CN102911226B - Erythromycin octadecanoate compounds thing entity and uses thereof - Google Patents
Erythromycin octadecanoate compounds thing entity and uses thereof Download PDFInfo
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- CN102911226B CN102911226B CN201110221493.8A CN201110221493A CN102911226B CN 102911226 B CN102911226 B CN 102911226B CN 201110221493 A CN201110221493 A CN 201110221493A CN 102911226 B CN102911226 B CN 102911226B
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- erythromycin
- octadecanoate
- erythromycin octadecanoate
- low molecule
- hydrate
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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Abstract
Erythromycin derivatives of the present invention, i.e. erythromycin octadecanoate crystalline hydrate, there is less water absorbability, preferably storage stability, be applicable to prepare the application in the treatment of the infectious diseases of the human or animal caused by Gram-positive or negative bacteria sensitive organism, chlamydozoan or mycoplasma and the medicine in preventing.
Description
Technical field
The present invention relates to medical art, be to provide anti-infectives erythromycin octadecanoate compounds thing entity and its production and use specifically, specifically erythromycin octadecanoate 1 hydrate and preparation thereof and purposes.
Background technology
Document only reports erythromycin octadecanoate [ErythromycinStearate, C
37h
67nO
13c
18h
36o
2, molecular weight 1018.42, No. CAS: 643-22-1] and uses thereof, up to the present, there is no open source literature report erythromycin derivatives---erythromycin octadecanoate 1 hydrate [C
37h
67nO
13c
18h
36o
2h
2o, and its production and use.
Summary of the invention
Hydrate of involved in the present invention is anti-infectives---erythromycin derivatives---erythromycin octadecanoate (ErythromycinStearate, No. CAS: 643-22-1) and uses thereof and preparation thereof and purposes.Erythromycin octadecanoate 1 hydrate of the present invention, its molecular formula is C
37h
67nO
13c
18h
36o
2h
2o, erythromycin octadecanoate hydrate of the present invention can have different crystal formations, in any case but, distinctive, the visible significantly endotherm(ic)peak (TG-DTA) of thermal analyses collection of illustrative plates of these hydrates of the present invention, namely have obvious endotherm(ic)peak under the weightless platform of TG-DTA collection of illustrative plates between 70 ~ 130 DEG C, the position of endotherm(ic)peak is usually closer between 75 ~ 130 DEG C, and these crystalline hydrates have no domestic and international any open source literature report.
Surprisingly, found by research, erythromycin octadecanoate 1 hydrate that the present invention obtains can be more stable existence, erythromycin octadecanoate etc. containing 1 crystal water is different from the characteristic of the easier moisture absorption of erythromycin octadecanoate anhydride, erythromycin octadecanoate containing 1 crystal water has good room temperature storage stability, be convenient to store and transport, can the more convenient preparation for pharmaceutical preparation.The result that Karl_Fischer method measures moisture result and thermal analyses collection of illustrative plates matches, thermal analyses collection of illustrative plates visible erythromycin octadecanoate 1 hydrate.
Erythromycin octadecanoate 1 hydrate of the present invention, can stable storage.Being sealed in cillin bottle by above-mentioned sample, with reference to CP2010, is weighting agent with octadecylsilane chemically bonded silica; Be moving phase with phosphate solution (get dipotassium hydrogen phosphate 8.7g, add water 1000ml, by 20% phosphoric acid adjust ph to 8.2)-acetonitrile (40:60); Column temperature 35 DEG C; Wavelength is 215nm, and flow velocity is the changing conditions of 1.0ml/min, detection level and related substance.Surprisingly, content and the related substance of erythromycin octadecanoate 1 hydrate in embodiments of the invention 1 and 2 did not have considerable change in pot life at room temperature in 12 months.With reference to CP2010, by each for inventive samples 5 grams at 25 DEG C, be placed in relative humidity 70% to carry out drawing moist test, surprisingly to draw the ratio of wet weightening finish less for erythromycin octadecanoate hydrate, erythromycin octadecanoate 1 hydrate of the present invention draws moist compared with erythromycin octadecanoate anhydride, draws moist lower, and it is higher namely to draw wet stability, more be conducive to its packing and storing, or be the form of more favourable stable storage than anhydride.In addition, the deliquescence of anhydride makes will to completely cut off air when processing and prevents adhesion etc., and hydrate has good sliding, thus improves the operability of preparation.Embodiment 2 the results are shown in following table 1.
In erythromycin octadecanoate 1 hydrate of the present invention, free stearic acid is much smaller than the free stearic acid in usual erythromycin octadecanoate, the invention provides a kind of preparation method prepared containing less free stearic erythromycin octadecanoate, in the erythromycin octadecanoate of commercially available or bibliographical information usually, stearic content is up to about 14%, in erythromycin octadecanoate, free stearic acid does not have therapeutic value, is to lack therapeutic potential yet.And this law embodiment to prepare erythromycin octadecanoate hydrate at least low by more than 1% than stearic content free in commercially available erythromycin octadecanoate, with reference to the free stearic acid content measuring method of CP2010, free stearic acid content in the result of discovery embodiment 1 is lower than 4%, free stearic acid content in the result of embodiment 2 is also far below bibliographical information, within 4%.
