CN101152203A - Lactobionic azithromycin aqua compound, production and use of the same - Google Patents
Lactobionic azithromycin aqua compound, production and use of the same Download PDFInfo
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- CN101152203A CN101152203A CNA2007100531547A CN200710053154A CN101152203A CN 101152203 A CN101152203 A CN 101152203A CN A2007100531547 A CNA2007100531547 A CN A2007100531547A CN 200710053154 A CN200710053154 A CN 200710053154A CN 101152203 A CN101152203 A CN 101152203A
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- azithromycin
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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Abstract
The invention provides an azithromycinl actobioate hydrate and the purpose. The formula of the azithromycinl actobioate hydrate of the invention is C<SUB>38</SUB>H<SUB>72</SUB>N<SUB>2</SUB>O<SUB>12</SUB>question mark 2C<SUB>12</SUB>H<SUB>22</SUB>O<SUB>12</SUB>question mark nH<SUB>2</SUB>O, in which n is between 2.0 to 5.5.the hydrate has good water solubility, high storage stability, and is applicable to treat and prevent human or animal infectious diseases caused by Gram positive or negative bacteria.
Description
Technical field
The present invention relates to medical technical field, specifically provide lactobionic azithromycin aqua compound and preparation thereof and purposes.
Background technology
Document has only been reported lactobionic acid azithromycin [C
38H
72N
2O
122C
12H
22O
12Molecular weight: 1465.58] (azithromycin lactobionate) and uses thereof, up to the present, still there is not disclosed bibliographical information lactobionic azithromycin aqua compound [C both at home and abroad
38H
72N
2O
122C
12H
22O
12NH
2O, n=2.0～5.5] and its production and use.
Summary of the invention
Involved in the present invention is lactobionic acid azithromycin (azithromycin lactobionate) hydrate and preparation and purposes.Lactobionic azithromycin aqua compound of the present invention, its molecular formula are C
38H
72N
2O
122C
12H
22O
12NH
2O, n=2.0～5.5, n can be 2,2.3,2.5,4.5,5.0,5.2,5.5 and between numeral.
Surprisingly, we are by discovering the lactobionic azithromycin aqua compound [C that contains water of crystallization that we obtain
38H
72N
2O
122C
12H
22O
12NH
2O, n=2.0～5.5] the stable existence of energy, the lactobionic acid azithromycin that contains water of crystallization is different from the characteristic that azithromycin is insoluble in water, the characteristic of the easy moisture absorption of anhydrous lactobionic acid azithromycin, the lactobionic acid azithromycin that contains water of crystallization is all soluble in water, has good room temperature storage stability, the preparation of being convenient to prepare easily directly dissolving and absorbing, be convenient to store and transportation, can conveniently be used for the preparation of pharmaceutical preparation.The weightless as can be seen platform of thermal analysis test (TG-DTG) collection of illustrative plates has corresponding endothermic peak (seeing accompanying drawing 1,2,3,4), match with Ka Erfei body method mensuration moisture result and hot analysis result, appended TG-DTG collection of illustrative plates is obviously found out 2.5 hydrate C of lactobionic azithromycin aqua compound behind the embodiment
38H
72N
2O
122C
12H
22O
122.5H
2O, lactobionic acid azithromycin 5 hydrate C
38H
72N
2O
122C
12H
22O
125H
2O, lactobionic azithromycin aqua compound 4.5 hydrate C
38H
72N
2O
122C
12H
22O
124.5H
2O.
Lactobionic azithromycin aqua compound of the present invention is an off-white powder, is different from azithromycin not diffluent characteristic in water, at room temperature has good water-solubility, is easy to make water miscible preparation.
Lactobionic azithromycin aqua compound of the present invention can stable storage.Above-mentioned sample is required to be sealed in the cillin bottle according to the CP2005 version, under 40 ℃, carry out accelerated stability test, with HPLC method (C
18Reversed-phase column, (regulating pH to 7.0 with triethylamine)-acetonitrile (70: 30) is a mobile phase to the potassium dihydrogen phosphate of 0.1M, and the detection wavelength is 210nm, and flow velocity is 1.0ml/min, the situation of change of detection level and related substance.Unexpectedly find, lactobionic azithromycin aqua compound content of the present invention and related substance do not have significant change, lactobionic acid azithromycin anhydride accelerated test 6 months was compared with 0 month, related substance increases multiple far above lactobionic azithromycin aqua compound, illustrates that lactobionic azithromycin aqua compound has good storage stability.
The results are shown in Table 1～table 4.
