CN101124198B - Medicine compound and composition - Google Patents

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 ora 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 inhalationsuspensions may be used.

Description

Medical compounds and composition

Technical field

The present invention relates to crystal sulfuric acid Levalbuterol, its polymorphic, for the preparation of method and the composition thereof of described crystalline substance.

The present invention relates to comprise the pharmaceutical composition of the effective isomer of salbutamol for the treatment of 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 usually 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 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).The fugitive beta-2-adrenoceptor of recommendation such as salbutamol and terbutaline are alleviated acute symptom, and preferably depot drug product such as Salmeterol, formoterol and bambuterol and other medicines combination are used for long-term asthma control.

Chronic obstructive pulmonary disease (COPD) is can prevent and medicable morbid state, it is characterized in that not exclusively reversible pneumatic restriction.COPD (chronic obstructive pulmonary disease) is for the term (umbrella term) of describing 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 be used to the pillar therapy with patient that chronic obstructive pulmonary disease (COPD) occurs, 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 for albuterol inhalation solution, system, test kit and the method for alleviating bronchospasm the children that suffer from asthma, wherein comprises about 0.63mg to about 1.25mg salbutamol.

US 6,251,368 relate to following medicinal aerosol formulations, it comprises specific medication and fluorocarbon or the hydrogeneous Chlorofluorocarbons propellent that is selected from the 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 the method is used optically pure salbutamol R (-) isomer, it does not comprise S (+) isomer basically, is for the effective bronchodilator of alleviating 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 for the acquisition salbutamol.

The several method for the preparation of Levalbuterol has been described in existing field, and for example the Application No. 20040115136 of KingCode has been described the method for the preparation of the tartrate Levalbuterol.It also relates to and has the L-TARTARIC ACID 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 for postponing 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 enantioselectivity sexual orientation of salbutamol 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 preparing from the salbutamol precursor of single protection the pure salbutamol of optically-active.

US2004114136 and WO2004052835 have described the method for the preparation of the L-TARTARIC ACID Levalbuterol of crystalline form; The pharmaceutical composition that comprises the L-TARTARIC ACID Levalbuterol of crystalline form; The metered-dose inhaler that comprises tank comprises the aerosol formulation of the L-TARTARIC ACID Levalbuterol of crystalline form in the tank; With use the L-TARTARIC ACID Levalbuterol, comprise that especially the L-TARTARIC ACID Levalbuterol of crystalline form is realized the bronchiectasic method of patient.

Carry at charcoal in 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.Only having 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 to treat in the different pharmaceutical kind 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 namely the form of micronized powder is mixed with at the suspensoid of aqueous phase and uses, 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 patients with lower respiratory tract is from the size of installing the particle that occurs.In order to ensure effectively infiltrating bronchiole and alveolar, 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 to have the particle of higher MMAD.

Learn that from GB2088877 itself has anti-inflammatory activity fluticasone propionate, can be used for treating 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 the acceptable solvate forms of physiology.

HK1009406 relates to for the metered-dose inhaler that distributes the Sucked medicine preparation, described preparation comprises fluticasone propionate or the acceptable solvate of its physiology 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 simultaneously 1,1,1,2,3,3,3-, seven fluoro-n-propanes as propellent, and said preparation does not comprise tensio-active agent.Described preparation also can comprise salbutamol, and comprises and be suitable for passing the tank of 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 hydrogeneous 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 for the treatment of 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 for the treatment of 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 for the treatment of or its salt, solvate, ester, derivative or polymorphous pharmaceutical composition, and described composition can be avoided the side effect relevant with higher racemoid dosage.

Also purpose of the present invention is the method for the preparation of following pharmaceutical composition, and described composition comprises the effective isomer of salbutamol for the treatment of, 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 the method comprises the pharmaceutical composition of the present invention of administering therapeutic significant quantity.

An object of the present invention is to provide the method that comprises the side effect of drug regimen in patient body of at least two kinds of medicines for minimizing, the 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.

Method for the preparation of following pharmaceutical composition also is provided, described composition comprises the effective isomer of salbutamol for the treatment of or its salt, solvate, ester, derivative or polymorphic, and combination has glucocorticoid medicine, and at least a pharmacology acceptable carrier, the 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 the method comprises the pharmaceutical composition of the present invention of administering therapeutic significant quantity.

