CN101124198A - Medicine compound and composition - Google Patents
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- CN101124198A CN101124198A CNA2005800484390A CN200580048439A CN101124198A CN 101124198 A CN101124198 A CN 101124198A CN A2005800484390 A CNA2005800484390 A CN A2005800484390A CN 200580048439 A CN200580048439 A CN 200580048439A CN 101124198 A CN101124198 A CN 101124198A
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Abstract
The invention provides three polymorphic forms of crystalline levosalbutamol sulphate designated herein as Forms (I), (II) and (III). Crystalline levosalbutamol sulphate Form I is characterised by a powder XRD pattern with peaks at 10.8, 11.9, 13.0, 18.3, 28.5 +- 0.2 degrees 2 theta. Crystalline levosalbutamol sulphate Form (II) is characterised by a powder XRD pattern with peaks at 8.7, 9.6, 15.2, 15.7, 19.1, 27.2, 30.7 +- 0.2 degrees 2 theta. Crystalline levosalbutamol sulphate Form (III) is characterised by a powder XRD pattern with peaks at 5.5, 6.9, 7.3, 18.7 +- 0.2 degrees 2 theta. Processes for making the new polymorphic forms and pharmaceutical compositions comprising them are also provided. A pharmaceutical composition comprises a therapeutically effective isomer of salbutamol or a salt, solvate, ester, derivative or polymorph thereof, a glucocorticoid and a pharmaceutically acceptable carrier or excipient and optionally one or more other therapeutic agents. Preferably the composition is an aerosol formulation comprising the drugs, a propellant and optionally one or more other ingredients, such as a surfactant, cosolvent, or bulking agent. Alternatively, DPI or inhalation suspensions may be used.
Description
Technical field
The present invention relates to crystal sulfuric acid Levalbuterol, its polymorphic, be used to prepare the method and the composition thereof of described crystalline substance.
The present invention relates to comprise the pharmaceutical composition of effective isomer of salbutamol of treatment and glucocorticosteroid, described composition can be used for treating respiratory disease, comprises bronchoconstriction, asthma, COPD and relative disease thereof.
Background technology
Asthma is described to comprise lung airway inflammation and the hyperreactive chronic disease of segmental bronchus, and its clinical manifestation is that common reversible downtake blocks.The physiopathology of asthma or relative disease comprises by the bronchoconstriction due to the bronchial muscular spasm with the airway inflammation of myxedema.Known use β-2 agonist, be also referred to as the beta-2-adrenoceptor agonist and can treat asthma and other relative disease.Known described beta-2-adrenoceptor agonist can be the patient provides bronchodilator effect, thereby alleviates the shortness of breath symptom.More specifically, known beta-2-adrenoceptor agonist can improve the specific conductivity of potassium channel among the air flue myocyte, thereby causes film hyperpolarization and relaxation (relaxation).Recommend to use fugitive beta-2-adrenoceptor such as salbutamol and terbutaline to alleviate acute symptom, control and preferably depot drug product such as Salmeterol, formoterol and bambuterol are used for long-term asthma with the other medicines combination.
Chronic obstructive pulmonary disease (COPD) is can prevent and medicable morbid state, it is characterized in that incomplete reversible pneumatic restriction.COPD (chronic obstructive pulmonary disease) is the term (umbrella term) that is used to describe the tuberculosis relevant with airflow obstruction.Pneumatic restriction is normally progressive, and relevant to the abnormal inflammatory response of the deleterious particle that mainly caused by smoking or gas with lung.
Bronchodilator is the pillar therapy that is used to have the patient that chronic obstructive pulmonary disease (COPD) has taken place, but at present, Most patients is used beta-2-agonists.
Salbutamol pressurized sucks and is listed in British Pharmacopoeia and be used for the treatment of asthma by official.
The patent US 6,702,997 of Dey pharmaceutical relates to albuterol inhalation solution, system, test kit and the method that is used for alleviating the children that suffer from asthma bronchospasm, wherein comprises about 0.63mg to about 1.25mg salbutamol.
US 6,251,368 relate to following medicinal aerosol formulations, it comprises certain drug and fluorocarbon or the hydrogenous Chlorofluorocarbons propellent that is selected from acceptable salt of Salmeterol, salbutamol, fluticasone propionate, beclometasone and physiology thereof and solvate, and disclosed preparation does not comprise tensio-active agent basically.
The US 5 of Sepracor, 547,994 have described the method that is used for the treatment of asthma, and this method is used optically pure salbutamol R (-) isomer, it does not comprise S (+) isomer basically, is the effective bronchodilator that is used to alleviate the illness relevant with individual asthma.
The CN1413976 of Suzhou Junning New Drug Dev CT (CN) has described the synthetic of levosalbutamol.
The Application No. US2004054215 of CIPLA Limited discloses the method for the pure R-isomer of optically-active that is used to obtain salbutamol.
The several method that is used to prepare Levalbuterol has been described in existing field, and for example the Application No. 20040115136 of KingCode has been described the method that is used to prepare the tartrate Levalbuterol.It also relates to and has the L-tartrate Levalbuterol that is applicable to metered-dose inhaler character.
Salbutamol (salbutamol/albuterol) is antihistamine compounds and beta-2-adrenoceptor agonist, and it is used for the treatment of asthma as bronchodilator, is used to postpone premature labor as uterine relaxant.Salbutamol has been used as racemic mixture and has sold, although β-2 agonist activity almost mainly exists only in (R)-enantiomer.The possibility that the enantio-selectivity of salbutamol tendency and (S)-salbutamol has a deleterious effect has caused having developed (R)-salbutamol preparation of enantiomeric pure, is called levosalbutamol (levosalbutamol/levalbuterol) (formula I).
Formula I
US5545745 discloses the method that is used for from the pure salbutamol of salbutamol precursor preparation optically-active of single protection.
US2004114136 and WO2004052835 have described the method for the L-tartrate Levalbuterol that is used to prepare crystalline form; The pharmaceutical composition that comprises the L-tartrate Levalbuterol of crystalline form; The metered-dose inhaler that comprises jar comprises the aerosol formulation of the L-tartrate Levalbuterol of crystalline form in jar; With use L-tartrate Levalbuterol, comprise that especially the L-tartrate Levalbuterol of crystalline form is realized the bronchiectasic method of patient.
Carry at charcoal under the situation of palladium existence, prepare levosalbutamol by hydrogenation R-benzyl salbutamol.
By United States Patent (USP) 5,545,745 described methods can prepare R-benzyl salbutamol.
Studies confirm that bronchodilator racemic salbutamol commonly used is two kinds of enantiomers of salbutamol, is 50: 50 mixtures of R-and S-isomer.Having only R-enantiomer (levosalbutamol) is effective β
2-adrenoceptor stimulator, and S-enantiomer (right salbutamol) shows that very little adrenoceptor is active or does not have activity.
Usually using in the different pharmaceutical kind for the treatment of respiratory tract disease by suction, glucocorticosteroid such as beclometasone (BDP), dexamethasone, flunisolide, budesonide, fluticasone propionate are extremely important.They can be with in small, broken bits, and promptly micronized form of powder is mixed with at the suspensoid of aqueous phase to be used, and water comprises any essential tensio-active agent and/or solubility promoter; When being intended to use with the form of quantitative aerosol spraying, they also should comprise lower boiling propellent.
The validity of administration form depends on the particle at active position place deposition q.s.The most important parameter that decision will arrive the inhalable drug ratio of patient's lower respiratory tract is from the size of installing the particle that occurs.In order to ensure infiltrating bronchiole and alveolar effectively, but and therefore guarantee high respirable fraction, the average air kinetic diameter (MMAD) of particle should be lower than the 5-6 micron.For nasal administration, need have the particle of higher MMAD.
Learn that from GB2088877 itself has anti-inflammatory activity fluticasone propionate, can be used for treating the metamorphosis and the inflammatory symptoms of nose, throat or lung, for example asthma and rhinitis comprise spring fever.The fluticasone propionate of aerosol form is accepted to be used for the treatment of asthma by medical circle, and sells with trade mark Flovent I and " Flonase ".Fluticasone propionate can also be used with physiology acceptable solvent thing form.
HK1009406 relates to and is used to distribute the metered-dose inhaler that sucks pharmaceutical preparation, described preparation comprises fluticasone propionate or its physiology acceptable solvent thing and fluorocarbon propellant, and randomly combination has one or more other pharmacological active substances or one or more vehicle.
We know, in the treatment of COPD, compare with using independent salbutamol or independent reflunomide, and salbutamol or the acceptable salt of its physiology are had clinical advantage with suction reflunomide applied in any combination.
United States Patent (USP) 6013245 relates to following medicinal mist agent formulation, and it comprises anhydrous beclometasone particulate, uses 1,1,1,2,3,3 simultaneously, and 3-seven fluoro-n-propanes are as propellent, and said preparation does not comprise tensio-active agent.Described preparation also can comprise salbutamol, and comprises the jar that is suitable for passing medicine and use the method that described preparation is treated respiratory disease by suction.
United States Patent (USP) 2004136920 relates to will suck the aerosol formulation of using, and described preparation comprises salbutamol particulate and the acceptable salt of physiology and solvate and fluorocarbon or hydrogenous Chlorofluorocarbons propellent, is substantially free of tensio-active agent.Described patent has also been described the method that the described medicinal aerosol formulations of using significant quantity by suction is treated respiratory disease.
Summary of the invention
The purpose of this invention is to provide drug composition effective, described composition comprises the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic, and combination has the reflunomide that can suck.
The purpose of this invention is to provide the pharmaceutical composition that comprises at least two kinds of medicines, wherein a kind of medicine is the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic, its combination has the reflunomide that can suck, and pharmacology acceptable carrier or vehicle and one or more optional other therapeutical agents.
Another object of the present invention provides and comprises the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphous pharmaceutical composition, and described composition can be avoided and the relevant side effect of higher racemoid dosage.