Table 1. lactobionic acid azithromycin 2.5 hydrate accelerated stability test results
| Sample time (moon) | Character | Indicate content (%) | Related substance (%) |
| 0 1 2 3 6 | Off-white powder off-white powder off-white powder off-white powder off-white powder | 99.9 100.2 99.8 100.5 99.6 | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ |
Table 2. lactobionic acid azithromycin 5 hydrate accelerated stability test results
| Sample time (moon) | Character | Indicate content (%) | Related substance (%) |
| 0 1 2 3 6 | Off-white powder off-white powder off-white powder off-white powder off-white powder | 99.9 100.6 99.9 100.1 99.8 | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ |
Table 3. lactobionic acid azithromycin 4.5 hydrate accelerated stability test results
| Sample time (moon) | Character | Indicate content (%) | Related substance (%) |
| 0 1 2 3 6 | Off-white powder off-white powder off-white powder off-white powder off-white powder | 100.2 100.1 100.3 99.6 100.5 | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ |
Table 4. lactobionic acid azithromycin anhydride and hydrate accelerated stability test result
| Sample time (June) | Compared the multiple of related substance with 0 month |
| Lactobionic acid azithromycin 2.5 hydrate lactobionic acid azithromycins 4.5 hydrate |
1.2 1.5 1.4 4.3 6.6 |
The lactobionic azithromycin aqua compound preparation method is:
Method A. is in reaction vessel, with rudimentary (C3-C6) ketone, as acetone, rudimentary (C2-C6) ester, water or low mass molecule alcohol C1-C5 such as methanol, ethanol, one or more of isopropyl alcohol are solvent, add lactobionic acid and azithromycin, stir between 0-40 ℃, dissolving, reaction is finished, slowly add rudimentary (C3-C6) ketone, as acetone, chloroform or low mass molecule alcohol such as methanol, ethanol, isopropyl alcohol, rudimentary (C2-C6) ether, rudimentary (C2-C6) ester is as ethyl acetate, one or more of formic acid second fat, cooling, treat that solid separates out, filter solids organic solvent low mass molecule alcohol C1-C5 such as methanol, ethanol, isopropyl alcohol, rudimentary (C3-C6) ketone is as acetone, rudimentary (C2-C6) ether such as ether, one or more rinses in the chloroform, drain the dry lactobionic azithromycin aqua compound that gets;
Perhaps method B is in reaction vessel, add lactobionic acid or its aqueous solution, add azithromycin, stir between 0-40 ℃, make dissolving, reaction is finished, slowly add rudimentary (C3-C6) ketone, as acetone, chloroform, rudimentary (C2-C6) ester is as ethyl acetate, formic acid second fat, or low mass molecule alcohol C1-C5 such as methanol, ethanol, one or more of isopropyl alcohol, cooling, treat that solid separates out, filter that solids is with organic solvent low mass molecule alcohol C1-C5 such as methanol, dehydrated alcohol, isopropyl alcohol, rudimentary (C3-C6) ketone, as acetone, rudimentary (C2-C6) ether, rudimentary (C2-C6) ester, as ethyl acetate, formic acid second fat, one or more rinses are drained in the chloroform, the dry lactobionic azithromycin aqua compound that gets;
Perhaps method C. with lactobionic acid and azithromycin in molar ratio (2: 1) drop in the reaction bulb, add water, between 0-40 ℃ of the control temperature, reaction 0.5-6h, question response finishes, and it is freezing to-60～-40 ℃, vacuum lyophilization gets lactobionic azithromycin aqua compound.
With of the alcoholic solution neutralization of gained sample with sodium bicarbonate or ammonia, sedimentation and filtration, washing, one or more recrystallization in water, methanol, ethanol or the acetone, data such as fusing point, specific rotatory power, IR, MS or collection of illustrative plates are all consistent with the raw material azithromycin dihydrate.
Under vacuum condition, between 50-105 ℃, phosphorus pentoxide is a desiccant with lactobionic azithromycin aqua compound, and vacuum drying got the lactobionic acid azithromycin anhydride more than 6 hours.
The lactobionic azithromycin aqua compound that the present invention is stable is used for lactobionic azithromycin aqua compound and is used to prepare injection freeze-dried powder or aseptic subpackaged powder injection formulation or great transfusion preparation or little water needle injection, through the intestinal canal administration preparation, comprise tablet, capsule, granule, through the ointment and the gel of skin administration, the suppository of effervescent tablet, vaginal jellies and transvaginal or rectally.
Be used to prepare tablet through the intestinal canal administration preparation, capsule, granule wherein can contain pharmaceutically acceptable filler, as starch, modified starch, lactose, microcrystalline Cellulose, cyclodextrin, sorbitol, mannitol, calcium phosphate, aminoacid etc.; Pharmaceutically acceptable disintegrating agent is as starch, modified starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, surfactant; Pharmaceutically acceptable wetting agent and binding agent are as gelling starch, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyvinylpyrrolidone, alginic acid and salt thereof; Pharmaceutically acceptable lubricant and fluidizer are as stearic acid, magnesium stearate, Macrogol 4000-6000, Pulvis Talci, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence are as aspartame, cyclamate, saccharin sodium, sucralose, edible essence etc.
Solid preparation of the present invention is different from the characteristic that the azithromycin difficulty is dissolved in water, cause the dissolution of its solid preparation to be subjected to the big characteristics of preparation technogenic influence, lactobionic azithromycin aqua compound easily is dissolved in water, so the solid preparation of its preparation has good dissolving out capability, make it be absorbed easily and enter blood circulation, improve bioavailability, and help bringing into play fast its antibacterial action.