Crystalline solid has chemical stability higher than amorphous form and low-crystallinity form and physical stability, and they also can show as the water absorbability of raising, bulk properties and or mobility.
The discovery of the useful compound on new polymorphic or the medicine of crystalline hydrate provides new chance once improving the action characteristic of medicament production, it expands the storehouse of formulation science man design example as the pharmaceutical dosage form and the material obtained with the medicine of targeted release profile or other desired characteristic, and this area needs erythromycin octadecanoate crystalline hydrate or its polymorph.
Table 1 erythromycin octadecanoate hydrate draw moist test-results (RH70%25 DEG C)
The preparation of erythromycin octadecanoate 1 hydrate comprises following method:
In reaction vessel, with water and C
1-C
6low mass molecule alcohol, C
2-C
6rudimentary nitrile, C
3-C
8low molecule ketone, C
1-C
6low molecule halohydrocarbon or C
2-C
8rudimentary ether in one or more be solvent, make erythromycin or erythromycin hydrate dissolution, add stearic acid or it is at C
1-C
6low mass molecule alcohol, C
2-C
6rudimentary nitrile, C
3-C
8low molecule ketone or C
2-C
8rudimentary ether in the solution of one or more, or by stearic acid or it is at C
1-C
6low mass molecule alcohol, C
2-C
6rudimentary nitrile, C
3-C
8low molecule ketone or C
2-C
8rudimentary ether in the solution of one or more and the solution of above-mentioned erythromycin mix, stir, be placed in-25 ~ 30 DEG C of placement (preferably-10 ~ 20 DEG C), treat that solid is separated out complete, filter to obtain solid; The solid of gained is placed in container refine, adds C
2-C
8low molecule ester, C
3-C
8low molecule ketone or C
5-C
10one or more in low molecule straight or branched alkane or naphthenic hydrocarbon, sherwood oil, stir, filter, separate solid, so refining once to for several times; Again by gained solid water and C
1-C
6low mass molecule alcohol, C
2-C
6low molecule nitrile, C
2-C
8low molecule ether, C
3-C
8low molecule ketone, C
1-C
6low molecule halohydrocarbon, C
2-C
8low molecule ester, C
5-C
10one or more in low molecule straight or branched alkane or naphthenic hydrocarbon, sherwood oil carry out one or many recrystallization for solvent, are cooled to-20 ~ 10 DEG C, filter, dry, obtain erythromycin octadecanoate 1 hydrate;
The solvent that erythromycin octadecanoate 1 hydrate is refined is selected from: C
2-C
8low molecule ester (ethyl acetate, butylacetate), C
3-C
8low molecule ketone (acetone, butanone, pentanone, hexanone, hexone) or C
5-C
10one or more in low molecule straight or branched alkane or naphthenic hydrocarbon, sherwood oil; Refining solvent is more preferably from one or more in ethyl acetate, acetone, normal hexane, hexanaphthene or sherwood oil, and these refining solvents are used for the free stearic acid reducing or remove in target product; The solvent that erythromycin octadecanoate hydrate is refining, C
2-C
8low molecule ester, C
3-C
8low molecule ketone or C
5-C
10the volume (ml) of one or more and solid in low molecule straight or branched alkane or naphthenic hydrocarbon, sherwood oil and weight (g) than being 0.1 ~ 50:1, its extraction temperature generally at 10 ~ 65 DEG C, preferably 30 ~ 50 DEG C.
The number of times of the recrystallization in above preparation method can be repeatedly carry out, and contributes to obtaining the higher product of the present invention of purity.Erythromycin octadecanoate crystalline hydrate can obtain under different preparation condition, is particularly included in different dry temperature condition inferior.
One or more preferably in: water and methyl alcohol, ethanol, Virahol, acetonitrile, ether, tetrahydrofuran (THF), acetone, hexone, methylene dichloride, chloroform, hexanaphthene, sherwood oil or ethyl acetate of erythromycin octadecanoate 1 crystal of hydrate or recrystallization solvent.
Lower alcohol in the present invention or the carbonatoms of low mass molecule alcohol are defined as C
1-C
6(that is: the alcohol of 1-6 carbon atom), as methyl alcohol, ethanol, Virahol, butanols etc.; C
2-C
6the carbonatoms of rudimentary nitrile be defined as C
2-C
6, as acetonitrile, propionitrile etc.; The carbonatoms of rudimentary ether or low molecule ether is defined as C
2-C
8, as ether, isopropyl ether, butyl ether etc.; The carbonatoms of lower halogenated hydrocarbon is defined as C
1-C
6(i.e. 1-6 carbon atom), comprises methylene dichloride, ethylene dichloride, chloroform etc.; The carbonatoms of lower member ester is defined as C
2-C
8(i.e. 2-8 carbon atom), comprises N-BUTYL ACETATE, ethyl acetate, ethyl formate etc.; The carbonatoms of low molecule straight or branched alkane or naphthenic hydrocarbon is defined as C
5-C
10(i.e. 5-10 carbon atom), comprises pentane, normal hexane, hexanaphthene, sherwood oil etc.; The carbonatoms of low molecule aromatic hydrocarbon is defined as C
6-C
12, comprise benzene, toluene etc.; C
3-C
8low molecule ketone be defined as the ketone of 3-8 carbon atom, comprise acetone, butanone, pentanone, hexanone, hexone etc.; Be described as " low molecule " as long as the marking method of the amount of carbon atom of compound occurs once in the text of the application about any class, other any unmarked carbonatoms being described as the similar compound of " low molecule " is consistent with the quantity indicated herein.