Known beta-2-adrenoceptor can by acting on the beta-2-adrenoceptor in airway smooth muscle and the bronchial smooth muscle, for the patient provides bronchodilator effect, thereby be alleviated the shortness of breath symptom.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 faster onset, 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 only having 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 ₂Large 100 times than (S)-salbutamol of the binding affinities of-acceptor.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, in 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 producing suitable effect near racemic salbutamol 1/4th dosage places, reduce the side effect of β-mediation simultaneously.

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 in the Inhalation in Treating.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 such 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 the R form by the use 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 the side effect relevant with 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, levosalbutamol tartrate, 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 obvious 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 obvious amount.Suitably, the content of described isomer will be not more than the activity of 10 % by weight, more preferably 1 % by 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 simultaneously combination 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 (such as sodium salt).The combination of salbutamol and fluticasone propionate or beclometasone or budesonide is preferred.With understanding for the composition that can suck such as aerosol formulation, will can the suction form provide described activeconstituents with suitable.

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, consist of 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 provides (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 provides (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 for the preparation of form I, II and III.

Method for the preparation of crystalline levosalbutamol sulphate form I comprises: a) prepare levosalbutamol in organic solvent; B) by adding the sulphur acid for adjusting pH at 1 to 10 ℃; C) at 0 to 10 ℃ of separated product (form I).

Method for the preparation of crystalline levosalbutamol sulphate form I comprises: a) that any form of levosalbutamol sulphate is water-soluble; B) will from step solution a) with can merge with the miscible organic solvent of water, thereby the precipitation of generation; C) unpack format I therefrom.

Method for the preparation of 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.

Comprise any other form of comminution by gas stream (jet milling) levosalbutamol sulphate, for example comminution by gas stream crystalline form I for the preparation of other method of form II.

Method for the preparation of crystalline levosalbutamol sulphate form III comprises: a) prepare levosalbutamol in organic solvent; B) by adding the sulphur acid for adjusting pH at 25 to 30 ℃; C) at 25 to 30 ℃ of separated products (form III).

Another kind of method for the preparation of form III comprises: a) that any form of levosalbutamol sulphate is water-soluble; B) will from step solution a) with can merge with the miscible organic solvent of water, thereby the precipitation of generation; 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

) 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.Then preferred filtering catalyst, preferably 0-10 ℃ with sulfuric acid, preferably with the vitriol oil pH of filtrate preferably is adjusted to 5-5.5, 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 8.701,9.636,15.180,15.657,19.139,27.199,30.702 ± 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.

Comprise any form of levosalbutamol sulphate is water-soluble and it is distilled into residue for the preparation of the method for levosalbutamol sulphate crystalline form II.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 by filtration, and vacuum-drying is to obtain levosalbutamol sulphate form II.

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 organic solvent of ethanol, 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 at ambient temperature (25 to 30 ℃) and regulate pH and (25 to 30 ℃) separated product at ambient temperature, separable form III.Preferably by filtering catalyst and washing, for example with the methylated spirits washing, implement these steps.(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.

Another kind of method for the preparation of 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 according to the manufacturing course of routine these preparations.

Particularly, compound of the present invention can be learned the active compound combination with one or more other medicines, and this will be obvious to those skilled in the art.Can use any suitable active substance combination, 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 with any suitable form, comprise its pharmacology acceptable derivates, comprise salt, ester, polymorphic, optically active form and racemoid.

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 by inhalation route, thus the general action that the local action of significant quantity is provided and therefore avoids being harmful to.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 inhaled 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, the mixture of 3,3,3-heptafluoro-propane (HFA227) or two or more described halohydrocarbon.

Can be prepared as follows aerosol formulation of the present invention:, in suitable container, medicine is dispersed in the selected propellent for example by means of ultrasonic.Hope is implemented the method under anhydrous condition, to avoid moisture to any deleterious effect of suspensoid stability.

Preparation of the present invention can form the slightly suspension of flocculation after placement, even but surprisingly find after long storage, these suspension still can by mild agitation redispersion easily, be applicable to pressurize the good suspension of passing the medicine feature of having of sucker to provide.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 can there is no taste and smell, 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 inhaled, 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, inhaled, 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, such as oil, such 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 relatively good suspended load discharge.In the situation that is used in combination levosalbutamol sulphate and beclometasone, preferred tensio-active agent is 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%.The concentration of tensio-active agent 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 affect in the aerosol through sending the ratio for the active substance that sucks.