Suppository of the present invention and gel are different from Azithromycin suppository or ointment, because the azithromycin difficulty is dissolved in water, need to add the adjuvant of oil-soluble generally speaking, be easy to pollute, and difficult the cleaning, lactobionic azithromycin aqua compound easily is dissolved in water, so the suppository of its preparation and gel have good release performance, make it be absorbed easily and enter blood circulation, improve bioavailability, and help bringing into play fast its antibacterial action.Need not to add the adjuvant of oil-soluble, be difficult for polluting, and than easy cleaning,
The suppository of lactobionic azithromycin aqua compound: lactobionic azithromycin aqua compound 5-50%, suppository base 50-95% form, and substrate can be ethanol, glycerol, glycerin gelatine, Macrogol 200-8000, poloxamer, semi-synthetic hard fatty acids fat, carbomer series (931,934,940,974, AA-1,1342 etc.), polysorbate60-80.Preparation method: principal agent is mixed with substrate, heating in water bath, stir, wait to melt, be stirred in the mould of suppository that even, rapid impouring scribbled lubricant, to overflowing the bolt mould a little, treat to scabble after cold, molding promptly.
The preparing gel of lactobionic azithromycin aqua compound: lactobionic azithromycin aqua compound is (in azithromycin, feed intake) with 50-95% substrate mixing, substrate can be ethanol, glycerol, triethanolamine, glycerin gelatine, Macrogol 200-8000, poloxamer, polyvinylpyrrolidone, semi-synthetic hard fatty acids fat, water solublity monoglyceride, carbomer series (931,934,940,974, AA-1,1342 etc.), polysorbate60-80.Can contain pharmaceutically receivable antiseptic and stabilizing agent in the suppository, can be during preparation respectively with the carbomer aqueous dispersion, add glycerol, Macrogol 200-8000, heating in water bath, mix, add the lactobionic azithromycin aqua compound, stirring of recipe quantity, with pharmaceutically receivable inorganic base or organic base are regulated about pH=6.0-7.0, add water to full dose, be stirred to even, packing, promptly.
The preparation method of freeze-dried powder is: get lactobionic azithromycin aqua compound (by anhydride), add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, add injection and blunge and make dissolving, pharmaceutically acceptable acid-alkali accommodation pH is 5.5-7.5, preferred pH is 6.2-7.0, adds activated carbon 0.005-0.5% (W/V) and stirs 15-45min, filters, moisturizing, aseptic filtration is by 75-500mg/ bottle (in principal agent) packing, lyophilization, tamponade gets finished product.
Lactobionic azithromycin aqua compound of the present invention prepares injection freeze-dried powder, aseptic subpackaged powder injection formulation, and (75～500mg) are dissolved in 10～15ml water the preparation of a unit dose, and its pH value is between 5.5～7.5.
Lactobionic azithromycin aqua compound is used to prepare great transfusion preparation: lactobionic azithromycin aqua compound adds injection water and pharmaceutically acceptable additives, for example pharmaceutically acceptable pH regulator agent, pharmaceutically acceptable antioxidant and stabilizing agent, pharmaceutically acceptable etc. opened regulator, the high capacity sterile solution for injection is made in filtration, degerming, its pH value is between 5.5～7.5, and preferred pH is 6.2-7.0.
Lactobionic azithromycin aqua compound injection with small volume and preparation technology thereof: lactobionic azithromycin aqua compound adds injection water and pharmaceutically acceptable additives, for example: pharmaceutically acceptable pH regulator agent, pharmaceutically acceptable antioxidant, noble gas, the sterilization injection with small volume is made in filtration, degerming, its pH value is between 5.5～7.5, preferred pH is 6.2-7.0
Its pharmaceutically acceptable pH regulator agent can be pharmaceutically acceptable mineral acid or organic acid, inorganic base or organic base, also can be generalized lewis acid or alkali, can contain one or several, can be hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, hydrobromic acid, propanoic acid, acetic acid and acetate, as sodium acetate etc., lactic acid and lactic acid pharmaceutical salts, as sodium lactate etc., citric acid, the citric acid pharmaceutical salts, as citric acid trisodium etc., sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, diammonium phosphate, dipotassium hydrogen phosphate, succinic acid and salt, tartaric acid and pharmaceutical salts thereof, as sodium bitartrate, DL-tartaric acid, sodium potassium tartrate tetrahydrate etc., Borax, boric acid, succinic acid, caproic acid, adipic acid, fumaric acid, maleic acid, ammonium carbonate, hypophosphorous acid, Polymeric sodium metaphosphate., Kurrol's salt, potassium metaphosphate, the trihydroxy aminomethane, triethanolamine, diethanolamine, ethanolamine, isopropanolamine, diisopropanolamine (DIPA), 2-amino-2-(methylol) 1, ammediol amine, 1, the 2-hexamethylene diamine, N-methyl Fructus Vitis viniferae amine, diisopropylamine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts, as glucuronic acid, gluconic acid, lactobionic acid, lactobionic acid, galacturonic acid, malic acid, threonic acid THREONIC ACID., glucoheptonic acid, nicotinic acid, glycyrrhetate, benzoic acid and salt, sodium benzoate, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, glyceric acid, glycine, lysine, arginine, methionine waits in aminoacid and the amino acid salts etc. one or several.