Moisture determination of the present invention adopts Karl_Fischer method, and the imidazoles anhydrous methanol with 10% is solvent, and the moisture in erythromycin octadecanoate 1 hydrate adopts Karl_Fischer method to measure, and its scope can be between 1.4 ~ 2.5%.On the impact of moisture determination, erythromycin standard substance and stearic acid standard substance or reference substance can be adopted for eliminating erythromycin and stearic acid in Karl_Fischer method mensuration process to be object of reference.The fusing point of erythromycin octadecanoate hydrate of the present invention measures at different time melting point apparatus, and melting point detector corrects.
Powder X-ray diffraction can be used to characterize and/or differentiate polymorph usually, for powder X-ray diffraction when characterizing and/or differentiate, before report peak value, uses modifier " about ".In view of the intrinsic change of peak value, this is the practice of solid-state chemical arts.The usual accuracy of the 2 θ x-axle values at powder collection of illustrative plates peak in ± 0.2 ° of 2 θ rank, therefore, so that " the powder X-ray diffraction peak that about 8.0 ° of 2 θ occurs means when measuring on most of x-ray diffractometer, and peak may between 7.8 ° of 2 θ and 8.2 ° of 2 θ.The change of peak intensity is each crystal result relative to external X-ray source how orientation in sampling receptacle, and orientation effect does not provide the structural information about crystal.
The present invention on the one hand, provides the different crystalline hydrate of erythromycin octadecanoate.
The present invention on the other hand, provides crystalline hydrate and their preparation method of different crystalline forms.
The present invention provides a kind of medicinal compositions on the other hand, comprising any one or the multiple erythromycin octadecanoate hydrate prepared by method of the present invention, and the acceptable vehicle of one or more pharmacy.
The present invention further provides the method for useful in preparing drug formulations, comprising the merging of any one or the multiple erythromycin octadecanoate hydrate prepared by method of the present invention and at least one or the acceptable vehicle of pharmacy.
The present invention further provides the crystalline hydrate of erythromycin octadecanoate hydrate and different crystal forms, infecting for the preparation for the treatment of, comprise bacteriological infection, Gram-positive and or the pharmaceutical composition that infects such as negative microbial infections, mycoplasma, chlamydozoan in purposes.
Erythromycin octadecanoate hydrate of the present invention can be used for preparing solid preparation, comprise tablet, capsule, granule, suspensoid, effervescent tablet, through the ointment of percutaneous drug delivery and gel, the application in the suppository of vaginal jellies and transvaginal or rectal administration etc.
For the preparation of tablet, capsule, granule, suspensoid, the effervescent tablet of solid preparation, wherein can contain pharmaceutically acceptable weighting agent, as starch, modified starch, lactose, Microcrystalline Cellulose, cyclodextrin, sorbyl alcohol, N.F,USP MANNITOL, calcium phosphate, amino acid etc.; Pharmaceutically acceptable disintegrating agent, as starch, modified starch, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, tensio-active agent; Pharmaceutically acceptable wetting agent and tackiness agent, as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyvinylpyrrolidone, Lalgine and salt thereof; Pharmaceutically acceptable lubricant and glidant, as stearic acid, Magnesium Stearate, Macrogol 4000 ~ 8000, talcum powder, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence, as aspartame, Sodium Cyclamate, soluble saccharin, Sucralose, food flavour etc.
Obtaining composition for the preparation of tablet or capsule filling can by wet granulation in preparation, in wet-granulation process, the activeconstituents of some or all or the vehicle of powder type mixed, and then mix further under the existence of liquid, this causes powder grumeleuse to become particle.This particle is sieved and or grinding, dry, then sieve, to the granularity expected, then this particle can make tablet, or before preparation, add other vehicle, such as glidant and/or lubricant.
The composition being prepared into tablet can be prepared by being dry mixed usually.Such as, the composition after activeconstituents and mixed with excipients can be compacted into as small pieces or thin slice, and be then ground into the particle of compacting, the particle of this compacting can be suppressed into tablet subsequently.
Substituting as dry granular method, mixed composition can dry method direct compression, direct compression obtain evenly tablet.The vehicle being particularly suitable for direct compression comprises Microcrystalline Cellulose, spray-dired lactose calcium phosphate and colloid silica.These and other vehicle is proper use of in direct compression is be known to the technician in this area with experience and technical ability.