In another experiment, with medicine and propellent 11 or propellent 114 or its combined hybrid, be filled in the tank, tighten (crimped) and be filled with 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, then are filled in the tank, and are filled with 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 for the preparation of following pharmaceutical composition, said composition comprises the effective isomer of salbutamol for the treatment of or its salt, solvate, ester, derivative or polymorphic and glucocorticosteroid in propellent, described method comprises mixes to form described composition with described composition.

In other embodiments of the present invention, method for the preparation of following medicinal aerosol composition is provided, 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 tank with propellent 11, propellent 114 or its combination; (b) with suitable valve tank is tightened; (c) be filled with 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 for the treatment of 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-HFA-227ea (HFA227) or its combination.

Provide the method for the preparation of above-mentioned aerosol combination also on the one hand of the present invention, the method comprises: (a) the effective isomer of salbutamol for the treatment of and glucocorticosteroid are added in the tank; (b) with quantitative valve tank is tightened; (c) in tank, be filled with HFA 134a (HFA134a), 1,1,1,2,3,3,3-HFA-227ea (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 for the treatment of or its salt, solvate, ester, derivative or polymorphic and glucocorticosteroid, and 1,1,1,2-Tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-HFA-227ea (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 such as ethanol.Typically, solubility promoter is ethanol.

Of the present invention preferred aspect, the method for the preparation of above-mentioned composition is provided, the method comprises: (a) two kinds of medicines are added in the tank; (b) in (a), add solubility promoter and ultrasonic; (c) with quantitative valve tank is tightened; (d) in tank, be filled with HFA 134a (HFA134a) or 1,1,1,2,3,3,3-HFA-227ea (HFA227) or its combination.

In going back a preferred embodiment, aerosol combination can comprise the effective isomer of salbutamol for the treatment of 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-HFA-227ea (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 the 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 for the preparation of above-mentioned composition, the method comprises: (a) medicine is added in the tank; (b) in (a), add solubility promoter and tensio-active agent and ultrasonic; (c) with quantitative valve tank is tightened; (d) in tank, be filled with HFA 134a (HFA134a) or 1,1,1,2,3,3,3-HFA-227ea (HFA227) or its combination.

In also one side of the present invention, aerosol combination can comprise the effective isomer of salbutamol for the treatment of, 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 for the preparation of above-mentioned aerosol combination is provided, the method comprises: (a) activeconstituents is added in the tank; (b) to (a) middle absorb fillers; (c) with quantitative valve tank is tightened; (d) in tank, be filled with 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-HFA-227ea (HFA227) or its combination.Tensio-active agent can be any suitable tensio-active agent, and for example listed above those 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 active substance gross weight.

Of the present invention preferred aspect, the method for the preparation of above-mentioned aerosol combination is provided, the method comprises: (a) medicine is added in the tank; (b) in (a), add tensio-active agent; (c) with quantitative valve tank is tightened; (d) in tank, be filled with HFA 134a (HFA134a) or 1,1,1,2,3,3,3-HFA-227ea (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, such as pectinose, glucose, fructose, ribose, seminose, sucrose, trehalose, lactose, maltose, starch, dextran or N.F,USP MANNITOL.Particularly preferred carrier is 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 for the preparation of the Diskus that comprises levosalbutamol and glucocorticosteroid also is provided, the method comprises randomly mixes activeconstituents with suitable carrier, and provides described composition in suitable Diskus.

For solution for inhalation, described medicine can be in suitable carrier and suitable vehicle such as tension adjustment agent, pH adjusting agent, sequestrant, wetting agent combination.Preferred powerful adjusting agent is sodium-chlor.PH adjusting 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 obvious 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 for the preparation of the solution for inhalation that comprises levosalbutamol and glucocorticosteroid.The method preferably includes the following step:

1. levosalbutamol and isotonic agent, sequestrant and wetting agent are dissolved in the purified water, then filter.

2. in another container, that glucocorticosteroid is ultrasonic in the water of part amount, then by suitable sterilising method sterilization.

3. above-mentioned two kinds of solution are mixed, so that final suction suspensoid to be provided, regulate pH (if necessary).Suspensoid is filled with 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 the 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 the asthma that is used for the treatment of Mammals such as people and the method that causes the disease of bronchoconstriction, and the 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 to 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 for explanation the present invention, is used for absolutely not limiting the scope of the invention.