Also purpose of the present invention is the method that is used to be prepared as follows pharmaceutical composition, and described composition comprises the effective isomer of salbutamol of treatment, and combination has the reflunomide that can suck.
Also purpose of the present invention provides respiratory disease such as the asthma that is used for the treatment of Mammals such as people, the method that causes the disease of bronchoconstriction, and this method comprises the pharmaceutical composition of the present invention of administering therapeutic significant quantity.
An object of the present invention is to provide and be used to reduce the drug regimen that comprises at least two kinds of medicines method in the intravital side effect of patient, this method comprises the steps: to there being this patient who needs to suck the pharmaceutical composition that comprises two kinds of medicines and propellent of using significant quantity at least.
According to the invention provides following pharmaceutical composition, it comprises treatment effective isomer of salbutamol or its salt, solvate, ester, derivative or polymorphic, glucocorticosteroid, and pharmacology acceptable carrier or vehicle and one or more optional other therapeutical agents.
The method that is used to be prepared as follows pharmaceutical composition also is provided, described composition comprises the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic, and combination has glucocorticoid medicine, and at least a pharmacology acceptable carrier, this method comprises mixes described composition to form described composition.
The present invention also provides the present composition as medicine.
Also provide to be used for the treatment of respiratory disease and associated conditions, comprised the present composition of bronchoconstriction, asthma and COPD.
The present invention also provides the method for respiratory disease such as the asthma that is used for the treatment of Mammals such as people, the disease that causes bronchoconstriction and chronic obstructive pulmonary disease (COPD), and this method comprises the pharmaceutical composition of the present invention of administering therapeutic significant quantity.
Known beta-2-adrenoceptor can for the patient provides bronchodilator effect, thereby be alleviated the shortness of breath symptom by acting on the beta-2-adrenoceptor in airway smooth muscle and the bronchial smooth muscle.More specifically, known they can improve the specific conductivity of potassium channel among the air flue myocyte, thereby cause film hyperpolarization and relaxation.Therefore they needing to be preferred for the treating asthma of the expansion bronchus unstriated muscle shortness of breath relevant with asthma with alleviating the patient.More specifically, fugitive beta-2-adrenoceptor is extremely useful, because they can provide onset faster, so mitigation is faster.
The present invention relates to a kind of this fugitive beta-2-adrenoceptor, i.e. salbutamol.Salbutamol can be used as the racemic mixture that comprises R and S form and obtains.But having only R-enantiomer (levosalbutamol) is effective β
2-adrenoceptor stimulator, and S-enantiomer (right salbutamol) shows that very little adrenoceptor is active or does not have activity.The bronchiectasis performance of racemic salbutamol is fully from (R)-salbutamol, and it is to β
2The binding affinity of-acceptor is bigger 100 times than (S)-salbutamol.External, report that (S)-salbutamol can promote the interior Ca of cell in the airway smooth muscle cells
2+Flow into and increase the cholinergic activity of airway smooth muscle.Therefore, under the situation that does not have (R)-salbutamol, (S)-salbutamol has the potentiality of the bronchoconstriction of inducing asthmatic patient.In the treatment of asthma and other airway disorders, the pharmacology of this difference is emphasized the needs to levosalbutamol rather than racemic salbutamol.
And when using as single enantiomer, compare with the racemic mixture of same amount, levosalbutamol is more effective bronchodilator.Levosalbutamol can reduce the side effect of β-mediation simultaneously producing suitable effect near racemic salbutamol 1/4th dosage places.
Therefore, the present invention also provides the aerosol formulation of the present invention that comprises two or more granule medicaments.Medicine can be selected from the appropriate combination of the described medicine of preamble, perhaps can be selected from any other the suitable medicine that can be used for sucking in the treatment.Preferably, the existence form of described medicine can be insoluble to selected propellent basically fully.
Therefore, suitable medicine for example can be selected from: anodyne such as morphine monomethyl ether, Paramorphan, Ergotamine, fentanyl or morphine; Antianginal preparation, for example Odizem; Anti-allergy agent, for example cromoglycate, ketotifen or nedocromil; Anti-infective is as cephalosporins, penicillins, Streptomycin sulphate, sulfamido, tetracyclines and pentamidine; Antihistaminic, for example methapyrilene; Antiphlogiston, for example flunisolide, budesonide, tipredane or Triamcinolone Acetonide; Antitussive, for example narcotine; Bronchodilator, for example ephedrine, suprarenin, Partusisten, formoterol, Racemic isoproterenol, Orciprenaline, synephrine, Phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, Isoetarine, tulobuterol, Orciprenaline or (-)-amino-3,5-two chloro-[α]-[[[6-[2-(2-pyridyl) oxyethyl group] hexyl] amino] methyl] phenylcarbinol; Hydragog(ue), for example guanamprazine; Anticholinergic, for example ipratropium bromide, coromegine or oxitropium bromide (oxitropium); Hormone, for example cortisone, hydrocortisone or prednisolone; Xanthine, for example aminophylline, Zy 15061, theophylline-lysine or theophylline; With treatment protein and peptide, for example Regular Insulin or hyperglycemic-glycogenolytic factor.It will be appreciated by one of skill in the art that, in due course, described medicine can be with salt (for example as an alkali metal salt or amine salt, or as acid salt) or use as ester (for example lower alkyl esters) or as the form of solvate (for example hydrate), optimizing the active and/or stable of described medicine, and/or the solvability of medicine in propellent minimized.
The commercially available salbutamol pharmaceutical composition that comprises racemic form comprises 100 to 200mcg salbutamols, but by the R form of using salbutamol is levosalbutamol, composition of the present invention comprise almost half or even dosage still less, but the treatment on more effective.Because dosage reduces, so the cardiovascular complication relevant with higher bronchiectasis pharmaceutical quantities still less.Therefore use the effective isomer of described treatment can cause patient compliance to increase.
Therefore, the invention provides to comprise and treat effective isomer of salbutamol or its salt, solvate, ester, derivative or polymorphous pharmaceutical composition, described composition can be avoided and the relevant side effect of higher racemoid dosage.
In whole specification sheetss and claims, use term " levosalbutamol " with wide significance, it not only comprises levosalbutamol itself, but also comprises the acceptable salt of its pharmacology, derivative or polymorphic.The acceptable salt of the pharmacology of levosalbutamol comprises levosalbutamol sulphate, tartrate levosalbutamol, levalbuterol hydrochloride.Used salt of levosalbutamol preferably sulfuric acid levosalbutamol.
Can prepare described active compound and various derivative thereof according to program well known in the art, this will be tangible to the technician.
The present invention uses the isomer of salbutamol that therapeutic activity is arranged most.Described composition does not comprise the isomer of low curative effect basically, this means that this isomer will not exist with any tangible amount.Suitably, the content of described isomer will be not more than the activity of 10 weight %, more preferably 1 weight % or still less.Therefore, for example, the composition that comprises levosalbutamol does not comprise the S-isomer of this compound basically.
Although can use the composition of any appropriate form, but particularly preferred composition is to comprise levosalbutamol (for example as free alkali or vitriol), and combination simultaneously has aerosol, DPI or the solution for inhalation/suspensoid of anti-inflammatory steroid such as beclomethasone ester (for example beclometasone) or fluticasone ester (for example fluticasone propionate) or anti-allergy agent such as cromoglycate (as sodium salt).The combination of salbutamol and fluticasone propionate or beclometasone or budesonide is preferred.With understanding, will can the suction form provide described activeconstituents with suitable for composition that can suck such as aerosol formulation.
In composition of the present invention, we preferably use the polymorphic forms of the levosalbutamol sulphate that is referred to herein as form I, form II and form III.They are new compounds, constitute another aspect of the present invention.
Therefore, on the one hand, crystalline levosalbutamol sulphate provided by the invention (form I) is characterised in that: powder X-ray RD pattern has the peak at 10.8,11.9,13.0,18.3,28.5 ± 0.2 degree, 2 θ places.
On the other hand, the crystalline levosalbutamol sulphate that is provided (form II) is characterised in that: powder X-ray RD pattern has the peak at 8.7,9.6,15.2,15.7,19.1,27.2,30.7 ± 0.2 degree, 2 θ places.
On the other hand, the crystalline levosalbutamol sulphate that is provided (form III) is characterised in that: powder X-ray RD pattern has the peak at 5.5,6.9,7.3,18.7 ± 0.2 degree, 2 θ places.
The present invention also provides the whole bag of tricks that is used to prepare form I, II and III.
The method that is used for preparing crystalline levosalbutamol sulphate form I comprises: a) prepare levosalbutamol at organic solvent; B) regulate pH by adding sulfuric acid at 1 to 10 ℃; C) at 0 to 10 ℃ of separated product (form I).
The method that is used to prepare crystalline levosalbutamol sulphate form I comprises: a) that any form of levosalbutamol sulphate is water-soluble; B) will precipitate thereby produce from the solution of step a) and organic solvent merging that can be miscible with water; C) unpack format I therefrom.
The method that is used to prepare crystalline levosalbutamol sulphate form II comprises: a) that any form of levosalbutamol sulphate is water-soluble; B) be distilled into residue; C) with organic solvent stripping residue; D) with solid slurrying in organic solvent; E) isolation of crystalline form II.
Other method that is used to prepare form II comprises any other form of comminution by gas stream (jet milling) levosalbutamol sulphate, for example comminution by gas stream crystalline form I.
The method that is used for preparing crystalline levosalbutamol sulphate form III comprises: a) prepare levosalbutamol at organic solvent; B) regulate pH by adding sulfuric acid at 25 to 30 ℃; C) at 25 to 30 ℃ of separated products (form III).
The another kind of method that is used to prepare form III comprises: a) that any form of levosalbutamol sulphate is water-soluble; B) will precipitate thereby produce from the solution of step a) and organic solvent merging that can be miscible with water; C) at 25 to 30 ℃ of unpack format III therefrom.