Its pharmaceutically acceptable antioxidant and stabilizing agent can be sulfurous acids, sulphite, bisulfites, pyrosulfite, dithionite, thiosulfate, the organosulfur compound thiourea, glutathion, dimercaptopropanol, BAL, TGA and salt, sodium sulfoxylate formaldehyde, thioglycerin, 2-mercaptopropionic acid and salt, thio-2 acid and salt, phenol compound, as gallic acid and salt, progallin A, propyl gallate, gallateoctylester, lauryl gallate, caffeic acid, the caffeiate, ferulic acid, ferulate, dibenzylatiooluene, butylated hydroxyarisol, the di-t-butyl Pyrogentisinic Acid, nordihydroguaiaretic acid (NDGA), 2, the 5-resorcylic acid, 2,5-resorcylic acid salt, the phenol or derivatives thereof, salicylic acid or its salt; Sodium glutamate, glycine, cysteine, methionine, aminoacid with and salt; Glycyrrhetate, glycyrrhetate, enols used, as ascorbic acid and Ascorbate, ascorbic acid Petiolus Trachycarpi ester, arabo-ascorbic acid and erythorbate, acetone close ascorbic acid, a-tocopherol, nicotiamide, tartaric acid, nitrate, phosphate, acetic acid pharmaceutical salts, citrate, EDTA and edta salt, as in EDTA disodium, EDTA four sodium, calcium disodium edetate, CDTA, DTPA, N-two (2-ethoxy) glycine, divinyl triamido penta acetic acid, diethyl triamine base penta acetic acid etc. one or several.
Its pharmaceutically acceptable isoosmotic adjusting agent can be one or more in glucose, fructose, xylitol, sorbitol, mannitol, Nulomoline, maltose, dextran, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, the sodium lactate etc.
Source and the degerming mode of reducing phlegm and internal heat can be the active carbon that the adds dosing amount 0.005-3% source of reducing phlegm and internal heat, and microporous filter membrane degerming and pressure sterilizing also can adopt heat sterilization, the source of reducing phlegm and internal heat.In the hyperfiltration process, that ultrafilter can be selected for use is flat, rolling, tubular type, doughnut formula and circle boxlike etc., preferred rolling and doughnut formula ultrafilter, it is after 50,000 to 300,000 filter membrane is removed most of heat generation material and antibacterial that relative molecular mass is held back in employing, adopt the ultrafilter membrane of holding back relative molecular mass 1000-30000 to remove the residue thermal source, the ultrafilter membrane of preferred relative molecular mass 1000-10000 again.
The lactobionic azithromycin aqua compound antibacterial activity carries out antibacterial culturing and mensuration according to the pharmacological experiment method, and its result is shown in table 5,6:
Table 5 lactobionic acid azithromycin 5 hydrate antibacterial activity MIC (mg/L)
| Bacterial infection | Bacterial strain | MIC | MIC(mg/L) MIC 50 | MIC 90 |
| Staphylococcus aureus epidermis Portugal pneumococcal pneumonia coccus Streptococcus viridans Hemolytic streptococcus peptostreptococcus hemophilus influenza Klebsiella pneumonia escherichia coli aerobacteria bacillus fragilis bacillus cloacae salmonella typhi shigella bacillus pyocyaneus | 20 15 22 19 18 13 23 15 21 15 21 17 14 13 15 | 0.06-4 16-250 1-16 0.06-16 0.25-16 0.06-8 0.03-32 31.25-＞125 0.06-4 2-125 0.6-＞125 0.5-32 1-16 1-16 16-＞250 | 0.125 64 2 0.6 2 2 0.6 125 1 8 8 8 2 2 62.25 | 0.5 250 4 2 4 4 16 ＞125 2 16 ＞125 32 8 8 125 |
Table 6 lactobionic acid azithromycin 2.5 hydrate antibacterial activity MIC (mg/L)
| Bacterial infection | Bacterial strain | MIC(mg/L) | ||
| MIC | MIC 50 | MIC 90 | ||
| Staphylococcus aureus epidermis Portugal pneumococcal pneumonia coccus Hemolytic streptococcus Klebsiella pneumonia escherichia coli aerobacteria salmonella typhi shigella bacillus pyocyaneus | 20 17 22 18 13 15 15 18 13 17 | 0.06-4 16-250 1-8 0.25-8 31.25-＞125 0.06-4 2-125 1-16 1-16 16-＞250 | 0.125 64 2 2 125 1 8 2 2 62.25 | 0.5 250 4 4 ＞125 2 16 8 8 125 |
The clinical practice of object of the present invention
Because stable lactobionic azithromycin aqua compound of the present invention is the Macrolide antimicrobial drug, the tool broad-spectrum antibacterial action, be applicable to Gram-positive or negative bacteria sensitive organism, comprise staphylococcus aureus, streptococcus pyogenes, streptococcus pneumoniae, Hemolytic streptococcus, Chlamydia pneumoniae, the trachoma mycoplasma, hemophilus influenza, legionella pneumophilia, the infectious disease of human or animal due to the mucositis mora bacterium etc. comprises respiratory tract, urinary system infection, gonorrhea, prostatitis, intestinal infection, liver and gall infect, skin soft-tissue infection, treatment such as ocular infection and prevention.
