CN102238939B - Pharmaceutical aerosol composition - Google Patents
Pharmaceutical aerosol composition Download PDFInfo
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- CN102238939B CN102238939B CN200980148430.5A CN200980148430A CN102238939B CN 102238939 B CN102238939 B CN 102238939B CN 200980148430 A CN200980148430 A CN 200980148430A CN 102238939 B CN102238939 B CN 102238939B
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- aerosol composition
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- 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
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- 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
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
A pharmaceutical aerosol composition comprising at least one hydrofluoroalkane propellant; at least one active agent complexed with an adjuvant; and, optionally, at least one pharmaceutically acceptable excipient.
Description
Invention field
The present invention relates to pharmaceutical aerosol composition.Particularly, the present invention relates to stable pharmaceutical aerosol composition, its preparation method is used for the treatment of the application of respiratory disorder (respiratory disorder) with it.
Background and prior art
Metered-dose inhaler (MDIs) be at present the most effectively and the most putative by small dose drug accurate delivery to the instrument of human respiratory.The therapeutic agent generally sent by inhalation route comprises bronchodilator (β-2 agonist and anticholinergic), corticosteroid and antiallergic agent.Sucking also can be for anti-infective, vaccination agent, general action reagent and diagnostic reagent, and the feasible way of anti-leukotriene and protease inhibitor.
MDI comprises pressure vessel, and it is the filling product micronized particle that is such as dissolved in the medicine in liquefied propellant or is suspended in liquefied propellant typically, and wherein said container is equipped with metering valve.Release sub-fraction spray product is allowed in the startup of metering valve, thus liquefied propellant pressure by dissolve or micronized drug particles transport container and arrive patient.Valve actuator is used to guide aerosol spray to enter the oropharynx of patient.
Chlorofluorocarbon (CFCs) has been widely used as the propellant be delivered to via metered-dose inhaler (MDI) in the pharmaceutical preparation of patient.But recent scientific evidence prompting CFC damages earth's ozone layer.Think that the ultraviolet that ozone barrier is harmful to and the loss of ozone layer can cause the generation of skin carcinoma.Result, CFC is now gradually by as the hydrogen fluorohydrocarbon (hydrofluorocarbon) of preferred MDI propellant or HFA (these titles are used interchangeably in this article), and (such as HFA 134a & HFA 227) substitutes.
Propellant HFA 134a, or HFA 134a (these titles are used interchangeably in this article) is nonflammable, has hypotoxicity and have to be suitable for aerocolloidal vapour pressure.But HFA 134a is very bad solvent, under the help not having cosolvent, it can not with valid density is dissolved or fully dispersion is conventional surfactant such as anhydrosorbitol trioleate, dehydrating sorbitol monooleate, lecithin and oleic acid.
Similarly, propellant HFA 227, or HFC-227ea (these titles are used interchangeably in this article) is nonflammable, has hypotoxicity and have to be suitable for aerocolloidal vapour pressure.But the polarity of HFA 227 and dissolubility are different from those of conventional CFC propellant, and many conventional surfactants are soluble or dispersibility is poor in HFA 227.
US5182097 relates to the aerosol preparations be made up of HFA 134a, medicine and oleic acid, described oleic acid as surfactant with the dispersion of ancillary drug in propellant.
US5612053 relates to respirable dry powder formulations, and it comprises the controllable release granule of the adhesive aggregation complex of medicine and carrier, and wherein said carrier is the natural polysaccharide glue added as filler.
EP0384371 discloses aerosol, wherein HFC-227ea or itself and propane, butane, iso-butane, dimethyl ether or 1,1, and the mixture of Difluoroethane serves as propellant.But this application does not disclose suspendible aerosol or pharmaceutical aerosol preparation.
WO93/11747 discloses the medicine mixed suspension preparation being suitable for Aerosol administration, and it is made up of with the propellant being selected from the group be made up of HFA 134a, HFA 227 or its mixture the medicine for the treatment of effective dose substantially.This application specifically discloses the preparation of formoterol fumarate (Formoterol Fumarate) in 1: 1 mixture of HFA 134a, HFA 227 and HFA 134a and HFA 227.Said preparation is not containing surfactant or ethanol.This explanation can regulate the mixture of HFA 134a and HFA 227, to obtain the density of mating with medicine.
WO93/11745 discloses pharmaceutical aerosol preparation, its substantially not containing comprise the surfactant of fluorocarbon or hydrogeneous chlorofluorocarbon propellant and at the most 5% polar co-solvent.Preferred propellant is HFA 134a and HFA 227, and they are preferably used alone.Preferred polar co-solvent is ethanol, and illustrates that the general polar co-solvent of such as 0.05-3.0%w/w in a small amount that only needs is to improve dispersion, and use amount adversely may tend to dissolved substance more than 5%w/w.
The medicinal aerosol formulations of the many HFA of utilization propellants systems is disclosed in, such as, and EP0372777, WO91/11173, and in WO91/14422.The pressurised aerosol preparation being used for drug administration is all paid close attention in these applications.All applications all propose that adding one or more adjuvant such as alcohol, alkane, dimethyl ether, surfactant (comprise and fluoridizing and non-fluorinated surfactants, carboxylic acid, polyethoxylate etc.) and even conventional chlorofluorocarbon propellant is in a small amount intended to minimize potential ozone layer destroying, but still can not determine any beyond thought advantage.
US6303103 discloses a kind of pharmaceutical aerosol preparation, it comprises particulate albuterol (salbutamol) and anticholinergic agents or physiology acceptable salt and solvate thereof, the chlorofluorocarbon propellant of fluorocarbon or hydrogen and substantially not containing or containing the surfactant (by drug weight) being less than 0.0001%.But, about support invention required for protection, not clearly by way of example or any stability study data prove.
