CN101233141A - Ascomycin crystalline forms and preparation thereof - Google Patents
Ascomycin crystalline forms and preparation thereof Download PDFInfo
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- CN101233141A CN101233141A CNA2005800413605A CN200580041360A CN101233141A CN 101233141 A CN101233141 A CN 101233141A CN A2005800413605 A CNA2005800413605 A CN A2005800413605A CN 200580041360 A CN200580041360 A CN 200580041360A CN 101233141 A CN101233141 A CN 101233141A
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Abstract
The present invention provides novel crystalline forms of ascomycin as well as processes for the preparation thereof and pharmaceutical compositions comprising such crystalline forms of ascomycin.
Description
Related application
60/709160 the rights and interests of submitting to 17,60/705681 and 2005 on Augusts of submitting to 3,60/662440,2005 on Augusts of submitting to 16,60/641869,2005 on the March of submitting to 5,60/641868,2005 on the January of submitting to 5,60/641697,2005 on the January of submitting to 5,60/633926,2005 on the January that the application requires the U.S. Provisional Patent Application No.60/632372 that submitted on December 1st, 2004, on December 6th, 2004 to submit to, the content that this paper introduces them in full as a reference.
Invention field
The present invention relates to the new crystalline form of macrolide ascosin and the method for these crystalline forms of generation.
Background of invention
Macrolide is for having one or more desoxy sugars as substituent polynary lactonic ring.Erythromycin, Azythromycin and clarithromycin are the macrolide with antibacterial and/or fungicidal activity.Ascosin, tacrolimus and pimecrolimus also all are macrolides.
Ascosin (CAS 11011-38-4) can be blocked the T-cell activation, suppresses release of cytokines and suppress the huge lactan of mastocyte activatory immunomodulatory for it is reported." mechanism of action of ascosin is very similar to the mechanism of S-Neoral and tacrolimus, but three kinds of compounds have different chemical structures ".C.E.Griffiths, Ascomycin:An Advance in theManagement of Atopic Dermatitis; Br.J.Dermatol.144 (4), 679-681 (April calendar year 2001).Disclose ascosin in the United States Patent (USP) 3244592, wherein compound is described to anti-mycotic agent, and it has chemical formula:
Ascosin
The application of ascosin as immunosuppressor described among the european patent application No.323865.
The crystalline form of solid compounds (or shortage of crystalline form) influence is for the important chemical compound lot character of formula of medicine.This character comprises for example flowability of comminuted solids.Flowability affects material processed easiness in being processed into the medicament production process.When the particle of powder compound can not easily flow through each other, the prescription expert must consider this fact when exploitation tablet or capsule formula, and this makes and must use glidant such as colloid silica, talcum, starch or tribasic calcium phosphate.
Another critical nature that may depend on crystalline medical compounds is its dissolution rate in aqueous fluids.The dissolution rate of activeconstituents in patient's gastric juice can have treatment influence, because it has forced the upper limit to the speed that the activeconstituents of oral administration can arrive patient's blood flow.The solid-state form of compound also can influence its behavior when compacting and its stability in storage.
These practical physical propertys are influenced by the conformation of molecule in the structure cell and orientation, and structure cell defines the concrete crystalline form of material.These conformations and orientation factor cause specific molecular interaction again, can pass through powder x-ray diffraction, solid-state thereby different crystalline forms can cause
13The different spectral qualities that the analytical technology of C NMR spectrometry and infrared spectra one class detects.Specific crystalline form also can cause being different from the thermal behavior of amorphous material or other crystalline form.In the laboratory, pass through capillary melting point, thermogravimetric analysis (TGA) and this class commercial measurement thermal behavior of dsc (DSC), and can be used for distinguishing part crystalline form and other.
The discovery of the new crystalline form of medicinal compound provides the new chance of improving the pharmaceutical preparation performance.This has enlarged scientific formulation man and can be used for the material list of design example as the pharmaceutical dosage form of medicine with target release profiles or other desired characteristic.Therefore, there are needs in this area to ascomycin crystalline forms.
Summary of the invention
The invention provides crystallization ascomycin crystalline forms and its solvate of being called crystal form A, be characterised in that data are selected from: the peak is at the powder x-ray diffraction figure of about 8.7,11.8 and 14.3 ± 0.2 degree, 2 θ; The peak is about 3443,1639,1194 and 1092cm
-1The FTIR spectrum at place; With the DSC thermogram of locating to demonstrate the heat absorption of two places at about 148-152 ℃ and about 158-162 ℃.
The invention provides crystallization ascomycin crystalline forms and its solvate of being called crystal form B, be characterised in that data are selected from: the peak is at the powder x-ray diffraction figure of about 7.5,14.7 and 19.2 ± 0.2 degree, 2 θ; The peak is about 3442,1639,1196 and 1093cm
-1The FTIR spectrum at place; With the DSC thermogram of locating to demonstrate an endotherm(ic)peak at about 152-155 ℃.
The invention provides crystallization ascomycin crystalline forms and its solvate of being called crystalline form C, be characterised in that data are selected from: the peak is at the powder x-ray diffraction figure of about 6.6,15.5 and 19.7 ± 0.2 degree, 2 θ; The peak is about 3459,1649,1196 and 1094cm
-1The FTIR spectrum at place; With the DSC thermogram of locating to demonstrate an endotherm(ic)peak at about 156-160 ℃.