Capsule filling of the present invention can comprise any above-mentioned mixture and particle or particle, and it describes with reference to being prepared into tablet, but they do not carry out the last step being prepared into tablet.
The suppository preparation of erythromycin octadecanoate hydrate: erythromycin octadecanoate hydrate 1 ~ 50%, suppository base 50 ~ 99% form, matrix can be ethanol, glycerine, glycogelatin, Macrogol 200 ~ 8000, poloxamer, semi-synthetic hard fatty acids fat, carbomer series (931,934,940,974, AA-1,1342 etc.), one or more in polysorbate60 ~ 80.Preparation method: mixed with matrix by main ingredient, heating in water bath, stirs, waits to melt, and being stirred to even, rapid impouring and having scribbled in the mould of the suppository of lubricant, to overflowing bolt mould a little, scabbling after cold, molding and get final product.
The ointment of erythromycin octadecanoate hydrate and gel preparation: erythromycin octadecanoate hydrate is (in erythromycin, feed intake) mix with 50 ~ 99% matrix, matrix can be ethanol, glycerine, trolamine, glycogelatin, Macrogol 200 ~ 8000, poloxamer, polyvinylpyrrolidone, semi-synthetic hard fatty acids fat, water-soluble mono-glycerides, Vaseline, whiteruss, carbomer series (931, 934, 940, 974, AA-1, 1342 etc.), one or more in polysorbate60 ~ 80 etc., wherein can contain sanitas and the stablizer of pharmaceutical acceptable, can respectively by carbomer water-dispersion time prepared by gel, add glycerine, Macrogol 200 ~ 8000, heating in water bath, be uniformly mixed, about adding the erythromycin octadecanoate hydrate of recipe quantity, stirring, regulating pH=5.0 ~ 7.5 with pharmaceutically acceptable acid or alkali, add water to full dose, be stirred to even, packing, to obtain final product.
The clinical application of erythromycin octadecanoate hydrate of the present invention:
Anti-infectives of the present invention---erythromycin derivatives---erythromycin octadecanoate 1 hydrate, tool broad-spectrum antibacterial action, is applicable to the humans and animals prepared caused by the sensitive organism of erythromycin-sensitive, mycoplasma, chlamydozoan and infects: comprising: acute tonsillitis, acute pharyngitis, sinusitis paranasal sinusitis that 1, Hemolytic streptococcus, streptococcus pneumoniae etc. are caused; Scarlet fever caused by Hemolytic streptococcus, phlegmon; Diphtheria and diphtheriaphor; Gas gangrene, anthrax, tetanus; Actinomycosis; Syphilis; Listeriosis etc.; 2. légionaires' disease; 3. mycoplasma pneumoniae pneumonia; 4. Chlamydia Pneumoniae; 5. Genitourinary System Infection caused by other chlamydiaceaes, Mycoplasma; 6. chlamydia trachomatis conjunctivitis; 7. gonococcal infection; 8. oral cavity infection caused by anerobe; 9. campylobacter jejuni enteritis.10. Whooping cough; When 11. rheumatic fever recurrences, infective endocarditis (rheumatic heart disease, congenital heart disease, Cardiac valve replacement), oral cavity, upper respiratory tract medical care precess etc. application in treatment or prophylactic thing.
Usage and consumption: generally, through gastrointestinal administration (in erythromycin), be grown up 0.75 ~ 2g on the one, divides 3 ~ 4 times, and children divide 3 ~ 4 times by body weight 20 ~ 30mg/kg every day.Treatment légionaires' disease, be grown up a 0.5 ~ 1.0g, 4 times on the one.As rheumatic fever recurrence prophylactic time, a 0.25g, 2 times on the one.During prophylactic as infective endocarditis, preoperative 1 hour oral 1g, takes 0.5g in postoperative 6 hours again.The animal of 10 ~ 70kg body weight, generally 50 ~ 500mg/ days, every 6-8 hour 1 time, through gastrointestinal administration.Suppository dosing dosage is generally 50 ~ 500mg/ days, every 6-24 hour 1 time; Mucosa delivery, is directly applied in corresponding affected part by appropriate ointment or gel, one day 1-3 time.
Accompanying drawing explanation
Fig. 1 is the thermal analyses collection of illustrative plates of erythromycin octadecanoate 1 hydrate.
Fig. 2 is the powder X-ray diffracting spectrum of erythromycin octadecanoate 1 hydrate.
Embodiment
During except there being instruction in an embodiment and separately, in specification sheets and claims, all numerical value used should be understood to be in all examples and modify with term " about ", therefore, unless the contrary indication, numerical parameter given in this specification sheets and appending claims is approximation, it can change according to by character required for sought by present disclosure, at least, and not the application being intended to limit doctrine of equivalents right, each numerical parameter should consider that the number of significant figure and the routine method of rounding up are explained.
Although numerical range and the parameter of the wide region of setting disclosure are approximations.But numerical value given in a particular embodiment is as far as possible accurately reported, any number comprises some error certainly led to by the standard deviation found in their respective tests in essence.