Also made great efforts to attempt only with surfactant or substitute to pharmaceutical pack quilt, but result still not very satisfaction.
WO91/04011 describes self-propelled Powder aerosol compositions, it contains that grind, pre-micronized solid drugs, the described solid drugs surface active dispersing agent of the single case where a non-perfluorinated be suspended in aerosol propellant wraps quilt, and described dispersant is substantially insoluble in described aerosol propellant.
PCT/GB2008/002029 describes a kind of preparation comprising tiotropium bromide (tiotropium bromide) with polyvinylpyrrolidone bag quilt.This method for coating has such shortcoming, and namely it needs multiple procedure of processing and spray due to over range and lack uniformity may cause being difficult to amplification scale.
The disclosure of all these patents and patent application is combined in herein all by reference.
The above prior art of major part proposes to use surfactant.But, the use of surfactant may not be feasible to all medicines, because finding suitable suspending agent or dissolving in hydrofluoroalkane (hydrofluoroalkane) and can stablize in the surfactant of drug suspension to have run into a large amount of difficulty.And, described preparation may be made unstable in conjunction with excipient and surfactant in addition.
Due to HFA larger and more moisture absorption than CFC polarity, so find entering of water more significantly in HFAMDI, and polarity, the miscible cosolvent of water, the use of such as alcohol also can make it more serious.Above phenomenon also can be subject to the impact of the character of drug substance or other excipient existed in preparation.The moisture of surrounding is diffused in MDI by valve washer, and by promoting drug particles growth and assembling the physical stability adversely affecting MDI preparation.The gathering of drug particles can block the valve port of aerosol container, thus cause this distributor to work, if or use metering valve, then it can cause inaccurate dosed administration, this can cause undesirable result in the situation of highly effective medicine.Except increase granularity and obstruction valve port, gathering can make suspension physics unstable, and obvious undesirable result, particularly in atomization preparation.
Therefore, still exist providing the method solving the problem that fine drug particles is assembled and the needs providing the stable aerosol composition utilizing hydrogen hydrofluorocarbon propellant.
Goal of the invention
The object of this invention is to provide a kind of stable pharmaceutical aerosol composition.
Another object of the present invention is to provide a kind of pharmaceutical aerosol composition, and wherein micronized drug composition granule is not assembled in preservation process.
Another object of the present invention is to provide the straightforward procedure for the preparation of pharmaceutical aerosol composition according to the present invention.
Another object of the present invention is to provide a kind of pharmaceutical aerosol composition, and it has dose uniformity in the whole life period of tank.
Further object of the present invention is to provide a kind of pharmaceutical aerosol composition, and it is used for the treatment of slight, the moderate of respiratory disorder or severe acute or chronic sympton or for prophylactic treatment respiratory disorder.
Summary of the invention
According to a first aspect of the invention; There is provided a kind of stable pharmaceutical aerosol composition, it comprises the active substance of one or more HFA propellant and at least one and adjuvant compound; Optionally, one or more pharmaceutical excipients are comprised.
According to a second aspect of the invention; There is provided a kind of stable pharmaceutical aerosol composition, it comprises the active substance of at least one and adjuvant compound; One or more HFA propellant; With other pharmaceutical excipient of at least one, such as at least one filler and/or cosolvent.
According to a third aspect of the invention we; A kind of method preparing described stable pharmaceutical aerosol composition is provided.
According to a forth aspect of the invention; There is provided a kind of pharmaceutical aerosol composition, it is used for the treatment of slight, the moderate of respiratory disorder such as asthma or severe acute or chronic sympton or for prophylactic treatment respiratory disorder such as asthma.
Detailed Description Of The Invention
As previously discussed, there is the demand to providing the fine drug particle aggregation solving aerosol composition and the new method keeping stable problem between whole storage life.
Unexpectedly, the present inventor has been found that the gathering of micronized drug composition granule significantly reduces when using medicine-adjuvant complex to prepare aerosol composition, and this causes said composition stable between whole storage life.
The present inventor also observes the dispersion of surfactant in the pharmaceutical aerosol composition with other pharmaceutical excipients causes said composition unstable during preservation.Particularly, observe fine particle quality do not keep identical during preservation or pass in time and reduce.But, be surprised to find that, as medicine and adjuvant such as PVP K 25, the compounds such as PVP K 17 or PVP K30, and add one or more propellant or optionally one or more filleies and/or cosolvent time, the gathering of fine drug particles significantly reduces and therefore makes said composition keep stable during preservation.Also find that said composition continues the characteristic representing uniform delivery dosage in the whole life period of MDI.
The invention provides a kind of pharmaceutical aerosol composition.More specifically, described pharmaceutical aerosol composition comprises the pharmaceutically active agents of at least one and adjuvant compound, at least one hydrofluoroalkane (HFA) propellant and optionally comprise other suitable excipient such as one or more filleies and/or cosolvent.
In particularly advantageous embodiment, adjuvant is polymer, preferably polyethylene ketopyrrolidine (PVP and other commercially available grades such as PVP K12, PVP K15.PVP K17, PVP K25, PVPK30, PVP K60, PVP K90), preferably there is PVP 2500 ~ PVP 1,200,000, preferred PVP2500 ~ PVP 1,000, the molecular weight in 000 scope.Have been found that when described polymer and medicine compound tense, they produce high-quality pharmaceutical aerosol suspension.