The present invention also provides the pharmaceutical composition that comprises The compounds of this invention and pharmacology acceptable carrier.
Described new compound and composition thereof as medicine also are provided, are particularly useful for treating respiratory disease and relevant illness.
Description of drawings
Fig. 1 shows the X-ray powder diffraction pattern of levosalbutamol sulphate form I.
Fig. 2 shows the IR collection of illustrative plates of levosalbutamol sulphate form I.
Fig. 3 shows the X-ray powder diffraction pattern of levosalbutamol sulphate form II.
Fig. 4 shows the IR collection of illustrative plates of levosalbutamol sulphate form II.
Fig. 5 shows the X-ray powder diffraction pattern of levosalbutamol sulphate form III.
Fig. 6 shows the IR collection of illustrative plates of levosalbutamol sulphate form III.
Table 1 provides the XRD data of Fig. 1 (form I).
Table 2 provides the XRD data of Fig. 3 (form II).
Table 3 provides the XRD data of Fig. 5 (form III).
Embodiment
Levosalbutamol sulphate crystalline form I is characterised in that the obvious reflection that is expressed as 2 θ values in the X-ray powder diffraction pattern is positioned at about 10.781,11.941,13.002,18.341,28.541 ± 0.2 degree, can be clear that from table 1.
The X-ray powder diffraction of levosalbutamol sulphate crystalline form I is illustrated in Fig. 1.Main peak and the intensity thereof of X-ray powder diffraction figure are shown in table 1.The intensity of reflection also is expressed as the per-cent of strong reflection.
Other the preferred obviously reflection that is expressed as the form I of 2 θ values comprises 12.66,15.819,17.4,20.939,21.72,22.5,23.14,24.341,26.12,31.28,31.93 ± 0.2 degree.On Rigaku d-max 2200 type X-ray diffractometers, use Cu K α radiation (λ=1.5405 ) to collect the X-ray powder diffraction figure of all polymorphic forms disclosed herein.
The feature of levosalbutamol sulphate crystalline form I also be the IR collection of illustrative plates 3568,3307,2980,2799,2561,2458,1615,1508,1440,1380,1342,1258,1200,1112,1082,1029,976,915,836,793,775,752,648,617,535,497,453cm
-1There is the peak at the place.
The IR collection of illustrative plates of Fig. 2 display format I.Use the Spectrum-1 of Perkin Elmer Sample and at 4000-400cm
-1The zone is interior to be analyzed as the KBr piller, thereby collects the IR collection of illustrative plates of all polymorphic forms disclosed herein.
When preparation levosalbutamol sulphate crystalline form I, preferably in a large amount of suitable organic solvents, use the catalyzer hydrogenation R-benzyl salbutamol that is preferably carbon-carried palladium catalyst.Preferred alcoholic solvent, the more preferably ethanol of using.Suit under hydrogen pressure, to carry out described process, preferred 30psi.Preferred then filtering catalyst, preferably 0-10 ℃ with sulfuric acid, preferably the pH of filtrate preferably is adjusted to 5-5.5 with the vitriol oil, so that crystal to be provided, then crystal is filtered and dry, to obtain levosalbutamol sulphate form I.Can be by obtaining product (form I) 0-10 ℃ of separation.
Levosalbutamol sulphate crystalline form II is characterised in that the obvious reflection that is expressed as 2 θ values in the X-ray powder diffraction pattern is positioned at about 8.701,9.636,15.180,15.657,19.139,27.199,30.7 θ, 2 ± 0.2 degree, can be clear that from table 2.
The X-ray powder diffraction of levosalbutamol sulphate form II is illustrated in Fig. 3.Main peak and the intensity thereof of X-ray powder diffraction figure are shown in table 2.The intensity of reflection also is expressed as the per-cent of strong reflection.
Other the preferred obviously reflection that is expressed as the form II of 2 θ values comprises the peak that is positioned at about 8.701,9.636,15.180,18.657,17.44,19.139,21.699,22.201,22.837,23.339,23.76,24.361,25.022,25.399,26.059,26.321,27.199,30.702 ± 0.2 degree.
The feature of levosalbutamol sulphate crystalline form II also be the IR collection of illustrative plates 3393,3026,2982,2822,2463,1630,1614,1513,1484,1448,1380,1321,1279,1258,1235,1204,1155,1093,1066,1036,1023,919,900,838,829,818,808,788,618,596,540,493,453,440cm
-1There is the peak at the place.
The IR collection of illustrative plates of Fig. 4 display format II.
The method that is used to prepare levosalbutamol sulphate crystalline form II comprises any form of levosalbutamol sulphate is water-soluble and it is distilled into residue.Further use organic solvent stripping residue, this solvent is preferably can be with water miscible and be preferably acetone, and with further slurrying in solvent of solid, described solvent is preferably identical solvent, preferably come separate solid, and vacuum-drying is to obtain levosalbutamol sulphate form II by filtration.
Levosalbutamol sulphate crystalline form III is characterised in that the obvious reflection that is expressed as 2 θ values in the X-ray powder diffraction pattern is positioned at about 5.496,6.901,7.340,18.660 ± 0.2 degree, can be clear that from table 3.
The X-ray powder diffraction of levosalbutamol sulphate form II is illustrated in Fig. 5.Main peak and the intensity thereof of X-ray powder diffraction figure are shown in table 3.The intensity at peak also is expressed as the per-cent of strong reflection.
Other the preferred obviously reflection that is expressed as the form III of 2 θ values comprises the peak that is positioned at about 5.496,6.901,7.340,8.18,8.399,10.978,11.758,14.298,16.321,17.98,18.18,18.660,18.86,19.189,20.179,20.72,20.019,22.219,23.121,23.64,23.858,24.638,25.339,27.62,28.79,29.319,30.80,32.341,33.218,33.781,34.181 ± 0.2 degree.
The feature of levosalbutamol sulphate crystalline form III also be the IR collection of illustrative plates 3533,3412,3086,2979,2823,2799,1613,1547,1505,1437,1397,1380,1365,1353,1303,1256,1243,1198,1110,1133,1086,1075,1055,1029,990,949,919,838,792,737,723,640,618,563,536,480,442,425cm
-1There is the peak at the place.
The IR collection of illustrative plates of Fig. 6 display format III.
When preparation levosalbutamol sulphate crystalline form III, preferably suitable preferred be alcoholic solvent, more preferably in the alcoholic acid organic solvent, usefulness is preferably the catalyzer hydrogenation R-benzyl salbutamol of carbon-carried palladium catalyst.Preferably under hydrogen pressure, carry out described process, preferred 30psi.Add sulfuric acid by (25 to 30 ℃) at ambient temperature and regulate pH and (25 to 30 ℃) separated product at ambient temperature, separable form III.Preferably, for example, implement these steps with the methylated spirits washing by filtering catalyst and washing.(25 to 30 ℃) use sulfuric acid preferably at ambient temperature, preferably the vitriol oil to 5-5.5, to obtain crystal, filters the pH regulator of filtrate and drying with crystal, to obtain levosalbutamol sulphate form III.Can be by obtaining product (form III) 25 to 30 ℃ of separation.
The another kind of method that is used to prepare levosalbutamol sulphate crystalline form II comprises the comminution by gas stream levosalbutamol sulphate.For example, but comminution by gas stream levosalbutamol crystalline form I to obtain form II.
Can be mixed with various pharmaceutical compositions with vehicle, auxiliary and the carrier of routine with understanding crystalline levosalbutamol sulphate disclosed herein and polymorphic forms thereof, include but not limited to tablet, capsule, pill, capsule sheet, MDI, DPI and Respule preparation and liquid oral such as syrup.In due course, can provide common or sustained release preparation.The technician in medicament field will know the conventional ingredient that can be used for preparing above-mentioned composition.Can prepare these preparations according to the manufacturing course of routine.
Particularly, compound of the present invention can be learned the active compound combination with one or more other medicines, and this will be tangible to those skilled in the art.Can use the combination of any suitable actives matter, as long as described combination is acceptable from the angle of pharmacology and management.Compound of the present invention can with for example following combinations of substances: reflunomide, for example fluticasone, beclometasone or budesonide; Anticholinergic, for example ipratropium bromide, tiotropium bromide or coromegine; Mucolytic, for example Transbroncho; Xanthine derivative, for example theophylline; Antihistaminic; Anodyne; And bronchodilator.Obviously, can provide described one or more extra active substances, comprise its pharmacology acceptable derivates, comprise salt, ester, polymorphic, optically active form and racemoid with any suitable form.
Therefore pharmaceutical composition provided by the invention comprises crystalline levosalbutamol sulphate, especially form I, form II or form III, and combination has one or more pharmacologic activity compounds and optional pharmacology acceptable carrier.
Preferably use composition of the present invention, thereby the local action of significant quantity is provided and therefore avoids deleterious general action by inhalation route.For suitable preparation is provided, this composition can further comprise the acceptable vehicle of pharmacology, and can be made into the form use of metered-dose inhaler.
Except levosalbutamol and anti-inflammatory steroid or suction glucocorticosteroid and at least a propellent, aerosol formulation of the present invention can randomly comprise other medicines and learn acceptable material such as solubility promoter, antioxidant or tensio-active agent.
For aerosol formulation, composition comprises propellent.Suitable propellent comprises propellent 11 (Refrigerant 12), propellent 12 (fluoro trichloromethane), propellent 114,1,1,1,2-Tetrafluoroethane (HFA134a) and 1,1,1,2,3,3, the mixture of 3-heptafluoro-propane (HFA227) or two or more described halohydrocarbon.
Can be prepared as follows aerosol formulation of the present invention:, in proper container, medicine is dispersed in the selected propellent for example by means of ultrasonic.This method is implemented in hope under anhydrous condition, to avoid any deleterious effect of moisture to suspensoid stability.