In preferred embodiments, the new crystalline form of ascosin of the present invention is pure with respect to other crystalline form of ascosin substantially, promptly new crystalline form comprise be less than about 10%, preferably be less than about 5% and even be more preferably less than other ascomycin crystalline forms of about 1% (by weight).In some embodiments, new crystalline form comprise be less than about 10%, preferably be less than about 5% and even be more preferably less than the non-crystalline state ascosin of about 1% (by weight).
The present invention also provides the novel method of preparation crystallization ascosin, comprising:
A) mix the ascosin and first polar organic solvent and obtain solution;
B) mixing solutions and second polar organic solvent and contrary solvent form mixture;
C) keep mixture up to the ascosin crystallization; With
D) reclaim the crystallization ascosin.
Preferably, the crystallization ascosin is crystal form A or crystalline form C.
The present invention also provides the other method of preparation crystallization ascosin, comprising: dissolve ascosin in ethyl acetate; Keep solution making an appointment with-20 ℃ to about 10 ℃ temperature; With recovery crystallization ascosin.
Preferably, the crystallization ascosin is a crystal form B.
The present invention also provides by keeping ascomycin crystalline forms A at least about the method that prepared ascomycin crystalline forms C in 30 minutes under about 100 ℃-Yue 160 ℃ temperature.
The invention provides and comprise that any and medicine among the ascomycin crystalline forms A, the B that treat significant quantity or the C can accept the pharmaceutical preparation of vehicle.
The present invention also provides the method for suffering from the patient of infectation of bacteria, atopic dermatitis or needing the patient of immunosuppressant therapy for the treatment of, be included as the step of patient's administration medicine preparation, wherein pharmaceutical preparation comprises any among the ascomycin crystalline forms A, the B that treat significant quantity or the C.
The accompanying drawing summary
Fig. 1: the X-ray powder diffraction pattern of ascomycin crystalline forms A.
Fig. 2: the X-ray powder diffraction pattern of ascomycin crystalline forms B.
Fig. 3: the X-ray powder diffraction pattern of ascomycin crystalline forms C.
Fig. 4: the DSC thermogram of ascomycin crystalline forms A.
Fig. 5: the DSC thermogram of ascomycin crystalline forms B.
Fig. 6: the DSC thermogram of ascomycin crystalline forms C.
Fig. 7: the TGA thermogram of ascomycin crystalline forms A.
Fig. 8: the TGA thermogram of ascomycin crystalline forms B.
Fig. 9: the TGA thermogram of ascomycin crystalline forms C.
Figure 10: the FT-IR spectrum of ascomycin crystalline forms A.
Figure 11: the FT-IR spectrum of ascomycin crystalline forms B.
Figure 12: the FT-IR spectrum of ascomycin crystalline forms C.
The X-ray powder diffraction pattern of the ascosin sample of Figure 13: embodiment 5.
Detailed Description Of The Invention
Term used herein " room temperature " refers to about 15 ℃-Yue 30 ℃ temperature, preferred about 18 ℃-About 25 ℃.
Term " on a small quantity " polar solvent refer to solvent mixture to polar solvent (or two or more The mixture of polar solvent) ratio is about 636/1 for about 140/1-, and preferably about 200/1-is about 500/1, Even more preferably from about 300/1-is about 350/1, in the volume/volume base. Find solvent mixture/utmost point The proper ratio of property solvent (or polar solvent mixture) comprising: 141/1,212/1,300/1, 318/1,325/1,350/1 and 636/1.
Perhaps, " on a small quantity " can be considered to polar solvent (or polar solvent mixture) greatly The molar equivalent of cyclic lactone is than relevant. Discovery is with respect to macrolide, and is little of 0.5 molar equivalent Polar solvent causes the crystallization of macrolide. Therefore, add in the method for the invention about 0.3, 0.4, the polar solvent (phase of 0.5,0.6,0.7 or 0.8 (or sometimes even higher) molar equivalent For macrolide) with the crystallization that realizes macrolide within the scope of the invention.
The invention provides crystallization ascomycin crystalline forms and its solvate of being called crystal form A, feature Be that data are selected from: the peak is at the powder x-ray diffraction of about 8.7,11.8 and 14.3 ± 0.2 degree, 2 θ Figure; The peak is about 3443,1639,1194 and 1092cm-1The FTIR spectrum at place; With at about 148-152 ℃ and about 158-162 ℃ locate to demonstrate the DSC thermal analysis curue that absorbs heat in two places.
Ascomycin crystalline forms A be further characterized in that the peak about 8.7,10.4,11.4,11.8,12.7, 13.9,14.3,17.1,17.4,19.2 and 20.0 ± 0.2 the degree 2 θ powder x-ray diffraction figure (substantially as shown in Figure 1). Crystal form A also can be characterised in that about 3665,1740,1723, 1691,1640,1280,1194,1173,1038,997,926,858,785,771, 722 and 686cm-1The place has the FTIR spectrum (substantially as shown in Figure 10) of additional peak. In addition Outward, ascomycin crystalline forms A can be characterised in that DSC thermal analysis curue substantially as shown in Figure 4.
Loss in weight during that the TGA by ascomycin crystalline forms A measures until fusing is for approximately 1.6-1.8%, this is (basic such as Fig. 7 corresponding to the water content by Karl Fischer titration determination Shown in).