Term " adjuvant " broad sense in whole description uses, not only to comprise polyvinylpyrrolidone (PVP) and other commercially available grades such as PVP K12 thereof, PVP K15.PVP K17, PVPK25, PVP K30, PVP K60, PVP K90, also comprise suitable water solublity and insoluble polymer or its mixture, cyclodextrin, Polyethylene Glycol (such as PEG 4000 and PEG 6000) and surfactant such as anhydrosorbitol trioleate, dehydrating sorbitol monooleate, tween, such as, polysorbas20, 40, 60, 80, 120, lipid, lecithin, oleic acid, citric acid, with polyoxyethylene-lauryl ether (such as Brij 30).
According to the present invention, the water-soluble polymer that can use as adjuvant comprises homopolymer and the copolymer of N-vinyl lactam, particularly NVP, the homopolymer of such as polyvinylpyrrolidone (PVP) and copolymer, the copolymer of PVP and vinyl acetate, the copolymer of NVP and vinyl acetate or propionate, the maltodextrin of dextrin such as each grade, cellulose esters and cellulose ether, the copolymer etc. of high molecular polyalkylene oxides such as poly(ethylene oxide) and poly(propylene oxide) and oxirane and expoxy propane.
According to the present invention, the insoluble polymer that can use as adjuvant comprises acrylic acid series copolymer such as Eudragit E100 or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze; Polyvinyl acetate, such as, Kollicoat SR 3OD; Cellulose derivative is ethyl cellulose such as, cellulose acetate etc.
According to the present invention, in medicine-adjuvant complex, the scope of the amount of adjuvant is 0.5%-500% (in drug weight), preferred 0.5%-100% (in drug weight).The suitable amount of adjuvant is 0.5%, 1%, 2%, 10%, 50% and 100% (in drug weight).
Medicine-adjuvant is in (Micronised form) in microgranule.Preferably, granularity such as to allow when described aerosol composition administration that basic all microgranule can potentially for being sucked in lung.Therefore, such as, preferably, at least 90 % by weight, more preferably the microgranule of at least 95 % by weight has and is less than 15 microns, preferably 0.5 ~ 15 micron, more preferably 0.5 ~ 10 micron, and the most preferably diameter of 0.5 ~ 5 micron.Most preferably the microgranule of at least 95 % by weight has the diameter of 0.5 ~ 5 micron.
According to the present invention, the any medicine be effective in anapnotherapy well known by persons skilled in the art can be comprised by the medicine of compound in aerosol composition, it comprises one or more in the following: such as, analgesic, such as codeine (codeine), paramorphan (dihydromorphine) (dihydromorphine), Ergotamine (ergotamine), fentanyl (fentanyl) or morphine (morphine), anginal preparations, such as diltiazem
(diltiazem), antiallergic agent, such as cromoglycate (cromoglycate), ketotifen (ketotifen) or nedocromil (nedocromil), anti-infective is cephalosporins (cephalosporins) such as, penicillins (penicillins), streptomycin (streptomycin), sulfa drugs (sulphonamides), Tetracyclines (tetracyclines) and pentamidine (pentamidine), hydryllin, such as methapyrilene (methapyrilene), anti-inflammatory agent, such as beclometasone (beclomethasone), flunisolide (flunisolide), budesonide (budesonide), tipredane (tipredane), triamcinolone acetonide (triamcinolone acetonide), or fluticasone (fluticasone), corticosteroid is budesonide such as, ciclesonide (ciclesonide), fluticasone, betamethasone (betamethasone), beclometasone, tixocortol (tixocortol), formocortal (formocortal), rimexolone (rimexolone), prednisolone (prednisolone), methylprednisolone (methylprednisolone), deflazacort (deflazacort), prednisone (prednisone), cortisone (cortisone), dexamethasone (dexamethasone), hydrocortisone (hyderocortisone), antitussive, such as narcotine (noscapine), bronchodilator, such as ephedrine (ephedrine), epinephrine (adrenaline), fenoterol (fenoterol), formoterol (formoterol), isoproterenol (isoprenaline), orciprenaline (metaproterenol), phenylephrine (phenylephrine), phenylpropanolamine (phenylpropanolamine), pirbuterol (pirbuterol), reproterol (reproterol), rimiterol (rimiterol), albuterol, salmaterol (salmeterol), terbutaline (terbutaline), isoetarine (isoetharine), tulobuterol (tulobuterol), orciprenaline (orciprenaline), or (-) 4-amino-3, the chloro-α of 5-bis--[[[6-[2-(2-pyridine radicals) ethyoxyl] hexyl] is amino] methyl] benzyl alcohol, diuretic, such as amiloride (amiloride), anticholinergic is tiotropium (tiotropium) such as, ipratropium (ipratropium), aclidinium bromide (aclidinium), atropine (atropine) or oxitropine (oxitropium), hormone, such as cortisone, hydrocortisone (hydrocortisone) or prednisolone, xanthine is aminophylline (aminophylline) such as, Oxtriphylline (choline theophyllinate), theophylline-lysine (lysine theophyllinate) or theophylline (theophylline), with human cytokines and peptide, such as insulin or glucagon or its pharmaceutical salts.
Those skilled in the art should be appreciated that this medicine can use with the form of its pharmaceutical salts, acceptable solvates, hydrate for medicinal use, medicinal enantiomer, medicinal derivative, medicinal enantiomer, pharmaceutical polymorphs, its acceptable prodrugs, thus the activity of compositions described in optimization and/or stability.
According to the present invention, the particularly preferred medicine for compound in aerosol composition comprises antiallergic agent, anticholinergic, bronchodilator and corticosteroid such as albuterol, beclometasone, ipratropium, formoterol, tiotropium, aclidinium bromide, salmaterol, fluticasone, budesonide, fenoterol, ciclesonide, mometasone (mometasone), or their pharmaceutical salts is particularly preferred.