Unless it is pointed out that in literary composition and illustrated in addition clearly, the singulative " " used in this specification and the appended claims, " one " and " being somebody's turn to do " comprise the plural form referring to thing, so, such as.If comprise the mixture of two or more compounds when mentioning the composition containing " a kind of compound ", unless it should be noted that in addition and illustrate in addition clearly herein, term "or" generally includes "and/or".
As used herein, term " obtains " referring to that valuable purity level is separated the compound obtained, and described purity level includes but not limited to be greater than 90%, the purity level of 95%, 96%, 97%, 98% and 99%.Described purity level can pass through high-performance liquid chromatogram determination or microbiology polymorphism.
Pharmaceutical composition
" pharmaceutical composition " used herein refers to the composition of medicine, and described pharmaceutical composition can contain the pharmaceutically acceptable carrier of at least one.
" pharmaceutically acceptable vehicle " used herein refers to the pharmaceutical carrier or solvent that are applicable to the compound administration occasionally provided herein, it comprises any examples of such carriers that well known to a person skilled in the art and be applicable to specific administration mode, such as, sterile diluent (such as, water for injection, salts solution, non-volatile wet goods) can be comprised for the solution of parenteral, intradermal, subcutaneous or topical application or suspension agent; The fatty solvent (such as, polyoxyethylene glycol, glycerine, propylene glycol etc.) of synthesis; Antioxidant (such as, xitix, sodium bisulfite etc.); Sequestrant (such as, EDTA etc.); With or buffer reagent (phosphoric acid salt, Citrate trianion etc.); Or their mixture.
As non-limiting example, erythromycin octadecanoate 1 hydrate can optionally and one or more pharmaceutically acceptable mixed with excipients, and can with following form oral administration: tablet, capsule, dispersible powder, granule or the suspensoid containing such as about 0.05-5% suspending agent, the syrup containing such as about 10-50% sucrose, the preparation containing such as about 20-50% ethanol; Or with the form parenteral admin of sterile solution agent or suspensoid, the suspending agent of described suspensoid also containing 0.05-5% in isotonic medium, these pharmaceutical preparations can contain activeconstituents and the carrier of such as about 25% to about 90%, the active ingredient more generally containing 5% to 60% (weight).
In order to understand the present invention further, below in conjunction with embodiment, the preferred embodiment of the invention is described, but should be appreciated that these describe just for further illustrating the features and advantages of the present invention, instead of limiting to the claimed invention.
With specific embodiment, effect of the present invention is described below, but protection scope of the present invention is not limited by the following examples.
Heat analysis method
Thermal analyses test condition: Setaram company Setsys16, about sample size 3-10mg, heat-up rate: 10K/min, N
2flow velocity: 50ml/min, temperature: about room temperature ~ 400 DEG C.
Surprisingly, distinctive, there is under the weightless platform of about about 70 ~ 130 DEG C of thermal analyses (TG-DTA or the TG-DSC) collection of illustrative plates of hydrate of the present invention corresponding endotherm(ic)peak.
Powder X-ray diffraction approach
Utilize D/MX-III AX x ray diffractometer x, voltage: 35kv, electric current: 30mA, sweep velocity: 10 °/min, step-length: 0.02 °/step; Copper target, monochromator: graphite monochromator; Wavelength wavelength (
): 1.54, diffraction angle 2 θ, sweep limit 3-60 °, determine the x-ray diffractogram of powder of erythromycin octadecanoate hydrate.
In an embodiment (implementing 1), powder X-ray diffractometry is utilized to measure, in diffraction angle 2 θ (3-60 °) useful range, erythromycin octadecanoate 1 hydrate of the present invention can have corresponding eigenwert in the position comprising following 2 θ values: about 3.24,4.56,5.71,7.98,8.46,8.7,9.18,10.64,11.6,12.22,12.74,13.84,14.2,15.6,16.36,17.1,18.14,18.62,19.52,19.9,20.18,20.64,21.34,22.9,24.78,25.72,26.9.
In an embodiment (implementing 2), utilize powder X-ray diffractometry to measure, in diffraction angle 2 θ (3-60 °) useful range, erythromycin octadecanoate 1 hydrate of the present invention can have corresponding eigenwert in the position comprising following 2 θ values: about 4.62,5.84,8.00,9.24,10.7,11.64,12.28,13.92,14.38,15.7,16.45,17.11,18.2,4,18.6,19.94,20.3,21.36,22.96.