Ascomycin crystalline forms A of the present invention has the rod-shpaed particle that can form aggregate. Preferably Maximum particle size is about 60 μ m.
The invention provides crystallization ascomycin crystalline forms and its solvate of being called crystal form B, feature Be that data are selected from: the peak is at the powder x-ray diffraction of about 7.5,14.7 and 19.2 ± 0.2 degree, 2 θ Figure; The peak is about 3442,1639,1196 and 1093cm-1The FTIR spectrum at place; With at about 152-155 ℃ locate to demonstrate the DSC thermal analysis curue of an endothermic peak.
Ascomycin crystalline forms B be further characterized in that the peak about 7.5,10.4,11.4,13.9,14.7, 15.4,16.2,17.4,19.2,19.7,21.4 and 23.8 ± 0.2 the degree 2 θ powder X-rays spread out Penetrate figure (substantially as shown in Figure 2). Crystal form B also can be characterised in that about 3579,3442,1739, 1721,1690,1649,1639,1279,1197,1093,1037,996,928,857 And 722cm-1The place has the FTIR spectrum (substantially as shown in Figure 11) at peak. In addition, son Capsule mycin crystal form B can be characterised in that DSC thermal analysis curue substantially as shown in Figure 5.
Loss in weight during that the TGA by ascomycin crystalline forms B measures until fusing is for approximately 1.0-1.2%, this is (basic such as Fig. 8 corresponding to the water content by Karl Fischer titration determination Shown in).
Ascomycin crystalline forms B of the present invention has the rod-shpaed particle that can form aggregate. Preferably Maximum particle size is about 100 μ m.
The invention provides crystallization ascomycin crystalline forms and its solvate of being called crystalline form C, feature Be that data are selected from: the peak is at the powder x-ray diffraction of about 6.6,15.5 and 19.7 ± 0.2 degree, 2 θ Figure; The peak is about 3459,1649,1196 and 1094cm-1The FTIR spectrum at place; With at about 156-160 ℃ locate to demonstrate the DSC thermal analysis curue of an endothermic peak.
Ascomycin crystalline forms C be further characterized in that the peak about 6.6,10.4,11.4,13.9,15.4, 17.4,19.3,19.7,23.9,25.1 and 25.6 ± 0.2 the degree 2 θ powder x-ray diffraction figure (substantially as shown in Figure 3). Crystalline form C also can be characterised in that about 3579,3457,1739, 1720,1690,1649,1279,1196,1094,1036,995,955,928,855, 789,774,721 and 682cm-1The place has the FTIR spectrum (substantially as shown in Figure 12) at peak. In addition, ascomycin crystalline forms C can be characterised in that DSC thermal analysis curue substantially as shown in Figure 6.
Loss in weight during that the TGA by ascomycin crystalline forms C measures until fusing be less than 0.3%, this is (basic such as Fig. 9 institute corresponding to the water content by Karl Fischer titration determination Show). Ascomycin crystalline forms C is anhydrous.
Ascomycin crystalline forms C of the present invention has rod-shpaed particle and the sheet that can form aggregate. Excellent The maximum particle size of choosing is the about 50 μ m of about 40-.
The new crystalline form of ascosin of the present invention is pure with respect to other crystalline form of ascosin substantially, promptly new crystalline form comprise be less than about 10%, preferably be less than about 5% and even be more preferably less than other ascomycin crystalline forms of about 1% (by weight).In some embodiments, new crystalline form comprise be less than about 10%, preferably be less than about 5% and even be more preferably less than the non-crystalline state ascosin of about 1% (by weight).
The present invention also provides the novel method of preparation crystallization ascosin, comprising:
A) mix the ascosin and first polar organic solvent and obtain solution;
B) mixing solutions and second polar organic solvent and contrary solvent form mixture;
C) keep mixture up to the ascosin crystallization; With
D) reclaim the crystallization ascosin.
Preferably, the crystallization ascosin is crystal form A or crystalline form C.
Preferably, first polar solvent in the step a) is selected from: ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 2-butanols, acetone, acetonitrile, tetrahydrofuran (THF), isobutyl acetate, n-butyl acetate, ethyl formate, n-propyl acetate, isopropyl acetate, methyl-ethyl ketone and their mixture.Most preferably, first polar organic solvent is an ethyl acetate.
In order to obtain clear solution, the temperature in the rising step a) is no more than about 50 ℃.
Perhaps, can or leach any particle by dilution and obtain clear solution.Can filter by paper, glass fibre or other mould material or finings such as C salt.According to the equipment that uses and the concentration and the temperature of solution, may need the preheating filtration unit to avoid premature crystallization.
Preferably, contrary solvent is selected from: hexanaphthene, hexane, heptane, octane, octane-iso and methylcyclohexane.Preferably, be hexanaphthene against solvent.
Randomly, can not have to carry out this method under the contrary solvent situation of step b).
Preferably, second polar organic solvent is selected from: water, N, dinethylformamide, methyl-sulphoxide, N,N-DIMETHYLACETAMIDE, N, N-diethylformamide and their mixture.Preferably, polar solvent is selected from: water, N, dinethylformamide and methyl-sulphoxide.Most preferably, polar solvent is water or N, dinethylformamide.
Randomly, add the small amount of polar solvent.
Preferably, in the solution of ascosin in solvent, more or less add contrary solvent and polar solvent simultaneously.
