore an aperture rapidly, be placed to room temperature, be gasified totally until propellant and wave to the greatest extent, bottle is separated with valve, cleans with ethanol, at room temperature dry, accurately weighed weight (W respectively
3), be calculated as follows every bottle of leakage rate per year.Average year slip should be less than 3.5%, and 1 bottle must not be had to be greater than 5%.
Experiment 5: every bottle is always pressed secondary
Get test sample 4 bottles, removing cap, shake well, in fume hood, pressing valve sprays continuously and (note each injection interval 5 seconds and slowly jolting) in the container adding appropriate absorbing liquid respectively, till spray to the greatest extent, calculate injecting times respectively, always press secondary its sign that all must not be less than for every bottle and always press secondary.
Experiment 6: dosage delivered homogeneity
According to method inspection under " suction preparation " (Chinese Pharmacopoeia version general rule 0111 in 2015) continuous item.Get this product one bottle, jolting 5 seconds, discards 1 spray, is inserted by suction apparatus in adapter, sprays 1 time, bleeds 5 seconds, take off suction apparatus.With ethanol purge filter paper and collecting pipe inside, merge washing liquid and be also diluted to 10ml.
Repeat said process, collect respectively measure sign to press time before (initial 3 dosage), in (n/2 picks up 4 dosage, and n always to press time for indicating), rear (last 3 dosage), totally 10 dosage.Detect according to chromatographic condition under assay item, meet the one of following condition, can be judged to and conform with the regulations:
In (1) 10 measurement result, if at least 9 between 75%-125% of meansigma methods, and all between 65% ~ 135% of meansigma methods.
In (2) 10 measurement results, 2-3 results exceed 75%-125%, separately get this product 2 bottles mensuration.If in 30 measurement results, exceed no more than 3 of the measured value of 75-125%, and all between 65%-135% of meansigma methods.
Experiment 7: often press drug content
Get test sample 1 bottle, shake well, removing cap, examination spray 5 times, running-on is cleaned with solvent, after abundant drying, be inverted in and add in the suitable beaker of a certain amount of ethanol, under running-on being immersed absorbing liquid liquid level (at least 25mm), spray 50 times (noting each injection interval 5 seconds and slowly jolting), take out test sample, clean inside and outside running-on with ethanol, merge absorbing liquid, to be transferred in 250ml measuring bottle and after being diluted to scale, by the chromatographic condition under assay item, sampling volume is 50 μ L; Another precision takes propanoic acid multiplying power rice pine reference substance, adds dissolve with ethanol and is quantitatively diluted to 10 μ g/ml, being measured in the same method.Acquired results, divided by sampling injecting times, is and on average often presses drug content.Often press drug content to should be and often press 80% ~ 120% of drug content labelled amount.
Experiment 8: microbial limit
According to non-sterile product limit test of microbe: microorganism count method (Chinese Pharmacopoeia 2015 editions general rules 1105) and Control bacteria examination method (Chinese Pharmacopoeia 2015 editions general rules 1106) and non-sterile product limitation standard in microbe (Chinese Pharmacopoeia 2015 editions general rules 1107) check, should conform with the regulations.
Other, every regulation (Chinese Pharmacopoeia version general rule 0113 in 2015) relevant under aerosol item should be met.
Experiment 9: assay:
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version general rule 0512 in 2015).
Be filler with octadecylsilane chemically bonded silica; With methanol-water (74:26) for mobile phase; Determined wavelength is 240nm.Number of theoretical plate calculates by beclometasone peak and is not less than 2500.
Get this product, take ethanol as absorbent, often press the method operation under major pharmaceutical quantifier according to aerosol (Chinese Pharmacopoeia version general rule 0113 in 2015), quantitatively dilute the solution made containing 0.1mg in every 1ml with ethanol, precision measures 20 μ L injection liquid chromatographies, record chromatogram; Separately get beclometasone reference substance, accurately weighed, add dissolve with ethanol and quantitatively dilute the solution made containing 0.1mg in every 1ml, being measured in the same method.By external standard method with calculated by peak area, to obtain final product.