Its consumption usage: generally speaking, get preparation 125～500mg of the present invention (in azithromycin) in 50～500 milliliters of 0.9% sodium chloride transfusion or 5% glucoses, do intravenous drip, every day 1 time, 3～7 is a course of treatment.
Oral administration consumption usage (in azithromycin): adult's consumption: 1. sexually transmitted disease (STD) due to chlamydia trachomatis or the responsive Diplococcus gonorrhoeae needs single oral this product 1.0g.2. to the treatment of other infection: the 1st day, 0.5g decoction being taken at a draught, the 2nd～5 day, 0.25g decoction being taken at a draught on the one; Or 0.5g decoction being taken at a draught on the one, serve on 3.Children's's consumption: 1. treat otitis media, pneumonia, the 1st, by body weight 10mg/kg decoction being taken at a draught (daily maximum is no more than 0.5g), the 2nd～5, every day was by body weight 5mg/kg decoction being taken at a draught (daily maximum is no more than 0.25g); Treatment children's pharyngitis, tonsillitis, one by body weight 12mg/kg decoction being taken at a draught (daily maximum is no more than 0.5g), logotype 5 days.
Suppository administration consumption usage (in azithromycin): adult the women once a day, one on the rectal suppository of single administration 0.125-0.75g or vagina bolt, adult the male once a day, one of the rectal suppository of single administration 0.125-0.75g; The child reduces by half.
Description of drawings
Fig. 1 is the thermal analysis curue spectrum of lactobionic acid azithromycin 2.5 hydrates.
Fig. 2 is the thermal analysis curue spectrum of lactobionic acid azithromycin 4.5 hydrates.
Fig. 3 is the thermal analysis curue spectrum of lactobionic acid azithromycin 5 hydrates.
Fig. 4 is the thermal analysis curue spectrum of lactobionic acid azithromycin 2.5 hydrates.
The specific embodiment
Embodiment 1 is in three-neck flask, add ethanol acetone and azithromycin dihydrate, stirring and dissolving adds lactobionic acid or its aqueous solution, 1～40 ℃ is constantly stirred, reaction is finished, slowly add formic acid second fat, be cooled to about 0-10 ℃, treat that solid separates out, filter, solids acetone rinse is drained, dry, get the off-white color crystalline powder, soluble in water, HPLC: the sample main peak is consistent with the retention time of azithromycin reference substance main peak, fusing point: 157-160 ℃, decompose (not proofreading and correct), it is 3.03% that the Ka Shi method is measured moisture, and this and sample contain result's (theoretical value 2.98%) of 2.5 water of crystallization in range of error.TG-DTA:60～130 ℃ weightlessness is about 3.108%, and this and sample contain the result of 2.5 water of crystallization in range of error, and TG-DTA shows to have tangible endothermic peak before 130 ℃, contains water of crystallization (seeing accompanying drawing 1) in the interpret sample.With of the alcoholic solution neutralization of gained sample with sodium bicarbonate or ammonia or organic amine, sedimentation and filtration, washing, 95% ethyl alcohol recrystallization, fusing point, specific rotatory power, IR, MS etc. are all consistent with the raw material azithromycin dihydrate.
Elementary analysis measured value: C 50.84%, H7.94%, N1.86%;
Theoretical value: C 50.81%, H7.98%, N1.91%;
Elementary analysis measured value: C48.18, H8.19, N1.80.
Theoretical value: C48.15, H8.15, N1.81.
Under vacuum condition, between 80-105 ℃, phosphorus pentoxide is a desiccant with lactobionic azithromycin aqua compound, and vacuum drying got the lactobionic acid azithromycin anhydride more than 6 hours.
Embodiment 3 with lactobionic acid and azithromycin in molar ratio example (2: 1) drop in the reaction bulb, add water, heating, stir, between 2-40 ℃ of the control temperature, reaction 10-90min, question response finishes, it is freezing to-50 ℃, kept 0.5-6 hour, and reduced condenser temperature to-55 ℃, evacuation, after making temperature rise to about-20 ℃ gradually by shelf, keeping about 24 hours about-20 ℃, continuing heating medicine is warming up to about 28 ℃, keeping 6 hours, get class from the color crystalline powder, yield 99%, sample is soluble in water, HPLC: the sample main peak is consistent with the retention time of azithromycin reference substance main peak.Fusing point: 153-157 ℃ (not proofreading and correct) decomposes; It is 6.05% that the Ka Shi method is measured moisture, and this and sample contain result's (theoretical value 5.79%) of 5 water of crystallization in range of error.TG-DTA: weightless about 5.895% between the platform, the result that this and sample contain 5 water of crystallization matches, and TG-DTA shows between the weightless zone between the platform to have tangible endothermic peak, contains water of crystallization (seeing accompanying drawing 3) in the interpret sample.With of the alcoholic solution neutralization of gained sample with sodium bicarbonate or ammonia or organic amine, sedimentation and filtration, washing, 95% ethyl alcohol recrystallization, fusing point, specific rotatory power, IR, MS etc. are all consistent with the raw material azithromycin dihydrate.