Preferably, keep reaction mixture in the step c) with induced crystallization at low temperatures.The preferred reaction mixture that keeps is being made an appointment with-15 ℃ to about 30 ℃ temperature.Preferably, keep reaction mixture about 0 ℃ to about 8 ℃ temperature.
Promote crystallization by the strong solution of bringing into use ascosin.Preferably, strength of solution is that about 0.06g/mL is to about 0.8g/mL.High density also can cause high yield.
The present invention also provides the other method of preparation crystallization ascosin, comprising: dissolve ascosin in ethyl acetate; Keep solution making an appointment with-20 ℃ to about 10 ℃ temperature; With recovery crystallization ascosin.Preferably, the crystallization ascosin that obtains by this method is a crystal form B.
Preferably, keep solution about 0 ℃ to about 8 ℃ temperature.
The present invention also provides by keeping ascomycin crystalline forms A at least about the method that prepared ascomycin crystalline forms C in 30 minutes under about 100 ℃-Yue 160 ℃ temperature.Preferably, keep crystal form A under about 150 ℃ temperature.Preferably, kept crystal form A about 1 hour.
The invention provides the pharmaceutical preparation that comprises that the ascomycin crystalline forms A, the B that treat significant quantity or at least a medicine any and some amount among the C can be accepted vehicle.
" treatment significant quantity " is meant that the quantity of crystalline form is enough to that this disease or symptom are had beneficial effect when being administered into the patient and being used for the treatment of disease or other and being out of favour medical symptom." treatment significant quantity " will be with crystalline form, disease or symptom and severity and variations such as the patient's age that will be treated, body weight.The treatment significant quantity of determining given crystalline form only needs routine test in those of ordinary skills' limit of power.
The present invention also provides the method for the treatment of the patient who suffers from infectation of bacteria, is included as the step of patient's administration medicine preparation, and wherein pharmaceutical preparation comprises the ascosin any in the above-mentioned ascomycin crystalline forms that is selected from of treatment significant quantity.Another embodiment of the present invention is included as the step of patient's administration medicine preparation for treating the patient's who suffers from atopic dermatitis method, and wherein pharmaceutical preparation comprises the ascosin any in the above-mentioned ascomycin crystalline forms that is selected from of treatment significant quantity.An also embodiment of the present invention is included as the step of patient's administration medicine preparation for treating the patient's who needs immunosuppressant therapy method, and wherein pharmaceutical preparation comprises the ascosin any in the above-mentioned ascomycin crystalline forms that is selected from of treatment significant quantity.
The crystalline form of the present invention that is used for useful in preparing drug formulations is pure with respect to other crystalline form substantially, promptly new crystalline form comprise be less than about 10%, preferably be less than about 5% and even be more preferably less than other ascomycin crystalline forms of about 1% (by weight).In some embodiments, new crystalline form comprise be less than about 10%, preferably be less than about 5% and even be more preferably less than the non-crystalline state ascosin of about 1% (by weight).
Pharmaceutical preparation of the present invention comprises the crystallization ascosin, and a kind of as in the above-mentioned crystalline form randomly is the mixture with other ascomycin crystalline forms.Except activeconstituents, pharmaceutical preparation of the present invention can comprise one or more vehicle.In preparation, add vehicle for various purposes.
Thinner can be added in the preparation of the present invention.Thinner has increased the volume of solid composite medicament, and makes the pharmaceutical dosage form easier processing for patient and care-giver that comprises composition.The thinner that is used for solids composition comprises that for example Microcrystalline Cellulose (for example
), fine cellulose, lactose, starch, pregelatinized starch, lime carbonate, calcium sulfate, sugar, dextrate, dextrin, dextrose, dicalcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesiumcarbonate, magnesium oxide, Star Dri 5, mannitol, polymethacrylate (for example
), Repone K, cellulose powder, sodium-chlor, Sorbitol Powder and talcum.
The solid composite medicament that can be compressed into formulation such as tablet can comprise that its function is included in the compression back and helps bonding activeconstituents and other vehicle to together vehicle.The tackiness agent of solid composite medicament (for example comprises gum arabic, alginic acid, carbomer (for example carbopol), Xylo-Mucine, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropylcellulose
), Vltra tears (for example
), Liquid Glucose, magnesium aluminum silicate, Star Dri 5, methylcellulose gum, polymethacrylate, polyvinylpyrrolidone (for example
), pregelatinized starch, sodiun alginate and starch.
Can improve the dissolution rate of solid composite medicament in patient's stomach of compression in the composition by adding disintegrating agent.Disintegrating agent comprises alginic acid, calcium carboxymethylcellulose, Xylo-Mucine (AC-DI-for example
), colloid silica, croscarmellose sodium, polyvinylpolypyrrolidone (for example
), guar gum, magnesium aluminum silicate, methylcellulose gum, Microcrystalline Cellulose, Polacrilin potassium, cellulose powder, pregelatinized starch, sodiun alginate, sodium starch glycollate (for example
) and starch.
Can add glidant to improve the not flowability and the accuracy that improves dosed administration of compacted solid composition.The vehicle that can be used as glidant comprises colloid silica, Magnesium Trisilicate, cellulose powder, starch, talcum and tribasic calcium phosphate.
