CN1239946A - Formulations and polymorphic forms of desferrioxamine and the preparation thereof - Google Patents
Formulations and polymorphic forms of desferrioxamine and the preparation thereof Download PDFInfo
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- CN1239946A CN1239946A CN97180523A CN97180523A CN1239946A CN 1239946 A CN1239946 A CN 1239946A CN 97180523 A CN97180523 A CN 97180523A CN 97180523 A CN97180523 A CN 97180523A CN 1239946 A CN1239946 A CN 1239946A
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Abstract
A parenterally injectable composition comprising particles of a desferrioxamine-B salt of an aliphatic sulphonic acid having at least 8 carbon atoms suspended in a parenterally administrable oil. New crystalline modifications of desferrioxamine B decanesulphonic salt are provided, and one crystal form with outstanding stability is disclosed.
Description
Summary of the invention
The present invention relates to the novel polymorphic xln and preparation method thereof and the pharmaceutical composition of the Deferoxamine-1-last of the ten Heavenly stems-sulfonate, the invention still further relates to purposes and preparation of drug combination method thereof that this xln is used for the treatment of purpose; The present invention also relates to other crystalline form.Generally, the invention still further relates to the new pharmaceutical composition of Deferoxamine-B salt that contain as active ingredient.Background of invention
The preparation method of Deferoxamine-B and pharmaceutically acceptable additive salt thereof has been described in US3247197.Such as this amine of describing in above-mentioned United States Patent (USP) and salt has and trivalent metal ion, especially iron ion forms the excellent ability of stable complex.Therefore, in such as the excessive treatment of diseases of the iron of β-thalassemia, as the medicine iron chelating agent, Deferoxamine-B (mesylate form, trade(brand)name Desferal) is extremely important.It is that the only a few that can buy in the market is used for the treatment of one of medicine of thalassemia.
As the excessive necessary method of blood transfusion iron in control β-thalassemia, what extensively adopt at present is to carry out Deferoxamine-B (form of mesylate) administration through slow h inf (8-12 hour).Yet this methods of treatment is for patient seem trouble, uncomfortable and inconvenient and expense height.Patient compliance is poor, promptly the inadaptability of iron chelation therapy has been considered to cause the most important reason of thalassemia patient death.Therefore being badly in need of a kind of more simple and convenient and iron chelation therapy that expense is lower, to be used for the treatment of iron excessive.
For a long time, this demand is conspicuous, and, for Deferoxamine-B of obtaining a kind of form (when adopting more convenient method to implement administration, Deferoxamine-the B of this form is effective in the excessive treatment of iron), carried out a large amount of trials for many years.Deferoxamine-B the organic sulfonate that is used for oral administration has been described in W093/24451.
In the chemistry and drug development of organic chemicals, the form of organic chemicals and polymorphism are extremely important.The material that single crystalline form is only arranged is known, and is same, also has the material with two, three or even more a plurality of polymorphic forms.Based on applied mathematics, can not calculate or predict possible form and structural variant and materialization relation curve separately, especially Thermodynamically stable linearity curve.With regard to crystalline form number and stability thereof, the polymorphism of relevant organic chemicals is so surprising.
If two kinds, three kinds of material or more kinds of crystalline form are known, so in general, their absolute and relative materialization stability can be measured.In whole chemistry and medication preparation process, unstable crystalline form can be brought much unfavorable, and this is that unstable crystalline form may partly or entirely be converted into stable crystalline forms because in each step of preparation process or in each relay storage process.Because metastability, unstable crystalline form can keep and nature finally may take place when certain is uncertain changing for a long time.This possibility that transforms to stable crystalline forms more prepares batch relevantly with each, and can not predict one by one.Thereby, may cause difficulty to chemical research and clinical drug research again.For example, by such as solubility change, these crystal phase transitions can make the bioavailability of medicine produce drastic change.
The preparation method of Deferoxamine-B and its pharmaceutically acceptable salt has been described in US3247197 for example.Such as this amine of in above-mentioned United States Patent (USP), describing and salt has and trivalent metal ion, iron ion Fe especially
3+Form the excellent ability of stable complex.Therefore, for example with the excessive diseases associated of iron, in the treatment as β-thalassemia, as adoptable iron chelating agent on the medicine, Deferoxamine-B (mesylate form, trade(brand)name Desferal) is very important.It is that the only a few that can buy in the market is used for the treatment of one of medicine of thalassemia.
By transfusional β-excessive method of thalassemia patient iron, what extensively adopt at present is to carry out Deferoxamine-B (form of mesylate) administration through slow h inf (8-12 hour) as control.Yet this methods of treatment is for patient seem trouble, uncomfortable and inconvenient and expense height.Therefore be badly in need of a kind of more simple and convenient and iron chelation therapy that expense is lower.
According to the present invention, have now found that, some Deferoxamine-B aliphatic sulfonate can mix by extended release preparation, and this preparation can adopt easily injection to carry out administered parenterally with less dosage at interval by reasonable time, and Deferoxamine-B salt discharges in shot to shot turnaround gradually.Therefore, the invention provides to contain and be suspended in the parenteral injection composition of administered parenterally with the aliphatic sulfonic acid Deferoxamine-B salt particle in the oil with at least 8 carbon atoms.
As the improvement to the Desferal of life-time service, 1-sulfonate in the last of the ten Heavenly stems with Deferoxamine-B is disclosed especially as iron chelating agent among the EP 643690.Yet, wherein do not put down in writing Deferoxamine-1-sulfonate in the last of the ten Heavenly stems and whether have other crystal modifications.It is shocking, had now found that some new crystalline forms of this material.Therefore, the invention still further relates to the new stable crystalline body and preparation method thereof of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems.Description of drawings
Accompanying drawing 1/3 is the xln A of Deferoxamine sulfonate in the last of the ten Heavenly stems
2The X-ray diagram.X-coordinate (X-axle): diffraction angle 2 θ (3 °-30 ° of scopes); Ordinate zou (Y-axle): relative intensity.
Accompanying drawing 2/3 is the xln A of Deferoxamine sulfonate in the last of the ten Heavenly stems
1The X-ray diagram.X-coordinate (X-axle): diffraction angle 2 θ (3 °-30 ° of scopes); Ordinate zou (Y-axle): relative intensity.
Accompanying drawing 3/3 is that the xln B of Deferoxamine sulfonate in the last of the ten Heavenly stems is (with xln A
11-A
13Mixture) the X-ray diagram.X-coordinate (X-axle): diffraction angle 2 θ (3 °-30 ° of scopes); Ordinate zou (Y-axle): relative intensity.Detailed Description Of The Invention
First preferred version of the present invention relates to the parenteral injection composition that contains the Deferoxamine-B salt particle that is suspended in the aliphatic sulfonic acid with at least 8 carbon atoms in the administered parenterally oil.
Generally, Deferoxamine-B salt can be the salt with aliphatic sulfonic acid of 8-20 carbon atom.Described acid comprises hydrocarbyl sulfonic, for example, alkansulfonic acid, alkene sulfonic acid and alkynyl sulfonic acid, as octane-1-sulfonic acid, octane-2-sulfonic acid, nonane-1-sulfonic acid, nonane-2-sulfonic acid, positive last of the ten Heavenly stems sulfonic acid, positive ten disulfonic acid, ten tetrasulfonic acids, 16 sulfonic acid, 18 sulfonic acid, octene-1-sulfonic acid, decylene-1-sulfonic acid, dodecylene-1-sulfonic acid, tetradecene-1-sulfonic acid, cetene-1-sulfonic acid or decyl ethynyl sulfonic acid, and alkyl is by such as hydroxyl, C1-C4 alkoxyl group, acyloxy, C1-C4 carbalkoxy, halogen or the amino above-mentioned acid that replaces.Can prepare this salt by the description among the WO93/24451.
Deferoxamine-B salt is preferably has 8-20 carbon atom, the salt of the aliphatic sulfonic acid of preferred 8-10 carbon atom, especially positive hot sulfonic acid or just the last of the ten Heavenly stems sulfonic acid salt.The preferred special stable crystalline forms of Deferoxamine-B that the present invention uses sulfonate in the positive last of the ten Heavenly stems is crystal modifications A2, hereinafter will be described in more detail this crystalline form.