Preparation of the present invention can form the suspension of flocculation slightly after placement, even but surprisingly find after long storage, these suspension still can be by mild agitation redispersion easily, so that the good suspension of passing the medicine feature that has that is applicable to the pressurization sucker to be provided.In aerosol formulation of the present invention, it also is useful that the use of formulation excipients such as tensio-active agent, solubility promoter etc. is minimized and avoid to use formulation excipients, because described preparation is insipidness and smell basically, and stimulation and toxicity are less than conventional formulation.
In a preferred embodiment of the invention, aerosol combination can comprise: treat effective isomer of salbutamol, its salt, solvate, ester, derivative or polymorphic, and anti-inflammatory steroid or suction glucocorticosteroid, propellent 11 or propellent 114 or its combination and propellent 12.
In another preferred embodiment of the present invention, aerosol can comprise: treat effective isomer of salbutamol, its salt, solvate, ester, derivative or polymorphic, suck glucocorticosteroid, and propellent 11, propellent 114 or its combination and propellent 12, and tensio-active agent.
In the experiment of said preparation, to observe when not having tensio-active agent, medicine can not form uniform dispersion.Attempted various tensio-active agent known in the art, as oil, as Semen Maydis oil, sweet oil, Oleum Gossypii semen and sunflower seed oil; Mineral oil such as whiteruss; Oleic acid; And phosphatide such as Yelkin TTS; Or fatty acid esters of sorbitan such as Span-80.When using the combination of levosalbutamol sulphate and fluticasone and budesonide, Yelkin TTS has obtained good relatively suspended load discharge.Under the situation that is used in combination levosalbutamol sulphate and beclometasone, preferred surfactants is an oleic acid.
The working concentration of tensio-active agent can be the 0.001-100% of active substance gross weight.Preferable range is 1%-50%.More preferably concentration is 5%-30%.Surfactant concentrations of the present invention is preferably 10% (being the gross weight by active substance).Typically, active substance will comprise two kinds of active medicines, for example levosalbutamol and glucocorticosteroid.
At the composition that is used for sucking, granularity is very important.Preferred size is 2 μ m to 5 μ m.Find that also granularity can obviously influence in the aerosol through sending the ratio of the active substance that is used to suck.
In another experiment, with medicine and propellent 11 or propellent 114 or its combined hybrid, be filled in the jar, tighten (crimped) and charge into propellent 12.Find to obtain so low FPD (fine particle dose).Therefore carry out further experiment, both all make up little grinding (micro-mill) with propellent 11 or propellent 114 or its its Chinese traditional medicine and/or tensio-active agent, starch with formation, are filled in the jar then, and charge into propellent 12.Compare with the CFC aerosol that does not carry out little grinding described herein, this has caused better FPD.Therefore in order to obtain better FPD, preferably carry out little grinding.
Aspect widely, the invention provides the method that is used to be prepared as follows pharmaceutical composition, said composition comprises the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic and glucocorticosteroid in propellent, described method comprises mixes described composition to form described composition.
In other embodiments of the present invention, provide and be used to be prepared as follows the medicinal aerosol method for compositions, said composition comprises treatment effective isomer of salbutamol or its salt, solvate, ester, derivative or polymorphic and glucocorticosteroid, and described method comprises: (a) with two kinds of medicines, randomly with tensio-active agent, add in the jar with propellent 11, propellent 114 or its combination; (b) with suitable valve jar is tightened; (c) charge into propellent 12 by valve.Preferably, in step (a), one or more active substances and propellent are ground or little grinding.
Of the present invention also one preferred aspect, aerosol combination can comprise the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic and glucocorticosteroid, and 1,1,1,2-Tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination.
Provide the method that is used to prepare above-mentioned aerosol combination also on the one hand of the present invention, this method comprises: (a) effective isomer of salbutamol of treatment and glucocorticosteroid are added in the jar; (b) with quantitative valve jar is tightened; (c) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination.Randomly, in step (a), also can add solubility promoter or weighting agent (bulking agent); Tensio-active agent; Or solubility promoter and tensio-active agent.
Of the present invention another preferred aspect, aerosol combination can comprise the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic and glucocorticosteroid, and 1,1,1,2-Tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination and solubility promoter.In this case, the polarity of solubility promoter is greater than the polarity of propellent.
Typically, the content of solubility promoter accounts for 0.01 to 5% of composition weight.Used solubility promoter can be any suitable solubility promoter, for example is selected from glycols, particularly propylene glycol, polyoxyethylene glycol and glycerine or alcohol as ethanol.Typically, solubility promoter is an ethanol.
Of the present invention preferred aspect, the method that is used to prepare above-mentioned composition is provided, this method comprises: (a) two kinds of medicines are added in the jar; (b) in (a), add solubility promoter and ultrasonic; (c) with quantitative valve jar is tightened; (d) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination.
In going back a preferred embodiment, aerosol combination can comprise the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic and glucocorticosteroid, and 1,1,1,2-Tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination, tensio-active agent and solubility promoter.
But tensio-active agent stabilization formulations and the valve system that helps to lubricate sucker.Some the most frequently used surface-active agents are that those are known in the art, and it is selected from: Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, Isopropyl myristate, oleic acid, Brij, ethyl oleate, triolein, glyceryl monolaurate, XU 61518.10, glyceryl monostearate, single ricinoleic acid glyceryl ester, hexadecanol, stearyl alcohol, the hexadecyl chloropyridine, block polymer, natural oil, polyvinylpyrrolidone, fatty acid esters of sorbitan such as sorbitan trioleate, the fatty acid esters of sorbitan of polyethoxylated (for example sorbitan trioleate of polyethoxylated), sorbimacrogol oleate, synthetic amphotenside (tritons), the oxyethane ether of octyl phenol formaldehyde condensation products, phosphatide such as Yelkin TTS, the fat of polyethoxylated, the Fatty Alcohol(C12-C14 and C12-C18) of triolein of polyethoxylated (oleotriglyceride) and polyethoxylated.
The preferable amount of surface-active agents is the 0.02-10% of active substance gross weight.
In another aspect of this invention, provide the method that is used to prepare above-mentioned composition, this method comprises: (a) medicine is added in the jar; (b) in (a), add solubility promoter and tensio-active agent and ultrasonic; (c) with quantitative valve jar is tightened; (d) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination.
In also one side of the present invention, aerosol combination can comprise the effective isomer of salbutamol of treatment, glucocorticosteroid, weighting agent and propellent, preferred HFA 134a or HFA 227 or its combination.Weighting agent makes medicine arrive lung as carrier.The concentration that weighting agent exists can be the 10-500% of active substance gross weight.Preferred scope is the 10-300% of active substance gross weight.Weighting agent can be selected from carbohydrate, comprises monose, disaccharides, polysaccharide and sugar alcohol such as pectinose, glucose, fructose, ribose, seminose, sucrose, trehalose, lactose, maltose, starch, dextran or N.F,USP MANNITOL.
Of the present invention preferred aspect, the method that is used to prepare above-mentioned aerosol combination is provided, this method comprises: (a) activeconstituents is added in the jar; (b) absorb fillers in (a); (c) with quantitative valve jar is tightened; (d) in jar, charge into propellent.
Of the present invention preferred aspect, described aerosol combination can comprise the effective isomer of salbutamol of at least a treatment or its salt, solvate, ester, derivative or polymorphic, glucocorticosteroid, tensio-active agent and 1,1,1,2-Tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination.Tensio-active agent can be any suitable tensio-active agent, and listed those above for example perhaps are selected from stearic salt or ester, for example Quicifal, Isopropyl myristate and Renascin.Preferred stearic magnesium salts, Isopropyl myristate.The preferable amount of tensio-active agent is 0.01% to 1% of an active substance gross weight.
Of the present invention preferred aspect, the method that is used to prepare above-mentioned aerosol combination is provided, this method comprises: (a) medicine is added in the jar; (b) in (a), add tensio-active agent; (c) with quantitative valve jar is tightened; (d) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination.
Composition of the present invention can randomly comprise antioxidant such as citric acid or benzalkonium chloride.
The combination of levosalbutamol and glucocorticosteroid can be used as dry powder formulations or provides with the form of solution for inhalation/suspensoid.For dry powder sucks, described medicine can use separately, or randomly use with pharmacology acceptable carrier in small, broken bits, described carrier preferably exist and can be selected from known in dry powder inhalation composition the material as carrier, for example sugared, comprise monose, disaccharides, polysaccharide and sugar alcohol, as pectinose, glucose, fructose, ribose, seminose, sucrose, trehalose, lactose, maltose, starch, dextran or N.F,USP MANNITOL.Particularly preferred carrier is a lactose.Dry powder may reside in gelatin or HPMC capsule or the bubble-cap, and perhaps, dry powder can be used as the storage storehouse and is comprised in the multiple doses powder inhaler.Method by routine, for example by grinding in air spray mill, ball mill or vibration mill, microdeposit, spraying drying, freeze-drying or from supercritical medium recrystallization, the granularity of contained activeconstituents and carrier in the dry powder composite can be reduced to required level.
According to the present invention, the method that is used to prepare the Diskus that comprises levosalbutamol and glucocorticosteroid also is provided, this method comprises randomly mixes activeconstituents with suitable carriers, and provides described composition in suitable Diskus.
For solution for inhalation, described medicine can be in suitable carriers and appropriate excipients such as tension adjustment agent, pH regulator agent, sequestrant, wetting agent combination.Preferred powerful adjustment agent is a sodium-chlor.The pH regulator agent can be selected from the acceptable mineral acid of pharmacology or organic acid or alkali.Preferred mineral acid is selected from hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.Preferred organic acid and organic acid salt are for for example but do not comprise acetate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, succinate, butyrates, valerate and fumarate.Preferred mineral alkali is selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide, yellow soda ash, calcium hydroxide.Preferred organic bases is selected from methylamine, ethyleneimine, quinhydrones, ethyleneimine, ethamine, dimethylamine, thanomin, butylamine, diethylamine.Preferred alkali is sodium hydroxide.Preferably, the pH scope of intranasal suction preparation provided by the invention is 3 to 5.