When by compression powdery preparation of compositions formulation such as tablet, make composition stand pressure from drift and punch die (punch and dye).Some vehicle and activeconstituents have the drift of being adhered to and the lip-deep trend of punch die, and this can make product have indenture and other surperficial irregularity.Can add lubricant in the composition to reduce adhesion and to make product demoulding easily from the punch die.Lubricant comprises Magnesium Stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyoxyethylene glycol, Sodium Benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talcum and Zinic stearas.
Perfume compound and odorant make formulation better to eat concerning the patient.Perfume compound commonly used that is used for pharmaceutical preparation and odorant that composition of the present invention can comprise comprise maltol, vanillin food grade,1000.000000ine mesh, vanirone, menthol, citric acid, fumaric acid, ethyl maltol and tartrate.
Also can use the acceptable tinting material of any medicine painted with the outward appearance of improving them and/or help the patient and discern product and unit dosage level to solid and liquid composition.
The present invention does not plan to comprise the true solution of ascosin, because the character of the crystalline structure of new crystalline form and the new crystalline form of differentiation ascosin of the present invention is lost.Therefore, the pharmaceutical composition of the present invention that comprises the new crystalline form of ascosin disclosed herein will be mainly solid composite medicament.But, use new crystalline form to prepare this solution (for example, so that in liquid pharmaceutical formulation, carry ascosin) in consideration of the present invention.
In the composition of liquid medicine that uses crystalline form preparation of the present invention, ascosin and any other solid excipient are dissolved or suspended in liquid vehicle such as water, vegetables oil, alcohol, polyoxyethylene glycol, propylene glycol or the glycerine.
Composition of liquid medicine can comprise emulsifying agent with in whole composition equably the dispersed activity composition or in liquid vehicle insoluble other vehicle.The emulsifying agent that can be used in the liquid composition of the present invention comprises for example gelatin, yolk, casein, cholesterol, gum arabic, tragacanth gum, carrageenin, pectin, methylcellulose gum, carbomer, hexadecanol stearyl alcohol and hexadecanol.
Composition of liquid medicine also can comprise the viscosity activator to be improved the mouthfeel of product and/or applies GI internal layer.This reagent comprises gum arabic, alginic acid bentonite, carbomer, calcium carboxymethylcellulose or sodium, hexadecanol stearyl alcohol, methylcellulose gum, ethyl cellulose, gelatin, guar gum, Natvosol, hydroxypropylcellulose, Vltra tears, Star Dri 5, polyvinyl alcohol, polyvinylpyrrolidone, propylene carbonate, Protanal Ester SD-LB, sodiun alginate, sodium starch glycollate, tragacanth gum starch and xanthan gum.
Can add sweeting agent such as Sorbitol Powder, asccharin, soluble saccharin, sucrose, aspartame's asccharin, fructose, mannitol and Nulomoline and improve taste.
The sanitas and the sequestrant that can add the security level of ingesting improve stability in storage as alcohol, Sodium Benzoate, Yoshinox BHT, butylated hydroxyanisol and ethylenediamine tetraacetic acid (EDTA).
Liquid composition also can comprise buffer reagent such as glyconic acid, lactic acid, citric acid or acetate, gluconic acid sodium salt, Sodium.alpha.-hydroxypropionate, Trisodium Citrate or sodium acetate.Scientific formulation man can be rule of thumb and the selection of considering that standard procedure in this area and reference work come easily to determine vehicle and consumption.
Solids composition of the present invention comprises pulvis, granule, coacervate and compressed compositions.Formulation comprises the formulation that is applicable to oral, oral cavity, rectum, parenteral (comprising subcutaneous, intramuscular and intravenously), suction and ocular administration.Although only administration will be depended on the character and the severity of the illness of just being treated under any given situation, most preferred route of the present invention is oral.Formulation can exist with unit dosage forms easily, and prepares by any method of knowing in the pharmaceutical field.
Formulation comprises solid dosage for example tablet, pulvis, capsule, suppository, face powder, lozenge and lozenge, and liquid sugar sirup, suspensoid and elixir.
Oral dosage form of the present invention is preferably the form of oral capsule, has the dosage of the about 160mg of about 10mg-, the about 80mg of 20mg-more preferably from about, most preferably 20,40,60 and the capsule of 80mg.Per daily dose can comprise 1,2 or a plurality of capsules per day.
Formulation of the present invention can be the capsule that comprises preferred powdery of the present invention of composition or particulate solid composition in duricrust or soft shell.Shell can be made by gelatin, and randomly comprises softening agent such as glycerine and Sorbitol Powder, and opalizer or tinting material.
The composition that can be used for film-making or capsule filling by the wet granulation preparation.In wet granulation, the vehicle of mixing portion or whole activeconstituents and powder type further mixes when the liquid that is generally water exists then, and this makes powder agglomates become particle.Screening and/or abrasive grains, required granularity is sieved and/or be ground to drying then.Particle then can be by film-making, or adds other vehicle before film-making, as glidant and/or lubricant.
Usually mix preparation film-making composition by doing.For example, the blend compositions compressed to slugs or the sheet of active substance and vehicle can be ground into the particle of compacting then.The particle of compacting can be compressed into tablet subsequently.
As the alternative method of non-slurry pelletizing, can use direct compress technique the blended composition directly to be compressed into the formulation of compacting.Directly compression produces more uniform tablet, does not have particle.The vehicle that is particularly suitable for directly compressing film-making comprises Microcrystalline Cellulose, spray-dired lactose, dicalcium phosphate dihydrate and colloid silica.The correct use of these and other vehicle in direct compression film-making sees service in directly compression film-making prescription requires in for this area and those technician of skill are known.