Embodiment 1:CFC sucker

A)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	10.08mg
2.	Fluticasone propionate (little grinding)	8.24mg
			3.	Yelkin TTS 10%	1.832mg
4.	Propellent 11	3.0gms
			5.	Propellent 12	7.7gms

(a) add levosalbutamol sulphate and Yelkin TTS and propellent 11;

(b) slurry is filled with in the tank;

(c) with suitable valve tank is tightened; With

(d) be filled with propellent 12 by valve.

B)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	15.12mg
2.	Beclometasone (50mcg)	12mg
			3.	Oleic acid 10%	2.712mg
4.	Propellent 11	4.7gms
			5.	Propellent 12	11.6gms

A) add medicine and oleic acid and propellent 11;

B) slurry is filled with in the tank;

C) with suitable valve tank is tightened; With

D) be filled with propellent 12 by valve.

C)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	10.08mg
2.	Budesonide	24mg
			3.	Yelkin TTS 10%	3.40mg
4.	Propellent 11	4.7gms
			5.	Propellent 12	11.6gms

A) add medicine and Yelkin TTS and propellent 11;

B) slurry is filled with in the tank;

C) with suitable valve tank is tightened; With

D) be filled with propellent 12 by valve.

Embodiment 2:HFA sucker

A)

Sr.No	Composition	Amount/tank
			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 tank;

B) with quantitative valve tank is tightened;

C) in tank, be filled with HFA 134a (HFA134a).

B)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	15.12mg
2.	Beclometasone (50mcg)	12mg
			3.	Abs.Alc.2.5％	0.455
4.	HFA 134a	17.74gms

A) two kinds of medicines, pure and mild part HFA134a are added in the tank;

B) tank is tightened also ultrasonic with quantitative valve;

C) in tank, be filled with HFA 134a (HFA134a).

C)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	10.08mg
2.	Budesonide (100mcg)	24mg
			3.	HFA 134a	18.2gms

A) two kinds of medicines are added in the tank;

B) with quantitative valve tank is tightened;

C) in tank, be filled with HFA 134a (HFA134a).

Embodiment 3:HFA sucker

A)

Sr.No	Composition	Amount/tank
			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 tank;

B) with quantitative valve tank is tightened;

C) in tank, be filled with 1,1,1,2,3,3,3-HFA-227ea (HFA227).

B)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	10.08mg
2.	Budesonide	24mg
			3.	HFA227	20.6gms

A) two kinds of medicines are added in the tank;

B) with quantitative valve tank is tightened;

C) in tank, be filled with 1,1,1,2,3,3,3-HFA-227ea (HFA227).

Embodiment 4:HFA sucker

A)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	10.08mg
2.	Fluticasone propionate (little grinding)	8.24mg
			3.	Abs.Alc.2％	0.256
4.	Yelkin TTS 0.02%	0.003664mg
			5.	HFA 134a	12.54gms

A) two kinds of medicines are added in the tank;

B) pure and mild surfactant soln is added in (a) and ultrasonic;

C) with quantitative valve tank is tightened;

D) in tank, be filled with HFA 134a (HFA134a).

B)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	15.12mg
2.	Beclometasone (50mcg)	12mg
			3.	Abs.Alc.2.5％	0.455
4.	Oleic acid 0.02%	0.00542
			5.	HFA 134a	17.74gms

A) two kinds of medicines are added in the tank;

B) pure and mild surfactant soln is added in (a) and ultrasonic;

C) with quantitative valve tank is tightened;

D) in tank, be filled with HFA 134a (HFA134a).

C)

Sr.No	Composition	Amount/tank
			1.	Levosalbutamol sulphate	10.08mg
2.	Budesonide	24mg
			3.	Abs.Alc.2％	0.364
4.	Yelkin TTS 0.02%	0.006816mg
			5.	HFA 134a	17.83gms

A) two kinds of medicines are added in the tank;

B) pure and mild surfactant soln is added in (a) and ultrasonic;

C) with quantitative valve tank is tightened;

D) in tank, be filled with HFA 134a (HFA134a).

Embodiment 5: the dry powder that is used for suction

Sr.No	Composition	mg/cap
			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.	EDETATE SODIUM	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, then filter.

2. in another container, that glucocorticosteroid is ultrasonic in the water of part amount, then by suitable sterilising method sterilization.