Suitable sequestrant or complexing agent can be used for composition of the present invention, and they can be for entering the molecule of complex bonds.Preferred described compound has complex cation, the cationic effect of most preferred metal.Preferred material is diethylamine tetraacethyl (EDTA) or its salt, for example disodium salt.Suitable wetting agent with well emulsify and wettability can be used for the present invention.Some typical examples comprise Isosorbide Dinitrate, PEG etc., and they are tangible to those skilled in the art.
The liquid vehicle that is used for the present composition (especially solution for inhalation or suspensoid) includes but not limited to polar solvent, includes but not limited to comprise the compound of hydroxyl or other polar group.These solvents include but not limited to water or alcohol, and for example ethanol, Virahol and glycol comprise propylene glycol, polyoxyethylene glycol, polypropylene glycol, glycol ether, glycerine and Volpo S 10.
Other polar solvent also comprises protonic solvent, includes but not limited to water, comprises salt brine solution, alcohol, glycol or its mixture of the acceptable salt of one or more pharmacology.For as solvent or as the salt brine solution of its composition, specially suitable salt is not show or only show those salt that can ignore pharmacologically active after using.
Antibiotic antiseptic can be added in the multiple-unit container.Suitable sanitas will be significantly to the technician, especially benzalkonium chloride or phenylformic acid or benzoate such as Sodium Benzoate, Sorbic Acid or sorbate such as potassium sorbate, and its concentration is known in existing field.
According to the present invention, also provide the method that is used to prepare the solution for inhalation that comprises levosalbutamol and glucocorticosteroid.This method preferably includes the following step:
1. levosalbutamol and isotonic agent, sequestrant and wetting agent are dissolved in the purified water, filter then.
2. in another container, that glucocorticosteroid is ultrasonic in the water of part amount, then by the sterilization of suitable sterile method.
3. above-mentioned two kinds of solution are mixed,, regulate pH (if desired) so that final suction suspensoid to be provided.Suspensoid is charged in dosage unit or the multiple dose vials.
In another alternate embodiment, can use solution for inhalation of the present invention by atomizer.Described atomizer includes but not limited to the atomizer of jet nebulizer, ultrasonic nebulizer and respiratory promoter.Preferably, the jet nebulizer of described atomizer for linking to each other with air compressor with enough air-flows.Described atomizer is equipped with mouthpiece or suitable face shield.Particularly, the atomizer that links to each other with compressor (having face shield or mouthpiece) can be used for sending solution for inhalation of the present invention to the patient.
The present invention also provides respiratory disease such as asthma that is used for the treatment of Mammals such as people and the method that causes the disease of bronchoconstriction, and this method comprises the pharmaceutical composition of the present invention of administering therapeutic significant quantity.
It will be apparent to one skilled in the art that without departing from the spirit of the invention, can carry out various substitutions and modifications invention disclosed herein.Therefore, although specifically disclose the present invention with understanding by preferred embodiment and optional feature, those skilled in the art can be to design correct disclosed herein and variation, and thinks that these modifications and variations fall within the scope of the present invention.
The following example only is used to illustrate the present invention, is used to absolutely not limit the scope of the invention.
Embodiment 1:CFC sucker
A)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 10.08mg |
| 2. | Fluticasone propionate (little grinding) | 8.24mg |
| 3. | |
1.832mg |
| 4. | Propellent 11 | 3.0 |
| 5. | Propellent 12 | 7.7gms |
(a) add levosalbutamol sulphate and Yelkin TTS and propellent 11;
(b) slurry is charged in the jar;
(c) with suitable valve jar is tightened; With
(d) charge into propellent 12 by valve.
B)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 15.12mg |
| 2. | Beclometasone (50mcg) | 12mg |
| 3. | |
2.712mg |
| 4. | Propellent 11 | 4.7 |
| 5. | Propellent 12 | 11.6gms |
A) add medicine and oleic acid and propellent 11;
B) slurry is charged in the jar;
C) with suitable valve jar is tightened; With
D) charge into propellent 12 by valve.
C)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 10.08mg |
| 2. | Budesonide | 24mg |
| 3. | |
3.40mg |
| 4. | Propellent 11 | 4.7 |
| 5. | Propellent 12 | 11.6gms |
A) add medicine and Yelkin TTS and propellent 11;
B) slurry is charged in the jar;
C) with suitable valve jar is tightened; With
D) charge into propellent 12 by valve.
Embodiment 2:HFA sucker
A)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 12.00mg |
| 2. | Fluticasone propionate (little grinding) (50mcg) | 8.24mg |
| 3. | Propellent 134a | 12.8gm |
A) two kinds of medicines are added in the jar;
B) with quantitative valve jar is tightened;
C) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a).
B)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 15.12mg |
| 2. | Beclometasone (50mcg) | 12mg |
| 3. | Abs.Alc.2.5％ | 0.455 |
| 4. | HFA134a | 17.74gms |
A) two kinds of medicines, pure and mild section H FA134a are added in the jar;
B) jar is tightened also ultrasonic with quantitative valve;
C) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a).
C)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 10.08mg |
| 2. | Budesonide (100mcg) | 24mg |
| 3. | HFA134a | 18.2gms |
A) two kinds of medicines are added in the jar;
B) with quantitative valve jar is tightened;
C) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a).
Embodiment 3:HFA sucker
A)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 10.08mg |
| 2. | Fluticasone propionate (little grinding) | 8.24mg |
| 3. | Propellent 227 | 11.2gms |
A) two kinds of medicines are added in the jar;
B) with quantitative valve jar is tightened;
C) in jar, charge into 1,1,1,2,3,3,3-seven fluoroethanes (HFA227).
B)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 10.08mg |
| 2. | Budesonide | 24mg |
| 3. | HFA227 | 20.6gms |
A) two kinds of medicines are added in the jar;
B) with quantitative valve jar is tightened;
C) in jar, charge into 1,1,1,2,3,3,3-seven fluoroethanes (HFA227).
Embodiment 4:HFA sucker
A)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 10.08mg |
| 2. | Fluticasone propionate (little grinding) | 8.24mg |
| 3. | Abs.Alc.2％ | 0.256 |
| 4. | Yelkin TTS 0.02% | 0.003664 |
| 5. | HFA134a | 12.54gms |
A) two kinds of medicines are added in the jar;
B) pure and mild surfactant soln is added in (a) and ultrasonic;
C) with quantitative valve jar is tightened;
D) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a).
B)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 15.12mg |
| 2. | Beclometasone (50mcg) | 12mg |
| 3. | Abs.Alc.2.5％ | 0.455 |
| 4. | Oleic acid 0.02% | 0.00542 |
| 5. | HFA134a | 17.74gms |
A) two kinds of medicines are added in the jar;
B) pure and mild surfactant soln is added in (a) and ultrasonic;
C) with quantitative valve jar is tightened;
D) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a).
C)
| Sr.No | Composition | Amount/ |
| 1. | Levosalbutamol sulphate | 10.08mg |
| 2. | Budesonide | 24mg |
| 3. | Abs.Alc.2％ | 0.364 |
| 4. | Yelkin TTS 0.02% | 0.006816 |
| 5. | HFA134a | 17.83gms |
A) two kinds of medicines are added in the jar;
B) pure and mild surfactant soln is added in (a) and ultrasonic;
C) with quantitative valve jar is tightened;
D) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a).
Embodiment 5: the dry powder that is used to suck
| Sr.No | Composition | mg/ |
| 1. | Levosalbutamol sulphate | 100.00mcg |
| 2. | Beclometasone | 100.00mcg |
| 3. | Lactose q.s. | 25.00mg |
Levosalbutamol sulphate and beclometasone are blended into lactose, are filled in the capsule.
Embodiment 6: the spraying suspensoid
| Sr.No | Composition | Amount (%w/w) |
| 1. | Levosalbutamol sulphate equals levosalbutamol | 15.500 |
| 2. | Beclometasone | 20.000 |
| 3. | Sodium-chlor | 0.900 |
| 4. | Tween 80 | 0.100 |
| 5. | The EDTA disodium | 0.020 |
| 6. | Trisodium Citrate | q.s |
| 7. | Purified water | Q.s. to 2.00ml |
1. levosalbutamol and isotonic agent, sequestrant and wetting agent are dissolved in the purified water, filter then.
2. in another container, that glucocorticosteroid is ultrasonic in the water of part amount, then by the sterilization of suitable sterile method.
3. above-mentioned two kinds of solution are mixed, so that final suction suspensoid to be provided, and regulate pH (if desired).Suspensoid is charged in dosage unit or the multiple dose vials.
Crystal polymorphic forms I, the II of the following example explanation levosalbutamol sulphate and the preparation of III.
Embodiment 7
R-benzyl salbutamol (20.0kg.), methyl alcohol (61.0ltr), methylated spirits (72ltrs.) are charged in the autoclave, add charcoal and carry palladium (5%) (1.30kg), under the 30psi hydrogen pressure, stir.After finishing reaction, filtering catalyst is with methyl alcohol (60lts.) and methylated spirits (60ltrs.) washing.At 0-10 ℃, with sulfuric acid with the pH regulator of clear filtrate to 5-5.5, the gained solid is stirred 1hr at 0-10 ℃, filter and wash with methyl alcohol (20lts.).With product at 30 ℃ of vacuum-drying 1hr, further at 50-60 ℃ of other dry 1hr, to obtain R-salbutamol form I (19.0kg.).