Elementary analysis measured value: C47.85, H8.21, N1.77
Theoretical value: C47.87, H8.16, N1.80
Under vacuum condition, between 80-105 ℃, phosphorus pentoxide is a desiccant with lactobionic azithromycin aqua compound, and vacuum drying got the lactobionic acid azithromycin anhydride more than 6 hours.
Embodiment 4 with lactobionic acid and azithromycin (30g) in molar ratio example (2: 1) drop in the reaction bulb, add water, heating, stir, between 2-40 ℃ of the control temperature, reaction 10-90min, question response finishes, it is freezing to-50 ℃, the mixed solvent crystallization of solid water that obtains and organic solvent ethanol, isopropyl alcohol, formic acid second fat, sucking filtration, use the ethanol rinse, drain, 60 ℃ of dryings get the off-white color crystalline powder, soluble in water, HPLC: the sample main peak is consistent with the retention time of azithromycin reference substance main peak.Fusing point: 158-160.2 ℃ (not proofreading and correct), it is 3.12% that the Ka Shi method is measured moisture, this and sample contain result's (theoretical value 2.98%) of 2.5 water of crystallization in range of error.Weightless about 2.84% between ℃ platform of TG-DTA:60～140, the result that this and sample contain 2.5 water of crystallization matches, and TG-DTA shows between the weightless zone between the platform to have tangible endothermic peak, contains water of crystallization (seeing accompanying drawing 4) in the interpret sample.With of the alcoholic solution neutralization of gained sample with sodium bicarbonate or ammonia or organic amine, sedimentation and filtration, washing, 95% ethyl alcohol recrystallization, fusing point, specific rotatory power, IR, MS etc. are all consistent with the raw material azithromycin dihydrate.
Elementary analysis measured value: C 50.77%, H8.03%, N1.89%.
Theoretical value: C 50.81%, H7.98%, N1.91%.
Embodiment 6 gets 5 hydrate 20g (by azithromycin) of lactobionic azithromycin aqua compound, with mannitol 40g, add 40-60 ℃ of water for injection 180～450ml stirring and make dissolving, Aspartic Acid acid and 1M sodium bicarbonate adjusting pH with 1M are 6.2～6.5, add activated carbon 0.01～0.5% (W/V) and stir 15～45min, filter, moisturizing to 220～500ml, hold back the ultrafiltration membrance filter of relative molecular mass 1000-8000 with 0.22 micron filtering with microporous membrane or employing, by 125mg/ bottle or 250mg/ bottle or 500mg/ bottle (by azithromycin) packing, lyophilization, tamponade gets finished product.
Embodiment 7 gets 2.5 hydrates of 4.5 hydrates of aseptic lactobionic azithromycin aqua compound or aseptic lactobionic azithromycin aqua compound or 5 hydrate 25Kg (by azithromycin) of aseptic lactobionic azithromycin aqua compound, press 125mg/ bottle or 250mg/ bottle or 500mg/ bottle (by azithromycin) packing in aseptic subpackaged technology, jump a queue, tamponade, roll aluminium lid and get finished product.
2.5 hydrates (in the azithromycin) 25.0g of embodiment 8 lactobionic azithromycin aqua compounds, add cysteine hydrochloride 0.8g, EDTA disodium 0.1g adds injection and blunges and make dissolving, and it is 6.5～7.0 that 2M lactic acid and sodium lactate are regulated pH, add activated carbon 0.01% (W/V) and stir 15～45min, filter, moisturizing is held back twice filtration of ultrafilter membrane of relative molecular mass 1000-8000 to 250ml with 0.22 micron filtering with microporous membrane or employing, press the packing of 5ml/ bottle, sterilize finished product.
The preparation of embodiment 10 lactobionic acid azithromycin hydration sodium chloride transfusion: with lactobionic acid azithromycin 4.5 hydrates (in azithromycin) 10.4g, sodium chloride 85g, sodium pyrosulfite 1.1g, EDTA disodium 0.2g, add in the water for injection, stirring makes dissolving fully, citric acid and liquor sodii citratis with 1M are regulated pH value in the scope of 6.3-6.8, add the injection water to 10000ml, the active carbon that adds dosing amount 0.05%, about heated and stirred 10-30 minute, filtering decarbonization, hold back the ultrafiltration membrance filter of relative molecular mass 1000-8000 again through 0.22um microporous filter membrane fine straining or employing, chemically examine through semi-finished product, treat its content, after pH value and clarity were qualified, embedding was in the vial of 50ml or 100ml or 250ml, through pressure sterilizing 30 minutes, finished product inspection, packing promptly.
