CN106943357B - Azithromycin freeze-dried powder injection and preparation method thereof - Google Patents
Azithromycin freeze-dried powder injection and preparation method thereof Download PDFInfo
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- CN106943357B CN106943357B CN201610002948.XA CN201610002948A CN106943357B CN 106943357 B CN106943357 B CN 106943357B CN 201610002948 A CN201610002948 A CN 201610002948A CN 106943357 B CN106943357 B CN 106943357B
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- azithromycin
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- dried powder
- freeze
- powder injection
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- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 title claims abstract description 86
- 229960004099 azithromycin Drugs 0.000 title claims abstract description 86
- 239000000843 powder Substances 0.000 title claims abstract description 29
- 238000002347 injection Methods 0.000 title claims abstract description 18
- 239000007924 injection Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 22
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 17
- 229930195725 Mannitol Natural products 0.000 claims abstract description 17
- 239000000594 mannitol Substances 0.000 claims abstract description 17
- 235000010355 mannitol Nutrition 0.000 claims abstract description 17
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 claims abstract description 17
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940109239 creatinine Drugs 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229930010555 Inosine Natural products 0.000 claims description 13
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 13
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- 238000012360 testing method Methods 0.000 description 11
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 8
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 7
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- DEORMZXNPDWMST-BICOPXKESA-N (2s,3r,4s,6r)-2-[[(2r,3s,4r,5r,8r,10r,11r,12s,13s,14r)-2-ethyl-3,4,10-trihydroxy-13-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-n,n,6-trimethyloxan-4-amine Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)[N+](C)(C)[O-])O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 DEORMZXNPDWMST-BICOPXKESA-N 0.000 description 1
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
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- 241000304886 Bacilli Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
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- 241000607768 Shigella Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
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- 206010046482 Urethritis chlamydial Diseases 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 1
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an azithromycin freeze-dried powder injection which is composed of azithromycin, mannitol and a cosolvent, wherein the cosolvent is a mixture composed of sodium formaldehyde sulfoxylate and creatinine. The product of the invention has good stability and more excellent product quality; the product of the invention has simple and easy production operation and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an azithromycin freeze-dried powder injection and a preparation method thereof.
Background
Azithromycin is the first variety of 15-membered ring macrolides, the azalide. It binds to the 50S subunit of bacterial ribosomes, inhibiting RNA-dependent protein synthesis. The product has good antibacterial effect on Streptococcus pyogenes, Streptococcus pneumoniae and Bacillus influenzae, and also has antibacterial activity on Staphylococcus. The azithromycin has slightly poorer antibacterial effect on gram-positive cocci such as staphylococcus and streptococcus than erythromycin, has 4-8 times and 2-4 times stronger antibacterial effect on influenza bacillus and catamoraxella than the erythromycin, and also has antibacterial effect on a few escherichia coli, salmonella and shigella. The azithromycin has good antimicrobial effect on anaerobic bacteria such as streptococcus, mycoplasma pneumoniae, chlamydia trachomatis and the like.
Azithromycin achieves the bacteriostatic action by inhibiting the process of converting bacteria into peptides, thereby inhibiting the synthesis of protein, the medicine is stable to acid, can be widely distributed in various tissues and organs of a human body, has stronger action on gram-positive bacteria, gram-negative cocci, bacilli and anaerobic bacteria, has high concentration and long half-life period in blood and tissues, and is suitable for the treatment of mixed infection. The blood concentration of the azithromycin is 2-10 times of that of the erythromycin, the penetration depth in tissues is 12-50 times of that of the blood concentration, and due to the fact that the administration dosage and times are correspondingly reduced, adverse reactions are low, and the azithromycin blood concentration preparation is more suitable for children and penicillin drug sensitive patients.