3. above-mentioned two kinds of solution are mixed, so that final suction suspensoid to be provided, and regulate pH (if necessary).Suspensoid is filled with 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 filled with 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-(-)-Albuterol form I (19.0kg.).

Embodiment 8

R-benzyl salbutamol (10.0kg.), methyl alcohol (30.0ltr.), methylated spirits (36ltrs.) are filled with 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.At ambient temperature (25 to 30 ℃), 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-(-)-Albuterol form III (19.0kg.).

Embodiment 9

In sulfuric acid R-(-)-Albuterol (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-(-)-Albuterol form II (11.1kg.).

Embodiment 10

In sulfuric acid R-(-)-Albuterol (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-(-)-Albuterol form I (8kg.).

Embodiment 11

In sulfuric acid R-(-)-Albuterol (20Kg) water-soluble (60.0ltrs.), filter to obtain settled solution, slowly be filled with 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-(-)-Albuterol form III (17kg.).

Embodiment 12

In sulfuric acid R-(-)-Albuterol (10gms) water-soluble (30ml).Be filled with 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, the sulfuric acid R-(-)-Albuterol is dissolved in methyl alcohol.Then with the reactant cool to room temperature, further be cooled to 5-10 ℃.With the gained solid filtering and 80 ℃ of dryings, to obtain sulfuric acid R-(-)-Albuterol form II.

Embodiment 14

I carries out comminution by gas stream to sulfuric acid R-(-)-Albuterol form, and to obtain sulfuric acid R-(-)-Albuterol 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-(-)-Albuterol form all can be used as raw material.

Table 1

Table 2

Table 3

Claims (69)

1. crystalline levosalbutamol sulphate form II is characterized in that powder X-ray RD pattern basically as shown in Figure 3.

2. the crystalline levosalbutamol sulphate of claim 1 is further characterized in that to have basically as shown in Figure 4 IR collection of illustrative plates.

3. each crystalline levosalbutamol sulphate in the claim 1 to 2 is characterized in that the peak of powder X-ray RD pattern is basically as shown in the table

4. for the preparation of the method for each crystalline levosalbutamol sulphate form II in the claims 1 to 3, it comprises: a) that any type of levosalbutamol sulphate is water-soluble; B) be distilled into residue; C) this residue of organic solvent stripping that usefulness can be miscible with water; D) with solid can with slurrying in the miscible organic solvent of water; E) isolation of crystalline form II.

5. the method for claim 4, wherein step a) comprise crystalline levosalbutamol sulphate form I or form III soluble in water, wherein said form I is characterised in that powder X-ray RD pattern is 10.781,11.941,13.002,18.341,28.541 ± 0.2 and 12.66,15.819,17.4,20.939,21.72,22.5,23.14,24.341,26.12,31.28,31.93 there is the peak at ± 0.2 degree 2 θ places, and described form III is characterised in that powder X-ray RD pattern is 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 there is the peak at ± 0.2 degree 2 θ places.

6. claim 4 or 5 method are wherein at step c) or steps d) or both in, described solvent is acetone.

7. pharmaceutical composition, it comprises in the claims 1 to 3 each compound and pharmacology acceptable carrier.

8. pharmaceutical composition, it comprises in the claims 1 to 3 each compound, also combination has one or more pharmacologic activity compounds and optional pharmacology acceptable carrier, and wherein said pharmacologic activity compound is one or more in fluticasone propionate, beclometasone, budesonide, ipratropium bromide, Transbroncho or the theophylline.

In the claims 1 to 3 composition of each compound or claim 7 or 8 for the preparation of the application in the medicine for the treatment of respiratory disease and associated conditions.

10. combination, it comprises in the claims 1 to 3 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, and wherein said pharmacologic activity compound is selected from reflunomide, anticholinergic, mucolytic, theophylline, antihistaminic, anodyne and bronchodilator.

11. pharmaceutical composition, it comprises such as the described levosalbutamol sulphate of one of claim 1-3, glucocorticosteroid and pharmacology acceptable carrier or vehicle and one or more optional other therapeutical agents, and wherein said therapeutical agent is selected from reflunomide, anticholinergic, mucolytic, theophylline, antihistaminic, anodyne and bronchodilator.

12. the pharmaceutical composition of claim 11, wherein said glucocorticosteroid are fluticasone propionate, beclometasone or budesonide.