Other preferred crystalline form of Deferoxamine-B that the present invention uses sulfonate in the positive last of the ten Heavenly stems is crystal modifications A
1, to record this crystalline form fusing point be 140-153 ℃ and have following characteristics diffracted ray (2 θ diffraction angle ± 0.1 °) in its X-ray diffraction pattern with DSC (dsc): 4.1 °, 6.3 °, 8.4 °, 10.5 °, 12.6 °, 16.9 °, 18.0 °, 19.8 °, 20.8 °, 22.1 °, 25.0 °, 25.6 ° and 26.4 ° (detailed description that vide infra).Xln A
1Not as good as xln A
2Stable, especially all the more so under the condition of water and polar solvent or the existence of its mixture.Yet, in the administered parenterally oil of the present composition, xln A
1It is dynamic stabilization.
Be lower than room temperature, preferably under 0-5 ℃ temperature, by with positive last of the ten Heavenly stems sulfonic acid alkali metal salts the aqueous solution join gradually in the aqueous solution of Deferoxamine-B mesylate, can make xln A
2Then, to the temperature that raises, preferred range is the boiling point of room temperature-this mixture, more preferably 30-80 ℃ with this mixture heating up.
Another kind of Deferoxamine-B sulfonate the crystalline form in the positive last of the ten Heavenly stems that is applicable to the present composition is xln A
1Mixture with xln B.Xln B fusing point is about 142 ℃ (measuring with the DSC method) and have following characteristics diffracted ray (2 θ diffraction angle ± 0.1 °) in its X-ray diffraction pattern: 3.5 °, 7.1 °, 8.9 °, 9.9 °, 11.3 °, 12.3 °, 19.0 °, 21.7 °, 22.1 ° and 23.8 °.Xln B is not as good as xln A
1Stable, when temperature rise rate was 10 ℃/min, it was converted into xln A
1As described in embodiment among the WO93/24451 1, decane-1-sulfonic acid and Deferoxamine-B free alkali reaction are generated crude salt, crude salt is dissolved in carries out recrystallization in the aqueous ethanol, filter gained solution, and under reduced pressure, remove part ethanol and separate out until product, can make xln A thus
1Mixture with xln B.
Deferoxamine-B salt particle the median size that is suspended in the oil is generally the 1-1000 micron, preferred 3-500 micron, especially 5-100 micron, more preferably 5-10 micron.
Administered parenterally can be the mixture that can accept oil on any pharmaceutically acceptable oil or the medicine with oil, and its viscosity should be suitable for drug administration by injection.Described oil comprises mineral oil, vegetables oil and animal oil and the fatty acid ester that is obtained by these oil, preferably vegetable oil or the fatty acid ester that obtains by vegetables oil, for example, refined wax oil, Viscotrol C, sesame oil, Oleum Gossypii semen, Trisun Oil R 80, Oleum Cocois, palm-kernel oil, peanut oil, wheat germ oil, ethyl oleate, Isopropyl myristate, coconut fatty acid ester and palm kernel fatty acid ester, promptly, the ester of sad and capric acid and glycerine or propylene glycol, and above-mentioned two or more oily mixtures.Administered parenterally oil preferably includes the mixture or the triglyceride level sad and the capric acid mixture of ethyl oleate, ethyl oleate and sesame oil.In particularly preferred embodiments, administered parenterally oil contains 25-100 weight % ethyl oleate and 0-75 weight % sesame oil, and perhaps administered parenterally oil contains sad and the triglyceride level capric acid mixture, and sad and weight ratio capric acid is 10: 9-13: 6.Described triglyceride level is commercially available, for example, and the Miglyol 812 that buys from German H ls AG.
In the present composition, Deferoxamine-B salt generally exists with the treatment significant quantity, and with oily, the amount of Deferoxamine-B salt is generally 0.05-0.4g for every milliliter of administered parenterally, preferred 0.1-0.3g.Composition is suitable for being present in the appropriate containers such as glass or plastic injector or bottle or polythene container with parenteral injection dosage, and described parenteral injection dosage is generally 0.5-10ml, preferred 3-7ml.Preferably composition is contained in prepackage (prefilled) syringe or seals in (bottlepack) polythene container and administration from this syringe or container.
In some cases, the present composition preferably also contains tensio-active agent (emulsifying agent).Containing emulsifying agent (content is preferably the 0.1-3 volume % of composition) in the composition can prevent the gathering tendency of solid Deferoxamine-B salt particle and help salt particle homodisperse more in oil.Suitable tensio-active agent comprises pharmaceutically acceptable nonionogenic tenside, preferred lipophilic surfactant, for example, sorbitan fatty acid esters, particularly sorbitan one lauric acid ester, sorbitan monooleate and sorbitan trioleate, polysorbate, as polyoxyethylene (20) sorbitan one lauric acid ester, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) anhydrosorbitol monooleate ester and polyoxyethylene (20) sorbitan trioleate, the C of polyoxygenated ethylidene glycol
10-C
20Alkyl oxide is as polyoxyethylene (4) lauryl ether and phosphatide tensio-active agent, as soybean lecithin.
Can also contain in the present composition other such as the vehicle that in conventional parenteral injection administration composition, uses, for example, osmotic pressure regulator, as glucose and sodium-chlor, sanitas, as the methyl esters and the propyl ester of phenylcarbinol, peruscabin and P-hydroxybenzoic acid, and oxidation inhibitor, as fourth cresols and tocopherol.
The present invention also provides the preparation method of the aforesaid present composition, and this method comprises mixes with administered parenterally Deferoxamine-B salt particle with oil and tensio-active agent (if present).In suitable embodiment, mix in two stages, wherein (a) is with salt and part oil grinds and (b) remaining oil is joined in the mixture that ground, if the use tensio-active agent then adds tensio-active agent in stage (a) and/or stage (b).If administrable oil contains the mixture of the different oil of viscosity, for example, contain the mixture of sesame oil and ethyl oleate, can before adding low viscous oil, salt be mixed easily with higher tack oil so.In preferred embodiments, Deferoxamine-B salt is joined in oil or oil and the surfactant mixtures, adopt preferably homogenizing gained mixture in colloidal mill etc. of pharmaceutically acceptable polishing, until the required salt particle diameter of acquisition.Perhaps, can use the air spray mill with the micronization of de-iron amine salt, use the utraturrax mixing tank with this salt suspension in oil phase, be filled into subsequently in the required container and with γ or β ray (10-100kGy kilogray (kGy) radiation dose) or thermal treatment to container and drug disinfection.
Deferoxamine-B the salt of under aseptic condition, purifying, use ordinary method, for example, using the aperture is that the strainer of 0.22 μ m filters or 170 ℃ of heating at least 2 hours oil sterilized, and under aseptic condition, aseptic oil is mixed with the Deferoxamine-B salt of purifying, can guarantee to make aseptic composite of the present invention thus.
Can carry out the administered parenterally of the present composition by for example muscle or subcutaneous injection.After carrying out present composition administered parenterally, Deferoxamine-B can slowly discharge through 48 hours.Can be to the Deferoxamine-B salt dosage of patient's administration up to about 4g every day, for example, every day 500mg-4g.Can finish the infusion of this dosage easily by carrying out every day or per two days bolus injection.The present invention includes that treatment iron excessive disease, aluminium are excessive, Alzheimer, malaria, reperfusion damage (reperfusion injury) or method for cancer, this method comprises the warm-blooded mammals that needs is carried out above-mentioned treatment, the especially human parenteral injection present composition defined above.
The invention still further relates to the new stable crystalline forms of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems (this salt is preferred in composition mentioned above and the preparation thereof) and the preparation method of this crystalline form.
The present invention relates to the Deferoxamine shown in the formula 1-1-sulfonate in last of the ten Heavenly stems crystalline form (the amino amyl group of N-[5-{3-[(5-)-hydroxylamino formyl radical]-propionamido }-amyl group]-3-[{5-(the amino amyl group of N-glycoloyl }-formamyl]-propionyl hydroxamic acid-1-sulfonate in the last of the ten Heavenly stems)
Under nitrogen, heating rate with 10 ℃/min is carried out dsc, the melting range that records this xln is 154-158 ℃, and has the following characteristics diffracted ray (2 θ diffraction angle ± 0.1 °) in its X-ray diagram: 3.1 °, 7.3 °, 9.4 °, 13.7 ° and 23.7 °.