Embodiment
The preparation of embodiment 1 erythromycin octadecanoate 1 hydrate: in 500ml three-necked flask, add acetone 200ml, tetrahydrofuran (THF) 5ml, ethanol 5ml, erythromycin 20g, 20 ~ 45 DEG C are stirred to dissolve, add the equimolar stearic acid with erythromycin, stirring reaction 1 hour, stir, the water adding 35 ~ 65 DEG C is about about 180ml, be cooled to-15 ~ 0 DEG C, treat that off-white color solid is separated out to finish, suction filtration, solids is placed in 500ml reaction flask, add sherwood oil 120ml, ethyl acetate 3ml, acetone 3ml, 30 ~ 50 DEG C are stirred about 4h, filter, obtain off-white color solid, as method is re-refined twice, after gained off-white color solid is used appropriate dissolve with ethanol again, add acetonitrile 2ml, methylene dichloride 1ml, add appropriate water recrystallization three times, suction filtration, 40ml sherwood oil washes 2 times, suction filtration, by gained off-white color solid, at about 40 DEG C, vacuum-drying about 8h under about 0.09MPa, obtain off-white color solid 13.7g, fusing point: 102 ~ 106 DEG C (correction), the retention time of HPLC: under identical conditions, its HPLC is consistent with the HPLC retention time of erythromycin reference substance, moisture (Karl_Fischer method): 1.96%, TG: weightlessness about 1.67% (theoretical value 1.74%) between 70 ~ 130 DEG C, infrared spectra: ν
kBr maxcm
-13552,3322,2921,2852,1724,1708,1586,1467,1405,1378,1347,1264,1173,1095,1053,1002,899,830,724, MS (ESI) m/z:1017, ultimate analysis measured value: C63.87, H10.44, N1.19, theoretical value: C63.74, H10.21, N1.35.
The preparation of embodiment 2. erythromycin octadecanoate 1 hydrate: under room temperature, in the three-necked flask of 500ml, add erythromycin 16g, add 80ml acetone, stirring makes it dissolve, drip the stearic acetone soln of 9g in stirring and be about 46ml, heating deionized water about 60ml, slowly be cooled to-24 ~ 4 DEG C, placement makes precipitation fully separate out, filter, solids is placed in 500ml reaction flask, add sherwood oil 100ml, 35 ~ 45 DEG C are stirred about 1h, filter, obtain off-white color solid, refining twice of operation like this, again gained solid is placed in 500ml reaction flask, add, 100ml hexanaphthene, 30 ~ 45 DEG C are stirred about 2h, filter, by gained off-white color solid 40ml ethanol, 20ml acetone and appropriate water carry out recrystallization, abundant precipitation to be precipitated, suction filtration, 30ml sherwood oil washes twice, suction filtration, twice, recrystallization like this, by gained solid at about 50 DEG C, vacuum-drying about 5h under about 0.07MPa, obtain off-white color crystallization 6.7g, fusing point: 103 ~ 106 DEG C (correction), the retention time of HPLC: under identical conditions, its HPLC is consistent with the HPLC retention time of erythromycin reference substance, it is 2.02% (theoretical value 1.74%) that Ka Shi method measures moisture, TG: between 70 ~ 130 DEG C, platform weightlessness about 1.77% (see accompanying drawing 1) and sample contain 1 crystal water in limit of error, and X-ray powder diffraction is shown in accompanying drawing 2, infrared spectra: ν
kBr maxcm
-13552,3317,2927,2855,1726,1709,1568,1465,1403,1378,1347,1265,1173,1119,1088,1053,1002,953,900,831,725, MS (ESI) m/z:1017, ultimate analysis measured value: C63.92, H10.41, N1.21, theoretical value: C63.74, H10.21, N1.35.
Embodiment 3. erythromycin octadecanoate hydrate tablet (250mg/ sheet, in erythromycin)
By erythromycin octadecanoate 1 hydrate (by embodiment 1 or embodiment 2 legal system standby), Microcrystalline Cellulose, sodium starch glycolate, aspartame cross 100 mesh sieves, polyvinylpyrrolidone (alcohol water of 75%) solution softwood processed in right amount with 5%, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel, Magnesium Stearate mixing, compressing tablet.
Embodiment 4 erythromycin octadecanoate 1 hydrate capsule (125mg/ grain, in erythromycin)
By erythromycin octadecanoate 1 hydrate (by embodiment 1 or embodiment 2 legal system standby), Microcrystalline Cellulose, lactose cross 100 mesh sieves, the gelling starch with 10% is softwood processed in right amount, crosses 24-30 mesh sieve and granulates, dry, after crossing the whole grain of 24-30 mesh sieve, add Magnesium Stearate mixing, filling capsule.Or erythromycin octadecanoate hydrate adds according to dosage direct filling capsule after appropriate starch or Microcrystalline Cellulose mixing.
Embodiment 5 erythromycin octadecanoate 1 hydrate capsule (125mg/ grain or 250mg/ grain, in erythromycin)
By erythromycin octadecanoate 1 hydrate (by embodiment 1 or embodiment 2 legal system standby) cross 14-80 mesh sieve, direct filling capsule.
Embodiment 6 erythromycin octadecanoate 1 hydrate capsule (125mg/ grain or 250mg/ grain, in erythromycin)
Or the erythromycin octadecanoate hydrate crossing 14-80 mesh sieve of above-described embodiment five is added and appropriate to cross after the Magnesium Stearate mixing of 14-80 mesh sieve according to dosage direct filling capsule.
