CN101098875A - Amorphous tacrolimus and preparation thereof - Google Patents
Amorphous tacrolimus and preparation thereof Download PDFInfo
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- CN101098875A CN101098875A CNA2006800017951A CN200680001795A CN101098875A CN 101098875 A CN101098875 A CN 101098875A CN A2006800017951 A CNA2006800017951 A CN A2006800017951A CN 200680001795 A CN200680001795 A CN 200680001795A CN 101098875 A CN101098875 A CN 101098875A
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- crystal formation
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Abstract
The present invention provides a process for the preparation of pimecrolimus from ascomycin in which ascomycin is reacted with a conversion reagent that converts ascomycin to its activated derivative at C-32. The activated ascomycin is then reacted with chloride ion. The process of the invention requires fewer process steps than prior art processes, and does not require the protection of the ascomycin C-24 hydroxyl group or the purification of the activated ascomycin derivative.
Description
Invention field
[0001] the present invention relates to the free drug particle form amorphous tacrolimus, preparation amorphous tacrolimus novel method and contain the tablet of amorphous tacrolimus.
Related application
[0002] the application requires respectively on January 5th, 2005 and the U.S. Provisional Application sequence number 60/641,868 of submission on August 3rd, 2005 and 60/705,681 rights and interests, and its content by reference and integral body is attached to herein.
Background of invention
[0003] Macrolide is that to have one or more desoxy sugars be substituent polynary lactonic ring.Erythromycin, Azythromycin and clarithromycin are the Macrolidees with antibacterial and/or fungicidal activity.Ascosin, tacrolimus and pimecrolimus also are Macrolidees.
[0004] tacrolimus (FK 506) is a macrolide antibiotics, also is immunosuppressor, is prepared by streptomyces tsukubaensis (Streptomyces tsukubaensis).Its chemistry 3S-[3R by name
*[E (1S
*, 3S
*, 4S
*)], 4S
*, 5R
*, 8S
*, 9E, 12R
*, 14R
*, 15S
*, 16R
*, 18S
*, 19S
*, 26aR
*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-16 hydrogen-5,19-dihydroxyl-3-[2-(4-hydroxyl-3-methoxyl group cyclohexyl)-1-methyl ethylene]-14,16-dimethoxy-4 ', 10,12,18-tetramethyl--8-(2-propenyl)-15,19-epoxy-3H-pyrido [2,1-c] [1,4] oxa-nitrogen heterocyclic 23 is because of (cyclotricosine)-1,7,20,21 (4H, 23H)-the tetraketone monohydrate, its chemical formula is:
Tacrolimus (C
44H
69NO
12H
2O)
MW：822.05
[0005] tacrolimus has the lymphocytic effect than the more effective selectivity inhibition T-of S-Neoral.
[0006] the present invention relates to the solid state physical properties of tacrolimus.Can obtain the condition of the tacrolimus of solid form by control, influence these character.Solid state physical properties for example comprises the flowability of comminuted solids.During being processed into medicament production, flowability can make raw material handle the easy of change.When the particle of powder compound was not easy to flow through mutually, formulation specialist must be considered this situation when exploitation tablet or capsule, and this may need to use glidant, for example colloid silica, talcum powder, starch or calcium phosphate.
[0007] the another kind of important solid state properties of medical compounds is its dissolution rate in aqueous fluids.The dissolution rate of activeconstituents in patient's gastric juice can have treatment result, because it gives the rate-limit that the Orally active composition can arrive patient's blood flow.In obtain syrup agent, elixir and other liquid preparation, also to consider dissolution rate.The solid-state form of compound also can influence its compression behavior and its stability in storage.
[0008] discovery of medicinal compound new form provides the new chance of improving the medicament production performance characteristic.It has enlarged formulation science man and can be used for design, for example has the raw material range of the pharmaceutical dosage form of target release characteristic or other desired feature.There are needs in this area to the tacrolimus of other form and/or their preparation method.
Summary of the invention
[0009] in one embodiment, the invention provides the amorphous tacrolimus of free drug particle form.This amorphous tacrolimus preferably contains and is no more than about 5% crystal formation tacrolimus, and this crystal formation tacrolimus is characterised in that the powder X-ray RD that the peak is arranged at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ.
[00010] in another embodiment, the invention provides the method for preparing amorphous tacrolimus, described method comprises tacrolimus is dissolved in organic polar solvent, and removes described organic polar solvent.Can repeat this process, produce amorphous tacrolimus.