Below in conjunction with application experiment, the present invention is further described:
The selection of correctives
For allowing user better accept this product, improve mouthfeel and the comfort level of this product, we have carried out experimentation to the correctives in prescription.With the subjective feeling of experimenter for inspection target, determine the impact of correctives on this product, related experiment is as follows.
The selection of correctives
Experimental result shows, when the consumption of Mentholum or aromatic oil is excessive, can makes the mouthfeel of product that serious change occurs, affect the mouthfeel of product, and also can clash with this product when the consumption of aromatic oil is very little, illustrate that this product should not use this type of adjuvant; But when the consumption in Mentholum system is 0.085% time, active influence can be produced to this product, contribute to experimenter and accept this product, therefore the Mentholum of choice for use 0.085% is as the correctives of this product.
Beclometasone is that one synthesizes adrenocortical hormone efficiently, and be the dipropionate of beclometasone, its chemical name is: 16 Beta-methyl-11 β, the pregnant steroid of 17 α, 21-trihydroxy-9 α-chlorine-Isosorbide-5-Nitrae-diene-3,20-diketone-17,21-dipropionate.This medical instrument has antiinflammatory, antiallergic and the effect such as antipruritic, can suppress bronchus exudate, eliminates bronchial mucosa swelling, removes bronchospasm.Pharmacological research shows, this medicine local contraction blood capillary act as 5000 times of hydrocortisone, and local anti-inflammatory effect is 5 times of fluocinolone acetonide and omcilon.This product belongs to existing national drug standards preparation, domestic existing propionic acid beclometasone aerosol list marketing, and according to the pertinent regulations of " drug registration management method ", the invention belongs to chemical medicine registration classification 6 class, its pharmacological toxicology Review Study is as follows:
Pharmacodynamics
Beclometasone is the potent external adrenal cortex hormones drug of synthetic.Propionic acid beclometasone aerosol external has:
1. antiinflammatory, antiallergic, antipruritic and minimizing transudation, can suppress bronchus exudate, eliminate a gas mucosa swelling, remove bronchospasm.
2. can alleviate and prevent tissue to the reaction of inflammation, the heating that local non-infectious inflammation causes, rubescent and swelling can be eliminated, thus the performance reduced inflammation.
3. immunosuppressive action: prevent or the immunoreation of T suppression cell intermediary, retardance anaphylaxis, and alleviate and formerly send out expansion immunoreactive.
4. this product topical application, to sodium retention and gluconeogenesis function of liver very weak, also without effect that is male, female and protein anabolic hormone sample, to body temperature and urine also have no significant effect, the curative effect that inhalation is panted to bronchus is more effective than oral.
Pharmacokinetics
Lipotropy of the present invention is comparatively strong, easily permeates.Can absorb from lung rapidly after this medicine aerosol sucks, its bioavailability is 10%-25%.After 75% of remainder is swallowed, in gastrointestinal absorption.Human body is distributed in rapidly the effect such as antiinflammatory, antiallergic that plays powerful 17-hydroxy-11-dehydrocorticosterone in bronchus, alveolar and is distributed in nasal cavity and reaches resisting allergic rhinitis effect after sucking this medicine, also can be distributed in the tissue such as liver, Placenta Hominis, based on liver in viscera tissue, Vd is 0.3L/kg.Swallow part in liver deactivation, some are hydrolyzed by tissue esterases.Half-life is 15 hours.Can extend during hepatic disease.Its metabolite 70% through bile, 10%-15% through homaluria.