Pharmaceutical salts, acceptable solvates, hydrate for medicinal use that the broad sense such as term " bronchodilator " or " corticosteroid " also comprises them for not only comprising beta-2-agonists or anticholinergic or corticosteroid itself, medicinal enantiomer, medicinal derivative, medicinal enantiomer, pharmaceutical polymorphs and acceptable prodrugs.
When appropriate, the following salt of above-mentioned medicine can be used: acetate, benzene sulfonate, benzoate, bicarbonate, biatrate, bromide, Ca-EDTA, d-camphorsulfonic acid salt (camsylate), carbonate, chloride, citrate, dihydrochloride, edetate, ethanedisulphonate (edisylate), Estolate (estolate), esilate (esylate), fumarate, fluceptate, gluconate, glutamate, Glu, to hydroxyl acetylamino phenyl-arsonate (glycollylarsanilate), hexylresorcinate, hydrobromate, hydrochlorate, Hydroxynaphthoate, iodide, isethionate, lactate, Lactobionate (lactobionate), malate, maleate, mandelate, mesylate (mesylate), MB, methyl nitrate, Methylsulfate, mucate, naphthalene sulfonate, nitrate, embonate (pamoate) (embonate), pantothenate, phosphate diphosphate, Polygalacturonate (polygalacturonate), Salicylate, stearate, basic acetate, succinate, sulfate, tannate (tannate), tartrate (tartrate), with triethiodide compound (triethiodide)
The β simulant (betamimetic agent) be effective in the present composition comprises, but be not limited only to, albuterol, formoterol, Levalbuterol (levalbuterol), Ka Moteluo (carmoterol), pirbuterol and salmaterol.The suitable pharmaceutical salts of β simulant include but not limited to, hydrochlorate, sulfate, maleate, tartrate, and citrate.Preferably, β simulant is selected from albuterol, salbutamol sulfate (salbutamol sulfate), levosalbutamol (levosalbutamol), levosalbutamol sulphate (levosalbutamol sulphate) or levosalbutamol tartrate (levosalbutamol tartarate).
The anticholinergic be effective in the present composition include but not limited to, oxitropine, ipratropium, aclidinium bromide and tiotropium.The suitable pharmaceutical salts of described anticholinergic include but not limited to, halide salts, such as bromide, chloride or iodide.Preferably, described anticholinergic is tiotropium or tiotropium bromide or tiotropium bromide monohydrate.
Preferred agents aerosol composition according to the present invention comprises: at least one of (a) effective dose and the medicine of adjuvant compound; (b) at least one hydrogen hydrofluorocarbon propellant; (c) optionally, at least one pharmaceutical excipient, comprises one or more filleies and/or cosolvent.
In particularly preferred embodiment of the present invention, provide stable pharmaceutical aerosol composition, it comprises: the pharmaceutically active substance of at least one of (a) effective dose and PVP K17 or PVP K30 compound, described pharmaceutically active substance is selected from tiotropium, aclidinium bromide, ipratropium, levosalbutamol, or its pharmaceutical salts; (b) at least one hydrogen hydrofluorocarbon propellant; (c) optional at least one filler such as lactose and/or cosolvent such as PEG400 (PEG 400) and other pharmaceutical excipients.
Those skilled in the art should be appreciated that aerosol composition according to the present invention is passable, if needed, comprise the combination of two or more medicines.Therefore, present invention also offers the aerosol composition comprising two or more medicines, wherein at least one medicine and adjuvant and one or more optional pharmaceutical excipient compounds.
Preferably, described pharmaceutical aerosol composition comprises bronchodilator such as tiotropium (such as bromide salt), albuterol (such as free alkali or as sulfate), levosalbutamol (such as sulfate), salmaterol (such as xinafoate (xinafoate)), aclidinium bromide, isoproterenol or their pharmaceutical salts, or (multiple) bronchodilator and one or more corticosteroid such as beclomethasone ester (such as dipropionate), the combination of budesonide or fluticasone ester (such as propionic ester) or their other pharmaceutical salts, wherein medicine described at least one and adjuvant compound.
Alternatively, described aerosol composition can comprise the combination of bronchodilator and antiallergic agent such as cromoglycate (such as sodium salt).The example of such combination comprises isoproterenol and sodium cromoglicate; Salmaterol and FLUTICASONE PROPIONATE; Or albuterol and beclomethasone dipropionate etc.According to a further aspect in the invention, provide a kind of pharmaceutical aerosol allotter, it comprises tank, and described tank has the room held according to pharmaceutical aerosol composition of the present invention; Outlet, described outlet is used for described pharmaceutical aerosol composition being delivered to the patient needing described pharmaceutical aerosol composition; And valve, described valve is for controlling described pharmaceutical aerosol composition from described room to the flowing of described outlet.Preferably, described tank is made up of metal, glass or plastic material such as polysulfone plastic such as polysulfones (PSU) and polyether sulfone (PES).Preferably, described pharmaceutical aerosol device is MDI.
Present invention also offers a kind of method preparing pharmaceutical aerosol allotter, described pharmaceutical aerosol allotter is for sending aerosol drug formulations to the patient needing described aerosol drug formulations, and described method comprises:
A () is weighed the drug particles of compound in suitable canister,
(b) optionally the drug particles of described compound and one or more are selected from cosolvent, filler, antioxidant, lubricant appropriate excipients and optionally with one or more surfactants or with other similar compounds or the medicament mixed of non-compound
C described tank is filled HFA propellant by suitable valve seaming (crimp) by ().