Capsule filling of the present invention can comprise any said mixture and the particle of describing in conjunction with film-making, and still, they are without last film-making step.
Activeconstituents and vehicle can be mixed with composition and formulation according to method as known in the art.
Preparation of the present invention there is no need only to comprise a kind of ascomycin crystalline forms.Crystalline form of the present invention can be used as one-component or is used in pharmaceutical preparation or the composition with the mixture of other ascomycin crystalline forms or non-crystalline state ascosin.But preferred pharmaceutical preparation of the present invention or composition comprise at least a new crystalline form of 25-100wt%, especially 50-100wt%, based on the total quantity of ascosin in preparation or the composition.
Preferably, the quantity of the new crystalline form of this ascosin is 75-100wt%, especially 90-100wt%.It is most preferred that the quantity of 95-100wt%.
Described the present invention with reference to specific preferred embodiment, considered specification sheets, other embodiment will be tangible to those skilled in the art.Further describe the present invention by following examples of describing preparation of compositions and using method of the present invention in detail.Obviously, to those skilled in the art, only otherwise depart from the scope of the present invention, just multiple change can made aspect material and the method.
Embodiment
Instrument
Can pass through powder x-ray diffraction (PXRD) and analyze the ascomycin crystalline forms that produces by method of the present invention, at X-ray powder diffraction instrument, ARL, θ-θ goniometer, the Cu-pipe has on the Peltier refrigerative solid-state detector and carries out the X-ray powder diffraction.Specimen holder is circular standard aluminum specimen holder, has the approximate zero background.Sweep parameter: scope: 2-40 degree 2 θ, continuous sweep, speed; 3 degree/min.
Also can analyze ascomycin crystalline forms by the heat analysis, this can carry out by digital scanning calorimetry (DSC) with by thermogravimetric analysis (TGA).Can be at DSC822
eObtain the DSC thermogram on the Mettler Toledo instrument (Advanced Instruments, San Juan, Puerto Rico).Example weight: 3-5mg; Heating rate: 10 ℃/min; Number of perforations in the crucible: 3.Can use standard A llumina dish on Mettler TGA/SDTA 851 instruments (AdvancedInstruments, San Juan, Puerto Rico), to obtain the TGA thermogram.Example weight: 7-15mg; Heating rate: 10 ℃/min.
Can measure granularity by following method: sieve, sedimentation, resistance induction (grain count instrument), microscope, low angle laser light scattering (LALLS).
Embodiment 1-prepares the method for ascomycin crystalline forms A
Be dissolved in crystallization ascomycin crystalline forms A (150.1g) in the ethyl acetate (1000ml) and be evaporated to dried.Repeat twice of this process.The oily mater of evaporation is dissolved in the ethyl acetate (300ml).In solution, add hexanaphthene (1800ml).In 3 hours, add less water (3.3ml).At room temperature stirred the mixture 1 hour.Filtration is the crystallized product of formation like this, and washs with hexanaphthene (300ml), and drying is 1.5 hours under 70 ℃ and in the vacuum.Obtain ascomycin crystalline forms A (133.6g).
Embodiment 2-prepares the method for ascomycin crystalline forms B
Ascosin crude product (6g) is dissolved in the ethyl acetate (48ml), and is evaporated to minimizing volume (9ml).At room temperature stirred the mixture 1 hour, and cultivated 24 hours down at 0-8 ℃ then.Filtration is the crystallized product of formation like this, and washs with hexanaphthene (18ml), and drying is 1.5 hours under 70 ℃ and in the vacuum.Obtain ascomycin crystalline forms B (3.51g).
Embodiment 3-prepares the method for ascomycin crystalline forms C
Ascosin crude product (6g) is dissolved in the ethyl acetate (60ml), and is evaporated to dried.Repeat twice of this process.The oily mater of evaporation is dissolved in the ethyl acetate (6ml).In solution, add hexanaphthene (36ml) and dimethyl formamide (0.12ml), and at room temperature stirred 1.5 hours.Filtration is the crystallized product of formation like this, and washs with hexanaphthene (18ml), and drying is 1 hour under 70 ℃ and in the vacuum.Obtain ascomycin crystalline forms C (2.76g).
Embodiment 4-prepares the method for ascomycin crystalline forms C
Crystallization ascomycin crystalline forms A (6g) is dissolved in the ethyl acetate (60ml), and is evaporated to dried.Repeat twice of this process.The oily mater of evaporation is dissolved in the ethyl acetate (6ml).In solution, add hexanaphthene (66ml) and dimethyl sulfoxide (DMSO) (0.24ml), and at room temperature stirred 1.5 hours.Filter the crystallized product that forms like this, and with hexanaphthene (18ml) washing, drying is 1 hour under 70 ℃ and decompression.Obtain ascomycin crystalline forms C (4.81g).
Embodiment 5-prepares the method for ascosin
Crystallization ascomycin crystalline forms A (6g) is dissolved in the ethyl acetate (60ml), and is evaporated to dried.Repeat twice of this process.The oily mater of evaporation is dissolved in the ethyl acetate (6ml).The mixture that in solution, adds hexanaphthene (36ml) and dimethyl formamide (0.06ml) and water (0.06ml).At room temperature stirred the mixture 1.5 hours.Filter the crystallized product that forms like this, and with hexanaphthene (18ml) washing, drying is 1 hour under 70 ℃ and decompression.Obtain ascomycin crystalline forms A (5.46g).