Since the 1950's, reported first used metered dose inhalation aerosol (pressuredmeterdoseinhaler, pMDI) to treat asthma, MDI obtains extensive use at treatment aspect of respiratory disease.At present, the whole world has 5000 ~ 6,000 ten thousand people to depend on MDI, and the MDI prescription outputed every year more than 500,000,000, and still has the trend of growth.In the MDI medicine for the treatment of asthma, the propellant of extensive use is CFC, and long-term Clinical practice shows to be that the suction preparation of propellant is cheap with CFC, and determined curative effect, safety is high.1998, the whole world about employed 8254 tons of CFC as pMDI propellant, mainly CFC11/12/114.Chloride ion contained by CFC, there is depletion of the ozone layer, in JIUYUE, 1987,40 countries have signed Montreal Protocol on Substances that Deplete the Ozone Layer at Montreal, CAN, to 5 kinds of CFC (11,12,113,114,115) forbidding timetable is proposed: developed country all will forbid in 2000, and developing country can postpone 10 years.In June nineteen ninety, 90 countries comprising China have passed in London " Montreal Protocol (amendment) ", expand the kind of forbidding, and are advanced by the forbidding time.China is in January, 1993, work out " Chinese ODS progressively eliminates national scheme ", although medicinal aerosol is because of closely related with the life and health of the people, obtain temporary transient exemption, but SFDA still made an announcement in 2006, the pMDI producing and use containing CFC will be stopped in 2010 comprehensively.
According to the requirement of State Council's " China progressively eliminates and consumes ozone material national scheme " and State Food and Drug Administration " notice about printing and distributing the inhalation aerosol that goes on the market and change the requirement of propellant investigative technique " No. [2011] 185, state's food medicine prison note, the propellant that the CFC used the propionic acid beclometasone aerosol (number of accepting: CYHS1190003) declared of our company is correlated with changes research work.
At present conventional metered dose inhalation aerosol refers to and jointly fills in the pressure vessel being encapsulated in and having special valve system containing drug solns or suspension with the propellant be suitable for, and is vaporific ejection by the pressure of propellant by content during use.CFC (chlorofluoro-alkane, freon) be the propellant the most often used in the past aerosol, chloride ion contained by CFC, very huge to the destruction of ozone layer, from the angle of environmental protection, the present invention uses HFA134a (tetrafluoroethane) CFC alternative, and requires the technical study of having carried out propellant change according to relevant art.
Existing a lot of not going on the market containing the propionic acid beclometasone aerosol of CFC both at home and abroad at present, representational kind has QVAR, the kinds such as IVAX.The propellant used is HFA134a, and solution aerosol, basic demand be medicine dissolution in propellant, form homogeneous solution, propellant volatilization after ejection, medicine reaches site of action with solid or liquid particle state, and its product gross weight is about 18g.
Foreign literature data shows, the present invention is at the LD of rodent
50be greater than 1g/kg.One is that the carcinogenicity testing of 95 weeks by a definite date of experimental subject shows with Mus, and rat sucks and gives this product and within 82 weeks, do not find carcinogenecity with the oral this product that gives in 13 weeks.And the mutagenicity of beclometasone is not because carrying out related experiment confirmation, therefore do not know.About the teratogenesis to pregnant women, because beclometasone equally belongs to hormone medicine with other adrenocortical hormone, Mus and rabbit parenteral route (subcutaneous administration) approach give this product, dosage is about 10 times of people, experiment shows that this product can cause tire son to gulp down again, upper cleft palate, without jaw, osculum, aglossate, the deformity such as delay, thymic dysplasia of ossify.And in Mus experiment, adopt and suck and the oral this product that gives, dosage is 10 times and 1000 times of the dosage of people respectively, and result does not find that this product has teratogenesis tire and stillborn fetus effect.But do not have and carry out this test with it anemia of pregnant woman, therefore pregnant women should be cautious use of, only when fully take into account use this product the advantages outweigh the disadvantages on the impact of fetus, could use.Pregnant women accepts to produce hypoadrenocorticism after corticotropin easily causes fetal birth at phenolics to have data to show, therefore should keep a close eye on observation after this kind of infant birth.Not yet know that whether beclometasone is from galactopoiesis excretion, but other steroid hormones have confirmed to secrete excretion from milk, therefore women breast-feeding their children should be cautious use of.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (6)