On the other hand, the invention provides a kind of method preparing the complex of activating agent and adjuvant, described method comprises:
A () be the described activating agent of mixing in organic solvent (such as acetone),
B mixture from step (a) is heated to suitable temperature and adds water to form the solution of clarification by ();
C () adds described adjuvant to the above-mentioned solution from step (b);
D () under reduced pressure, the solution of preferably concentrated described clarification is under vacuo to form residue;
E () washs residue by the same solvent used in step (a); With
Dry the washing from step (e) of (f) (such as in suitable temperature, or preferably at 50 DEG C)
The residue washed is to form medicine-adjuvant complex.
The solvent used in above method can be selected from acetonitrile, methanol, water, dimethyl formamide, acetone, oxolane, dimethyl sulfoxide.Most preferred solvent is acetone.
Alternatively, activating agent can by lyophilization or by using appropriate technology as known in the art such as spray-drying flashed solvent to be separated with the complex of adjuvant.About flash evaporation technology of the present invention mean by apply heat and vacuum remove solvent.
The activating agent used in the method for the complex of preparation according to the present invention and adjuvant can adopt amorphous, crystallization, monohydrate or anhydrous form or its derivant or polymorph or prodrug.
Can optionally containing one or more excipient that routine uses in pharmaceutical aerosol preparation field or carrier according to pharmaceutical aerosol composition of the present invention.Selectable excipient like this include but not limited to, taste masked agent, buffer agent, antioxidant, water and chemical stabilizer.
The example of suitable filler include but not limited to, one or more saccharides such as monosaccharide, disaccharide, many Saccharide and saccharide alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starch, glucosan or mannitol.Described filler can with 0.005-500%, and the concentration more preferably within the scope of 0.005-300% exists (by complex weighing scale).Preferred filler is lactose.
The example of cosolvent include but not limited to, Polyethylene Glycol (" PEG "), propylene glycol, one or more in isopropyl myristate or glycerol.Suitably, described cosolvent is PEG, such as PEG200 or PEG 400.Cosolvent can exist with the scope being about 0.05%-about 15% by composition weight meter.Suitably, cosolvent exists with the scope being about 0.05%-about 1% or about 0.05%-about 0.3% by composition weight meter.
The present invention can optionally comprise antioxidant as citric acid, benzalkonium chloride (benzalkonium chloride).
As discussed, aerosol composition is traditionally containing CFC propellant.Due to the concern to environment, HFA propellant now than CFC propellant more preferably.As those skilled in the art should be appreciated that, the HFA propellant suitable for the present invention is include but not limited to, HFA 134a (HFA-134a) and HFC-227ea (HFA-227).Optionally, the mixture of the halogen substiuted hydrocarbon that two or more can also be used such.
The present invention is useful especially, utilizes HFA propellant to obtain medicinal stabilising dispersions as aerosol propellant because it is allowed.Aerosol composition of the present invention can use the mixture of independent HFA propellant or HFA propellant and the miscible adjuvant of another kind to prepare, and the polarity of described adjuvant is equal to or less than the polarity of described HFA propellant.
Further, the invention provides according to pharmaceutical aerosol composition of the present invention, it is used for the treatment of slight, the moderate of respiratory disorder such as asthma or severe acute or chronic sympton, or for prophylactic treatment respiratory disorder, such as asthma.
In preferred embodiments, the invention provides pharmaceutical aerosol composition according to the present invention for the preparation of slight, the moderate for the treatment of respiratory disorder such as asthma or severe acute or chronic sympton, or for the application in the medicine of prophylactic treatment respiratory disorder such as asthma.
In another preferred embodiment, provide slight, the moderate for the treatment of respiratory disorder such as asthma or severe acute or chronic sympton, or for the method for prophylactic treatment respiratory disorder such as asthma, described method comprises the patient pharmaceutical aerosol composition according to the present invention for the treatment of effective dose being applied to the described method of needs.
Following instance only illustratively object of the present invention, and be not intended to limit the scope of the invention by any way.
Embodiment
Prepare the method for tiotropium bromide-PVP complex
1) 5g tiotropium bromide is introduced in reaction vessel.Add acetone.Reactant mixture is heated to the temperature of 50-55 DEG C.Water (15ml) is added further, to obtain the solution of clarification in reactant mixture.2.5g PVP-K-17 is added in this solution.Concentrated solution is to obtain residue under vacuum.This residue acetone (15ml) washs and drying at 50 DEG C under vacuum, to obtain title compound (6g).
2) 5g tiotropium bromide is introduced in reaction vessel.Add water (15ml) to reactant mixture, to obtain the solution of clarification.2.5g PVP-K-17 is added in this solution.This solution concentrated is to obtain residue under vacuum.This residue acetone (15ml) washs and drying at 50 DEG C under vacuum, to obtain title complex (6g).
3) by tiotropium bromide-PVP complex that lyophilization is formed
By 5g tiotropium bromide and 2.5g polyvinylpyrrolidone (PVP) in 50ml water, stir at 25-30 DEG C until dissolve.By this solution quick freezing in the dry ice bath.This solution fine vacuum exist under, lyophilizing under the condenser temperature of about 0 DEG C.Consequent title complex obtains with solid (5.8g) form.
4) by the tiotropium bromide-PVP complex of evaporation formation
By 2.5g tiotropium bromide and 1.25g polyvinylpyrrolidone (PVP) in 10ml ethanol, stir at 25-30 DEG C until dissolve.This solution is poured in polyethylene pan, and under nitrogen current exists, ethanol evaporation in vacuum drying oven.Be separated consequent solid body title product (2.5g).
5) by tiotropium bromide-PVP complex that spraying dry is formed
2.5g tiotropium bromide is dissolved in 25ml methanol.1.25g PVP is dissolved in methanol (15ml).By these two kinds of solution mixing also spraying dry.Parameter for the preparation of medicine-adjuvant complex is as follows:
Equipment-Labultima LU-222ADVANCE SPRAY DRYER
Temperature-50-55 DEG C
Vacuum-40mmWC
N
2pressure-1-2kg
Delivery rate-3ml/min.