[00011] in another embodiment again, the invention provides pharmaceutical preparation, this pharmaceutical preparation contains the amorphous tacrolimus and the pharmaceutically acceptable vehicle of free drug particle form.
[00012] in one embodiment, the invention provides the tablet that contains amorphous tacrolimus.
[00013] in a further embodiment, the invention provides the tablet that contains amorphous tacrolimus, described amorphous tacrolimus contains and is no more than about 5% crystal formation tacrolimus, it is characterized in that having at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ the powder X-ray RD at peak.
[00014] in another embodiment again, the invention provides treatment gram positive bacteria infection patient's method, described method comprises the step that gives patient's said medicine preparation.Also be provided as the patient who needs immunosuppressant method is provided, described method comprises the step that gives patient's said medicine preparation.
The accompanying drawing summary
Fig. 1 illustrates the powder x-ray diffraction collection of illustrative plates of the amorphous tacrolimus of free drug particle form;
Fig. 2 illustrates the powder x-ray diffraction collection of illustrative plates of the free drug particle form amorphous tacrolimus that embodiment 2 obtains; With
Fig. 3 illustrates the MIcrosope image of the amorphous tacrolimus of free drug particle form.
Describe in detail
[00015] when being used for this paper, term " room temperature " refers to about 15 ℃ to about 30 ℃, and is preferred Be about 18 ℃ to about 25 ℃.
[00016] when being used for this paper, term " free drug " refers to fully not be embedded in altogether Solid particle in the sediment.
[00017] when being used for this paper, term " particle " refers to one or more independent particles.
[00018] the invention provides the amorphous tacrolimus of free drug particle form. This Bright amorphous tacrolimus is characterised in that basically as depicted in figs. 1 and 2 powder X-ray-penetrate The ray diffraction diagram spectrum. The microscope image of the amorphous tacrolimus of free drug particle form is seen Shown in Figure 3.
[00019] amorphous tacrolimus of the present invention comprises and is no more than about 5% crystal formation Ta Kemo Department, this crystal formation tacrolimus is characterised in that at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ to be had The powder X-ray RD at peak. Preferably, amorphous tacrolimus of the present invention comprises and is no more than about 3% Above-mentioned crystal formation, most preferably, amorphous tacrolimus of the present invention comprises and is no more than about 1% Described crystal formation. Amorphous tacrolimus has than the better physical property of crystalline tacrolimus, Stripping and/or the dissolubility for example improved.
[00020] with known method such as X-ray powder diffraction or solid-state13C-NMR can see Examine crystalline tacrolimus in the amorphous form of batch active component or in Pharmaceutical composition Exist. Usually can be used for the X-ray powder diffraction in laboratory or any instrument of solid state NMR Device all is applicable to his gram of crystallization in monitoring a large amount of amorphous tacrolimus or the Pharmaceutical composition Do not take charge of.
[00021] use the tacrolimus of free drug particle form more favourable, because can control size distribute than co-precipitation tacrolimus.
[00022] the present invention also provides the novel method of preparation amorphous tacrolimus, and described method comprises: tacrolimus is dissolved in organic polar solvent, and removes described organic polar solvent to obtain amorphous tacrolimus.This process can repeat.
[00023] preferred, organic polar solvent is selected from C
1-6Alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol and 2-butanols for example; C
3-8Alkyl ester is ethyl acetate, isobutyl acetate, n-butyl acetate, ethyl formate, n-propyl acetate and isopropyl acetate for example; C
2-8Alkyl ketone is acetone and methylethylketone for example; C
2-8Alkyl oxide is tetrahydrofuran (THF) for example; Acetonitrile; And composition thereof.Most preferably, organic polar solvent is ethyl acetate or acetone.
[00024] preferred, can for example evaporate by any method known in the art, remove organic polar solvent.Preferably, with the organic polar solvent evaporation, further be cooled to about room temperature subsequently.
[00025] preferably is evaporated to drying.Can be in rotatory evaporator, evaporating solns under decompression or normal pressure.Can for example in the test tube, commercial test tube of rotatory evaporator, under reduced pressure evaporate, or in what its glass reactor in office, under normal pressure or decompression, evaporate at any heating container.
[00026] by under reduced pressure, add gradually or add continuously in the heating installation, can immediately complete soln be placed in the container.In order to obtain exsiccant spumescence amorphous tacrolimus, preferred thermal capacity is identical with adding speed, or thermal capacity is higher than adding speed.When thermal capacity is not enough to immediately to remove when desolvating, may need further solvent distillation content.