1. a preparation method for propionic acid beclometasone aerosol, is characterized in that, the preparation method of described propionic acid beclometasone aerosol comprises:
Sampling: operate in clean area, take the principal agent beclometasone of recipe quantity, adjuvant anhydrous alcohol for medical use and Mentholum etc., for subsequent use;
Preparating liquid: operate in clean area, adds in anhydrous alcohol for medical use by beclometasone, Mentholum, is constantly circulated by medicinal liquid through stirring and circulating pump, through sufficient circulation stirring, makes medicinal liquid disperse suspendible even;
Intermediate products detect: get the molten medicinal liquid prepared, detect assay item, drug content controls at 92%-108%;
Filter: operate in clean area, use filtering with microporous membrane medicinal liquid;
Wash bottle: aluminium pot hot-water soak 15 minutes afterflush of more than 60 DEG C, then use deionized water rinsing, drying in oven put into by aluminium pot, temperature 70-80 DEG C, and the time is greater than 10 hours;
Fill: according to measured intermediates content, adjusts theoretical fill amount, and according to fill amount quantitative perfusion liquid on quantitative filling machine, detect content uniformity, controlling deviation of weight is ± 5%;
Roll valve: to be rolled by proportional valve with inhalator jar sealing machine and be encapsulated in tank mouth;
Fill propellant: on quantitative propellant can packing machine, quantitatively press-fit HFA 134a by recipe quantity, the weighing products press-fited, check fill weight differential, control to fill difference in ± 5% scope, reject underproof product;
Leak detection: by inhalator jar complete for filling, through leak detection in 5 minutes in 50 DEG C of water-baths, bubble-free is overflowed; Moisture content is dried up fast after taking-up;
Stamp labeling: inhalator jar label print the date of manufacture, lot number, valid until content, paste label;
Packaging: capsule print the date of manufacture, lot number, valid until content, by inhalator jar, together with actuator, description, load capsule;
Product inspection: let pass after the assay was approved;
Load corrugated case, stamp is put in storage.
2. the preparation method of propionic acid beclometasone aerosol as claimed in claim 1, is characterized in that, described in take recipe quantity beclometasone be 34.5mg, anhydrous alcohol for medical use is 3kg and is Mentholum 45mg.
3. the propionic acid beclometasone aerosol prepared of the preparation method of propionic acid beclometasone aerosol as claimed in claim 1, is characterized in that, described propionic acid beclometasone aerosol is 85.0% ~ 120.0% of labelled amount containing beclometasone.
4. propionic acid beclometasone aerosol as claimed in claim 3, is characterized in that, the medicinal liquid of described propionic acid beclometasone aerosol in pressure vessel should be colourless to micro-yellow liquid; Pressing valve, the i.e. ejection in droplet of medicinal liquid.
5. propionic acid beclometasone aerosol as claimed in claim 3, it is characterized in that, described propionic acid beclometasone aerosol is every bottle 200 and presses, and often presses containing beclometasone 50 μ g.
6. the using method of propionic acid beclometasone aerosol prepared of the preparation method of a propionic acid beclometasone aerosol as claimed in claim 1, it is characterized in that, the using method of this propionic acid beclometasone aerosol comprises: open and jointly fill containing drug solns or suspension and suitable propellant the pressure vessel being encapsulated in and having special valve system, pressing valve, be vaporific ejection by the pressure of propellant by content, vaporific ejecta is sucked by pulmonary or is directly sprayed onto tract mucosa, skin and space.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510942974.6A CN105476961B (en) | 2015-12-16 | 2015-12-16 | A kind of beclometasone dipropionate aerosol and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510942974.6A CN105476961B (en) | 2015-12-16 | 2015-12-16 | A kind of beclometasone dipropionate aerosol and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105476961A true CN105476961A (en) | 2016-04-13 |