13. each pharmaceutical composition in the claim 11 to 12, it comprises the acceptable vehicle of suitable pharmacology, to form aerosol formulation, dry powder formulations or solution for inhalation/suspensoid.

14. each pharmaceutical composition in the claim 11 to 13, wherein said drug regimen are levosalbutamol sulphate and fluticasone propionate.

15. each pharmaceutical composition in the claim 11 to 13, wherein said drug regimen are levosalbutamol sulphate and beclometasone.

16. each pharmaceutical composition in the claim 11 to 13, wherein said drug regimen are levosalbutamol sulphate and budesonide.

17. each pharmaceutical composition in the claim 11 to 16 also comprises the propellent that is selected from following group: propellent 11, propellent 12, propellent 114,1,1,1,2-Tetrafluoroethane and 1,1,1,2, the mixture of 3,3,3-heptafluoro-propane or two or more described halohydrocarbon.

18. the pharmaceutical composition of claim 17, wherein said propellent comprise at least a propellent in propellent 11, propellent 12 or the propellent 114.

19. the pharmaceutical composition of claim 18 is wherein with levosalbutamol sulphate and glucocorticosteroid and propellent 11, propellent 114 or its combined hybrid through grinding.

20. claim 17,18 or 19 pharmaceutical composition, also comprises surfactant.

21. the pharmaceutical composition of claim 20, wherein said tensio-active agent is: oil, oleic acid, phosphatide or fatty acid esters of sorbitan or the mixture of two or more wherein.

22. the pharmaceutical composition of claim 21, wherein said oil are Semen Maydis oil, sweet oil, Oleum Gossypii semen or sunflower seed oil.

23. the pharmaceutical composition of claim 21, wherein said oil are mineral oil.

24. the pharmaceutical composition of claim 23, wherein said mineral oil are whiteruss.

25. the pharmaceutical composition of claim 21, wherein said phosphatide are Yelkin TTS.

26. the pharmaceutical composition of claim 21, wherein said fatty acid esters of sorbitan are Span-80.

27. the pharmaceutical composition of claim 20 or 21, the concentration of wherein said tensio-active agent are the 0.001-100% of active substance weight.

28. the pharmaceutical composition of claim 27, the concentration of wherein said tensio-active agent are the 1-50% of active substance weight.

29. the pharmaceutical composition of claim 28, the concentration of wherein said tensio-active agent are the 5-30% of active substance weight.

30. the pharmaceutical composition of claim 17, wherein said propellent comprises: HFA 134a, 1,1,1,2,3,3,3-HFA-227ea or its combination.

31. the pharmaceutical composition of claim 30, it comprises at least a solubility promoter.

32. the pharmaceutical composition of claim 31, wherein said solubility promoter are glycol; Glycerine or ethanol, or the mixture of two or more wherein.

33. the pharmaceutical composition of claim 32, wherein said glycol are propylene glycol or polyoxyethylene glycol.

34. claim 31,32 or 33 pharmaceutical composition, the content of wherein said solubility promoter is 0.01 to 5% of composition weight.

35. claim 30,31,32,33 or 34 pharmaceutical composition, its also comprises surfactant.

36. the pharmaceutical composition of claim 35, wherein said tensio-active agent are selected from following group: polysorbas20, tween 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, the fatty acid esters of sorbitan of polyethoxylated, the anhydrous sorbitol polyoxyethylene oleic acid ester, synthetic amphoterics, the oxyethane ether of octyl phenol formaldehyde condensation products, phosphatide, the fat of polyethoxylated, the triolein of polyethoxylated and the Fatty Alcohol(C12-C14 and C12-C18) of polyethoxylated.

37. the pharmaceutical composition of claim 36, wherein said fatty acid esters of sorbitan are sorbitan trioleate.

38. the pharmaceutical composition of claim 36, the fatty acid esters of sorbitan of wherein said polyethoxylated are the sorbitan trioleate of polyethoxylated.

39. the pharmaceutical composition of claim 36, wherein said phosphatide are Yelkin TTS.

40. the pharmaceutical composition of claim 35 or 36, the concentration of wherein said tensio-active agent are the 0.02-10% of active substance weight.

41. each pharmaceutical composition in the claim 30 to 40 also comprises weighting agent.