Embodiment 11 lactobionic acid azithromycin tablets (the 250mg/ sheet is in azithromycin)
Prescription: lactobionic azithromycin aqua compound 250g (in azithromycin)
Microcrystalline Cellulose 200g
Carboxymethyl starch sodium 20g
Aspartame 2g
Polyvinylpyrrolidone 10% is an amount of
Micropowder silica gel 1g
Magnesium stearate 2g
Lactobionic azithromycin aqua compound, microcrystalline Cellulose, carboxymethyl starch sodium, aspartame are crossed 100 mesh sieves, and the polyvinylpyrrolidone with 10% is made soft material in right amount, crosses the 18-24 mesh sieve and granulates, dry, after crossing 14-20 mesh sieve granulate, add micropowder silica gel, magnesium stearate mixing, tabletting.
Prescription: lactobionic acid azithromycin 2.5 hydrate 125g (in azithromycin)
Microcrystalline Cellulose 100g
Lactose 20g
Magnesium stearate 2g
Lactobionic acid azithromycin 2.5 hydrates, microcrystalline Cellulose, lactose are crossed 100 mesh sieves, and the gelling starch with 10% is made soft material in right amount, and the 18-24 mesh sieve is granulated excessively, and drying behind the 14-20 mesh sieve granulate, adds magnesium stearate and mixes the fill capsule excessively.
The granule of embodiment 13 lactobionic acid azithromycins (the 125mg/ bag is in azithromycin)
Prescription: lactobionic azithromycin aqua compound 125g (in azithromycin)
Mannitol 100g
Lactose 20g
Cyclamate 2g
Solid edible essence 1g
Polyvinylpyrrolidone 8% is an amount of
Lactobionic azithromycin aqua compound, mannitol, lactose, cyclamate, edible essence are crossed 100 mesh sieves, and the polyvinylpyrrolidone with 8% is made soft material in right amount, crosses the 18-24 mesh sieve and granulates, and is dry below 60 ℃, cross 14-20 mesh sieve granulate after, divide packing.
The suppository of embodiment 14 lactobionic azithromycin aqua compounds (the 250mg/ grain is in azithromycin)
Prescription: lactobionic azithromycin aqua compound 25g (in azithromycin, 100 feed intake)
Macrogol 4000 80g
Glycerol 5ml
Poloxamer 50g
Lactobionic azithromycin aqua compound, glycerol, Macrogol 4000, poloxamer, Tween 80 are mixed, heating in water bath, stir, wait to melt, be stirred in the mould of suppository that even, rapid impouring scribbled lubricant, to overflowing the bolt mould a little, treat to scabble after cold, molding promptly.
The gel of embodiment 15 lactobionic azithromycin aqua compounds (250mg/ is in azithromycin)
Prescription: lactobionic azithromycin aqua compound 25g (, feeding intake) in azithromycin
Polyethylene glycol 6000 50g
PEG400 10g
Glycerol 5ml
Carbomer 934 10g
Carbomer 1342 5g
Water 40-60ml
Will be respectively with carbomer 1342 and carbomer 934 aqueous dispersion, add glycerol, polyethylene glycol 6000, PEG400, mix, add lactobionic azithromycin aqua compound, heating in water bath, be stirred in the mould of suppository that even, rapid impouring scribbled lubricant, to overflowing the bolt mould a little, treat to scabble after cold, molding promptly.
The present invention is not limited to the foregoing description.
Claims (9)
1. lactobionic azithromycin aqua compound, it is characterized in that: lactobionic azithromycin aqua compound is C
38H
72N
2O
122C
12H
22O
12NH
2O, n=2.0～5.5, the weightless platform correspondence of TG-DTG has the feature endothermic peak.
2. lactobionic azithromycin aqua compound according to claim 1 is characterized in that: lactobionic acid azithromycin 5 hydrates are C
38H
72N
2O
12C
12H
22O
125H
2O.
3. lactobionic azithromycin aqua compound according to claim 1 is characterized in that: lactobionic acid azithromycin 4.5 hydrates are C
38H
72N
2O
122C
12H
22O
124.5H
2O.
4. lactobionic azithromycin aqua compound according to claim 1 is characterized in that: lactobionic acid azithromycin 2.5 hydrates are C
38H
72N
2O
12C
12H
22O
122.5H
2O.