Embodiment 7 erythromycin octadecanoate 1 hydrate particle (125mg/ wraps, in erythromycin)
By erythromycin octadecanoate hydrate (by embodiment 1 or embodiment 2 legal system standby), N.F,USP MANNITOL, lactose, Sodium Cyclamate, food flavour cross 100 mesh sieves, polyvinylpyrrolidone (alcohol water of 75%) solution softwood processed in right amount with 5%, cross 18-24 mesh sieve to granulate, less than 50 DEG C dry, after crossing the whole grain of 14-24 mesh sieve, point packaging.
Embodiment 8 erythromycin octadecanoate 1 hydrate suspensoid (125mg/ wraps, in erythromycin)
By erythromycin octadecanoate hydrate (by embodiment 1 or embodiment 2 legal system standby), lactose, Sodium Cyclamate cross 100 mesh sieves, polyvinylpyrrolidone (alcohol water of 75%) solution softwood processed in right amount with 5%, cross 18-24 mesh sieve to granulate, less than 50 DEG C dry, after crossing the whole grain of 14-24 mesh sieve, mix with the xanthan gum crossing 100 mesh sieves, packing, packs and get final product.
The suppository (250mg/ grain, in erythromycin) of embodiment 9 erythromycin octadecanoate 1 hydrate
By erythromycin octadecanoate 1 hydrate (by embodiment 1 or embodiment 2 legal system standby), glycerine, Macrogol 4000, poloxamer, tween 80 mixing, heating in water bath, stir, wait to melt, being stirred to even, rapid impouring has scribbled in the mould of the suppository of lubricant, to overflowing bolt mould a little, scabble after cold, molding and get final product.
Embodiment 10 erythromycin octadecanoate 1 hydrate gel
Respectively by carbomer 934 and the appropriate water-dispersion of carbomer934, add glycerine, propylene glycol, trolamine, be uniformly mixed, add erythromycin octadecanoate 1 hydrate (by embodiment 1 or embodiment 2 legal system standby), heating in water bath, stirring, hydrochloric acid 1M or sodium hydroxide 1M regulate between pH value 6-7.5, be stirred to even, vacuum outgas, to obtain final product.
Embodiment 11 erythromycin octadecanoate 1 hydrate ointment
By glycerine, white vaseline, whiteruss, ethyl p-hydroxybenzoate, sodium laurylsulfate, the mixing of suitable quantity of water heated and stirred, add erythromycin octadecanoate 1 hydrate (by embodiment 1 or embodiment 2 legal system standby) be dissolved in mix heating in water bath in dimethyl sulfoxide (DMSO), by both, be stirred to even, cooling, to obtain final product.
Embodiment 12 erythromycin octadecanoate 1 hydrate effervescent tablet (250mg/ sheet, in erythromycin)
The erythromycin octadecanoate 1 hydrate 10g, tartrate 28g, the lactose 30g that pulverize, cross 80 mesh sieves respectively are fully mixed, makes softwood, dry; Again respectively by pulverizing, cross sodium bicarbonate 48g, the PVP K30 1.5g of 80 mesh sieves, hexanodioic acid 15g, essence 0.5g, correctives 0.5g join in dried particles, mixing, compressing tablet.
Embodiment 13
Erythromycin octadecanoate hydrate (embodiment 2) anti-microbial activity carries out microbial culture and mensuration (test tube doubling dilution) according to Pharmacological Test Method, its result (MIC is minimum inhibitory concentration) as shown in table 2:
Table 2 erythromycin octadecanoate 1 hydrate anti-microbial activity MIC (mg/L)
Be appreciated that, from this professional angle, the change of a lot of details is possible, therefore this do not limit the scope of the invention and spirit, and the present invention is not limited to above-described embodiment.
Claims (12)
1. erythromycin octadecanoate compounds entity, is characterized in that: erythromycin octadecanoate compounds entity is erythromycin octadecanoate 1 hydrate, and molecular formula is C
37h
67nO
13c
18h
36o
2h
2o.
2. erythromycin octadecanoate compounds entity according to claim 1, is characterized in that: the thermal analyses collection of illustrative plates of erythromycin octadecanoate 1 hydrate, namely has obvious endotherm(ic)peak under the weightless platform of TG-DTA collection of illustrative plates between 70 ~ 130 DEG C.
3. erythromycin octadecanoate compounds entity according to claim 2, is characterized in that: utilize powder X-ray diffractometry to measure, and in the useful range of diffraction angle 2 θ, 3-60 °, has corresponding eigenwert: 3.24,4.56 in the position of following 2 θ values, 5.71,7.98,8.46,8.7,9.18,10.64,11.6,12.22,12.74,13.84,14.2,15.6,16.36,17.1,18.14,18.62,19.52,19.9,20.18,20.64,21.34,22.9,24.78,25.72,26.9.
4. erythromycin octadecanoate compounds entity according to claim 2, is characterized in that: utilize powder X-ray diffractometry to measure, and in the useful range of diffraction angle 2 θ, 3-60 °, has corresponding eigenwert: 4.62 in the position of following 2 θ values, 5.84,8.00,9.24,10.7,11.64,12.28,13.92,14.38,15.7,16.45,17.11,18.24,18.6,19.94,20.3,21.36,22.96.