[00027], can guarantee the successive soln input with pump or kapillary injection by under reduced pressure.Kapillary allows solution slowly to enter in the container.The pipe of available any minor diameter substitutes kapillary.
[00028] evaporative process is preferably carried out under about 40 ℃ to about 60 ℃.
[00029] the invention provides pharmaceutical preparation, this pharmaceutical preparation contains the amorphous tacrolimus and the pharmaceutically acceptable vehicle of free drug particle form.
[00030] the present invention also provides the tablet that contains amorphous tacrolimus.
[00031] the present invention also provides the tablet that contains amorphous tacrolimus, and this amorphous tacrolimus comprises and is no more than about 5% crystal formation tacrolimus, it is characterized in that having at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ the powder X-ray RD at peak.Preferably, this tablet comprises and contains the amorphous tacrolimus that is no more than about 3% above-mentioned crystal formation tacrolimus, and most preferably, this tablet comprises and contains the amorphous tacrolimus that is no more than about 1% crystal formation tacrolimus.
[00032] the present invention also provides treatment gram positive bacteria infection patient's method, and this method comprises the step that gives patient's pharmaceutical preparation, and this pharmaceutical preparation contains the amorphous tacrolimus of the free drug particle form for the treatment of significant quantity.Another embodiment of the present invention is that this method comprises the step that gives patient's pharmaceutical preparation for the patient that needs are arranged provides immunosuppressant method, and this pharmaceutical preparation contains the amorphous tacrolimus of the free drug particle form for the treatment of significant quantity.
[00033] " treatment significant quantity " is meant when giving the patient with treatment disease or other uncomfortable medical conditions, is enough to the amount to the amorphous form of this disease or illness generation beneficial effect." treatment significant quantity " will be according to disease or illness and seriousness thereof, changes such as the patient's age for the treatment of, body weight.The treatment significant quantity of determining given amorphous form needs routine test to determine in the common skill scope of this area at the most.
[00034] except that activeconstituents, pharmaceutical preparation of the present invention can comprise one or more vehicle.For various purposes, vehicle is added in the preparation.
[00035] thinner can be added in the preparation of the present invention.Thinner increases the volume of solid pharmaceutical composition, and can make the pharmaceutical dosage form that contains composition be easier to patient and paramedic's processing.The thinner that is used for solids composition comprises for example Microcrystalline Cellulose (for example AVICEL ), micro mist Mierocrystalline cellulose, lactose, starch, pregelatinized Starch, lime carbonate, calcium sulfate, sugar, dextrates, dextrin, glucose, dicalcium phosphate dihydrate, calcium phosphate, kaolin, magnesiumcarbonate, magnesium oxide, maltodextrin, N.F,USP MANNITOL, polymethacrylate (for example EUDRAGIT ), Repone K, Solka-floc, sodium-chlor, sorbyl alcohol and talcum powder.
[00036] be compressed into formulation for example the solid pharmaceutical composition of tablet can comprise vehicle, the function of this vehicle is included in compression back and helps activeconstituents and other vehicle are bonded together.The tackiness agent that is used for solid pharmaceutical composition comprises gum arabic, alginic acid, carbomer (for example carboxyvinyl polymer), Xylo-Mucine, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, Natvosol, hydroxypropylcellulose (for example KLUCEL ), Vltra tears (for example METHOCEL ), Liquid Glucose, neusilin, maltodextrin, methylcellulose gum, polymethacrylate, polyvidone (for example KOLLIDON , PLASDONE ), pregelatinized Starch, sodiun alginate and starch.
[00037], can improve the dissolution rate of compression solid medicinal compositions in patient's stomach by disintegrating agent is added in the composition.Disintegrating agent comprises alginic acid, calcium carboxymethylcellulose, Xylo-Mucine (for example AC-DI-SOL , PRIMELLOSE ), colloid silica, croscarmellose sodium, polyvinylpolypyrrolidone (for example KOLLIDON , POLYPLASDONE ), guar gum, neusilin, methylcellulose gum, Microcrystalline Cellulose, Polacrilin potassium, Solka-floc, pregelatinized Starch, sodiun alginate, primojel (for example EXPLOTAB ) and starch.
[00038] can add the flowability that glidant improves non-compacted solid composition, and improve quantitative accuracy.The vehicle that can be used as glidant comprises colloid silica, Magnesium Trisilicate, Solka-floc, starch, talcum powder and calcium phosphate.