The invention particularly relates to the xln of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems, under nitrogen, heating rate with 10 ℃/min is carried out dsc, the melting range that records this xln is 154-158 ℃, and has the following characteristics diffracted ray (2 θ diffraction angle ± 0.1 °) in its X-ray diagram: 3.1 °, 4.2 °, 7.3 °, 8.4 °, 9.4 °, 10.5 °, 13.7 °, 16.8 °, 17.4 °, 18.0 °, 18.4 °, 19.6 °, 20.1 °, 20.9 °, 22.3 °, 23.7 °, 25.1 ° and 25.6 °.
(the present invention is called " xln A to this new specific crystalline form
2") characteristic be better than the characteristic of all other known crystalline forms of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems.In common temperature range, xln A
2Materialization and the thermodynamic stability known crystalline form that is better than other, thereby be more suitable for using in the production of solid state chemistry material and exploitation, production and the treatment of pharmaceutical preparation.More precisely, with xln A
2Compare, all known crystalline forms are metastable.Therefore, no matter in producing, storing and in the treatment application process, (for example storing after the injection) what the dispersion agent that uses is, has only xln A
2Solid state transformation can not take place.And, xln A
2Than xln A
1Be easy to grind.
In melting range, xln A
2Has good thermostability.Under the heating rate of 10 ℃/min, xln A
2In 148-162 ℃ temperature range, (comprise 154-158 ℃ of melting temperature scope) and melt.
The preferred especially xln A that characterizes by accompanying drawing 1/3X ray diagram
2
Except xln A
2Outward, the present invention also provides the xln of other less stable.Xln A
1Melting range be 140-153 ℃.The crystalline form that it is equivalent to put down in writing among the EP643690.More accurate dsc (DSC) shows, xln A
1Be to be the subgrain shape A of 148 ℃, 150 ℃, 152 ℃ and 153 ℃ by 4 fusing points
11, A
12, A
13And A
14Form.These subgrain shapes are also to generate xln A with different quantity together than acquisition in the preparation process of material
1
Xln B can appear in the preparation process of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems equally.DSC shows that its fusing point is about 142 ℃, and under the heating rate of 10 ℃/min, can observe xln B and be converted into A
1One or more subgrain shape, i.e. A
11-A
14
Specifically, obtained the following column data of relevant different crystal forms by DSC:
The xln A of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems
2DSC figure, sample is heavy: 2.177mg, under nitrogen, with the heating rate of 10 ℃/min, recording fusing point is T
42 Fusing point=155 ℃.
The xln A of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems
11, A
12And A
13DSC figure, sample is heavy: 2.747mg under nitrogen, with the heating rate of 10 ℃/min, records following fusing point: TA
11 Fusing point=148 ℃; TA
12 Fusing point=150 ℃ and TA
13 Fusing point=152 ℃.
The xln A of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems
1DSC figure, sample is heavy: 2.683mg under nitrogen, with the heating rate of 10 ℃/min, records following fusing point: TA
12 Fusing point=149 ℃; TA
13 Fusing point=151 ℃ and TA
14 Fusing point=153 ℃.
The xln B of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems is (with xln A
11-A
13Mixture) DSC figure, sample is heavy: 2.285mg under nitrogen, with the heating rate of 10 ℃/min, records following fusing point: T
B Fusing point=142 ℃.
Except fusing point, can also distinguish crystalline form according to X ray powder figure.In discipline Buddhist nun's leaf camera of transmission geometry (transmission geometry), use Cu-K α
1Ray clap X ray powder figure be preferred for characterizing organic solid.Particularly the X-ray diffraction pattern has been successfully used to measure the different crystal forms of material.In order to characterize the xln A of Deferoxamine of the present invention-1-sulfonate in the last of the ten Heavenly stems
2, at room temperature detect and record X-ray photographs in 3 °-30 ° diffraction angle (2 θ) scope.For Cu-K α
1Ray has been listed all diffraction angle 2 θ of the present invention.Table 1: the xln A of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems
2X-ray diffraction pattern (diffraction angle of most important diffracted ray and intensity) (Fig. 5)
| ????2θ | Intensity |
| ????3.1° | By force |
| ????4.2° | By force |
| ????7.3° | A little less than |
| ????8.4° | A little less than |
| ????9.4° | A little less than |
| ????10.5° | By force |
| ????13.7° | A little less than |
| ????16.8° | A little less than |
| ????17.4° | Very weak |
| ????18.0° | By force |
| ????18.4° | Very weak |
| ????19.6° | Very strong |
| ????20.1° | Medium |
| ????20.9° | Medium |
| ????22.3° | A little less than |
| ????23.7° | A little less than |
| ????25.1° | By force |
| ????25.6° | A little less than |
Table 2 and 3 has repeated above-mentioned xln A
1X-ray diffraction pattern with xln B.The xln A of table 2 Deferoxamine-1-sulfonate in the last of the ten Heavenly stems
1X-ray diffraction pattern (diffraction angle of most important diffracted ray and intensity) (Fig. 6)
The X-ray diffraction pattern (diffraction angle of most important diffracted ray and intensity) of the xln B of table 3 Deferoxamine-1-sulfonate in the last of the ten Heavenly stems (Fig. 6)
| ????2θ | Intensity |
| ????4.1° | Very strong |
| ????6.3° | A little less than |
| ????8.4° | A little less than |
| ????10.5° | By force |
| ????12.6° | A little less than |
| ????16.9° | A little less than |
| ????18.0° | Medium |
| ????19.8° | By force |
| ????20.8° | Medium |
| ????22.1?° | Very weak |
| ????25.0° | Medium |
| ????25.6° | Very weak |
| ????26.4° | Very weak |
| ????2θ | Intensity |
| ????3.5° | A little less than |
| ????7.1° | A little less than |
| ????8.9° | Very weak |
| ????9.9° | Very weak |
| ????11.3° | Very weak |
| ????12.3° | A little less than |
| ????19.0° | By force |
| ????21.7° | Medium |
| ????22.1° | By force |
| ????23.8° | Medium |
The X-ray diffraction pattern has proved uses A
1, A
2The xln of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems of representing with B is diverse polymorphic crystal.The X-ray diffraction pattern with can record xln A
1The DSC method (referring to above) of 4 different melting points compare, its difference is that the X-ray diffraction pattern is too little, can not reflect the obvious deviation corresponding to the reflection angle 2 θ values of table 2.
Another suitable parameters that is used to distinguish xln is their moisture absorptivity normally, can judge the stability of xln thus.For example, in the atmosphere of known relative humidity, in the preferred nitrogen atmosphere, can record the water-absorbent of substances by the water vapour specific absorption of weighing.Table 4: at 25 ℃, xln A
1And A
2Suction percentage ratio
| Relative humidity (%) | ????A 1Water-absorbent (%) | ????A 2Water-absorbent (%) |
| ????0 | ????0 | ????0 |
| ????10 | ????0.1 | ???＜0.1 |
| ????20 | ????0.2 | ???＜0.1 |
| ????30 | ????0.2 | ????0.1 |
| ????40 | ????0.3 | ????0.1 |
| ????50 | ????0.3 | ????0.1 |
| ????60 | ????0.4 | ????0.1 |
| ????70 | ????0.5 | ????0.2 |
| ????80 | ????0.6 | ????0.2 |
| ????90 | ????0.9 | ????0.3 |
| ????95 | ????2.1 | ????0.5 |
| ????98 | ????4.7 | ????0.8 |
With xln A
1Compare xln A
2Have obviously lower water-absorbent, this shows xln A of the present invention
2Stability higher.
The invention still further relates to the xln A of production Deferoxamine of the present invention-1-sulfonate in the last of the ten Heavenly stems
2Method.
The method is characterized in that at least one operation, the suspension of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems in polar solvent that unknown or unspecified crystal formation is formed keeps at elevated temperatures; Perhaps at least one operation, make the Deferoxamine-strong solution of 1-sulfonate in the last of the ten Heavenly stems in polar solvent at elevated temperatures, under 2 ℃/min or lower rate of cooling, carry out crystallization then.
Polar solvent is a polar organic compound for example, for example, and lower alcohol, lower ketones, rudimentary nitrile and rudimentary cyclic ethers and water or its mixture.Term " rudimentary " is meant and contains 1-4 carbon atom and one or two heteroatomic organic compound such as oxygen, nitrogen and/or sulphur.Preferred polar organic solvent is a water-miscible organic solvent, for example, and methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone, ethyl methyl ketone, acetonitrile, tetrahydrofuran (THF) or para-dioxane.The mixture of water or water-miscible organic solvent, particularly methyl alcohol, ethanol, n-propyl alcohol and/or Virahol and water is particularly advantageous in preparation xln A2 of the present invention.Water most preferably.
Described " temperature of rising " is meant the temperature range of " room temperature-solvent or solvent mixture boiling point ", preferred 30-80 ℃, perhaps be meant the temperature range of " room temperature-polar solvent boiling point ", and this temperature range is general also lower, preferred 35-60 ℃.
Described " strong solution " is meant the solution that contains a certain amount of dissolved substance, and when cooling off this solution to lesser temps, dissolved substances will partial crystallization.Preferred strong solution is saturated or oversaturated slightly solution.If elevated temperature not, then saturated the or supersaturated solution of material will can not dissolve any material again.Such as, by being quickly cooled under the lower slightly temperature, saturated solution can make supersaturated solution.It is particularly advantageous using saturated solution.
Preferred solution rate of cooling is 2 ℃/min or lower.1 ℃/min or lower rate of cooling are especially favourable.
In the preferred embodiment of this method, add at least one crystal seed.
For example, by suspension being remained under the temperature of described rising, can make suitable crystal seed by the crystalline form of less stable or the mixture of several less stable crystalline forms.
In this method particularly preferred embodiment, deferoxamine mesylate salts solution in the preparation polar solvent, be heated to temperature required, then will be in same or other polar solvent etc. the part of mole 1-sulfonate solution in the last of the ten Heavenly stems join wherein, add at least one crystal seed, keep this state until crystallization takes place, then will the remainder that waits mole 1-sulfonate solution in the last of the ten Heavenly stems in same or other polar solvent slowly adding wherein keep temperature required afterwards; Perhaps make the hot saturated solution of the Deferoxamine-1-sulfonate in the last of the ten Heavenly stems in the polar solvent at elevated temperatures, after adding at least one crystal seed, be cooled to lower elevated temperature with 1 ℃/min or lower rate of cooling, crystallization takes place during this period, and crystal suspension is remained under this lesser temps.
Described " 1-sulfonate in the last of the ten Heavenly stems " can be the salt that for example has better deliquescent all 1-sulfonic acid in the last of the ten Heavenly stems in the polar solvent of selecting for use than Deferoxamine-1-sulfonate in the last of the ten Heavenly stems.These salt can be the salt with alkali, for example, corresponding alkali metal salt, as the salt of sodium salt or sylvite or ammonia or organic amine, described ammonia or organic amine for example are, cyclammonium, as one, two or trialkylamine, as hydroxy lower alkyl amine, as one, two or trihydroxy--low-grade alkylamine, hydroxy lower alkyl-low-grade alkylamine or poly-hydroxy-low-grade alkylamine.Cyclammonium is for example morpholine, thiomorpholine, piperidines or tetramethyleneimine.One low-grade alkylamine can be for example ethyl and tert-butylamine, and two low-grade alkylamines can be for example diethyl and diisopropylamine, and three low-grade alkylamines can be for example trimethylammonium and triethylamine.Corresponding hydroxy lower alkyl amine is for example one, two and trolamine, and hydroxy lower alkyl-low-grade alkylamine is N for example, and N-dimethylamino and N, N-DEAE diethylaminoethanol, poly-hydroxy-low-grade alkylamine can be glycosamines for example.Acceptable salt, especially sodium salt on the preferred agents.
With known substantially mode separated and collected crystal from mother liquor, for example, being in or be not in pressurization and/or vacuumizing under the condition and filters, or carrying out centrifugally, and carry out drying subsequently.
The invention still further relates to the xln A of the Deferoxamine-1-sulfonate in the last of the ten Heavenly stems that contains as active ingredient
2With the pharmaceutical preparation of pharmaceutically acceptable carrier, preferably as mentioned and hereinafter described.The invention still further relates to the preparation method of this pharmaceutical preparation, preferably as indicated above.The invention still further relates to the xln A of Deferoxamine-1-sulfonate in the last of the ten Heavenly stems
2The disease of, Alzheimer excessive in treatment chosen from Fe excessive disease, aluminium, malaria, reperfusion damage (reperfusioninjury) and cancer is especially treated the purposes in the thalassemia or is treated purposes in the pharmaceutical preparation of above-mentioned disease in preparation.The invention further relates to that treatment chosen from Fe excessive disease, aluminium are excessive, the method for the disease of Alzheimer, malaria, reperfusioninjury and cancer, relate in particular to the exsanguine method in treatment Mediterranean Sea, this method comprises that the patient to the above-mentioned treatment of needs uses Deferoxamine-1-sulfonate in the last of the ten Heavenly stems xln A of doses
2, the dosage that uses is medicine effective quantity in described treatment of diseases.
In all cases, the dosage of active ingredient and per-cent are consistent with routine dose and per-cent, especially are above and dosage hereinafter described and per-cent.Embodiment:
The present invention describes with following embodiment, and wherein except as otherwise noted, part is represented with weight.But the present invention is not subjected to the restriction of embodiment.Used Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems among the embodiment, sample I is prepared as follows: at 0-5 ℃, through 60 minutes, the 1-sodium decylsulfonate salt brine solution with 10% joined in Deferoxamine-B mesylate aqueous solution of 20%, and the last of the ten Heavenly stems, the mol ratio of sulfonate and mesylate was 1: 1.Be settled out Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems.Before filter collecting product, in 0-5 ℃, with this suspension restir 1-2 hour.Wash product with water, and 40 ℃ of vacuum-dryings 20 hours, sieving at last prevented the product caking.Used Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems among the embodiment, sample II is prepared as follows: at 30-40 ℃, Deferoxamine-B mesylate (12.3 parts) is dissolved in the water (47 parts), at 50 ℃, through several minutes, to the water that wherein adds positive sodium decylsulfonate (0.7 part) (12.0 parts) solution.Add Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems (0.08 part) and make solution crystallization, stirred gained suspension 30 minutes, then,, under agitation condition,, slowly add water (64 parts) solution of positive sodium decylsulfonate (3.8 parts) once more through 3-4 hour at 50-52 ℃ at 50 ℃.At 50-52 ℃, with gained suspension restir 1-2 hour and cool overnight to 40 ℃.Filter and collect product, wash with water, 50 ℃ of vacuum-dryings 20 hours, sieving at last prevented the product caking.Used Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems among the embodiment, sample III is prepared as follows: at 40 ℃, will be dissolved in the mixture of ethanol (3000ml) and water (600 ml) by thick Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems that the Deferoxamine of describing among the embodiment 1 of positive last of the ten Heavenly stems sulfonic acid and WO93/24451-B free alkali (548g) reaction makes.Filtering solution and at 40 ℃ of decompressions (40mbar) distillations concentrated filtrate.The dense suspension that water (3000) dilution obtains filters and collects product, washes with water, and 50 ℃/20mbar vacuum-drying 20 hours, sieving at last prevented the product caking.
In embodiment 1-16, obtain described Deferoxamine-B salt parenteral injection composition.And provided the various suspension Deferoxamines-median size of B salt and the result of particle size dispersion of gained.Embodiment 1: composition A
Deferoxamine-B sulfonate sample in positive last of the ten Heavenly stems I (1g) is mixed with sesame oil (3.75ml) and polyoxyethylene (20) anhydrosorbitol monooleate ester (0.02ml) until obtaining not having piece suspension.In gained suspension, add ethyl oleate (1.25ml) and use pestle and mortar immediately its thorough mixing.The result: median size is 59.18 μ m; Particle size dispersion is: 90% less than 113.19 μ m, 50% less than 50.08 μ m and 10% less than 5.41 μ m.Embodiment 2: composition B
Replace its consumption in embodiment 1 with 2.5ml sesame oil and 2.5ml ethyl oleate, repeat embodiment 1.The result: median size is 66.34 μ m; Particle size dispersion is: 90% less than 121.78 μ m, 50% less than 62.34 μ m and 10% less than 6.49 μ m.Embodiment 3: composition C
Replace its consumption in embodiment 1 with 1.25ml sesame oil and 3.75ml ethyl oleate, repeat embodiment 1.The result: median size is 68.97 μ m; Particle size dispersion is: 90% less than 119.31 μ m, 50% less than 66.97 μ m and 10% less than 7.97 μ m.Embodiment 4: composition D
Replace its consumption in embodiment 2 with 0.043ml polyoxyethylene (20) anhydrosorbitol monooleate ester, repeat embodiment 2.The result: median size is 57.02 μ m; Particle size dispersion is: 90% less than 107.45 μ m, 50% less than 54.65 μ m and 10% less than 4.99 μ m.Embodiment 5: composition E
Without polyoxyethylene (20) anhydrosorbitol monooleate ester, repeat embodiment 2.The result: median size is 60.04 μ m; Particle size dispersion is: 90% less than 112.84 μ m, 50% less than 56.42 μ m and 10% less than 5.25 μ m.Embodiment 6: composition F
Replace its consumption in embodiment 1 with 2.5ml sesame oil, 2.5ml ethyl oleate and 0.043ml polyoxyethylene (20) anhydrosorbitol monooleate ester, and in the fs of preparation, above-mentioned component is mixed with sorbitan trioleate (0.057ml), repeat embodiment 1.The result: median size is 60.36 μ m; Particle size dispersion is: 90% less than 109.36 μ m, 50% less than 58.14 μ m and 10% less than 5.12 μ m.Embodiment 7: composition G
Polyoxyethylene (20) anhydrosorbitol monooleate ester with using among soybean lecithin (0.011g) the replacement embodiment 2 repeats embodiment 2.The result: median size is 43.13 μ m; Particle size dispersion is: 90% less than 93.62 μ m, 50% less than 34.26 μ m and 10% less than 4.98 μ m.Embodiment 8: composition H
Replace its consumption in embodiment 7 with the 0.027g soybean lecithin, repeat embodiment 7.The result: median size is 52.07 μ m; Particle size dispersion is: 90% less than 117.62 μ m, 50% less than 39.98 μ m and 10% less than 5.99 μ m.Embodiment 9: composition I
Deferoxamine-B sulfonate sample in positive last of the ten Heavenly stems II (1g) is mixed with sesame oil (2.5ml) and polyoxyethylene (20) anhydrosorbitol monooleate ester (0.02ml) until obtaining not having piece suspension.In gained suspension, add ethyl oleate (2.5ml) and with being about to its thorough mixing.The result: median size is 41.48 μ m; Particle size dispersion is: 90% less than 99.19 μ m, 50% less than 26.31 μ m and 10% less than 5.24 μ m.Embodiment 10: composition J
Replace its consumption in embodiment 9 with 0.004ml polyoxyethylene (20) anhydrosorbitol monooleate ester, repeat embodiment 9.The result: median size is 43.60 μ m; Particle size dispersion is: 90% less than 104.11 μ m, 50% less than 26.63 μ m and 10% less than 5.22 μ m.Embodiment 11: composition K
Replace its consumption in embodiment 9 with 0.043ml polyoxyethylene (20) anhydrosorbitol monooleate ester, repeat embodiment 9.The result: median size is 30.60 μ m; Particle size dispersion is: 90% less than 73.40 μ m, 50% less than 17.18 μ m and 10% less than 5.22 μ m.Embodiment 12: composition L
Without polyoxyethylene (20) the anhydrosorbitol monooleate ester that uses among the embodiment 9, repeat embodiment 9.The result: median size is 43.75 μ m; Particle size dispersion is: 90% less than 104.80 μ m, 50% less than 25.32 μ m and 10% less than 5.3 μ m.Embodiment 13: composition M
With 3.75ml sesame oil and 1.25ml ethyl oleate replace its in embodiment 9 consumption and without polyoxyethylene (20) the anhydrosorbitol monooleate ester that uses among the embodiment 9, repeat embodiment 9.The result: median size is 50.52 μ m; Particle size dispersion is: 90% less than 118.97 μ m, 50% less than 31.87 μ m and 10% less than 6.91 μ m.Embodiment 14: composition N
With 1.25ml sesame oil and 3.75ml ethyl oleate replace its in embodiment 9 consumption and without polyoxyethylene (20) the anhydrosorbitol monooleate ester that uses among the embodiment 9, repeat embodiment 9.The result: median size is 35.83 μ m; Particle size dispersion is: 90% less than 86.60 μ m, 50% less than 19.85 μ m and 10% less than 5.92 μ m.Embodiment 15: composition 0
Without polyoxyethylene (20) the anhydrosorbitol monooleate ester that uses among the embodiment 9, repeat embodiment 9.The result: median size is 39.50 μ m; Particle size dispersion is: 90% less than 96.33 μ m, 50% less than 22.08 μ m and 10% less than 6.23 μ m.Embodiment 16: composition P
With the 5.00ml ethyl oleate replace its in embodiment 9 consumption and do not use among the embodiment 9 sesame oil that uses, repeat embodiment 9.The result: median size is 35.44 μ m; Particle size dispersion is: 90% less than 79.52 μ m, 50% less than 19.79 μ m and 10% less than 5.85 μ m.Embodiment 17: the plasma concentration I in hamster
In triple-roller mill, Deferoxamine-B sulfonate sample in positive last of the ten Heavenly stems I (1g) is ground with the mixture of the sesame oil (2.5ml), ethyl oleate (2.5ml), polyoxyethylene (20) mono-laurate (0.057ml) and polyoxyethylene (20) the anhydrosorbitol monooleate ester (0.043ml) that slowly add.As described below, the parenteral injection suspension of gained is used to carry out the vivo releasing test of Deferoxamine-B salt:
Press the nape place subcutaneous injection above-mentioned suspension of the dosage of 1ml/kg at the male gold hamster of 100 ± 20g.With regular anesthetized animal of the different timed intervals, obtain blood sample by cardiac puncture, blood collecting is also centrifugal in the heparinization syringe.Remove blood plasma, the total concn of Deferoxamine-B and meta-bolites B in the immunoassay blood plasma.For the different timed intervals, the result represented with the mean value of three animals is as follows:
Time (hour) Deferoxamine-B in the blood plasma
Total concn (μ g/ml) with meta-bolites B
3??????????????????24.57
6??????????????????14.36
24?????????????????0.53
30?????????????????0.58
48?????????????????2.31
54?????????????????0.77
72?????????????????0.48
168????????????????0.45
Adopt the solid-phase enzyme immunoassay method to carry out immunoassay, described solid-phase enzyme immunoassay method can detect such as iron chelate Desferal in the biofluid of blood plasma and urine
TMAnd the existence of main metabolites B (MetB).For this reason, developed multi-clone rabbit antibody.This antibody capable is distinguished parent molecule Deferoxamine (DFO) and inner complex form-sideramines (FO) thereof.The cardinal principle of this method is as follows: the connection by vitamin H/streptavidin is applied to FO in the hole of 96 orifice plates (Nunc Maxisorb).Draw the typical curve of DFO or meta-bolites B with containing dilution (1/20 damping fluid) biofluid (serum, urine etc.) of ironic citrate (1mM) as source of iron.In same fluid, test sample is carried out corresponding dilution.The anti-sideramines antibody that adding is suitably diluted also reacts.Not binding antibody is removed in washing.Use goat antirabbit lgG Fc fragment horseradish peroxidase and peroxidase substrate detection binding antibody with antibodies.Colo(u)r specification that produces and the amount of the DFO/MetB in the sample are inversely proportional to.
Antibody Preparation is as follows:
Prepare immunogenic bovine serum albumin (BSA)/Deferoxamine conjugate according to standard method and (use (SPDP) activated b SA of N-succinimido (succinimidyl) 3-(2-pyridyl dithio)-propionic ester (proprionate), remove excessive DPDP by dialysis, reduce with dithiothreitol (DTT), obtain combining the BSA of sulfydryl, dialysis, add SPDP, DFO and N-methylmorpholine then, after one hour, at 1000g centrifugal 5 minutes, and 4 ℃ to phosphate buffered saline buffer (PBS) dialysis 17 hours, preserve the gained solution at-80 ℃.Can obtain keyhole limpet hemocyanin (KLH)/DFO conjugate with similar method).Then will be respectively alternately be injected to (450 μ g BSA-DFO 0 month in Dutch rabbit (Harlan-Olac) body through subcutaneous with Freund's incomplete adjuvant blended BSA-DFO conjugate and KLH-DFO conjugate (mixing) by 1: 1,300 μ g KLD-DFO January, the 250 μ g BSA-DFO2 months, 150 μ g KLH-DFO March, 150 μ g BSA-DFO June, the 150 μ g KLH-DFO10 months).Separating blood, the serum that makes-20 ℃ of preservations.With ordinary method separation antibody on a-protein-agarose.
In the presence of N-methylmorpholine, by vitamin H-LC-NHS in water/dimethyl formamide and FO reaction, preparation vitamin H-FO/DFO conjugate.
Medicine and bound drug that competitive assay is based in the sample are that binding antibody is vied each other, and antibody can detect with the horseradish peroxidase that combines anti-kind of antibody.Measure drug concentrations by the typical curve of the DFO that in suitable biofluid/buffer solution mixture, dilutes and the typical curve (molar equivalent concentration) of meta-bolites B (MetB).Antibody only can be discerned iron mating type DFO or any iron chelating type meta-bolites, and they can transform on the spot by add the 1mM ironic citrate in sample buffer.In two kinds of different damping fluids, detect two kinds of PBS pH6.4 or 0.3M borate pH7.4 that different damping fluids is 0.3M.Adding 1mM ironic citrate (1/2) also can make blood plasma or urine sample be converted into iron combining form.
At pH is that 9.6 0.1M carbonate is coated with and soaks in the damping fluid (carbonate coatingbuffer), streptavidin is diluted to 0.1 μ g/ml, and it is joined in the hole (100 μ l/ hole) of titer plate, then 22 ℃ of overnight incubation.With PBS/ tween (Tween) (polysorbas20, Sigma, Poole, Dorset) washing hole is four times.At 37 ℃, cultivate 1 hour with adsorption site remaining on the saturated plate with containing 0.1% caseic 200 μ l PBS.With PBS/Tween washing hole four times.Vitamin H-FO (427 μ g/ml) is diluted to 1ng/ml and in hole (100 μ l/ hole), was cultivating 2 hours under 22 ℃ with the PBS/ casein.With PBS/Tween washing hole four times.The standard specimen (2.80500-0.00273/0.00000 μ M) of DFO and MetB is joined in the duplicate hole (50 μ l/ hole) of 12 covers.With the damping fluid of pH 6.4 or 7.4 the anti-sideramines antibody of dilution proportion rabbit, and it is joined in the same trepanning (50 μ l/ hole), in small-sized wobbler, mixed 30 seconds and cultivated 2 hours at 22 ℃ by 1: 800.With any one damping fluid dilute sample and use the same method as the FO standard and to handle.With PBS/Tween washing hole four times.(Biogenesis, Poole is Dorset) and in 4 ℃ of overnight incubation in hole (100 μ l/ hole) to combine the sero-fast horseradish peroxidase of anti-rabbit igg Fc by 1: 2500 dilution proportion.With PBS/Tween washing hole four times.In the dark plate was cultivated 20 minutes, still had the sero-fast enzyme of combining of remaining bonding force after can obtaining washing with the two hydrochloric acid O-Phenylene Diamines in 100 μ l/ holes.Add 1M hydrochloric acid (100 μ l/ hole) termination reaction.Measure colourity at 490 μ m places with Dynatech MR600 photometer.Embodiment 18: the dense II of the blood plasma in hamster
With the triple-roller mill among agate pestle and the agate mortar replacement embodiment 17, grind other component of salt and suspension, repeat embodiment 17.As embodiment 17, test with the parenteral injection suspension of gained.The result is as follows:
Time (hour) Deferoxamine-B in the blood plasma
Total concn (μ g/ml) with meta-bolites B
3????????????????????????18.19
6????????????????????????10.72
24?????????????????????0.91
30?????????????????????0.63
48?????????????????????0.53
54?????????????????????1.06
72?????????????????????0.51
168 1.69 embodiment 19: the plasma concentration III in hamster
Deferoxamine-B salt the I that uses among sample III (1g) the replacement embodiment 17 with Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems repeats embodiment 17.As embodiment 17, test with gained parenteral injection suspension.The result is as follows:
Time (hour) Deferoxamine-B in the blood plasma
Total concn (μ g/ml) with meta-bolites B
3?????????????????????????20.05
6?????????????????????????18.03
24?????????????????????????1.06
30?????????????????????????1.09
48?????????????????????????1.05
54?????????????????????????1.96
72?????????????????????????0.84
168 0.78 embodiment 20: the plasma concentration IV in hamster
Deferoxamine-B salt the I that uses among sample III (1g) the replacement embodiment 18 with Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems repeats embodiment 18.As embodiment 17, test with gained parenteral injection suspension.The result is as follows:
Time (hour) Deferoxamine-B in the blood plasma
Total concn (μ g/ml) with meta-bolites B
3???????????????????????????17.61
6???????????????????????????17.15
24???????????????????????0.67
30???????????????????????0.41
48???????????????????????0.60
54???????????????????????0.88
72???????????????????????0.50
168 0.47 embodiment 21: the plasma concentration V in hamster
With agate pestle and agate mortar Deferoxamine-B sulfonate sample in positive last of the ten Heavenly stems III (1g) is ground with the mixture of sesame oil (2.5ml), ethyl oleate (2.5ml), sorbitan trioleate (0.075ml) and the polyoxyethylene-4-lauryl ether (0.025ml) that slowly adds.As embodiment 17, test with gained parenteral injection suspension.The result is as follows:
Time (hour) Deferoxamine-B in the blood plasma
Total concn (μ g/ml) with meta-bolites B
3???????????????????????????5.93
6???????????????????????????14.10
24???????????????????????????7.91
30???????????????????????????0.41
48???????????????????????????4.91
54???????????????????????????0.89
96 0.17 embodiment 22: composition Q
Deferoxamine-B sulfonate sample in positive last of the ten Heavenly stems II (12.15 parts) is joined among the Miglyol812 (47.25 parts).Gained suspension is the 5-10 micron with the colloidal mill homogenizing until the median size of suspension salt, thereby makes parenteral injection suspension.Embodiment 23: to the influence of choleresis
Replace its consumption in embodiment 22 with 19.8 parts of Deferoxamine-B sulfonate sample II in the positive last of the ten Heavenly stems and 99 parts of Miglyol 812, repeat embodiment 22.Test with gained parenteral injection suspension, measure its iron secretion influence bile duct cannulate rat.Collecting contrast with bile and urine sample after 3 hours, with suspension (591 μ l/kg are 117mg/kg with respect to the dosage of Deferoxamine) in being subcutaneously injected into rat (male Fischer) body.Collected bile sample and measured wherein iron level every 3 hours then.Injected the test-results following (mean values of three rats) of the rat of suspension:
Time after the injection (hour) Fe content (mg/kg) in the bile
0???????????????????????11.0
3???????????????????????86.9
6???????????????????????111.8
9???????????????????????105.1
12??????????????????????96.1
15??????????????????????92.7
18??????????????????????88.2
21??????????????????????86.2
24??????????????????????92.0
27??????????????????????76.7
30??????????????????????67.0
33??????????????????????52.7
36??????????????????????35.5
39??????????????????????16.1
42??????????????????????9.6
45??????????????????????8.4
48 7.2 embodiment 24: composition R
Behind air spray barreling mill (the center granular size is 5-10 μ m) Deferoxamine-B sulfonate sample in positive last of the ten Heavenly stems II, the gained material is mixed in oil phase (ratio and component such as embodiment 22 or 23).With homogeneous suspension liquid pack into container (vial, the prepackage (prefilled) syringe or seal (bottlepack) container) in, with γ or β ray heat treated sterilization.Embodiment 25: the eliminating of iron in the hamster body
The mixture of sesame oil (2.0ml), ethyl oleate (2.0ml), sorbitan trioleate (7.5 μ l) and polyoxyethylene-4-lauryl ether (25 μ l) is slowly joined in Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems, grind with agate pestle and agate mortar simultaneously, obtain parenteral injection suspension.Test the influence that this suspension is got rid of the intravital iron of the male gold hamster of loading with iron, tested through intravenous injection
59Fe spike ferritin.After 1 hour, through the subcutaneous injection administration, wherein the dosage of Deferoxamine is 150 μ mol/kg with suspension in the ferritin administration.After 24 or 48 hours, measure in urine and the ight soil with γ-counter
59Fe content.The contrast of having injected the test-results (mean values of 6 animals) of the hamster of suspension and not accepted iron chelating agent is as follows with the test-results (mean values of 5 animals) of hamster:
Get rid of
59The amount of Fe (%)
Injection hamster contrast hamster
Twenty-four-hour urine sample 0.74 0.026
Ight soil 7.09 1.14 in 24 hours
Urine sample 0.052 0.037 in 48 hours
48 hours ight soil 2.59 1.00 embodiment 26: xln A
2
Be the preparation crystal seed, will be by xln B and xln A
184g Deferoxamine-1-sulfonate in the last of the ten Heavenly stems of forming of mixture join and contain in the 820ml distilled water of trace tinovetin (mixture of lauryl ether sulfuric ester (lauryl ether sulphate) and ethoxylized nonylphenol) as wetting agent.In 80 ℃ of water-baths, the suspension that forms is incubated 1 hour, stirs simultaneously.Use suction filter filtered while hot suspension subsequently.In logical nitrogen atmosphere, the filtering material of drying at room temperature.Measure the chemical purity and the form homogeneity of gained crystal seed, if xln A
2Impure, then repeat said process.Can obtain title compound like this.Embodiment 27: xln A
2
With 145mg Deferoxamine-1-sulfonate in last of the ten Heavenly stems xln B and xln A
1(by a spot of A
11A with about equal portions
12And A
13Composition) mixture is suspended in and contains in the 1.2ml distilled water of trace tinovetin as wetting agent.In 80 ℃ of water-baths,, stir simultaneously suspension insulation 2 hours.Use suction filter filtered while hot suspension subsequently.The filtering material of drying at room temperature in logical nitrogen atmosphere.Can obtain title compound like this.Embodiment 28: xln A
2
In room temperature, 20.1kg deferoxamine mesylate salt is dissolved in the water and is heated to 50 ℃.The part (15%) of 7.3kg1-sodium decylsulfonate is dissolved in 50 ℃ of water, and the solution that obtains is once joined in the deferoxamine mesylate salts solution.In solution, introduce A
2Crystal seed stirred 30 minutes at 50 ℃ subsequently, crystallization occurred.Then, a part (85%) 1-sodium decylsulfonate aqueous solution joined through 3-4 hour and finishes crystallization in the hot suspension in addition.50 ℃ with suspension restir 90 minutes, slowly cool to 40 ℃ then.Moisture eliminator leaches product after filtration, washes product and vacuum-drying with water, obtains title compound.Embodiment 29: xln A
2
At 30-40 ℃, 12.3kg deferoxamine mesylate salt is dissolved in the 47.0kg water.With the solution Sterile Filtration, filtrate is transferred in the crystallization kettle.At 45-50 ℃,, add 0.08kg Deferoxamine-1-sulfonate in last of the ten Heavenly stems xln A with the aseptic aqueous solution of the 0.7kg1-sodium decylsulfonate of time in wherein being added in 12.0kg water of several minutes
2, the beginning crystallization.,, add wherein after 30 minutes 50 ℃ of stirrings, stir gently simultaneously through 3-4 hour aseptic aqueous solution with the other 3.8kg1-sodium decylsulfonate in 64.0kg water at about 50-52 ℃.Under 50-52 ℃, suspension was placed 1-2 hour more then, cool overnight is to about 40 ℃ subsequently.Suction filtration goes out product under aseptic condition, with 54kg moisture washed product several times, and 50 ℃ of decompressions (＜20hPa) dry 24-40 hour.Obtain title compound.Embodiment 30: xln A
2
Under reflux temperature (about 78 ℃), 20.0kg Deferoxamine-1-sulfonate in the last of the ten Heavenly stems is dissolved in the 80.0kg dehydrated alcohol filtering solution.The filtrate of having replenished 8.0kg alcohol flushing liquid is cooled to 40 ℃ through 1-2 hour, can in the time of about 75 ℃, in clear liquor, introduces a spot of Deferoxamine-1-sulfonate in last of the ten Heavenly stems xln A like this
2Make crystal seed, thereby crystallization takes place.Suspension was kept 30 minutes at 40 ℃, with about 1 hour suspension is cooled to 0 ℃ then, under this temperature restir 1-2 hour.Suction filtration goes out product, and product divides washing several times with 24.0kg ethanol, in 50 ℃ of decompressions down (＜20hPa) drying.Obtain title compound.Embodiment 31: xln A
2
Under reflux temperature (about 78 ℃), 20.0kg Deferoxamine-1-sulfonate in the last of the ten Heavenly stems is dissolved in the 80.0kg dehydrated alcohol Sterile Filtration solution.The filtrate of having replenished 8.0kg alcohol flushing liquid progressively is cooled to 44 ℃ through about 2 hours, can in the time of about 68 ℃, in clear liquor, introduces a spot of Deferoxamine-1-sulfonate in last of the ten Heavenly stems xln A like this
2Make crystal seed, thereby crystallization takes place.Suspension was kept 30 minutes at 44 ℃, with about 1-2 hour suspension is cooled to 0 ℃ then, and under this temperature about 1 hour of restir.Suction filtration goes out product, and product divides washing several times with ethanol, and in 50 ℃ of decompressions (＜20hPa) drying.
Claims (18)
1. administered parenterally composition contains and is suspended in the Deferoxamine-B salt particle of administered parenterally with the aliphatic sulfonic acid with at least 8 carbon atoms in the oil.
2. according to the composition of claim 1, wherein salt be positive hot sulfonate or positive last of the ten Heavenly stems sulfonate.
3. according to the composition of claim 1, wherein salt is Deferoxamine-B sulfonate in the positive last of the ten Heavenly stems of certain crystalline form, and its fusing point is 154-158 ℃ and has following characteristics diffracted ray (2 θ diffraction angle ± 0.1 °) in its X-ray diffraction pattern: 3.1 °, 7.3 °, 9.4 °, 13.7 °, 23.7 °.
4. according to the composition of arbitrary claim among the claim 1-3, wherein the median size of salt particle is the 5-10 micron.
5. according to the composition of arbitrary claim among the claim 1-4, wherein oil comprises at least a vegetables oil or the fatty acid ester that is obtained by vegetables oil.
6. according to the composition of arbitrary claim among the claim 1-5, wherein administered parenterally oil contains sad and the triglyceride level capric acid mixture, and sad and weight ratio capric acid is 10: 9-13: 6.
7. according to the composition of arbitrary claim among the claim 1-6, also contain tensio-active agent.
8. the preparation of compositions method of arbitrary claim among the claim 1-7, this method comprise Deferoxamine-B salt particle and administered parenterally oil and tensio-active agent, if present, mix.
9. excessive, the Alzheimer of treatment iron excessive disease, aluminium, malaria, reperfusion damage or method for cancer, this method comprise that composition parenteral injection with arbitrary claim among the claim 1-8 is in the warm-blooded mammals body of this treatment of needs.
10. the Deferoxamine shown in the formula 1-1-sulfonate in last of the ten Heavenly stems xln (N-[5-{3-[(5-amino amyl group)-hydroxylamino formyl radical]-propionamido)-amyl group]-3-[{5-(the amino amyl group of N-glycoloyl }-formamyl]-propionyl hydroxamic acid-1-sulfonate in the last of the ten Heavenly stems),
Under nitrogen, heating rate with 10 ℃/min is carried out dsc, the melting range that records this xln is 154-158 ℃, and has the following characteristics diffracted ray (2 θ diffraction angle ± 0.1 °) in its X-ray diagram: 3.1 °, 7.3 °, 9.4 °, 13.7 ° and 23.7 °.
11., in its X-ray diagram, have following characteristics diffracted ray (2 θ diffraction angle ± 0.1 °): 3.1 °, 4.2 °, 7.3 °, 8.4 °, 9.4 °, 10.5 °, 13.7 °, 16.8 °, 17.4 °, 18.0 °, 18.4 °, 19.6 °, 20.1 °, 20.9 °, 22.3 °, 23.7 °, 25.1 ° and 25.6 ° according to the xln of claim 10.
12. the preparation method of the xln of claim 10 or 11 is characterized in that: at least one operation, unknown or the suspension of unspecified morphotic Deferoxamine-1-sulfonate in the last of the ten Heavenly stems in polar solvent are kept at elevated temperatures; Perhaps at least one operation, make the Deferoxamine-strong solution of 1-sulfonate in the last of the ten Heavenly stems in polar solvent at elevated temperatures, under 2 ℃/min or lower rate of cooling, carry out crystallization then.
13. the method according to claim 12 is characterized in that: polar solvent is the mixture of lower alcohol, water or water and lower alcohol, and the temperature range of described rising is between room temperature-polar solvent boiling point.
14. the method according to claim 13 is characterized in that: add at least one crystal seed.
15. method according to claim 14, it is characterized in that: the deferoxamine mesylate salts solution in the preparation polar solvent, be heated to the temperature of required rising, then will be in same and/or other polar solvent etc. the part of mole 1-sulfonate solution in the last of the ten Heavenly stems join wherein, add at least one crystal seed, until crystallization takes place, then will be in same and/or other polar solvent etc. the remainder of mole 1-sulfonate solution in the last of the ten Heavenly stems slowly add wherein, keep the temperature of required rising afterwards; Perhaps make the Deferoxamine-hot saturated solution of 1-sulfonate in the last of the ten Heavenly stems in polar solvent at elevated temperatures, after adding at least one crystal seed, be cooled to the temperature of lower rising with 1 ℃/min or lower rate of cooling, crystallization takes place during this period, and crystal suspension is remained under this lesser temps.
16. a pharmaceutical preparation contains the xln A of the Deferoxamine-1-sulfonate in the last of the ten Heavenly stems of claim 12 or 13
2With pharmaceutically acceptable carrier, described xln A
2As active ingredient.
17. the Deferoxamine of claim 12 or 13-1-sulfonate in last of the ten Heavenly stems xln A
2Purposes in the pharmaceutical preparation of the disease of, Alzheimer excessive, malaria, reperfusion damage and cancer in the excessive disease of preparation treatment chosen from Fe, aluminium.
18. treatment chosen from Fe excessive disease, aluminium are excessive, the method for the disease of Alzheimer, malaria, reperfusion damage and cancer, this method comprises that the patient to the above-mentioned treatment of needs uses the claim 12 of doses or the xln A of 13 described Deferoxamines-1-sulfonate in the last of the ten Heavenly stems
2, the dosage that uses is medicine effective quantity in described disease treatment.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH302496 | 1996-12-10 | ||
| CH3024/96 | 1996-12-10 | ||
| GB9625878.5 | 1996-12-12 | ||
| GBGB9625878.5A GB9625878D0 (en) | 1996-12-12 | 1996-12-12 | Compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1239946A true CN1239946A (en) | 1999-12-29 |
Family
ID=25691970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97180523A Pending CN1239946A (en) | 1996-12-10 | 1997-12-08 | Formulations and polymorphic forms of desferrioxamine and the preparation thereof |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0944586A2 (en) |
| KR (1) | KR20000069376A (en) |
| CN (1) | CN1239946A (en) |
| AR (1) | AR009655A1 (en) |
| AU (1) | AU5983998A (en) |
| BR (1) | BR9713570A (en) |
| CA (1) | CA2274761A1 (en) |
| CO (1) | CO4910160A1 (en) |
| CZ (1) | CZ204499A3 (en) |
| ID (1) | ID22388A (en) |
| IL (1) | IL130203A0 (en) |
| PE (1) | PE27799A1 (en) |
| PL (1) | PL334316A1 (en) |
| TR (1) | TR199901260T2 (en) |
| WO (1) | WO1998025887A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360208C (en) * | 2002-05-29 | 2008-01-09 | 拜尔农作物科学股份公司 | Method for producing specific crystalline modifications of polymorphous substances |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003532656A (en) * | 1999-12-23 | 2003-11-05 | ニューロケム インコーポレーティッド | Compounds and methods for modulating amyloid vasculopathy in the brain |
| GB0117645D0 (en) | 2001-07-19 | 2001-09-12 | Isis Innovation | Therapeutic stratergies for prevention and treatment of alzheimers disease |
| AU2016342309B2 (en) | 2015-10-23 | 2021-10-21 | Vifor (International) Ag | Ferroportin inhibitors |
| JOP20180036A1 (en) | 2017-04-18 | 2019-01-30 | Vifor Int Ag | Novel ferroportin-inhibitor salts |
| TW202102478A (en) | 2019-04-01 | 2021-01-16 | 瑞士商威佛（國際）股份有限公司 | Novel iron chelators |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH438351A (en) * | 1959-09-25 | 1967-06-30 | Ciba Geigy | Process for the production of new growth substances |
| FR1898M (en) * | 1961-04-07 | 1963-07-08 | Ciba Geigy | New substance usable in therapy. |
| GB9211779D0 (en) * | 1992-06-03 | 1992-07-15 | Ciba Geigy Ag | Amine salts |
-
1997
- 1997-12-05 AR ARP970105722A patent/AR009655A1/en unknown
- 1997-12-05 PE PE1997001097A patent/PE27799A1/en not_active Application Discontinuation
- 1997-12-08 BR BR9713570-4A patent/BR9713570A/en not_active Application Discontinuation
- 1997-12-08 ID IDW990473A patent/ID22388A/en unknown
- 1997-12-08 AU AU59839/98A patent/AU5983998A/en not_active Abandoned
- 1997-12-08 CA CA002274761A patent/CA2274761A1/en not_active Abandoned
- 1997-12-08 CN CN97180523A patent/CN1239946A/en active Pending
- 1997-12-08 PL PL97334316A patent/PL334316A1/en unknown
- 1997-12-08 CZ CZ992044A patent/CZ204499A3/en unknown
- 1997-12-08 TR TR1999/01260T patent/TR199901260T2/en unknown
- 1997-12-08 KR KR1019997005104A patent/KR20000069376A/en not_active Application Discontinuation
- 1997-12-08 IL IL13020397A patent/IL130203A0/en unknown
- 1997-12-08 WO PCT/EP1997/006849 patent/WO1998025887A2/en not_active Application Discontinuation
- 1997-12-08 EP EP97954727A patent/EP0944586A2/en not_active Withdrawn
- 1997-12-10 CO CO97072069A patent/CO4910160A1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360208C (en) * | 2002-05-29 | 2008-01-09 | 拜尔农作物科学股份公司 | Method for producing specific crystalline modifications of polymorphous substances |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5983998A (en) | 1998-07-03 |
| CZ204499A3 (en) | 1999-09-15 |
| PL334316A1 (en) | 2000-02-14 |
| KR20000069376A (en) | 2000-11-25 |
| TR199901260T2 (en) | 1999-10-21 |
| WO1998025887A3 (en) | 1998-08-13 |
| PE27799A1 (en) | 1999-03-18 |
| AR009655A1 (en) | 2000-04-26 |
| WO1998025887A2 (en) | 1998-06-18 |
| CO4910160A1 (en) | 2000-04-24 |
| CA2274761A1 (en) | 1998-06-18 |
| BR9713570A (en) | 2000-03-14 |
| ID22388A (en) | 1999-10-07 |
| EP0944586A2 (en) | 1999-09-29 |
| IL130203A0 (en) | 2000-06-01 |
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