Described solid resultant product collection is in catcher (2.0g).
The example of pharmaceutical aerosol composition
Compositions 1: the pharmaceutical aerosol composition containing tiotropium (Tiotropium)-PVP complex (0.5%), cosolvent and HFA propellant.
Method:
A active component is added in tank by ().
B () described tank metering valve seaming also fills the solution of propellant and PEG.
Compositions 2: the pharmaceutical aerosol composition comprising tiotropium-PVP complex (100%), cosolvent and HFA propellant.
Method:
A active component is added in tank by ().
B () described tank metering valve seaming also fills the solution of propellant and PEG.
Compositions 3: the pharmaceutical aerosol composition containing tiotropium-PVP complex (0.5%) and HFA propellant.
Method:
A active component is added in tank by ().
(b) described tank metering valve seaming.
C HFA227 filled by () described tank.
Compositions 4: the pharmaceutical aerosol composition containing ipratropium bromide (Ipratropium bromide)-PVP complex (0.5%) and HFA propellant.
Method:
A active component is added in tank by ().
(b) described tank metering valve seaming.
C HFA227 filled by () described tank.
Compositions 5: the pharmaceutical aerosol composition containing tiotropium-PVP complex (100%) and HFA propellant.
Method:
A active component is added in tank by ().
(b) described tank metering valve seaming.
C HFA227 filled by () described tank.
Compositions 6: the pharmaceutical aerosol composition containing tiotropium-PVP complex (0.5%), filler, cosolvent and HFA propellant.
Method:
A active component is added in tank by ().
B lactose is added to (a) by ()
C () described tank metering valve seaming also fills propellant.
Compositions 7: the pharmaceutical aerosol composition containing levosalbutamol sulphate-PVP complex (0.5%), filler and HFA propellant.
Method:
A active component is added in tank by ().
B lactose is added to (a) by ()
C () described tank metering valve seaming also fills propellant.
Compositions 8: the pharmaceutical aerosol composition containing levosalbutamol tartrate-PVP complex (0.5%), filler and HFA propellant.
Method:
A active component is added in tank by ().
B lactose is added to (a) by ()
C () described tank metering valve seaming also fills propellant.
Compositions 9: the pharmaceutical aerosol composition containing tiotropium-PVP complex (0.5%), filler, cosolvent and HFA propellant.
Method:
A active component is added in tank by ().
B lactose is added to (a) by ()
C () described tank metering valve seaming also fills the solution of propellant and PEG.
Compositions 10: the pharmaceutical aerosol composition containing tiotropium-PVP complex (0.5%), filler, cosolvent and HFA propellant.
Method:
A active component is added in tank by ().
B lactose is added to (a) by ()
C () described tank metering valve seaming also fills the solution of propellant and PEG.
Compositions 11: the pharmaceutical aerosol composition containing tiotropium-PVP complex (0.5%), filler, cosolvent and HFA propellant.
Method:
A active component is added in tank by ().
B lactose is added to (a) by ()
C () described tank metering valve seaming also fills the solution of propellant and PEG.
compositions 12:
Method:
A active component is added in tank by ().
(b) described tank metering valve seaming.
C HFA227 filled by () described tank.
compositions 13:
Method:
A active component is added in tank by ().
(b) described tank metering valve seaming.
C HFA227 filled by () described tank.
compositions 14:
Method:
A active component is added in tank by ().
(b) described tank metering valve seaming.
C HFA227 filled by () described tank.
Compositions 15:
Method:
A active component is added in tank by ().
(b) described tank metering valve seaming.
C HFA227 filled by () described tank.
Compositions 16:
Method:
A active component is added in tank by ().
B the solution of propellant and PEG filled by () described tank metering valve seaming and described tank.
Comprise the stability study data of the pharmaceutical aerosol composition of medicine-adjuvant complex and HFA
Carry out acceleration for stabilization Journal of Sex Research, with relatively following three different compositions groups: (1) medicine and HFA propellant; (2) medicine-adjuvant complex and HFA propellant; (3) medicine, cosolvent, surfactant, filler and HFA propellant.
Find that the aerosol composition containing medicine-adjuvant complex when preserving under accelerated stability condition, represents consistent fine particle size in research process.
For those skilled in the art it is apparent that under the condition not departing from spirit of the present invention, different substituting and amendment can be carried out to the present invention disclosed herein.Therefore, should be appreciated that, although specifically disclose the present invention by preferred embodiment and optional feature, those skilled in the art can take remodeling and the modification of concept disclosed herein, and think that such remodeling and modification comprise within the scope of the invention.
Should be appreciated that, word used herein and term be objects in order to describe and should not be considered to restrictive." comprise " herein, the use of " comprising " or " having " or its variant means to forgive the every and equivalent enumerated thereafter and other every.
Must be noted that, when using in the specification and the appended claims, singulative " (a) ", " one (an) " and " described (the) " comprise plural thing, unless context specifies clearly in addition.Therefore, such as, mention that " a kind of propellant " comprises single propellant and two or more different propellant; Mention that one " cosolvent " refers to the combination of single cosolvent or two or more cosolvent, etc.