[00039] when by compression powdery preparation of compositions formulation for example during tablet, said composition stands the pressure of drift and punch die.Some vehicle and activeconstituents have the tendency that adheres to drift and punch die surface, and this can cause that product has depression and other surface irregularity.Lubricant can be added in the composition, to reduce adhesion and to make product be easy to from punch die, discharge.Lubricant comprises Magnesium Stearate, calcium stearate, Zerol, glycerine palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyoxyethylene glycol, Sodium Benzoate, Sodium Lauryl Sulphate BP/USP, stearyl-sodium fumarate, stearic acid, talcum powder and Zinic stearas.
[00040] correctives and tasty agents make formulation more agreeable to the taste to the patient.The common correctives and the tasty agents that are used for the medicament production that the present composition can comprise comprise voitol, Vanillin, vanillal, menthol, Citric Acid, fumaric acid, veltol plus and tartrate.
[00041] also can use any pharmaceutically acceptable tinting material, with the dyeing of solid and liquid composition, with the outward appearance of improving them and/or help the patient to differentiate product and unit dosage level.
[00042] the present invention does not plan to comprise the pure solution of tacrolimus, and this pure solution has lost the structure of new form and distinguished the character of new form tacrolimus of the present invention.Therefore, the medicinal compositions of the present invention that comprises new amorphous form tacrolimus disclosed herein mainly is a solid pharmaceutical composition.Yet, use the new form tacrolimus to prepare solution (for example in order to discharge tacrolimus) and think in the scope that the present invention considers with liquid pharmaceutical formulation.
[00043] in the liquid pharmaceutical composition with amorphous form preparation of the present invention, tacrolimus and any other solid excipient dissolve or are suspended in liquid vehicle, for example in water, vegetables oil, alcohol, polyoxyethylene glycol, propylene glycol or the glycerine.
[00044] liquid pharmaceutical composition can comprise emulsifying agent, is evenly dispersed in the composition with activeconstituents or other vehicle that will be insoluble to liquid vehicle.The emulsifying agent that can be used for liquid composition of the present invention comprises for example gelatin, yolk, casein, cholesterol, gum arabic, tragacanth gum, carrageenin, pectin, methylcellulose gum, carbomer, cetostearyl alcohol (cetostearyl alcohol) and hexadecanol.
[00045] liquid pharmaceutical composition also can comprise tackifier, with the mouthfeel of improving product and/or cover GI internal layer mucous membrane.Such tackifier comprise gum arabic, alginic acid bentonite, carbomer, calcium carboxymethylcellulose or Xylo-Mucine, cetostearyl alcohol, methylcellulose gum, ethyl cellulose, gelatin, guar gum, Natvosol, hydroxypropylcellulose, Vltra tears, maltodextrin, polyvinyl alcohol, polyvidone, propylene carbonate, propylene glycol alginate, sodiun alginate, primojel, starch, tragacanth gum and xanthan gum.
[00046] can add sweeting agent for example Sorbitol Powder, asccharin, soluble saccharin, sucrose, aspartame, fructose, N.F,USP MANNITOL and Nulomoline, to improve the sense of taste.
[00047] can be absorbing security level adding sanitas and sequestrant for example alcohol, Sodium Benzoate, Yoshinox BHT, butylated hydroxy anisole (BHA) and ethylenediamine tetraacetic acid (EDTA), to improve stability in storage.
[00048] liquid composition also can contain buffer reagent for example gluconic acid, lactic acid, Citric Acid or acetate, Sunmorl N 60S, Sodium.alpha.-hydroxypropionate, Sodium Citrate or sodium acetate.Formulation science man can easily determine the amount of the selection and the use of vehicle rule of thumb with to the consideration of standard method with reference to the work of this area.
[00049] solids composition of the present invention comprises the composition of powder, particle, aggregate and compression.Dosage comprises the dosage that is applicable to oral, mouthful cheek, rectum, parenteral (comprising subcutaneous, intramuscular and intravenously), suction and dosing eyes.Though provide under the situation any, sanatory character of institute and seriousness are depended in optimal administration, and most preferred route of administration of the present invention is oral.Dosage can provide by unit dosage easily, and any method preparation of knowing in can pharmaceutical field.
[00050] formulation comprises solid dosage such as tablet, powder, capsule, suppository, sachet, dragee and lozenge, and liquid sugar sirup, suspensoid and elixir.
[00051] can be by wet granulation, preparation is used for the composition of compressing tablet or capsule filling.In wet granulation, with some or all powdered activated composition and vehicle blend, be generally in the presence of the water at liquid then and further mix, this causes the powder aggegation to become particle.Particle is sieved and/or grind, drying, sieve then and/or be ground to desired granularity.Then with the particle compressing tablet, or can before compressing tablet, add other vehicle for example glidant and/or lubricant.