In recent years, the sensitivity of some regions around the world to common erythromycin has gradually decreased to 40%, so that the cure of diseases is delayed, the sensitivity rate is as high as 98.04% particularly in terms of the gonococcus strains, and is more than 1 time higher than that of common penicillin, and the use of azithromycin is promoted. With the increasing international exchange and the change of human conception, the incidence and infection of human immunodeficiency are high, and the incidence rate of non-gonococcal urethritis is also increased, therefore, the American FDA anti-infection counseling committee has recommended that azithromycin is used for infection of respiratory tract, genitourinary tract, skin and soft tissue caused by sensitive bacteria, and the medicine has good activity to mycoplasma pneumoniae, chlamydia trachomatis and treponema pallidum, and the cure rate to non-complex gonorrhea, chlamydia urethritis and cervicitis reaches more than 99%.
Azithromycin is generally used clinically as an oral preparation because of low water solubility and incapability of being directly prepared into a preparation, but the oral preparation has low bioavailability which is only 40 percent of effect. In the prior art, azithromycin is prepared into water-soluble salt, for example, patent application 98124980 discloses a complex salt formed by citric acid and azithromycin, and patent 03150874.X discloses a preparation method of azithromycin water-soluble phosphate, but the pH value of the salt is low, and the complex solubility and stability are still to be improved.
Therefore, the invention provides the azithromycin freeze-dried powder injection with good redissolution property and stability.
Disclosure of Invention
The invention aims to provide a novel azithromycin freeze-dried powder injection which has good re-solubility and stability.
The invention also aims to provide a preparation method of the azithromycin freeze-dried powder injection, which is suitable for industrial production.
Specifically, the present invention provides:
an azithromycin freeze-dried powder injection consists of azithromycin, mannitol and a cosolvent, wherein the cosolvent is a mixture consisting of sodium formaldehyde sulfoxylate and creatinine.
The azithromycin freeze-dried powder injection of claim 1, which consists of 30 to 60 weight portions of azithromycin, 15 to 100 weight portions of mannitol, 5 to 30 weight portions of creatinine and 5 to 10 weight portions of sodium formaldehyde sulfoxylate.
The method for preparing the freeze-dried powder injection from the pharmaceutical composition comprises the following steps:
(a) dissolving 5-30 parts by weight of inosine in 500 ~ 1000 parts by weight of water;
(b) adding 5-10 parts by weight of sodium formaldehyde sulfoxylate to the solution of step (a) and adjusting the pH to 7.0 ~ 7.9.9;
(c) adding 30-60 parts by weight of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 15 ~ 100 parts by weight of mannitol into the solution in the step (c), and stirring for dissolving;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Compared with the prior art, the invention has the following advantages and positive effects:
1. the product of the invention has good stability, and the content of related substances is less than or equal to 0.3 percent.
2. The product of the invention has simple and easy production operation and is suitable for industrial production.
Detailed Description
The present invention is further described in the following description of the specific embodiments, which is not intended to limit the invention, but various modifications and improvements can be made by those skilled in the art according to the basic idea of the invention, within the scope of the invention, as long as they do not depart from the basic idea of the invention.
The method comprises the steps of preparing a sample solution, precisely measuring 1ml, placing the sample solution in a 100ml measuring flask, diluting the sample solution to a scale with a solvent, shaking the sample solution to obtain a control solution, testing by high performance liquid chromatography (appendix V D of the second part of the Chinese pharmacopoeia 2010 edition), using octadecylsilane chemically bonded silica as a filler, using a 1.80G/L anhydrous disodium hydrogen phosphate solution (pH is adjusted to 8.9 by dilute phosphoric acid or dilute sodium hydroxide solution) as a mobile phase A, using methanol-acetonitrile (250:750) as a mobile phase B, performing linear gradient elution according to the following table, performing linear gradient elution by using the following table, measuring the column temperature at 60 ℃, the flow rate at 1.0 ml/min, measuring the detection wavelength at 210nm, using an azithromycin system applicability control (containing impurities F, H and J) as a chromatogram, adding 1ml to dissolve the sample solution, using an azithromycin system applicability test solution as a system applicability test solution, taking an impurity peak identifier (containing impurities = 56 and P), measuring the impurity concentration of impurities = 8.9.9G) as an impurity concentration peak of the impurity, measuring the impurity concentration of the impurity, measuring the concentration of the impurity, measuring impurity concentration of the impurity, measuring impurity of the concentration of the impurity, using a concentration of the impurity, using a concentration of the impurity, using a concentration of the impurity of the concentration of the impurity, and the concentration of the.