Embodiment 8
R-benzyl salbutamol (10.0kg.), methyl alcohol (30.0ltr.), methylated spirits (36ltrs.) are charged in the autoclave, add charcoal and carry palladium (5%) (0.65kg), under the 30psi hydrogen pressure, stir.After finishing reaction, filtering catalyst is with methylated spirits (25ltrs.) washing.(25 to 30 ℃) at ambient temperature, with sulfuric acid with the pH regulator of clear filtrate to 5-5.5, and at 25 to 30 ℃ with the gained solid filtering and with methyl alcohol (10lts.) washing.With product 50-60 ℃ of vacuum-drying, to obtain sulfuric acid R-salbutamol form III (19.0kg.).
Embodiment 9
In sulfuric acid R-salbutamol (14.80Kg) water-soluble (60.0ltrs.), filter and obtain settled solution.Filtrate is become residue 60 ℃ of vacuum distillings.With residue stripping twice, further add acetone (148.0ltrs.) with acetone (74.0ltrs.), the gained slurry is stirred 2hr.To starch and filter and at 60 ℃ of vacuum-drying 10-12hr, to obtain sulfuric acid R-salbutamol form II (11.1kg.).
In sulfuric acid R-salbutamol (10Kg) water-soluble (30.0ltrs.), stir 10-15min.The settled solution of gained is filtered.At room temperature in clear filtrate, slowly add methyl alcohol (150ltrs.), and stir 30min, further be cooled to 0-5 ℃.With the gained solid filtering and use methanol wash.With product at 60 ℃ of vacuum-drying 3-4hr, to obtain sulfuric acid R-salbutamol form I (8kg.).
Embodiment 11
In sulfuric acid R-salbutamol (20Kg) water-soluble (60.0ltrs.), filter to obtain settled solution, slowly charge into 300ltr acetone at 25-30 ℃, the gained mixture is at room temperature stirred 2hr.The gained slurry is filtered, at 80 ℃ of vacuum-drying 10-12hr, to obtain sulfuric acid R-salbutamol form III (17kg.).
Embodiment 12
In sulfuric acid R-salbutamol (10gms) water-soluble (30ml).Charge into methyl alcohol (150ml) at 25-30 ℃, add Virahol (75ml), mixture is cooled to 5-10 ℃ of 2hr, filter and at 80 ℃ of vacuum-drying 15-20hr, to obtain form II.
Embodiment 13
Under reflux temperature, sulfuric acid R-salbutamol is dissolved in methyl alcohol.With the reactant cool to room temperature, further be cooled to 5-10 ℃ then.With the gained solid filtering and 80 ℃ of dryings, to obtain sulfuric acid R-salbutamol form II.
Embodiment 14
I carries out comminution by gas stream to sulfuric acid R-salbutamol form, and to obtain sulfuric acid R-salbutamol form II, wherein 90% granularity is less than 5 microns, and 100% is lower than 12.5 microns.
Notice that in embodiment 9 to 13 any sulfuric acid R-salbutamol form all can be used as raw material.
Table 1
| Levosalbutamol S04-form I | ||||||
| Peak number | 2 θ (degree) | d(A) | Highly | | FWHM | |
| 1 | 10.781 | 8.1998 | 10389 | 59.5 | 0.237 | |
| 2 | 11.941 | 7.4053 | 2043 | 11.7 | 0.237 | |
| 3 | 12.660 | 6.9865 | 1090 | 6.2 | 0.232 | |
| 4 | 13.005 | 6.8036 | 1080 | 6.2 | 0.167 | |
| 5 | 15.819 | 5.5975 | 1576 | 9.0 | 0.266 | |
| 6 | 17.400 | 5.0924 | 2170 | 12.4 | 0.236 | |
| 7 | 18.341 | 4.8332 | 2847 | 16.3 | 0.268 | |
| 8 | 19.019 | 4.6624 | 621 | 3.6 | 0.271 | |
| 9 | 20.939 | 4.2390 | 2564 | 14.7 | 0.265 | |
| 10 | 21.720 | 4.0883 | 3195 | 18.3 | 0.282 | |
| 11 | 22.500 | 3.9482 | 2001 | 11.5 | 0.202 | |
| 12 | 23.140 | 3.8406 | 17446 | 100.0 | 0.234 | |
| 13 | 24.341 | 3.6537 | 1870 | 10.7 | 0.243 | |
| 14 | 26.120 | 3.4087 | 1108 | 6.4 | 0.285 | |
| 15 | 28.541 | 3.1249 | 1379 | 7.9 | 0.281 | |
| 16 | 31.280 | 2.8572 | 914 | 5.2 | 0.378 | |
| 17 | 31.939 | 2.7997 | 955 | 5.5 | 0.451 | |
| 18 | 33.980 | 2.6361 | 686 | 3.9 | 0.361 | |
| 19 | 34.279 | 2.6138 | 419 | 2.4 | 0.350 | |
| 20 | 35.739 | 2.51036 | 712 | 4.1 | 0.329 | |
| 21 | 36.340 | 2.4702 | 635 | 3.6 | 0.391 | |
Table 2
| Levosalbutamol S04-form II | |||||
| Peak number | 2 θ (degree) | d(A) | Highly | Height % | FWHM |
| 1 | 8.701 | 10.1542 | 8249 | 100.0 | 0.205 |
| 2 | 9.636 | 9.1706 | 2610 | 31.6 | 0.195 |
| 3 | 13.422 | 6.5914 | 365 | 4.4 | 0.184 |
| 4 | 15.180 | 5.8318 | 6090 | 73.8 | 0.213 |
| 5 | 15.657 | 5.6550 | 2247 | 27.2 | 0.201 |
| 6 | 17.440 | 5.0809 | 2091 | 25.3 | 0.193 |
| 7 | 19.139 | 4.6335 | 1416 | 17.2 | 0.272 |
| 8 | 19.360 | 4.5811 | 900 | 10.9 | 0.385 |
| 9 | 19.583 | 4.5294 | 666 | 8.1 | 0.376 |
| 10 | 20.221 | 4.3879 | 462 | 5.6 | 0.156 |
| 11 | 21.439 | 4.1413 | 7819 | 94.8 | 0.256 |
| 12 | 21.699 | 4.0921 | 3525 | 42.7 | 0.356 |
| 13 | 22.201 | 4.0008 | 2317 | 28.1 | 0.128 |
| 14 | 22.837 | 3.8907 | 1299 | 15.7 | 0.091 |
| 15 | 23.339 | 3.8083 | 4096 | 49.7 | 0.308 |
| 16 | 23.760 | 3.7417 | 2345 | 28.4 | 0.236 |
| 17 | 24.361 | 3.6508 | 1107 | 13.4 | 0.165 |
| 18 | 25.022 | 3.5558 | 829 | 10.0 | 0.080 |
| 19 | 25.399 | 3.5038 | 1127 | 13.7 | 0.176 |
| 20 | 26.059 | 3.4166 | 1162 | 14.1 | 0.271 |
| 21 | 26.321 | 3.3832 | 1437 | 17.4 | 0.256 |
| 22 | 27.199 | 3.2759 | 2718 | 32.9 | 0.255 |
| 23 | 28.740 | 3.1037 | 622 | 7.5 | 0.193 |
| 24 | 29.263 | 3.0493 | 356 | 4.3 | 0.628 |
| 25 | 30.077 | 2.9687 | 721 | 8.7 | 0.162 |
| 26 | 30.702 | 2.9097 | 1586 | 19.2 | 0.211 |
| 27 | 31.640 | 2.8255 | 631 | 7.6 | 0.351 |
| 28 | 32.001 | 2.7944 | 700 | 8.5 | 0.464 |
| 29 | 32.319 | 2.7677 | 680 | 8.2 | 0.354 |
| 30 | 33.859 | 2.6452 | 368 | 4.5 | 0.382 |
| 31 | 34.242 | 2.6165 | 730 | 8.8 | 0.315 |
| 32 | 35.002 | 2.5615 | 424 | 5.1 | 0.244 |
| 33 | 35.299 | 2.5406 | 316 | 3.8 | 0.542 |
| 34 | 35.838 | 2.5036 | 376 | 4.6 | 0.239 |
| 35 | 36.238 | 2.4769 | 427 | 5.2 | 0.232 |
| 36 | 36.737 | 2.443 | 254 | 3.1 | 0.313 |
| 37 | 37.999 | 2.3660 | 297 | 3.6 | 0.245 |
| 38 | 38.265 | 2.3502 | 319 | 3.9 | 0.658 |
| 39 | 38.777 | 2.3203 | 491 | 6.0 | 0.380 |
Table 3
| Levosalbutamol S04-form III | |||||
| Peak number | 2 θ (degree) | d(A) | Highly | Height % | FWHM |
| 1 | 5.496 | 16.0657 | 2337 | 41.8 | 0.206 |
| 2 | 6.901 | 12.799 | 320 | 5.7 | 0.295 |
| 3 | 7.340 | 12.034 | 1938 | 34.6 | 0.217 |
| 4 | 8.181 | 10.7983 | 2348 | 42.0 | 0.645 |
| 5 | 8.399 | 10.5187 | 5559 | 99.4 | 0.251 |
| 6 | 10.978 | 8.0527 | 577 | 10.3 | 0.190 |
| 7 | 11.758 | 7.5203 | 978 | 17.5 | 0.178 |
| 8 | 12.778 | 6.9221 | 365 | 6.5 | 0.186 |
| 9 | 14.298 | 6.1895 | 565 | 10.1 | 0.233 |
| 10 | 14.701 | 6.0206 | 428 | 7.7 | 0.165 |
| 11 | 16.321 | 5.4266 | 4839 | 86.5 | 0.292 |
| 12 | 16.981 | 5.2172 | 498 | 8.9 | 0.134 |
| 13 | 17.980 | 4.9293 | 1110 | 19.8 | 0.319 |
| 14 | 18.180 | 4.8758 | 1421 | 25.4 | 0.532 |
| 15 | 18.660 | 4.7512 | 4455 | 79.6 | 0.432 |
| 16 | 18.860 | 4.7013 | 3247 | 58.0 | 0.243 |
| 17 | 19.189 | 4.6215 | 636 | 11.4 | 0.100 |
| 18 | 20.179 | 4.3969 | 797 | 14.2 | 0.529 |
| 19 | 20.720 | 4.2833 | 2355 | 42.1 | 0.315 |
| 20 | 22.019 | 4.0335 | 5594 | 100.0 | 0.306 |
| 21 | 22.219 | 3.9976 | 2598 | 46.4 | 0.595 |
| 22 | 23.121 | 3.8436 | 761 | 13.6 | 0.563 |
| 23 | 23.640 | 3.7604 | 2729 | 48.8 | 0.460 |
| 24 | 23.858 | 3.7265 | 2189 | 39.1 | 0.547 |
| 25 | 24.638 | 3.6103 | 654 | 11.7 | 0.168 |
| 26 | 25.339 | 3.5120 | 1235 | 22.1 | 0.276 |
| 27 | 25.721 | 3.4607 | 445 | 8.0 | 0.215 |
| 28 | 26.299 | 3.3859 | 414 | 7.4 | 0.352 |
| 29 | 26.518 | 3.3585 | 550 | 9.8 | 0.354 |
| 30 | 26.879 | 3.3142 | 493 | 8.8 | 0.249 |
| 31 | 27.620 | 3.2270 | 1316 | 23.5 | 0.274 |
| 32 | 28.799 | 3.0974 | 719 | 12.9 | 0.655 |
| 33 | 29.319 | 3.0437 | 827 | 14.8 | 0.654 |
| 34 | 30.800 | 2.9006 | 565 | 10.1 | 0.319 |
| 35 | 31.242 | 2.8606 | 430 | 7.7 | 0.207 |
| 36 | 32.341 | 2.7659 | 867 | 15.5 | 0.232 |
| 37 | 33.218 | 2.6948 | 719 | 12.9 | 0.313 |
| 38 | 33.781 | 2.6512 | 565 | 10.1 | 0.245 |
| 39 | 34.181 | 2.6211 | 1029 | 18.4 | 0.267 |
| 40 | 36.646 | 2.4502 | 325 | 5.8 | 0.557 |
| 41 | 37.140 | 2.4187 | 376 | 6.7 | 0.252 |
| 42 | 37.522 | 2.3950 | 478 | 8.5 | 0.306 |
| 43 | 39.397 | 2.2852 | 356 | 6.4 | 0.427 |
Claims (87)
1. crystalline levosalbutamol sulphate (form I) is characterized in that powder X-ray RD pattern has the peak at 10.8,11.9,13.0,18.3,28.5 ± 0.2 degree, 2 θ places.