Claims (17)
1. a pharmaceutical aerosol composition, it comprises at least one hydrofluoroalkane (HFA) propellant; The activating agent of at least one and adjuvant compound; Optionally comprise one or more pharmaceutical excipients,
Wherein said adjuvant is polyvinylpyrrolidone;
Wherein said activating agent is selected from tiotropium, ipratropium, aclidinium bromide, atropine or oxygen holder ammonium; And
Wherein said activating agent and described adjuvant compound by the following method, described method comprises:
A () mixes described activating agent in organic solvent,
B () mixture from step (a) is heated to suitable temperature and to add water clear to be formed
Clear solution;
C () adds described adjuvant to the solution from step (b);
(d) under reduced pressure the concentrated solution from step (c) to form residue;
E () washs the residue from step (d) by the same solvent used in step (a); With
F () dry washed residue from step (e) is to form medicine-adjuvant complex.
2. pharmaceutical aerosol composition according to claim 1, wherein said polyvinylpyrrolidone is molecular weight ranges is 2500-1, the polyvinylpyrrolidone of 200,000.
3. pharmaceutical aerosol composition according to claim 1 and 2, in the complex of wherein said activating agent and described adjuvant, the scope of the amount of adjuvant is the weighing scale 0.5%-500% by described activating agent.
4. pharmaceutical aerosol composition according to claim 1 and 2, the complex of wherein said activating agent and described adjuvant be microgranule and have such particle size distribution namely at least 90% microgranule there is the diameter being less than or equal to 15 microns.
5. pharmaceutical aerosol composition according to claim 1, wherein said ipratropium is ipratropium bromide; And described tiotropium is tiotropium bromide or tiotropium bromide monohydrate.
6. pharmaceutical aerosol composition according to claim 1 and 2, wherein said pharmaceutical excipient comprise filler, cosolvent or the two.
7. pharmaceutical aerosol composition according to claim 6, wherein said pharmaceutical excipient also comprises taste masked agent, buffer agent, antioxidant, water and chemical stabilizer.
8. pharmaceutical aerosol composition according to claim 6, wherein said filler comprises one or more sugar and/or one or more sugar alcohols.
9. pharmaceutical aerosol composition according to claim 6, wherein said cosolvent comprise in Polyethylene Glycol, propylene glycol, isopropyl myristate and glycerol one or more.
10. pharmaceutical aerosol composition according to claim 1 and 2, wherein said HFA propellant is HFA 134a (HFA-134a), HFC-227ea (HFA-227) or its mixture.
11. pharmaceutical aerosol compositions according to claim 1 and 2, it is used for the treatment of slight, the moderate of respiratory disorder or severe acute or chronic sympton, or for prophylactic treatment respiratory disorder.
12. pharmaceutical aerosol compositions according to claim 11, wherein said respiratory disorder is asthma.
13. pharmaceutical aerosol compositions according to any one of claim 1-10 for the preparation of slight, the moderate for the treatment of respiratory disorder or severe acute or chronic sympton, or for the application in the medicine of prophylactic treatment respiratory disorder.
14. application according to claim 13, wherein said respiratory disorder is asthma.
15. 1 kinds of pharmaceutical aerosol allotters, it comprises tank, and described tank has the room of the pharmaceutical aerosol composition held according to aforementioned any one claim; Outlet, described outlet is used for described pharmaceutical aerosol composition being delivered to the patient needing described compositions; And valve, described valve is for controlling described pharmaceutical aerosol composition from described room to the flowing of described outlet.
16. 1 kinds of methods preparing pharmaceutical aerosol allotter, described pharmaceutical aerosol allotter is for sending the pharmaceutical composition according to any one of claim 1-10, and described method comprises:
A the described activating agent of scheduled volume and the complex of described adjuvant are placed in suitable tank by (),
B described complex optionally mixes with one or more pharmaceutical excipients by ();
C described tank is filled HFA propellant by suitable valve seaming by ().
17. 1 kinds of methods preparing the complex of activating agent and adjuvant, described method comprises:
A () mixes described activating agent in organic solvent,
B mixture from step (a) is heated to suitable temperature and adds water to form the solution of clarification by ();
C () adds described adjuvant to the solution from step (b);
(d) under reduced pressure the concentrated solution from step (c) to form residue;
E () washs the residue from step (d) by the same solvent used in step (a); (f) the dry washed residue from step (e) is to form medicine-adjuvant complex, and wherein said adjuvant is polyvinylpyrrolidone;
Wherein said activating agent is selected from tiotropium, ipratropium, aclidinium bromide, atropine or oxygen holder ammonium.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2351MU2008 | 2008-11-04 | ||
| IN2351/MUM/2008 | 2008-11-04 | ||
| IN2402/MUM/2008 | 2008-11-14 | ||
| IN2402MU2008 | 2008-11-14 | ||
| GBPCT/GB2009/002575 | 2009-10-29 | ||
| PCT/GB2009/002575 WO2010052450A1 (en) | 2008-11-04 | 2009-10-29 | Tiotropium bromide having a low degree of crystallinity |