[00052] can mix the preparation Tableted compositions by doing usually.For example, the blend composition of activeconstituents and vehicle can be pressed into piece or sheet, be ground into compressing grains then.This compressing grains can be pressed into tablet subsequently.
[00053] as the substituting of dry granulation, available direct compress technique directly is pressed into compressed dosage forms with blended composition.Directly compression prepares agranular more even tablet.The vehicle that is particularly well suited to direct compression comprises Microcrystalline Cellulose, spray-dired lactose, dicalcium phosphate dihydrate and colloid silica.Aspect the special formulation challenges of direct compression, known these vehicle and other vehicle of suitably using of those skilled in the art of experience and technical ability arranged in direct compression.
[00054] capsule of the present invention is filled the particle that can comprise any above-mentioned blend and describe about compressing tablet, yet they are without final compressing tablet step.
[00055] can activeconstituents and vehicle be mixed with composition and formulation according to the currently known methods of this area.
[00056] amorphous tacrolimus of the present invention can be used as one-component or with the mixture that the tacrolimus of other form forms, is used for pharmaceutical preparation or composition.Yet based on the tacrolimus total amount meter in preparation or the composition, preferred pharmaceutical preparation of the present invention or composition comprise 25-100% weight, particularly the new form tacrolimus of 50-100% weight.Preferably, this amount of new form tacrolimus is 75-100% weight, particularly 90-100% weight.The amount of 95-100% weight very preferably.
[00057] described the present invention, but to those skilled in the art, by the consideration of this specification sheets, other embodiment will be conspicuous in conjunction with some embodiment preferred.By with reference to the preparation of the following detailed description present composition and the embodiment of using method, further define the present invention.To those skilled in the art, can implement many about raw material and method improvement and not deviate from scope of the present invention be conspicuous.
Embodiment
Instrument
[00058] can be analyzed by powder x-ray diffraction (PXRD) by the amorphous tacrolimus of method preparation of the present invention, PXRD carries out on the solid-state detector of X-ray powder diffraction instrument, ARL, θ-θ goniometer, copper-pipe, band Peltier refrigerating unit.Specimen mounting is the circular standard aluminum specimen mounting with circular zero background.Sweep parameter: scope: 2-40 degree 2 θ, continuous sweep; Speed: 3 degree/min.
[00059] amorphous tacrolimus also can be analyzed by thermal analysis system, and thermal analysis system can carry out by digital scanning calorimetry (DSC) with by thermogravimetry (TGA).Can be at DSC822
eObtain the DSC thermogram on the Mettler Toledo instrument (Advanced Instruments, San Juan, Puerto Rico).Sample weight: 3-5mg; Heating rate: 10 ℃/min; Hole count in the crucible: 3.Use the standard aluminum dish, can on Mettler TGA/SDTA 851 instrument (AdvancedInstruments, San Juan, Puerto Rico), obtain the TGA thermogram.Sample weight: 7-15mg; Heating rate: 10 ℃/min.
[00060] crystalline tacrolimus (2g) is dissolved in ethyl acetate (6ml), and is evaporated to drying.This process repeats twice.The foam-like material of evaporation gained is cooled to room temperature.At room temperature, obtain the white amorphous granular (2.00g) that glistens.
Embodiment 2
[00061] the 140g crystalline tacrolimus is dissolved in the 112ml acetone.Solution is injected the null device that has been heated to 40-60 ℃.This equipment maintains under the decompression state.Can be observed foam-like material,, be lower than 0.5% up to the acetone content of product then at 35-45 ℃ of drying under reduced pressure.Obtain white amorphous products.
Claims (23)
1. amorphous tacrolimus, described amorphous tacrolimus is the free drug particle form.
2. the amorphous tacrolimus of claim 1, described amorphous tacrolimus basically as depicted in figs. 1 and 2.
3. the amorphous tacrolimus of claim 1, described amorphous tacrolimus basically as shown in Figure 3.
4. the amorphous tacrolimus of claim 1, described amorphous tacrolimus contains no more than about 5% crystal formation tacrolimus, and wherein said crystal formation is characterised in that the powder X-ray RD collection of illustrative plates that the peak is arranged at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ.
5. the amorphous tacrolimus of claim 1, described amorphous tacrolimus contains no more than about 3% crystal formation tacrolimus, and wherein said crystal formation is characterised in that the powder X-ray RD collection of illustrative plates that the peak is arranged at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ.