2. the crystalline levosalbutamol sulphate of claim 1, it basically as shown in Figure 1.
3. claim 1 or 2 crystalline levosalbutamol sulphate, its feature also are to have basically IR collection of illustrative plates as shown in Figure 2.
4. each crystalline levosalbutamol sulphate in the claim 1 to 3 is characterized in that the peak of powder X-ray RD pattern is as shown in table 1 basically.
5. the crystalline levosalbutamol sulphate of claim 1 (form II) is characterized in that powder X-ray RD pattern has the peak at 8.7,9.6,15.2,15.7,19.1,27.2,30.7 ± 0.2 degree, 2 θ places.
6. the crystalline levosalbutamol sulphate of claim 5, it basically as shown in Figure 3.
7. claim 5 or 7 crystalline levosalbutamol sulphate, its feature also are to have basically IR collection of illustrative plates as shown in Figure 4.
8. each crystalline levosalbutamol sulphate in the claim 5 to 7 is characterized in that the peak of powder X-ray RD pattern is as shown in table 2 basically.
9. crystalline levosalbutamol sulphate (form III) is characterized in that powder X-ray RD pattern has the peak at 5.5,6.9,7.3,18.7 ± 0.2 degree, 2 θ places.
10. the crystalline levosalbutamol sulphate of claim 9, it basically as shown in Figure 5.
11. the crystalline levosalbutamol sulphate of claim 9 or 10, its feature also are to have basically IR collection of illustrative plates as shown in Figure 6.
12. each crystalline levosalbutamol sulphate in the claim 9 to 11 is characterized in that the peak of powder X-ray RD pattern is as shown in table 3 basically.
13. be used for preparing each the method for crystalline levosalbutamol sulphate form I of claim 1 to 4, it comprises: a) levosalbutamol of preparation in organic solvent; B) regulate pH by adding sulfuric acid at 0 to 10 ℃; C) at 0 to 10 ℃ of separated product (form I).
14. the method for claim 13, wherein said organic solvent are alcoholic solvent.
15. the method for claim 14, wherein said solvent comprise methylated spirits or methyl alcohol or both mixtures.
16. claim 13,14 or 15 method, wherein in step b), with pH regulator to 5-5.5.
17. be used for preparing each the method for crystalline levosalbutamol sulphate form II of claim 5 to 8, it comprises: a) that any type of levosalbutamol sulphate is water-soluble; B) be distilled into residue; C) with this residue of organic solvent stripping; D) with solid slurrying in organic solvent; E) isolation of crystalline form II.
18. the method for claim 17, wherein step a) comprises crystalline levosalbutamol sulphate form I or form III soluble in water.
19. the method for claim 17 or 18, wherein in step c) or step d) or both, described solvent is an acetone.
20. be used for preparing each the method for crystalline levosalbutamol sulphate form III of claim 9 to 12, it comprises: a) levosalbutamol of preparation in organic solvent; B) regulate pH by adding sulfuric acid at 25 to 30 ℃; C) at 25 to 30 ℃ of separated products (form III).
21. the method for claim 20, wherein said organic solvent are alcoholic solvent.
22. the method for claim 21, wherein said solvent comprise methylated spirits or methyl alcohol or both mixtures.
23. claim 20,21 or 22 method, wherein in step b), with pH regulator to 5-5.5.
24. be used for preparing each the method for crystalline levosalbutamol sulphate form I of claim 1 to 4, it comprises: a) that any type of levosalbutamol sulphate is water-soluble; B) will from the solution of step a) with can mix with the miscible organic solvent of water, thereby the precipitation of generation; C) unpack format I therefrom.
25. the method for claim 24, wherein said can be methyl alcohol with the miscible organic solvent of water.
26. the method for claim 24 or 25 wherein before step c), is cooled to 0 ℃ to 5 ℃ with solution.
27. be used for preparing each the method for crystalline levosalbutamol sulphate form II of claim 5 to 8, it comprises the levosalbutamol sulphate of any other form of comminution by gas stream.
28. the method for claim 27, wherein with crystalline levosalbutamol sulphate form I comminution by gas stream to obtain described form II.
29. be used for preparing each the method for crystalline levosalbutamol sulphate form III of claim 9 to 12, it comprises: a) that any type of levosalbutamol sulphate is water-soluble; B) will from the solution of step a) with can mix with the miscible organic solvent of water, thereby the precipitation of generation; C) unpack format III therefrom at ambient temperature.
30. the method for claim 29, wherein said can be acetone with the miscible organic solvent of water.
31. the method for claim 29 or 30, wherein said method is carried out under 25 ℃ to 30 ℃.
32. pharmaceutical composition, it comprises in the claim 1 to 12 each compound and pharmacology acceptable carrier.
33. pharmaceutical composition, it comprises in the claim 1 to 12 each compound, and also combination has one or more pharmacologic activity compounds and optional pharmacology acceptable carrier.
34. the pharmaceutical composition of claim 33, wherein said other active compound are one or more in fluticasone propionate, beclometasone, budesonide, ipratropium bromide, Transbroncho or the theophylline.
35. each compound or claim 32 in the claim 1 to 12,33 or 34 composition, it is as medicine.
36. the compound of claim 35 or composition, it is used for the treatment of respiratory disease and associated conditions.
37. a combination, it comprises in the claim 1 to 12 each compound, one or more pharmacologic activity compounds and optional at least a pharmacology acceptable carrier; It is used for simultaneously, uses respectively or in succession.
38. pharmaceutical composition, it comprises the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic, glucocorticosteroid and pharmacology acceptable carrier or vehicle and one or more optional other therapeutical agents.
39. the pharmaceutical composition of claim 38, wherein said glucocorticosteroid are fluticasone propionate, beclometasone or budesonide.
40. the pharmaceutical composition of claim 38 or 39, the effective isomer of salbutamol of wherein said treatment are levosalbutamol or its salt, solvate, ester, derivative or polymorphic.
41. the pharmaceutical composition of claim 40, the salt of wherein said levosalbutamol is selected from: levosalbutamol sulphate, levalbuterol hydrochloride or tartrate levosalbutamol.
42. the pharmaceutical composition of claim 40 or 41, the salt of wherein said levosalbutamol are levosalbutamol sulphate.
43. the pharmaceutical composition of claim 42, wherein levosalbutamol sulphate exists as each levosalbutamol sulphate in the claim 1 to 12, and perhaps the mixture as two or more claimed compounds exists.
44. each pharmaceutical composition in the claim 38 to 43, it comprises the acceptable vehicle of suitable pharmacology, to form aerosol formulation, dry powder formulations or solution for inhalation/suspensoid.
45. each pharmaceutical composition in the claim 38 to 44, wherein said drug regimen are levosalbutamol sulphate and fluticasone propionate.
46. each pharmaceutical composition in the claim 38 to 44, wherein said drug regimen are levosalbutamol sulphate and beclometasone.
47. each pharmaceutical composition in the claim 38 to 44, wherein said drug regimen are levosalbutamol sulphate and budesonide.