[ Nitrogen oxides ] A mixture under the content determination item is precisely weighed, and a proper amount of 0.02mol/L potassium phosphate buffer solution-acetonitrile (76.5:23.5) (pH value is adjusted to 8.0 by 5mol/L potassium hydroxide solution) is added for dissolution and quantitative dilution to prepare a solution containing about 0.6mg of azithromycin in each 1ml as a test solution; taking an azithromycin reference substance, precisely weighing, dissolving by using acetonitrile, quantitatively preparing a solution containing about 0.6mg of azithromycin in each 1ml, precisely weighing 1ml, placing in a 100ml measuring flask, diluting to a scale by using potassium phosphate buffer solution-acetonitrile (76.5:23.5) (regulating the pH value to 8.0 by using 5mol/L potassium hydroxide solution), and shaking uniformly to obtain a reference substance solution; an azithromycin control substance and a nitrogen oxide control substance are taken, dissolved and diluted by potassium phosphate buffer solution-acetonitrile (76.5:23.5) (the pH value is adjusted to 8.0 by 5mol/L potassium hydroxide solution) to prepare mixed solutions of about 0.45mg and 1.5 mug in each 1ml, and the mixed solutions are used as system applicability test solutions. Performing high performance liquid chromatography (appendix V D of the second part of the 2010 edition of Chinese pharmacopoeia). An amperometric electrochemical detector with a double-wave carbon electrode is used, an oxidation screen mode with an electrode 1+0.70 +/-0.05V, an electrode 2 +0.82 +/-0.05V and a background current of 95 +/-25 nanoamperes is adopted for the test, a ZiraChrom-PBD (150mm multiplied by 4.6mm, 5 mu m) chromatographic column is adopted, and potassium phosphate buffer solution-acetonitrile (76.5:23.5) (the pH value is adjusted to 11.0 by 5mol/L potassium hydroxide solution) is taken as a mobile phase; the flow rate was 1.2ml per minute; the autosampler temperature was 15 ℃. And (3) injecting 25 mu l of the system applicability test solution into a liquid chromatograph, recording a chromatogram, sequentially recording the appearance sequence of nitric oxide and azithromycin, wherein the number of theoretical plates is not less than 1000 according to the azithromycin peak, and the tailing factor is less than 1.5. Precisely measuring 25 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
[ CONTENT DETERMINATION ] is determined according to high performance liquid chromatography (appendix V D of the second part of the 2010 edition of Chinese pharmacopoeia).
Octadecyl bonded polyvinyl alcohol is used as a filler for chromatographic conditions and system applicability tests; acetonitrile-phosphate buffer solution (0.04 mol/L dipotassium hydrogen phosphate solution is taken, and 5mol/L potassium hydroxide solution is used for adjusting the pH value to 11.0) (60:40) is used as a mobile phase; the detection wavelength was 210 nm. The number of theoretical plates is not less than 3000 calculated according to the azithromycin peak, and the tailing factor is less than 1.5.
Measuring content under different content items, mixing, precisely weighing appropriate amount, dissolving with solvent, quantitatively diluting to obtain solution containing 0.5mg per 1ml, precisely measuring 10 μ l, injecting into liquid chromatograph, and recording chromatogram; and taking an azithromycin reference substance, and determining by the same method. Calculating according to the peak area by an external standard method to obtain the product.