Embodiment 6-is 150 ℃ of methods that prepare ascomycin crystalline forms C
Begin by crystal form A, cultivated 1 hour down, produce ascomycin crystalline forms C at 150 ℃ with character of listing in the table 1.
Table 1
Claims (51)
1. ascomycin crystalline forms A is characterised in that data are selected from: the peak is at the powder x-ray diffraction figure of about 8.7,11.8 and 14.3 ± 0.2 degree, 2 θ; The peak is about 3443,1639,1194 and 1092cm
-1The FTIR spectrum at place; With the DSC thermogram of locating to demonstrate the heat absorption of two places at about 148-152 ℃ and about 158-162 ℃.
2. the ascomycin crystalline forms A of claim 1 is characterised in that the powder x-ray diffraction figure of peak at about 8.7,11.8 and 14.3 ± 0.2 degree, 2 θ.
3. the ascomycin crystalline forms A of claim 2 is further characterized in that the powder x-ray diffraction figure of peak at about 10.4,11.4,12.7,13.9,17.1,17.4,19.2 and 20.0 ± 0.2 degree, 2 θ.
4. the ascomycin crystalline forms A of claim 3 is characterised in that the powder x-ray diffraction figure shown in Fig. 1.
5. the ascomycin crystalline forms A of claim 1 is characterised in that the peak is about 3443,1639,1194 and 1092cm
-1The FTIR spectrum at place.
6. the ascomycin crystalline forms A of claim 5 is further characterized in that about 3665,1740,1723,1691,1640,1280,1194,1173,1038,997,926,858,785,771,722 and 686cm
-1The place has the FTIR spectrum at peak.
7. the ascomycin crystalline forms A of claim 6 is characterised in that the FTIR spectrum shown in Figure 10.
8. the ascomycin crystalline forms A of claim 1 is characterised in that the DSC thermogram of locating to demonstrate the heat absorption of two places at about 148-152 ℃ and about 158-162 ℃.
9. the ascomycin crystalline forms A of claim 8 is characterised in that the DSC thermogram shown in Fig. 4.
10. ascomycin crystalline forms B is characterised in that data are selected from: the peak is at the powder x-ray diffraction figure of about 7.5,14.7 and 19.2 ± 0.2 degree, 2 θ; The peak is about 3442,1639,1196 and 1093cm
-1The FTIR spectrum at place; With the DSC thermogram of locating to demonstrate an endotherm(ic)peak at about 152-155 ℃.
11. the ascomycin crystalline forms B of claim 10 is characterised in that the powder x-ray diffraction figure of peak at about 7.5,14.7 and 19.2 ± 0.2 degree, 2 θ.
12. the ascomycin crystalline forms B of claim 11 is further characterized in that the powder x-ray diffraction figure of peak at about 10.4,11.4,13.9,15.4,16.2,17.4,19.7,21.4 and 23.8 ± 0.2 degree, 2 θ.
13. the ascomycin crystalline forms B of claim 12 is characterised in that the powder x-ray diffraction figure shown in Fig. 2.
14. the ascomycin crystalline forms B of claim 10 is characterised in that the peak is about 3442,1639,1196 and 1093cm
-1The FTIR spectrum at place.
15. the ascomycin crystalline forms B of claim 14 is further characterized in that about 3579,1739,1721,1690,1649,1279,1197,1173,1093,1037,996,928,857 and 722cm
-1The place has the FTIR spectrum at peak.
16. the ascomycin crystalline forms B of claim 15 is characterised in that the FTIR spectrum shown in Figure 11.
17. the ascomycin crystalline forms B of claim 10 is characterised in that the DSC thermogram of locating to demonstrate an endotherm(ic)peak at about 152-155 ℃.
18. the ascomycin crystalline forms B of claim 17 is characterised in that the DSC thermogram shown in Fig. 5.
19. ascomycin crystalline forms C is characterised in that data are selected from: the peak is at the powder x-ray diffraction figure of about 6.6,15.5 and 19.7 ± 0.2 degree, 2 θ; The peak is about 3459,1649,1196 and 1094cm
-1The FTIR spectrum at place; With the DSC thermogram of locating to demonstrate an endotherm(ic)peak at about 156-160 ℃.
20. the ascomycin crystalline forms C of claim 19 is characterised in that the powder x-ray diffraction figure of peak at about 6.6,15.5 and 19.7 ± 0.2 degree, 2 θ.
21. the ascomycin crystalline forms C of claim 20 is further characterized in that the powder x-ray diffraction figure of peak at about 10.4,11.4,13.9,15.5,17.4,19.3,23.9,25.1 and 25.6 ± 0.2 degree, 2 θ.
22. the ascomycin crystalline forms C of claim 21 is characterised in that the powder x-ray diffraction figure shown in Fig. 3.
23. the ascomycin crystalline forms C of claim 19 is characterised in that the peak is about 3459,1649,1196 and 1094cm
-1The FTIR spectrum at place.
24. the ascomycin crystalline forms C of claim 23 is further characterized in that about 3579,3457,1739,1720,1690,1279,1036,995,955,928,855,789,774,721 and 682cm
-1The place has the FTIR spectrum at peak.