5. lactobionic azithromycin aqua compound preparation method is characterized in that:
Method A. is in reaction vessel, with rudimentary (C3-C6) ketone, as acetone, rudimentary (C2-C6) ester, water or low mass molecule alcohol C1-C5 such as methanol, ethanol, one or more of isopropyl alcohol are solvent, add lactobionic acid and azithromycin, stir between 0-40 ℃, dissolving, reaction is finished, slowly add rudimentary (C3-C6) ketone, as acetone, chloroform or low mass molecule alcohol such as methanol, ethanol, isopropyl alcohol, rudimentary (C2-C6) ether, rudimentary (C2-C6) ester is as ethyl acetate, one or more of formic acid second fat, cooling, treat that solid separates out, filter solids organic solvent low mass molecule alcohol C1-C5 such as methanol, ethanol, isopropyl alcohol, rudimentary (C3-C6) ketone is as acetone, rudimentary (C2-C6) ether such as ether, one or more rinses in the chloroform, drain the dry lactobionic azithromycin aqua compound that gets;
Perhaps method B is in reaction vessel, add lactobionic acid or its aqueous solution, add azithromycin, stir between 0-40 ℃, make dissolving, reaction is finished, slowly add rudimentary (C3-C6) ketone, as acetone, chloroform, rudimentary (C2-C6) ester is as ethyl acetate, formic acid second fat, or low mass molecule alcohol C1-C5 such as methanol, ethanol, one or more of isopropyl alcohol, cooling, treat that solid separates out, filter that solids is with organic solvent low mass molecule alcohol C1-C5 such as methanol, dehydrated alcohol, isopropyl alcohol, rudimentary (C3-C6) ketone, as acetone, rudimentary (C2-C6) ether, rudimentary (C2-C6) ester, as ethyl acetate, formic acid second fat, one or more rinses are drained in the chloroform, the dry lactobionic azithromycin aqua compound that gets;
Perhaps method C. with lactobionic acid and azithromycin in molar ratio (2: 1) drop in the reaction bulb, add water, between 0-40 ℃ of the control temperature, reaction 0.5-6h, question response finishes, and it is freezing to-60～-40 ℃, vacuum lyophilization gets lactobionic azithromycin aqua compound.
6. lactobionic azithromycin aqua compound purposes, it is characterized in that: lactobionic azithromycin aqua compound is used to prepare injection freeze-dried powder or aseptic subpackaged powder injection formulation or great transfusion preparation or little water needle injection, through the intestinal canal administration preparation, comprise tablet, capsule, granule is through the ointment and the gel of skin administration, the suppository of effervescent tablet and transvaginal or rectally.
7. lactobionic azithromycin aqua compound purposes according to claim 6 is characterized in that: the preparation method of freeze-dried powder is: get lactobionic azithromycin aqua compound, add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, adding injection blunges and makes dissolving, pharmaceutically acceptable acid-alkali accommodation pH is 5.5～7.5, adds activated carbon 0.01～0.5% (W/V) and stirs 15～45min, filters, moisturizing, aseptic filtration, packing, lyophilization, tamponade gets finished product;
Perhaps preparing the great transfusion preparation method is: lactobionic azithromycin aqua compound is added injection water and pharmaceutically acceptable additives, can add pharmaceutically acceptable pH regulator, pharmaceutically acceptable antioxidant and stabilizing agent, the regulator of opening such as pharmaceutically acceptable, the high capacity sterile solution for injection is made in filtration, degerming, and its pH value is between 5.5～7.5;
Perhaps preparing little water needle injection method is: lactobionic azithromycin aqua compound is added injection water and pharmaceutically acceptable additives, can add pharmaceutically acceptable pH regulator, pharmaceutically acceptable antioxidant and stabilizing agent, noble gas, filter, sterilize and make the little liquid drugs injection of sterilization, its pH value is between 5.5～7.5.
8. according to claim 1,7 described lactobionic azithromycin aqua compounds and injection freeze-dried powder, aseptic subpackaged powder injection formulation, it is characterized in that: the preparation of a unit dose (specification is 75-500mg) is dissolved in the 10-15ml water, and its pH value is between 5.5～7.5.
9. lactobionic azithromycin aqua compound purposes, it is characterized in that: lactobionic azithromycin aqua compound is the Macrolide antimicrobial drug, be used to be applicable to Gram-positive or negative bacteria sensitive organism, comprise staphylococcus aureus, streptococcus pyogenes, streptococcus pneumoniae, Hemolytic streptococcus, Chlamydia pneumoniae, the trachoma mycoplasma, hemophilus influenza, legionella pneumophilia, the infectious disease of human or animal due to the mucositis mora bacterium etc. comprises respiratory tract, urinary system infection, gonorrhea, prostatitis, intestinal infection, liver and gall infect, skin soft-tissue infection, treatment such as ocular infection and prevention.
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| CNA2007100531547A CN101152203A (en) | 2007-09-05 | 2007-09-05 | Lactobionic azithromycin aqua compound, production and use of the same |
| CN2008102157774A CN101381386B (en) | 2007-09-05 | 2008-09-05 | Lactose-azithromycin hydrate, preparation and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102099366A (en) * | 2008-07-15 | 2011-06-15 | 格力康公司 | Crystalline carbohydrate derivative |
| CN104402947A (en) * | 2014-11-06 | 2015-03-11 | 哈药集团制药总厂 | Preparation method of aseptic azithromycin lactobionate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830835A (en) * | 2010-03-26 | 2010-09-15 | 刘力 | Sodium paeonol sulfonate crystalline hydrate as well as preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102099366A (en) * | 2008-07-15 | 2011-06-15 | 格力康公司 | Crystalline carbohydrate derivative |
| CN104402947A (en) * | 2014-11-06 | 2015-03-11 | 哈药集团制药总厂 | Preparation method of aseptic azithromycin lactobionate |
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| CN101381386B (en) | 2013-01-09 |
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