Impurity B: 3-deoxyazithromycin (azithromycin B)
The molecular formula is as follows: c38H72N2O11Molecular weight: 732.99
The name of Chinese: (2R,3R,4S,5R,8R,10R,11R,12S,13S,14R) -13- [ (2, 6-dideoxy-3-C-methyl-3-O-methyl- α -L-ribo-pyranosyl) oxy ] -2-ethyl-4, 10-dihydroxy-3, 5,6,8,10,12, 14-heptamethyl-11- [ [3,4, 6-trideoxy-3- (dimethylamino) - β -D-xylo-pyranosyl ] oxy ] -1-oxa-6-azacyclopentadecan-15-one.
Impurity E: 3' - (N,N-dedimethyl) azithromycin (aminoazithromycin)
The molecular formula is as follows: c36H68N2O12Molecular weight: 720.93
The name of Chinese: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -13- [ (2, 6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-pyranosyl) oxy ] -2-ethyl-3-4, 10-trideoxy-3, 5,6,8,10,12, 14-heptamethyl-11- [ [ 3-amino-3, 4, 6-trideoxy-beta-D-xylopyranosyl ] oxy ] -1-oxa-azacyclopentadecan-15-one
Impurity J: 13-O-decoladidine-pond azithromycin
The molecular formula is as follows: c30H58N2O9Molecular weight: 590.79
The name of Chinese: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -2-ethyl-3, 4,10, 13-hydroxy-3, 5,6,8,10,12, 14-heptamethyl-11- [ [3,4, 6-trideoxy-3-dimethylamino-. beta. -D-xylo-pyranosyl ] oxy ] -1-oxa-6-azacyclopentadecan-15-one.
Impurity L: azithromycin 3' -N-oxide
The molecular formula is as follows: c38H72N2O13Molecular weight: 764.98
The name of Chinese: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -13- [ (2, 6-dideoxy-3-C-methyl-3-O-methyl- α -L-ribo-pyranosyl) oxy ] -2-ethyl-3-4, 10-trihydroxy-3, 5,6,8,10,12, 14-heptamethyl-11- [ [3,4, 6-trihydroxy-3- (dimethyldiazanyl) - β -D-xylopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecan-15-one.
Impurity O: 2-deethyl-2-propylazithromycin
The molecular formula is as follows: c39H74N2O12Molecular weight: 763.01
The name of Chinese: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -13- [ (2, 6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-pyranosyl) oxy ] -2-propyl-3-4, 10-trihydroxy-3, 5,6,8,10,12, 14-hexamethyl-11- [ [3,4, 6-trihydroxy-3- (dimethylamino) -beta-D-xylopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecan-15-one dihydrate
Test example 1: prescription screening test
TABLE 1 Co-solvent recipe screening protocol
Preparation method
(a) Dissolving a cosolvent in 1000g of water;
(b) adding azithromycin to the solution of the step (a) to dissolve the azithromycin to form a solution;
(c) adding mannitol into the solution in the step (b), and stirring to dissolve;
(d) removing heat source and sterilizing;
(e) and (d) carrying out freeze drying on the solution obtained in the step (d) to obtain azithromycin freeze-dried powder.
The azithromycin sterile freeze-dried product prepared by the method is tested for the dissolution rate of azithromycin, and the result is shown in table 2:
TABLE 2 cosolvent recipe screening test results
The test result shows that: by measuring the solubility of the azithromycin in the solution with the same amount of different cosolvents, the cosolvent consisting of the sodium formaldehyde sulfoxylate and the inosine has the best solubilizing effect on the azithromycin.
Test example 2: accelerated test
Under the condition of pseudo-designed packaging, the azithromycin freeze-dried powder injection prepared in the embodiment 3 of the invention and the azithromycin freeze-dried powder injection sample prepared in the embodiment 1 of the patent 201010221418.7 are examined for appearance properties, clarity, color, clarity, pH value, related substances, azithromycin content and the like in an accelerated test for 6 months, and the results are shown in Table 3.
TABLE 3 Azithromycin lyophilized powder injection sample accelerated test data
Packaging: commercial package, consider conditions: the temperature is 40 +/-2 ℃, and the humidity is 75% +/-5%
And (4) conclusion: as can be seen from the above table, the product prepared by the process of the present invention has better stability under high humidity, high temperature and light than the comparative example.
Preparation example
Example 1
Prescription
Preparation method
(a) Dissolving 35g of inosine in 500g of water;
(b) adding 6.5g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 40g of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 15 ~ 100g of mannitol into the solution in the step (c), and stirring for dissolving;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 2
Prescription
Preparation method
(a) Dissolving 6g of inosine in 1000g of water;
(b) adding 6g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 40g of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 38g of mannitol into the solution obtained in step (c), and stirring for dissolving;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 3
Prescription
Preparation method
(a) Dissolving 12g of inosine in 500g of water;
(b) adding 10g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 40g of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 45g of mannitol into the solution obtained in the step (c), and stirring to dissolve;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 4
Prescription
Preparation method
(a) 8.3g of inosine was dissolved in 600g of water;
(b) adding 8g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 40g of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 54g of mannitol into the solution obtained in the step (c), and stirring to dissolve;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 5
Prescription
Preparation method
(a) Dissolving 10g of inosine in 500g of water;
(b) adding 7g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 40g of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 37g of mannitol into the solution obtained in the step (c), and stirring to dissolve;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 6
Prescription
Preparation method
(a) Dissolving 23g of inosine in 1000g of water;
(b) adding 9g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 60g of azithromycin into the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 85g of mannitol into the solution in the step (c), and stirring to dissolve;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 7
Prescription
Preparation method
(a) Dissolving 9.3g of inosine in 900g of water;
(b) adding 7g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 45g of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 53g of mannitol into the solution obtained in the step (c), and stirring to dissolve;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 8
Prescription
Preparation method
(a) Dissolving 24g of inosine in 600g of water;
(b) adding 6.8g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 40g of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 48g of mannitol into the solution obtained in step (c), and stirring for dissolving;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 9
Prescription
Preparation method
(a) 6.8g of inosine was dissolved in 500g of water;
(b) adding 5g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 30g of azithromycin into the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 60g of mannitol into the solution obtained in the step (c), and stirring to dissolve;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Example 10
Prescription
Preparation method
(a) Dissolving 9.3g of inosine in 800g of water;
(b) adding 5.7g of sodium formaldehyde sulfoxylate to the solution of step (a);
(c) adding 35g of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 91g of mannitol into the solution obtained in the step (c), and stirring to dissolve;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain azithromycin freeze-dried powder.
Claims (2)
1. An azithromycin freeze-dried powder injection is characterized in that: the freeze-dried powder injection consists of 30 to 60 weight portions of azithromycin, 15 to 100 weight portions of mannitol, 5 to 30 weight portions of creatinine and 5 to 10 weight portions of sodium formaldehyde sulfoxylate.
2. The azithromycin freeze-dried powder injection of claim 1, wherein the preparation method of the freeze-dried powder injection comprises the following steps:
(a) dissolving 5-30 parts by weight of inosine in 500-1000 parts by weight of water;
(b) adding 5-10 parts by weight of sodium formaldehyde sulfoxylate into the solution obtained in the step (a), and adjusting the pH to 7.0-7.9;
(c) adding 30-60 parts by weight of azithromycin to the solution obtained in the step (b) to dissolve the azithromycin to form a solution;
(d) adding 15-100 parts by weight of mannitol into the solution in the step (c), and stirring for dissolving;
(e) removing heat source and sterilizing;
(f) and (e) carrying out freeze drying on the solution obtained in the step (e) to obtain the azithromycin freeze-dried powder injection.
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