6. the amorphous tacrolimus of claim 1, described amorphous tacrolimus contains no more than about 1% crystal formation tacrolimus, and wherein said crystal formation is characterised in that the powder X-ray RD collection of illustrative plates that the peak is arranged at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ.
7. method for preparing amorphous tacrolimus, described method comprise tacrolimus are dissolved in the organic polar solvent, and remove described organic polar solvent to obtain amorphous tacrolimus.
8. the method for claim 7, wherein said organic polar solvent is selected from C
1-6Alcohol, C
3-8Alkyl ester, C
2-8Alkyl ketone, C
2-8Alkyl oxide, acetonitrile and composition thereof.
9. the method for claim 8, wherein said organic polar solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 2-butanols, ethyl acetate, isobutyl acetate, n-butyl acetate, ethyl formate, n-propyl acetate, isopropyl acetate, acetone, methylethylketone, tetrahydrofuran (THF), acetonitrile and composition thereof.
10. the method for claim 9, wherein said organic polar solvent is ethyl acetate or acetone.
11. the method for claim 7, described method repeats.
12. the method for claim 7, wherein said solvent is removed by evaporation.
13. the method for claim 8, wherein said evaporation is carried out in the test tube of rotatory evaporator, rotatory evaporator or commercial test tube.
14. the method for claim 8, wherein said evaporation is carried out under normal pressure or decompression.
15. the method for claim 14, wherein said evaporation is under reduced pressure carried out.
16. the method for claim 8, wherein said evaporation is carried out under about 40 ℃ to about 60 ℃.
17. a pharmaceutical preparation, described pharmaceutical preparation comprise the amorphous tacrolimus and the pharmaceutically acceptable vehicle of claim 1.
18. a tablet, described tablet comprises amorphous tacrolimus.
19. the tablet of claim 18, described tablet contain no more than about 5% crystal formation tacrolimus, wherein said crystal formation is characterised in that the powder X-ray RD collection of illustrative plates that the peak is arranged at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ.
20. the tablet of claim 18, described tablet contain no more than about 3% crystal formation tacrolimus, wherein said crystal formation is characterised in that the powder X-ray RD collection of illustrative plates that the peak is arranged at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ.
21. the tablet of claim 18, described tablet contain no more than about 1% crystal formation tacrolimus, wherein said crystal formation is characterised in that the powder X-ray RD collection of illustrative plates that the peak is arranged at about 10.5,11.3 and 13.8 ± 0.2 degree, 2 θ.
22. a method for the treatment of the gram positive bacteria infection patient, described method comprises the step of the pharmaceutical preparation that gives described patient's claim 17.
23. a method for the treatment of the gram positive bacteria infection patient, described method comprises the step of the tablet that gives described patient's claim 18.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US64186805P | 2005-01-05 | 2005-01-05 | |
| US60/641,868 | 2005-01-05 | ||
| US60/705,681 | 2005-08-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101098875A true CN101098875A (en) | 2008-01-02 |
Family
ID=39012074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800017951A Pending CN101098875A (en) | 2005-01-05 | 2006-01-05 | Amorphous tacrolimus and preparation thereof |
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| CN (1) | CN101098875A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083892A (en) * | 2016-06-13 | 2016-11-09 | 杭州中美华东制药有限公司 | High-purity tacrolimus compound and preparation method thereof |
| CN106880597A (en) * | 2015-12-14 | 2017-06-23 | 山东新时代药业有限公司 | A kind of everolimus piece |
| US10660963B2 (en) | 2014-11-21 | 2020-05-26 | Hangzhou Solipharma Co., Ltd. | Pharmaceutical composition containing tacrolimus and preparation methods thereof |
-
2006
- 2006-01-05 CN CNA2006800017951A patent/CN101098875A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10660963B2 (en) | 2014-11-21 | 2020-05-26 | Hangzhou Solipharma Co., Ltd. | Pharmaceutical composition containing tacrolimus and preparation methods thereof |
| CN106880597A (en) * | 2015-12-14 | 2017-06-23 | 山东新时代药业有限公司 | A kind of everolimus piece |
| CN106083892A (en) * | 2016-06-13 | 2016-11-09 | 杭州中美华东制药有限公司 | High-purity tacrolimus compound and preparation method thereof |
| CN106083892B (en) * | 2016-06-13 | 2019-02-19 | 杭州中美华东制药有限公司 | Tacrolimus compound and preparation method thereof |
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