48. each pharmaceutical composition in the claim 38 to 47, also comprise the propellent that is selected from following group: propellent 11, propellent 12, propellent 114,1,1,1,2-Tetrafluoroethane (HFA134a) and 1,1,1,2,3,3, the mixture of 3-heptafluoro-propane (HFA227) or two or more described halohydrocarbon.
49. the pharmaceutical composition of claim 48, wherein said propellent comprise at least a propellent in propellent 11, propellent 12 or the propellent 114.
50. the pharmaceutical composition of claim 49 wherein will be treated effectively levosalbutamol isomer and glucocorticosteroid and propellent 11, propellent 114 or its combined hybrid through grinding.
51. claim 48,49 or 50 pharmaceutical composition, also comprises surfactant.
52. the pharmaceutical composition of claim 51, wherein said tensio-active agent is: oil, as Semen Maydis oil, sweet oil, Oleum Gossypii semen and sunflower seed oil; Mineral oil such as whiteruss; Oleic acid; Phosphatide such as Yelkin TTS; Or fatty acid esters of sorbitan such as Span-80; Or the mixture of two or more wherein.
53. the pharmaceutical composition of claim 51 or 52, wherein said surfactant concentrations are the 0.001-100% of active substance weight.
54. the pharmaceutical composition of claim 53, wherein said surfactant concentrations are the 1-50% of active substance weight.
55. the pharmaceutical composition of claim 54, wherein said surfactant concentrations are the 5-30% of active substance weight.
56. the pharmaceutical composition of claim 48, wherein said propellent comprises: 1,1,1, and 2-Tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination.
57. the pharmaceutical composition of claim 56, it comprises at least a solubility promoter.
58. the pharmaceutical composition of claim 57, wherein said solubility promoter are glycol, as propylene glycol or polyoxyethylene glycol; Glycerine or ethanol, or the mixture of two or more wherein.
59. the pharmaceutical composition of claim 57 or 58, the content of wherein said solubility promoter are 0.01 to 5% of composition weight.
60. claim 56,57,58 or 59 pharmaceutical composition, its also comprises surfactant.
61. the pharmaceutical composition of claim 60, wherein said tensio-active agent are selected from following group: Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, Isopropyl myristate, oleic acid, Brij, ethyl oleate, triolein, glyceryl monolaurate, XU 61518.10, glyceryl monostearate, single ricinoleic acid glyceryl ester, hexadecanol, stearyl alcohol, the hexadecyl chloropyridine, block polymer, natural oil, polyvinylpyrrolidone, fatty acid esters of sorbitan such as sorbitan trioleate, the fatty acid esters of sorbitan of polyethoxylated such as the sorbitan trioleate of polyethoxylated, sorbimacrogol oleate, synthetic amphotenside (tritons), the oxyethane ether of octyl phenol formaldehyde condensation products, phosphatide such as Yelkin TTS, the fat of polyethoxylated, the triolein of polyethoxylated and the Fatty Alcohol(C12-C14 and C12-C18) of polyethoxylated.
62. the pharmaceutical composition of claim 60 or 61, wherein said surfactant concentrations are the 0.02-10% of active substance weight.
63. each pharmaceutical composition in the claim 56 to 62 also comprises weighting agent.
64. the pharmaceutical composition of claim 63, wherein said weighting agent is selected from following group: sugar comprises monose, disaccharides, polysaccharide and sugar alcohol such as pectinose, glucose, fructose, ribose, seminose, sucrose, trehalose, lactose, maltose, starch, dextran or N.F,USP MANNITOL.
65. the pharmaceutical composition of claim 63 or 64, the concentration of wherein said weighting agent are 10 to 500% of active substance weight.
66. the pharmaceutical composition of claim 65, the concentration of wherein said weighting agent are 10 to 300% of active substance weight.
67. each pharmaceutical composition in the claim 56 to 66, it comprises the tensio-active agent that is selected from following group: stearic salt, or ester such as Quicifal, Isopropyl myristate and Renascin.
68. each pharmaceutical composition in the claim 56 to 67 wherein grinds every kind of medicine.
69. each pharmaceutical composition in the claim 38 to 47, it is the form of dry powder formulations.
70. the pharmaceutical composition of claim 69, wherein except active substance, described composition also comprises the acceptable vehicle of pharmacology of the composition that is fit to be formed for Diskus.
71. the pharmaceutical composition of claim 69 or 70, wherein except active substance, described composition also comprises pharmacology acceptable carrier in small, broken bits.
72. Diskus, it comprises in the claim 69 to 71 each composition.
73. be used to prepare the method for the Diskus of claim 72, it comprises activeconstituents is randomly mixed with suitable carriers, and described composition is provided in Diskus.
74. each pharmaceutical composition in the claim 38 to 47, it is for sucking the form of suspensoid.
75. the pharmaceutical composition of claim 74, it comprises and is fit to form the acceptable vehicle of pharmacology that sucks suspensoid.
76. the pharmaceutical composition of claim 74 or 75, except active substance, it also comprises polar solvent, tension adjustment agent, wetting agent, sequestrant and optional acid.
77. be used to prepare the method for claim 74,75 or 76 pharmaceutical composition, it comprises: activeconstituents randomly is suspended in the liquid vehicle with sequestrant, tension adjustment agent and wetting agent and other optional suitable vehicle, and randomly regulates pH.
78. be used for the method for pharmaceutical compositions, described composition is included in the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic and the glucocorticosteroid in the propellent, and this method comprises mixes described composition to form described composition.
79. the method for claim 78, it comprises: (a) will treat effective isomer of salbutamol and glucocorticosteroid and optional tensio-active agent, and propellent 11, propellent 114 or its combination are added in the jar to; (b) with suitable valve described jar is tightened; (c) charge into propellent 12 by valve.
80. the method for claim 79 wherein will be treated effective isomer of salbutamol and/or glucocorticosteroid and propellent 11, propellent 114 or its combination and be ground.
81. the method for claim 78, it comprises: (a) will treat effective isomer of salbutamol, glucocorticosteroid and optional solubility promoter or weighting agent; Tensio-active agent; Or solubility promoter and tensio-active agent add in the jar; (b) with quantitative valve jar is tightened; (c) in jar, charge into 1,1,1,2-Tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its combination.
82. the method for claim 81 wherein will be treated effective isomer of salbutamol, solubility promoter or weighting agent, tensio-active agent or solubility promoter and tensio-active agent and 1,1,1,2-Tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-seven fluoroethanes (HFA227) or its make up little grinding.
83. each composition in claim 38 to 71 or 74 to 76, it is as medicine.
84. each composition in claim 38 to 71 or 74 to 76, it is used for the treatment of respiratory disease and associated conditions, comprises bronchoconstriction, asthma and COPD.
85. be used for the treatment of Mammals such as people's respiratory disease such as asthma and cause the method for the disease of bronchoconstriction, it comprises in the claim 38 to 71 or 74 to 76 of administering therapeutic significant quantity each pharmaceutical composition.
86. the treatment that is combined among long-term control asthma and the COPD of salbutamol or acceptable salt of its physiology and glucocorticosteroid is used.
87. a combination, it comprises the effective isomer of salbutamol of treatment or its salt, solvate, ester, derivative or polymorphic, and glucocorticosteroid and optional at least a pharmacology acceptable carrier; It is used for simultaneously, uses respectively or in succession.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1356MU2004 | 2004-12-17 | ||
| IN1356/MUM/2004 | 2004-12-17 | ||
| IN40MU2005 | 2005-01-14 | ||
| IN40/MUM/2005 | 2005-01-14 | ||
| IN343/MUM/2005 | 2005-03-24 | ||
| IN343MU2005 | 2005-03-24 | ||
| PCT/GB2005/004935 WO2006064283A1 (en) | 2004-12-17 | 2005-12-19 | Pharmaceutical compounds and compositions |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102166213A (en) * | 2009-11-12 | 2011-08-31 | 北京利乐生制药科技有限公司 | Composition using levalbuterol and ipratropium bromide as active ingredients |
| WO2012041031A1 (en) * | 2010-09-28 | 2012-04-05 | 健乔信元医药生技股份有限公司 | Compound composition for inhalation used for treating asthma |
| CN105001100A (en) * | 2015-06-11 | 2015-10-28 | 山西云鹏制药有限公司 | Method for refining salbutamol sulfate |
| CN112691088A (en) * | 2020-09-16 | 2021-04-23 | 苏州君宁新药开发中心有限公司 | Method for delivering levalbuterol to lung by inhalation of dry powder |
-
2005
- 2005-12-19 ZA ZA200704378A patent/ZA200704378B/en unknown
- 2005-12-19 CN CN2005800484390A patent/CN101124198B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102166213A (en) * | 2009-11-12 | 2011-08-31 | 北京利乐生制药科技有限公司 | Composition using levalbuterol and ipratropium bromide as active ingredients |
| WO2012041031A1 (en) * | 2010-09-28 | 2012-04-05 | 健乔信元医药生技股份有限公司 | Compound composition for inhalation used for treating asthma |
| US8877740B2 (en) | 2010-09-28 | 2014-11-04 | Intech Biopharm Ltd. | Compound composition for inhalation used for treating asthma |
| AU2011307899B2 (en) * | 2010-09-28 | 2015-03-12 | Intech Biopharm Ltd. | Compound composition for inhalation used for treating asthma |
| CN105001100A (en) * | 2015-06-11 | 2015-10-28 | 山西云鹏制药有限公司 | Method for refining salbutamol sulfate |
| CN112691088A (en) * | 2020-09-16 | 2021-04-23 | 苏州君宁新药开发中心有限公司 | Method for delivering levalbuterol to lung by inhalation of dry powder |
| WO2022057839A1 (en) * | 2020-09-16 | 2022-03-24 | 苏州君宁新药开发中心有限公司 | Use of dry powder inhalation formulation prepared from levosalbutamol sulfate |
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| CN101124198B (en) | 2013-04-10 |
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