5. the preparation method of erythromycin octadecanoate compounds entity according to claim 1, its step is as follows:
In reaction vessel, with water and C
1-C
6low mass molecule alcohol, C
3-C
8low molecule ketone or C
2-C
8rudimentary ether in one or more be solvent, erythromycin is dissolved, adds stearic acid or it is at C
1-C
6low mass molecule alcohol, C
3-C
8low molecule ketone or C
2-C
8rudimentary ether in the solution of one or more, or by stearic acid or it is at C
1-C
6low mass molecule alcohol, C
3-C
8low molecule ketone or C
2-C
8rudimentary ether in the solution of one or more and the solution of above-mentioned erythromycin mix, stir, be placed in-25 ~ 30 DEG C of placement, treat that solid is separated out complete, filter to obtain solid; The solid of gained is placed in container refine, adds C
2-C
8low molecule ester, C
3-C
8low molecule ketone or C
5-C
10one or more in low molecule straight or branched alkane or naphthenic hydrocarbon, sherwood oil, stir, filter, separate solid, so refining once to for several times; Again by gained solid water and C
1-C
6low mass molecule alcohol, C
2-C
6low molecule nitrile, C
3-C
8low molecule ketone, C
1-C
6low molecule halohydrocarbon in one or more carry out one or many recrystallization for solvent, be cooled to-20 ~ 10 DEG C, filter, dry, obtain erythromycin octadecanoate 1 hydrate.
6. the method preparing erythromycin octadecanoate compounds entity according to claim 5, is characterized in that, refining solvent is selected from: C
2-C
8low molecule ester, C
3-C
8low molecule ketone or C
5-C
10one or more in low molecule straight or branched alkane or naphthenic hydrocarbon, sherwood oil.
7. the method preparing erythromycin octadecanoate compounds entity according to claim 5, is characterized in that, C
2-C
8low molecule ester, C
3-C
8low molecule ketone or C
5-C
10the envelope-bulk to weight ratio of one or more and solid in low molecule straight or branched alkane or naphthenic hydrocarbon, sherwood oil is 0.1 ~ 50:1, and wherein volume unit is ml, and weight unit is g, to calculate its proportionlity.
8. the method preparing erythromycin octadecanoate compounds entity according to claim 6, is characterized in that, refining solvent is selected from: one or more in ethyl acetate, acetone, hexanaphthene or sherwood oil.
9. the method preparing erythromycin octadecanoate compounds entity according to claim 5, it is characterized in that, recrystallization solvent is selected from: one or more in water and ethanol, Virahol, acetonitrile, acetone, methylene dichloride, chloroform.
10. the purposes of erythromycin octadecanoate compounds entity according to claim 1, is characterized in that: in preparation containing the application on the composition of this erythromycin octadecanoate compounds entity.
The purposes of 11. erythromycin octadecanoate compounds entities according to claim 1, is characterized in that: preparing tablet, capsule, granule, suspensoid, application on the ointment of skin or mucosa delivery or gel and suppository.
The purposes of 12. erythromycin octadecanoate compounds entities according to claim 1, is characterized in that: the application in the treatment preparing the infection of the humans and animals caused by the sensitive organism to sensitivity, mycoplasma, chlamydozoan or prophylactic thing; Infection is selected from: oral cavity infection caused by acute tonsillitis, acute pharyngitis, sinusitis paranasal sinusitis, scarlet fever, phlegmon, diphtheria and diphtheriaphor, gas gangrene, anthrax, tetanus, actinomycosis, syphilis, listeriosis, légionaires' disease, mycoplasma pneumoniae pneumonia, chlamydia trachomatis conjunctivitis, anerobe, campylobacter jejuni enteritis, Whooping cough, rheumatic fever recurrence, infective endocarditis.
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|---|---|---|---|---|
| US2881163A (en) * | 1953-11-16 | 1959-04-07 | Abbott Lab | Process of preparing salts |
| WO2002018403A1 (en) * | 2000-09-01 | 2002-03-07 | Chugai Seiyaku Kabushiki Kaisha | Process for producing erythromycin derivative |
| CN1474828A (en) * | 2000-10-12 | 2004-02-11 | 中外制药株式会社 | Erythromycin derivative having novel crystal structures and process for their production |
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2011
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|---|---|---|---|---|
| US2881163A (en) * | 1953-11-16 | 1959-04-07 | Abbott Lab | Process of preparing salts |
| WO2002018403A1 (en) * | 2000-09-01 | 2002-03-07 | Chugai Seiyaku Kabushiki Kaisha | Process for producing erythromycin derivative |
| CN1474828A (en) * | 2000-10-12 | 2004-02-11 | 中外制药株式会社 | Erythromycin derivative having novel crystal structures and process for their production |
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| 硬脂酸红霉素生产工艺研究;陈泳州，等;《湖北师范学院学报（自然科学版）》;19961231;第16卷(第3期);第99-101、120页 * |
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