25. the ascomycin crystalline forms C of claim 24 is characterised in that the FTIR spectrum shown in Figure 12.
26. the ascomycin crystalline forms C of claim 19 is characterised in that the DSC thermogram of locating to demonstrate an endotherm(ic)peak at about 156-160 ℃.
27. the ascomycin crystalline forms C of claim 26 is characterised in that the DSC thermogram shown in Fig. 6.
28. prepare the method for crystallization ascosin, comprising:
A) mix the ascosin and first polar organic solvent and obtain solution;
B) mixing solutions and second polar organic solvent and contrary solvent form mixture;
C) keep mixture up to the ascosin crystallization; With
D) reclaim the crystallization ascosin.
29. the method for claim 28, wherein the crystallization ascosin is crystal form A or crystalline form C.
30. the method for claim 28, wherein first polar solvent in the step a) is selected from: ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 2-butanols, acetone, acetonitrile, tetrahydrofuran (THF), isobutyl acetate, n-butyl acetate, ethyl formate, n-propyl acetate, isopropyl acetate, methyl-ethyl ketone and their mixture.
31. the method for claim 30, wherein first polar organic solvent is an ethyl acetate.
32. the method for claim 28, the temperature in the step a) that wherein raises is to being no more than about 50 ℃.
33. the method for claim 28, wherein any particle in the step a) all is filtered or dilutes.
34. the method for claim 28, wherein the solution in the step a) has the concentration of the about 0.8g/mL of about 0.06g/mL-.
35. the method for claim 28, wherein the contrary solvent in the step b) is selected from: hexanaphthene, hexane, heptane, octane, octane-iso and methylcyclohexane.
36. the method for claim 35, wherein the contrary solvent in the step b) is a hexanaphthene.
37. the method for claim 28, wherein second polar organic solvent in the step b) is selected from: water, N, dinethylformamide, methyl-sulphoxide, N,N-DIMETHYLACETAMIDE, N, N-diethylformamide and their mixture.
38. the method for claim 37, wherein second polar organic solvent in the step b) is water or N, dinethylformamide.
39. the method for claim 28 wherein more or less adds the contrary solvent and second polar organic solvent simultaneously in the solution of ascosin in solvent.
40. the method for claim 28 wherein keeps the reaction mixture in the step c) making an appointment with-15 ℃ to about 30 ℃ temperature.
41. the method for claim 40, wherein keep in the step c) reaction mixture about 0 ℃ to about 8 ℃ temperature.
42. prepare the method for crystallization ascosin, comprising: in ethyl acetate, dissolve ascosin; Keep solution making an appointment with-20 ℃ to about 10 ℃ temperature; With recovery crystallization ascosin.
43. the method for claim 42, wherein the crystallization ascosin is a crystal form B.
44. the method for claim 42, wherein keep solution about 0 ℃ to about 8 ℃ temperature.
45. the method for ascomycin crystalline forms C of preparation claim 19 is included under the about 100 ℃-Yue 160 ℃ temperature and keeps ascomycin crystalline forms A at least about 30 minutes.
46. the method for claim 45 wherein keeps crystal form A under about 150 ℃ temperature.
47. the method for claim 45 wherein kept crystal form A about 1 hour.
48. a pharmaceutical preparation comprises the ascomycin crystalline forms A of the claim 1 for the treatment of significant quantity, the ascomycin crystalline forms B of claim 10 or the ascomycin crystalline forms C of claim 19.
49. a treatment suffers from the patient's of infectation of bacteria method, is included as the step of the pharmaceutical preparation of patient's administration claim 48.
50. a treatment suffers from the patient's of atopic dermatitis method, is included as the step of the pharmaceutical preparation of patient's administration claim 48.
51. a treatment needs the patient's of immunosuppressant therapy method, is included as the step of the pharmaceutical preparation of patient's administration claim 48.
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| Application Number | Priority Date | Filing Date | Title |
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| US63237204P | 2004-12-01 | 2004-12-01 | |
| US60/632,372 | 2004-12-01 | ||
| US60/633,926 | 2004-12-06 | ||
| US60/641,868 | 2005-01-05 | ||
| US60/641,697 | 2005-01-05 | ||
| US60/641,869 | 2005-01-05 | ||
| US60/662,440 | 2005-03-16 | ||
| US60/705,681 | 2005-08-03 | ||
| US60/709,160 | 2005-08-17 |
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| CN 200580041024 Pending CN101068818A (en) | 2004-12-01 | 2005-12-01 | Methods of preparing pimecrolimus |
| CN 200580041025 Pending CN101068819A (en) | 2004-12-01 | 2005-12-01 | Processes for producing crystalline macrolides |
| CNA2005800413605A Pending CN101233141A (en) | 2004-12-01 | 2005-12-01 | Ascomycin crystalline forms and preparation thereof |
| CN 200580041236 Pending CN101068820A (en) | 2004-12-01 | 2005-12-01 | Non-hygroscopic and powdery amorphous pimecrolimus |
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| CN106854228B (en) * | 2015-12-08 | 2020-05-29 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of pimecrolimus |
| CN106117243B (en) * | 2016-06-24 | 2018-05-25 | 福建省微生物研究所 | The purification process of Elidel |
| PL3619215T3 (en) * | 2017-05-01 | 2022-03-21 | Meda Pharma Gmbh & Co. Kg | Process to convert crude ascomycin into purified pimecrolimus |
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