| CN105476961B CN105476961B (en) | 2019-01-04 |
Family
ID=55664480
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510942974.6A Active CN105476961B (en) | 2015-12-16 | 2015-12-16 | A kind of beclometasone dipropionate aerosol and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105476961B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111007159A (en) * | 2019-06-28 | 2020-04-14 | 四川普锐特医药科技有限责任公司 | Detection method of beclomethasone dipropionate related substance |
| CN115414321A (en) * | 2022-10-20 | 2022-12-02 | 山东新时代药业有限公司 | Beclomethasone dipropionate emulsifiable paste and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1265887A (en) * | 2000-02-15 | 2000-09-13 | 丛繁滋 | Quick-acting asthma-relieving aerosol and its preparation method |
| CN1298699A (en) * | 2000-02-15 | 2001-06-13 | 丛繁滋 | Quick acting aerosol for treating asthma and preparing process thereof |
| CN103517706A (en) * | 2011-05-13 | 2014-01-15 | 墨西哥化学阿玛科股份有限公司 | Pharmaceutical compositions |
-
2015
- 2015-12-16 CN CN201510942974.6A patent/CN105476961B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1265887A (en) * | 2000-02-15 | 2000-09-13 | 丛繁滋 | Quick-acting asthma-relieving aerosol and its preparation method |
| CN1298699A (en) * | 2000-02-15 | 2001-06-13 | 丛繁滋 | Quick acting aerosol for treating asthma and preparing process thereof |
| CN103517706A (en) * | 2011-05-13 | 2014-01-15 | 墨西哥化学阿玛科股份有限公司 | Pharmaceutical compositions |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111007159A (en) * | 2019-06-28 | 2020-04-14 | 四川普锐特医药科技有限责任公司 | Detection method of beclomethasone dipropionate related substance |
| CN115414321A (en) * | 2022-10-20 | 2022-12-02 | 山东新时代药业有限公司 | Beclomethasone dipropionate emulsifiable paste and preparation method thereof |
| CN115414321B (en) * | 2022-10-20 | 2023-06-20 | 山东新时代药业有限公司 | Beclomethasone dipropionate cream and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105476961B (en) | 2019-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103796636B (en) | Intranasal testosterone bioadhesiveness gel preparation and its purposes for treating male hypogonadism | |
| US20080102037A1 (en) | Stable pharmaceutical budesonide preparation for producing propellant-free aerosols | |
| CN105101955B (en) | Composition comprising at least two dry powders obtained by spray drying to increase the stability of the formulation | |
| CN105476961A (en) | Beclomethasone aerosol and preparation method thereof | |
| Ehrick et al. | Considerations for the development of nasal dosage forms | |
| Yakubu et al. | Aerodynamic dose emission characteristics of dry powder inhalers using an Andersen Cascade Impactor with a mixing inlet: The influence of flow and volume | |
| CN107205936A (en) | The composition of dry powder comprising at least one increase preparation stability obtained by spray drying | |
| CN101569684B (en) | Inhalation aerosol of plant extract for treating asthma and preparation method | |
| JP2023547040A (en) | Method for treating cognitive dysfunction with pyrrolopyridine-aniline compounds | |
| CN108175763A (en) | A kind of preparation method of budesonide sterile raw material and its sucking suspension | |
| CN117263848A (en) | Inhalation spray of raffinacin | |
| Waldrep et al. | High dose cyclosporin A and budesonide-liposome aerosols. | |
| CN101889993B (en) | Surface-modified salbutamol suspension type non-Freon inhalation aerosol and preparation method thereof | |
| CN107688060A (en) | The detection method of fluticasone propionate nasal spray | |
| ITMI20130571A1 (en) | PHARMACEUTICAL COMPOSITION CONTAINING BUDESONIDE AND FORMOTEROL | |
| CN106551919B (en) | Novel inhalation formulations | |
| CN105055169B (en) | A method of preparing Imipenem and Cilasatin Sodium aseptic powdery | |
| CN103864628B (en) | Ambroxol hydrochloride compound and orally disintegrating tablet | |
| Moreau-Neidhardt et al. | Assessing of low-tech solutions for aerosol delivery: Comparative performance study of manufactured versus homemade spacers | |
| CN105878219A (en) | Trajenta oral membrane agent and preparation method thereof | |
| CN101007008A (en) | Ciclesonide medicinal spraying agent and its preparation method | |
| CA2963445C (en) | Pharmaceutical composition containing budesonide and formoterol | |
| Toader et al. | Aspiration of Nasal Secretions and Aerosol Therapy in Pediatric ENT Pathology | |
| CN106474063A (en) | A kind of aerosol for external use containing desonide | |
| CN106177973B (en) | A kind of Cetirizine Hydrochloride solid pharmaceutical preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |