CN105169407A - Sulfobutyl ether-beta-cyclodextrin inclusion compound of trimethoprim and powder injection preparation thereof - Google Patents
Sulfobutyl ether-beta-cyclodextrin inclusion compound of trimethoprim and powder injection preparation thereof Download PDFInfo
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- CN105169407A CN105169407A CN201510667107.6A CN201510667107A CN105169407A CN 105169407 A CN105169407 A CN 105169407A CN 201510667107 A CN201510667107 A CN 201510667107A CN 105169407 A CN105169407 A CN 105169407A
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- trimethoprim
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Abstract
The invention discloses an inclusion compound formed by inclusion of trimethoprim and sulfobutyl ether-beta-cyclodextrin, and a powder injection preparation formed by a corresponding inclusion compound. The powder injection preparation comprises trimethoprim, different substitured sulfobutyl ether-beta-cyclodextrin and a pharmaceutical material, wherein an inclusion molar ratio of the trimethoprim to the sulfobutyl ether-beta-cyclodextrin is (1.0-3.0):1.0; and the substitution degrees of the sulfobutyl ether-beta-cyclodextrin are 1, 4 and 7. Through adoption of the inclusion compound and the powder injection preparation, the water solubility of the trimethoprim is increased, and the aim of preparing corresponding aqueous solution dosage forms and powder injection dosage forms of the trimethoprim is fulfilled.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to the clathrate that trimethoprim and sulfobutyl ether-beta-cyclodextrin enclose are formed, the powder injection formulation that corresponding clathrate is formed.
Background technology
Inclusion technique refers to that a kind of molecule is all or part of and is embedded in the void structure of another kind of molecule by bag, forms the technology of clathrate.In recent decades, the research of researcher in inclusion technique of pharmaceuticals industry mainly comprises: 1. enclose investigation of materials, and enclose material conventional is at present beta-schardinger dextrin-(β-CD) and derivant thereof.2. the research and probe of inclusion method, mainly comprises saturated water solution method, polishing, ultrasonic method, freeze-drying and spray drying method etc.3. clathrate characterizing method, as: ultraviolet spectrophotometry, infrared spectrometry, nuclear magnetic resonance method, X diffraction approach and differential thermal analysis etc.4. the effect before and after enclose is evaluated by envelop rate and drug loading, as water solublity, taste masking, transdermal characteristic and biocidal property etc.
Now conventional enclose material is beta-cyclodextrin derivative, object be originally increase beta-schardinger dextrin-dissolubility, reduce its toxic and side effects.Afterwards, people, according to different needs, beta-schardinger dextrin-introduce the groups such as hydrophilic, hydrophobicity, ionizing, thus reach increase dissolubility, fall hypotoxic object.Common water soluble cyclodextrin derivant has glucose-beta-schardinger dextrin-, HP-β-CD, sulfobutyl ether-beta-cyclodextrin, sulfopropyl ether-beta-schardinger dextrin-and methyl-B-cyclodextrin etc.After introducing glucityl, cyclodextrin water solublity significantly increases, and cyclodextrin molecular introduces hydroxypropyl, some insoluble drug dissolubility and stability can be impelled to increase as enclose material.HP-β-CD Dichlorodiphenyl Acetate cortisone (CA) has good solubilization, and the dissolubility of cortisone acetate is directly proportional to the concentration of HP-β-CD.List of references is shown in [Bao Huike, Ma Yinhu, Yuan east is superfine. the UV absorber [J] of HP-β-CD and cortisone acetate inclusion complex. and University Of Science and Technology Of Tianjin's journal, 2009,24 (6): 13-15.].Research finds, sulfobutyl ether-beta-cyclodextrin has better safety compared with other beta-cyclodextrin derivative, stronger solubilising and Binding ability, and easily excretion, nephrotoxicity are little.List of references is shown in [Liu Chundong, Wang Jianhua. sulfobutyl ether-beta-cyclodextrin is to the solubilization [J] of medicine. Chinese Journal of Modern Applied Pharmacy, 2006,23 (9): 742-745.].Sulfobutyl ether-beta-cyclodextrin is the product of beta-schardinger dextrin-and Isosorbide-5-Nitrae-butane sultone generation substitution reaction, belongs to the sulfonic group derivant of beta-schardinger dextrin-.Common are a replacement, four to replace and seven sulfobutyl ether-beta-cyclodextrins replaced, be white or faint yellow amorphous solid powder.List of references is shown in [Gu Fugen, Gao Yongliang, Cui Fude. sulfobutyl ether-beta-cyclodextrin and the application in pharmaceutics [J] thereof. Chinese Journal of New Drugs, 2004,13 (1): 15-19.].After beta-schardinger dextrin-is modified by sulphur butyl, molecule charge there occurs change, and the hydrophobic interaction of beta-schardinger dextrin-cavity and the geometric size of cyclodextrin ring have also changed.Contribute to like this strengthening clathration, reduce medicine to the zest of local organization and toxic and side effects.List of references is shown in [Wang Jianhua, Song Aijing. a kind of pharmaceutical applications progress [J] of novel adjuvant sulfobutyl ether-beta-cyclodextrin. material Leader, 2007,21 (3): 40-43.].
Trimethoprim is also known as trimethoprim, methoxy benzyl pyrimidine, and chemistry is called 5-[(3,4,5-trimethoxyphenyl) methyl]-2,4-thonzylamine.For white or off-white color crystalline powder, odorless, bitter in the mouth.Atomic water-soluble, slightly molten in chloroform, slightly soluble in ethanol or acetone, easily molten in glacial acetic acid.Trimethoprim molecular formula is C14H18N4O3, and relative molecular mass is 290, pKa value is 7.12, and structure is as follows:.
Trimethoprim is broad spectrum antibiotic, normal and sulfa drugs conbined usage, also referred to as trimethoprim (TMP) [ClaudiaGarnero, ArianaZoppi, DiegoGenovese, Deng. the preparation research [J] of trimethoprim hydroxypropylβ-cyclodextrin coordination compound. carbohydrate compound research, 2010,345:2550-2556.ClaudiaGarnero,ArianaZoppi,DiegoGenovese,etal.Studiesontrimethoprim:hydroxypropyl-β-cyclodextrin:aggregateandcomplexformation[J].CarbohydrateResearch,2010,345:2550-2556.]。Be used alone diseases such as can be used for respiratory tract infection, urinary tract infection, intestinal infection; As antibacterial synergist, also poultry bacterial infection and coccidiosis can be treated.But compared with in the body that strong hydrophobicity makes trimethoprim, dissolution rate is low, bioavailability is little, greatly limit the use of this medicine and the performance [Zhang Wei of drug effect, Fu Hualin, oldly waiting quietly. HP-β-CD handbag closes the research [J] of trimethoprim. Chinese animal and veterinary, 2011,38 (11): 66-68.].And trimethoprim and sulfonamides compatibility are prepared injection and are mostly trimethoprim to be directly dissolved in the organic solvent mixed in production, this not only increases cost, and the poor stability of medicine, biostimulation are large, drug absorption also comparatively slow [Zou Yuzhu, Fu Hualin, Zhang Wei etc. the development of trimethoprim hydroxypropyl-beta-cyclodextrin inclusion and at Pharmacokinetics in Rabbits research [J]. Chinese veterinary science, 2010,40 (12): 1285-1290.].
Be not difficult to find out, trimethoprim bitter in the mouth, atomic water-soluble, general difficulty sees trimethoprim water-soluble dosage forms and injectable powder type for clinical, although market there is the Trimethoprim lactate of water-soluble to emerge [Zhang Xu section, Liu Xingjin, Zhang Xiaohui, Li Xingguo etc. preparation method [P] .CN101416973A of a kind of novel composite anti-coccidium, antibiotic preparation], although but enclose type trimethoprim has report, the situation also along with salify while enclose has no listing.
As everyone knows, the bioavailability of medicine is along with route of administration, release target and the difference acting on targeting, different to the requirement of its lipid, although trimethoprim improves its water solublity by the mode of lactic acid salify, but, crude drug and its crude drug salt formed, the pharmacology of medicine, drug effect, degree of absorption and bioavailability may have difference more or less.Meanwhile, after enclose, the character of medicine also can change.List of references is shown in [Liu Yuhai. the progress [J] of beta-cyclodextrin inclusion compound application. Chemical Engineering and equipment, 2008, (6): 94-95.], [Lu Yapeng, Ren Yong, Wang Yana, Deng. amoxicillin-beta-cyclodextrin inclusion compound Effect study [J]. Chinese Pharmaceutical Journal, 2005, 40 (10): 757-759.], [Wang Jianhua, Huang Zhen. the preparation of methyl-B-cyclodextrin and flunixin super molecular complex and sign [J] thereof. synthetic chemistry, 2009, 17 (3): 394-39.], [Wang Jianhua, Feng Jing. the thermodynamics of supramolecular materials cyclodextrin and ibuprofen enclose measures [J]. University Of Chongqing's journal, 2009, 32 (6): 653-657.], [Wang Jianhua, Huang Zhen. the preparation of flunixin and beta-schardinger dextrin-super molecular complex and sign [J] thereof. material Leader, 2009, 23 (3): 93-96.], [Wang Jianhua, Li Xing. the preparation of nitrendipine-Benexate Hydrochloride and analysis [J]. University Of Chongqing's journal (natural science edition), 2007, 30 (7) 124-129].
Therefore, under the prerequisite keeping trimethoprim structure constant, change medicine effect or availability by clathration, clinically certain difference existed more or less.The present invention utilizes inclusion technique formation to have exactly can improve the water miscible method of raw material, realizes the expansion target preparing trimethoprim aqueous solution dosage form, injectable powder type.
Summary of the invention
In view of this, an object of the present invention is the clathrate providing a kind of trimethoprim and sulfobutyl ether-beta-cyclodextrin enclose to be formed, two of object is the powder injection formulation providing corresponding clathrate to be formed, and three of object is that the clathrate that provides can application in pharmacy and Animal diseases prevention and control and treatment field.
For achieving the above object, the invention provides following technical scheme:
The clathrate that the sulfobutyl ether-beta-cyclodextrin that the invention provides a kind of trimethoprim and different degree of substitution is formed, wherein the enclose mol ratio of the sulfobutyl ether-beta-cyclodextrin of trimethoprim and different degree of substitution is 1.0 ~ 3.0:1.0; Be preferably 2.0:1.0.
In described clathrate, sulfobutyl ether-beta-cyclodextrin substitution value is not 1,4,7.
Particularly, in clathrate, the enclose mol ratio of the sulfobutyl ether-beta-cyclodextrin of trimethoprim and different degree of substitution refers to trimethoprim: SBE
1-β-CD is 2:1, trimethoprim: SBE
4-β-CD is 2:1, trimethoprim: SBE
7-β-CD is 2:1.
Further, the invention provides the preparation method of described clathrate, step comprises:
A. accurately take trimethoprim, by dissolution with solvents, obtain reserve liquid;
B. take the sulfobutyl ether-beta-cyclodextrin of the different degree of substitution of respective amount by enclose mol ratio, dissolve with distilled water.It is slowly added drop-wise in above-mentioned reserve liquid, distilled water diluting standardize solution;
C. regulate ultrasonic frequency to be 25KHz, temperature is 60 DEG C, and by ultrasonic for above-mentioned mixed liquor enclose after 45 minutes, cooling, the refrigerator freezing of-28 DEG C 48 hours, lyophilization in freezer dryer, obtains fluffy solid, obtains clathrate.
Further, solvent described in clathrate preparation method step a refers to Isosorbide-5-Nitrae-dioxane, oxolane, DMF solvent; Wherein preferred solvent is Isosorbide-5-Nitrae-dioxane.
Particularly, wherein the substitution value of sulfobutyl ether-beta-cyclodextrin is 1,4,7.
Further, the powder injection formulation that the sulfobutyl ether-beta-cyclodextrin that the invention provides trimethoprim and different degree of substitution is formed, powder injection formulation comprises trimethoprim, the sulfobutyl ether-beta-cyclodextrin of different degree of substitution and excipient substance thereof, and wherein the mol ratio of the sulfobutyl ether-beta-cyclodextrin of trimethoprim and different degree of substitution is preferably 2.0:1.0; The substitution value of sulfobutyl ether-beta-cyclodextrin is 1,4,7.
Particularly, the unit dosage of the powder injection formulation provided is containing 50 ~ 200mg trimethoprim.
Particularly, the powder injection formulation Chinese medicine adjuvant provided refers to mannitol.
Further, the sulfobutyl ether-beta-cyclodextrin inclusion compound that the invention provides trimethoprim and different degree of substitution is preparing the application in Animal diseases prevention and control and medicine.
For checking technique scheme, the present invention adopts equimolar series method, enclose mol ratio is recorded also known as continuous alternation concentration method, namely keep the total mol concentration of trimethoprim and sulfobutyl ether-beta-cyclodextrin constant, change the ratio of two components, with the sulfobutyl ether-beta-cyclodextrin solution of corresponding same concentrations for blank, measure each mixed liquor and the absorbance with acute drug solution.After medicine and sulfobutyl ether-beta-cyclodextrin generation enclose, can there is slight change in the conjugated system of former medicine, uv absorption can increase.Therefore, map to molar fraction with mixed liquor absorbance and the difference (△ A) with the drug solution absorbance of concentration, enclose mol ratio is exactly curve break place.
The relevant document relating to clathrate or patent have many, and due to the impact by cyclodextrin cavity, the enclose mol ratio that general clathrate is formed is cyclodextrin: medicine=1:1 or 2:1 or 3:1.The present invention is different from traditional clathrate patent, because the coating material selected belongs to the sulfobutyl ether-beta-cyclodextrin of different degree of substitution, the sulfobutyl ether radical amount had under different degree of substitution is also not quite similar, during formation clathrate except cyclodextrin cavity enclose, sulfobutyl ether substituent group also has the ability with alkaline trimethoprim medicine salify simultaneously, namely in trimethoprim of the present invention and sulfobutyl ether-beta-cyclodextrin enclose process, except with except medicine enclose, the sulfonic group of side chain also with trimethoprim salify, form the great large increase of mol ratio in conjunction with ratio (apparent enclose mol ratio) Chinese medicine on practical significance.Different from the mol ratio of traditional enclose product, the mole of trimethoprim is higher than the enclose mole of medicine general in traditional literature herein.
Specific to trimethoprim then for the mol ratio of the sulfobutyl ether-beta-cyclodextrin of trimethoprim and different degree of substitution is preferably 2.0:1.0, i.e. SBE
1-β-CD, SBE
4-β-CD and SBE
7-β-CD and trimethoprim form the result of enclose one mole of trimethoprim, salify one mole of trimethoprim (1:2).
For checking technique scheme, the present invention has carried out the structural characterization of scanning electron microscope method and X diffraction approach to the clathrate formed.
The scanning electron microscope of trimethoprim, different degree of substitution sulfobutyl ether-beta-cyclodextrin, trimethoprim and different degree of substitution sulfobutyl ether-beta-cyclodextrin inclusion compound and mixture the results are shown in accompanying drawing 1 and accompanying drawing 2.SBE can be found out from above-mentioned accompanying drawing
1-β-CD, SBE
4-β-CD and SBE
7the shape of-β-CD, the shape of trimethoprim crude drug are all not identical with the shape of different clathrate, and after enclose, clathrate there occurs larger change compared with the crystal habit of crude drug and different degree of substitution sulfobutyl ether-beta-cyclodextrin enclose material thereof; Obviously can see the mixing phenomena of two kinds of crystal forms in the mixture figure of crude drug and enclose material, and form does not change too much separately.
The X diffraction patterns of trimethoprim, different degree of substitution sulfobutyl ether-beta-cyclodextrin, clathrate and mixture is shown in accompanying drawing 3.Can find out that from above-mentioned accompanying drawing four kinds of crude drug have obvious crystalline structure, present multiple clear sharp-pointed crystal form peak.Different degree of substitution sulfobutyl ether-beta-cyclodextrin has amorphous structure, presents amorphous state broadening and derives peak.Medicine and the physical mixture peak shape of different degree of substitution sulfobutyl ether-beta-cyclodextrin are that the diffraction maximum of corresponding two kinds of single materials superposes, and crystal form peak is also sharply clear simultaneously to have part broadening to derive peak.Different pharmaceutical is not then simple superposition with the collection of illustrative plates of different degree of substitution sulfobutyl ether-beta-cyclodextrin inclusion compound, and wherein disappearing or weakening appears in the crystal form peak of crude drug, and shows have new thing to generate mutually with the new peak formation of some strength.
Trimethoprim target clathrate provided by the invention, significantly improves the water solublity of crude drug, carries out solubility test according to specifying under dissolubility item in 2010 editions Chinese Pharmacopoeias to testing sample.Appropriate trimethoprim crude drug and obtained trimethoprim clathrate are fully ground to form fine powder, takes 0.1g powder respectively in the distilled water of a certain amount of 25 DEG C.In powerful jolting 30 second every 5 minutes, observe the dissolving situation in 30 minutes.When there is no visual visible particles of solute, be and dissolve completely.Record the volume dissolving distilled water corresponding to 0.1g powder.Compared with the explanation corresponding with dissolubility vocabulary of terms in pharmacopeia by result, draw respective substance solubility test result.The results are shown in Table 1.As can be seen from Table 1, trimethoprim crude drug is after enclose process, and the trimethoprim clathrate obtained is all soluble in water, and in water, dissolubility is greatly improved.
The dissolving situation of table 1 crude drug and different clathrate thereof
| Determinand | Distilled water volume (ml) | Dissolubility |
| Trimethoprim | 250.00 | Atomic molten |
| Jia oxygen Bian Ding ?SBE 1?β ?CD clathrate | 0.88 | Yi Rong |
| Jia oxygen Bian Ding ?SBE 4?β ?CD clathrate | 0.86 | Yi Rong |
| Jia oxygen Bian Ding ?SBE 7?β ?CD clathrate | 0.82 | Yi Rong |
The present invention utilizes inclusion technique formation to have can improve the water miscible method of raw material, realizes the expansion target preparing the corresponding aqueous solution dosage form of trimethoprim, injectable powder type.
Accompanying drawing explanation
The electron-microscope scanning figure of the sulfobutyl ether-beta-cyclodextrin of Fig. 1 tri-kinds of different degree of substitution, wherein (a) is SBE
1-β-C, (b) is SBE
4-β-CD, (c) is SBE
7-β-CD;
Fig. 2 trimethoprim raw material, different degree of substitution sulfobutyl ether-beta-cyclodextrin inclusion compound and mixture electron-microscope scanning figure, wherein (a) is trimethoprim crude drug, and (b) is trimethoprim-SBE
1-beta-CD inclusion, (c) is trimethoprim and SBE
1-β-CD mixes, (d) trimethoprim-SBE
4-beta-CD inclusion, (e) trimethoprim and SBE
4-β-CD mixture, (f) trimethoprim-SBE
7-beta-CD inclusion, (g) trimethoprim and SBE
7-β-CD mixture;
Fig. 3 trimethoprim, enclose material and clathrate thereof, mixture X diffracting spectrum.
Detailed description of the invention
In order to make the object, technical solutions and advantages of the present invention clearly, below the preferred embodiments of the present invention are described in detail.
Embodiment 1, trimethoprim and SBE
1prepared by-beta-CD inclusion
Accurately take 0.2mol trimethoprim crude drug, dissolve with Isosorbide-5-Nitrae-dioxane solvent, obtain reserve liquid; The substitution value taking 0.1mol by enclose mol ratio is the sulfobutyl ether-beta-cyclodextrin of 1, dissolves with distilled water.Isosorbide-5-Nitrae-dioxane solution containing medicine is slowly added drop-wise in above-mentioned reserve liquid, distilled water diluting standardize solution 200ml; Adjustment ultrasonic frequency is 25KHz, and temperature is 60 DEG C, and by ultrasonic for above-mentioned mixed liquor enclose after 45 minutes, cooling, the refrigerator freezing of-28 DEG C 48 hours, lyophilization in freezer dryer, obtains puffy white solid, obtains the trimethoprim-SBE that mol ratio is 2:1
1-beta-CD inclusion.
Embodiment 2, trimethoprim and SBE
4prepared by-beta-CD inclusion
Accurately take 0.2mol trimethoprim crude drug, dissolve with Isosorbide-5-Nitrae-dioxane solvent, obtain reserve liquid; The substitution value taking 0.1mol by enclose mol ratio is the sulfobutyl ether-beta-cyclodextrin of 4, dissolves with distilled water.Isosorbide-5-Nitrae-dioxane solution containing medicine is slowly added drop-wise in above-mentioned reserve liquid, distilled water diluting standardize solution 200ml; Adjustment ultrasonic frequency is 25KHz, and temperature is 60 DEG C, and by ultrasonic for above-mentioned mixed liquor enclose after 45 minutes, cooling, the refrigerator freezing of-28 DEG C 48 hours, lyophilization in freezer dryer, obtains puffy white solid, obtains the trimethoprim-SBE that mol ratio is 2:1
4-beta-CD inclusion.
Embodiment 3, trimethoprim and SBE
7prepared by-beta-CD inclusion
Accurately take 0.2mol trimethoprim crude drug, dissolve with Isosorbide-5-Nitrae-dioxane solvent, obtain reserve liquid; The substitution value taking 0.1mol by enclose mol ratio is the sulfobutyl ether-beta-cyclodextrin of 7, dissolves with distilled water.Isosorbide-5-Nitrae-dioxane solution containing medicine is slowly added drop-wise in above-mentioned reserve liquid, distilled water diluting standardize solution 200ml; Adjustment ultrasonic frequency is 25KHz, and temperature is 60 DEG C, and by ultrasonic for above-mentioned mixed liquor enclose after 45 minutes, cooling, the refrigerator freezing of-28 DEG C 48 hours, lyophilization in freezer dryer, obtains puffy white solid, obtains the trimethoprim-SBE that mol ratio is 2:1
7-beta-CD inclusion.
The trimethoprim clathrate injectable powder of embodiment 4, unit dosage 50mg
Calculate by often propping up cillin bottle solid content net weight 5g, take and often prop up trimethoprim clathrate that cillin bottle Determination of Trimethoprim is 50mg and often prop up the mannitol that cillin bottle supplies the remaining heavy part of 5g, be dissolved in purified water, after 0.22 μm of microporous filter membrane is degerming, load in cillin bottle, lyophilization 48 hours, aseptic lower cover, obtains the trimethoprim clathrate injectable powder of unit dosage 50mg.
The trimethoprim clathrate injectable powder of embodiment 5, unit dosage 100mg
Calculate by often propping up cillin bottle solid content net weight 5g, take and often prop up trimethoprim clathrate that cillin bottle Determination of Trimethoprim is 100mg and often prop up the mannitol that cillin bottle supplies the remaining heavy part of 5g, be dissolved in purified water, after 0.22 μm of microporous filter membrane is degerming, load in cillin bottle, lyophilization 48 hours, aseptic lower cover, obtains the trimethoprim clathrate injectable powder of unit dosage 100mg.
The trimethoprim clathrate injectable powder of embodiment 6, unit dosage 200mg
Calculate by often propping up cillin bottle solid content net weight 5g, take and often prop up trimethoprim clathrate that cillin bottle Determination of Trimethoprim is 200mg and often prop up the mannitol that cillin bottle supplies the remaining heavy part of 5g, be dissolved in purified water, after 0.22 μm of microporous filter membrane is degerming, load in cillin bottle, lyophilization 48 hours, aseptic lower cover, obtains the trimethoprim clathrate injectable powder of unit dosage 200mg.
Claims (9)
1. the clathrate that formed of the sulfobutyl ether-beta-cyclodextrin of trimethoprim and different degree of substitution, wherein the enclose mol ratio of trimethoprim and sulfobutyl ether-beta-cyclodextrin is 1.0 ~ 3.0:1.0, and sulfobutyl ether-beta-cyclodextrin substitution value is 1,4,7.
2. clathrate according to claim 1, is characterized in that, the enclose mol ratio of trimethoprim and sulfobutyl ether-beta-cyclodextrin is 2.0:1.0, wherein forms enclose one mole of trimethoprim, salify one mole of trimethoprim.
3. the preparation method of clathrate described in claim 1 or 2, is characterized in that, comprising:
Accurately take trimethoprim, by dissolution with solvents, obtain reserve liquid;
Take the sulfobutyl ether-beta-cyclodextrin of respective amount by enclose mol ratio, dissolve with distilled water, it is slowly added drop-wise in above-mentioned reserve liquid, distilled water diluting standardize solution;
Adjustment ultrasonic frequency is 25KHz, and temperature is 60 DEG C, and by ultrasonic for above-mentioned mixed liquor enclose after 45 minutes, cooling, the refrigerator freezing of-28 DEG C 48 hours, lyophilization in freezer dryer, obtains fluffy solid, obtains clathrate.
4. clathrate preparation method according to claim 3, is characterized in that, solvent refers to Isosorbide-5-Nitrae-dioxane, oxolane, DMF solvent.
5. clathrate preparation method according to claim 4, is characterized in that, wherein solvent is Isosorbide-5-Nitrae-dioxane.
6. utilize the powder injection formulation that clathrate described in claim 1-2 is formed, it is characterized in that, wherein powder injection formulation comprises trimethoprim, the sulfobutyl ether-beta-cyclodextrin of different degree of substitution and excipient substance thereof, and wherein the mol ratio of the sulfobutyl ether-beta-cyclodextrin of trimethoprim and different degree of substitution is preferably 2.0:1.0; Sulfobutyl ether-beta-cyclodextrin substitution value is 1,4,7.
7. powder injection formulation according to claim 6, is characterized in that, the unit dosage of wherein said powder injection formulation is containing 50 ~ 200mg trimethoprim.
8. powder injection formulation according to claim 6, is characterized in that, wherein excipient substance refers to mannitol.
9. the clathrate described in claim 1-2 is in the application in preparation Animal diseases prevention and control and medicine.
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Application publication date: 20151223 |