42. the pharmaceutical composition of claim 41, wherein said weighting agent are selected from following group: sugar comprises monose, disaccharides, polysaccharide and sugar alcohol.

43. the pharmaceutical composition of claim 42, wherein said monose, disaccharides, polysaccharide and sugar alcohol are pectinose, glucose, fructose, ribose, seminose, sucrose, trehalose, lactose, maltose, starch, dextran or N.F,USP MANNITOL.

44. the pharmaceutical composition of claim 41 or 42, the concentration of wherein said weighting agent are 10 to 500% of active substance weight.

45. the pharmaceutical composition of claim 44, the concentration of wherein said weighting agent are 10 to 300% of active substance weight.

46. each pharmaceutical composition in the claim 30 to 45, it comprises the tensio-active agent that is selected from following group: stearic salt, or ester.

47. the pharmaceutical composition of claim 46, wherein said ester are Quicifal, Isopropyl myristate or Renascin.

48. each pharmaceutical composition in the claim 30 to 46 wherein grinds every kind of medicine.

49. each pharmaceutical composition in the claim 11 to 16, it is the form of dry powder formulations.

50. the pharmaceutical composition of claim 49, wherein except active substance, described composition also comprises the acceptable vehicle of pharmacology of the composition that is fit to be formed for Diskus.

51. the pharmaceutical composition of claim 49 or 50, wherein except active substance, described composition also comprises pharmacology acceptable carrier in small, broken bits.

52. Diskus, it comprises in the claim 49 to 51 each composition.

53. for the preparation of the method for the Diskus of claim 52, it comprises activeconstituents is randomly mixed with suitable carrier, and described composition is provided in Diskus.

54. each pharmaceutical composition in the claim 11 to 16, it is for sucking the form of suspensoid.

55. the pharmaceutical composition of claim 54, it comprises and is fit to form the acceptable vehicle of pharmacology that sucks suspensoid.

56. the pharmaceutical composition of claim 54 or 55, except active substance, it also comprises polar solvent, tension adjustment agent, wetting agent, sequestrant and optional acid.

57. the method for the preparation of claim 54,55 or 56 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.

58. for the preparation of the method for pharmaceutical composition, described composition be included in the propellent such as the described levosalbutamol sulphate of one of claim 1-3 and glucocorticosteroid, the method comprises mixes to form described composition with described composition.

59. the method for claim 58, it comprises: (a) with described levosalbutamol sulphate and glucocorticosteroid, and optional tensio-active agent, and propellent 11, propellent 114 or its combination are added in the tank; (b) with suitable valve described tank is tightened; (c) be filled with propellent 12 by valve.

60. the method for claim 59 is wherein with described levosalbutamol sulphate and/or glucocorticosteroid and propellent 11, propellent 114 or its combination grinding.

61. the method for claim 60, it comprises: (a) with described levosalbutamol sulphate, glucocorticosteroid and optional solubility promoter or weighting agent; Tensio-active agent; Or solubility promoter and tensio-active agent add in the tank; (b) with quantitative valve tank is tightened; (c) in tank, be filled with HFA 134a, 1,1,1,2,3,3,3-HFA-227ea or its combination.

62. the method for claim 61, wherein with described levosalbutamol sulphate, solubility promoter or weighting agent, tensio-active agent or solubility promoter and tensio-active agent and HFA 134a, 1,1,1,2,3,3,3-HFA-227ea or its make up little grinding.

63. each composition is for the preparation of the application in the medicine for the treatment of respiratory disease and associated conditions in claim 11 to 51 or 54 to 56.

64. the application of claim 63, wherein said respiratory disease and associated conditions comprise bronchoconstriction, asthma and COPD.

65. each pharmaceutical composition is for the preparation of the mammiferous respiratory disease for the treatment of with cause application in the medicine of disease of bronchoconstriction in claim 11 to 51 or 54 to 56.

66. the application of claim 65, wherein said Mammals is behaved.

67. the application of claim 65, wherein said respiratory disease are asthma.

68. being combined in for the preparation of the application in the medicine of long-term control asthma and COPD of the described crystalline levosalbutamol sulphate of one of claim 1-3 and glucocorticosteroid.

69. a combination, it comprises the described levosalbutamol sulphate such as one of claim 1-3, and glucocorticosteroid and optional at least a pharmacology acceptable carrier; It is used for simultaneously, uses respectively or in succession.

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