| PCT/GB2009/002617 WO2010052466A2 (en) | 2008-11-04 | 2009-11-04 | Pharmaceutical aerosol composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102238939A CN102238939A (en) | 2011-11-09 |
| CN102238939B true CN102238939B (en) | 2015-05-20 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN200980148430.5A Expired - Fee Related CN102238939B (en) | 2008-11-04 | 2009-11-04 | Pharmaceutical aerosol composition |
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| Country | Link |
|---|---|
| EP (1) | EP2362766A2 (en) |
| JP (1) | JP2012507574A (en) |
| KR (1) | KR20110096538A (en) |
| CN (1) | CN102238939B (en) |
| AU (1) | AU2009312598A1 (en) |
| BR (1) | BRPI0916047A2 (en) |
| CA (1) | CA2742718A1 (en) |
| MX (1) | MX2011004730A (en) |
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| RU (1) | RU2565438C2 (en) |
| WO (1) | WO2010052466A2 (en) |
| ZA (1) | ZA201103347B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2493827C1 (en) * | 2012-10-03 | 2013-09-27 | Шолекс Девелопмент Гмбх | Stable combined solution of fenoterol hydrobromide and ipratropium bromide |
| AU2013336492A1 (en) | 2012-10-23 | 2015-04-09 | Cipla Limited | Pharmaceutical composition comprising tiotropium and a hydrofluoroalkane |
| GB201306984D0 (en) * | 2013-04-17 | 2013-05-29 | Mexichem Amanco Holding Sa | Composition |
| KR101484481B1 (en) * | 2014-08-07 | 2015-01-20 | 주식회사 다림바이오텍 | Manufacturing method of subligual spray composition comprising PDE-5 inhibitor, and subligual spray composition manufactured by the same |
| CN107320464A (en) * | 2017-04-28 | 2017-11-07 | 北京北朋科技有限公司 | The preparation method of the budesonide suspension of high pH value |
| GB2573297A (en) * | 2018-04-30 | 2019-11-06 | Mexichem Fluor Sa De Cv | Pharmaceutical composition |
| EP3860580A4 (en) * | 2018-10-01 | 2022-07-20 | Kindeva Drug Delivery L.P. | Formulation and aerosol canisters, inhalers, and the like containing the formulation |
| CN114796166A (en) * | 2021-01-29 | 2022-07-29 | 北京远大九和药业有限公司 | Aerosol containing terpene volatile oil and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6641800B1 (en) * | 1991-09-25 | 2003-11-04 | Fisons Ltd. | Pressurized aerosol compositions comprising powdered medicament dispersed in hydrofluoroalkane |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4684698A (en) * | 1986-05-02 | 1987-08-04 | Gaf Corporation | Water soluble multicomplex of chlorothiazide, furosemide and poly(N-vinyl-2-pyrrolidone) |
| EP0655237A1 (en) * | 1993-11-27 | 1995-05-31 | Hoechst Aktiengesellschaft | Medicinal aerosol formulation |
| ATE254450T1 (en) * | 1995-09-19 | 2003-12-15 | Fujisawa Pharmaceutical Co | AEROSOL COMPOSITIONS |
| JP2001517692A (en) * | 1997-09-29 | 2001-10-09 | インヘール セラピューティック システムズ， インコーポレイテッド | Stabilized preparation for use in a nebulizer |
| DE10214031A1 (en) * | 2002-03-27 | 2004-02-19 | Pharmatech Gmbh | Process for the production and application of micro- and nanoparticles by micronization |
| PL1682542T3 (en) * | 2003-11-03 | 2010-06-30 | Boehringer Ingelheim Int | Novel crystalline anhydride with anticholinergic effect |
| CN101166738B (en) * | 2005-05-02 | 2011-06-01 | 贝林格尔·英格海姆国际有限公司 | Novel crystalline forms of tiotropium bromide |
| PL1869035T5 (en) * | 2005-12-19 | 2016-01-29 | Sicor Inc | Novel crystalline form of tiotropium bromide and process for preparation thereof |
| EP2124915A2 (en) * | 2007-02-19 | 2009-12-02 | Cipla Limited | Pharmaceutical combinations of at least two bronchodilators or of a bronchodilator with a corticosteroid |
| GB0801876D0 (en) * | 2008-02-01 | 2008-03-12 | Vectura Group Plc | Suspension formulations |
-
2009
- 2009-11-04 MX MX2011004730A patent/MX2011004730A/en not_active Application Discontinuation
- 2009-11-04 KR KR1020117012589A patent/KR20110096538A/en not_active Application Discontinuation
- 2009-11-04 NZ NZ592861A patent/NZ592861A/en not_active IP Right Cessation
- 2009-11-04 BR BRPI0916047A patent/BRPI0916047A2/en not_active IP Right Cessation
- 2009-11-04 AU AU2009312598A patent/AU2009312598A1/en not_active Abandoned
- 2009-11-04 CA CA2742718A patent/CA2742718A1/en not_active Abandoned
- 2009-11-04 EP EP09753178A patent/EP2362766A2/en not_active Withdrawn
- 2009-11-04 RU RU2011122652/15A patent/RU2565438C2/en not_active IP Right Cessation
- 2009-11-04 JP JP2011535158A patent/JP2012507574A/en active Pending
- 2009-11-04 WO PCT/GB2009/002617 patent/WO2010052466A2/en active Application Filing
- 2009-11-04 CN CN200980148430.5A patent/CN102238939B/en not_active Expired - Fee Related
-
2011
- 2011-05-09 ZA ZA2011/03347A patent/ZA201103347B/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6641800B1 (en) * | 1991-09-25 | 2003-11-04 | Fisons Ltd. | Pressurized aerosol compositions comprising powdered medicament dispersed in hydrofluoroalkane |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA201103347B (en) | 2012-01-25 |
| MX2011004730A (en) | 2011-05-30 |
| JP2012507574A (en) | 2012-03-29 |
| NZ592861A (en) | 2013-01-25 |
| RU2565438C2 (en) | 2015-10-20 |
| WO2010052466A2 (en) | 2010-05-14 |
| CN102238939A (en) | 2011-11-09 |
| CA2742718A1 (en) | 2010-05-14 |
| KR20110096538A (en) | 2011-08-30 |
| WO2010052466A3 (en) | 2010-11-04 |
| WO2010052466A8 (en) | 2011-11-24 |
| EP2362766A2 (en) | 2011-09-07 |
| AU2009312598A1 (en) | 2010-05-14 |
| BRPI0916047A2 (en) | 2015-11-10 |
| RU2011122652A (en) | 2012-12-20 |
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