CN105362236A - Sisomicin sulfate freeze-dried powder injection and preparation method thereof - Google Patents

Sisomicin sulfate freeze-dried powder injection and preparation method thereof Download PDF

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Publication number
CN105362236A
CN105362236A CN201510776798.3A CN201510776798A CN105362236A CN 105362236 A CN105362236 A CN 105362236A CN 201510776798 A CN201510776798 A CN 201510776798A CN 105362236 A CN105362236 A CN 105362236A
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Prior art keywords
freeze
mensiso
dried powder
preparation
mannitol
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CN201510776798.3A
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CN105362236B (en
Inventor
刘景萍
刘全国
陈克领
林文君
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HAINAN GOURD DOLL PHARMACEUTICAL CO Ltd
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HAINAN GOURD DOLL PHARMACEUTICAL CO Ltd
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    • 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
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses sisomicin sulfate freeze-dried powder injection and a preparation method thereof. The sisomicin sulfate freeze-dried powder injection is prepared from sisomicin sulfate, mannitol, polyethylene glycol and a pH value regulator. Through the pH value regulator, the pH value of a system is controlled to be 6.0-6.5; sisomicin sulfate is plump in appearance, uniform in color and luster, relatively low in water content, high in content of main drugs, and low in content of related substances; the hygroscopicity of a product obtained accidentally is small; and the requirements on the relative humidity of the environment is low.

Description

A kind of mensiso freeze-dried powder and preparation method thereof
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of mensiso freeze-dried powder and preparation method thereof.
Background technology
Mensiso is the aminoglycoside antibiotics of a new generation, and utilization is clinically extensive, because it not only compensate for the deficiency of traditional aminoglycoside antibiotics, and comparatively in traditional aminoglycoside antibiotics, its antimicrobial spectrum is more extensive.Be applicable to the following infection caused by gram-negative bacteria (comprising Pseudomonas aeruginosa), staphylococcus and other sensitive organisms: respiratory system infection, urogenital infections, biliary tract infection, Skin and soft tissue infection, infectious diarrhea and septicemia etc.
Publication number is the method for making that the Chinese patent application of CN104546699A discloses sisomicin sulfate inj compositions, comprise the steps: to get the 60-80% that recipe quantity mensiso and disodium edetate are dissolved in water for injection total amount, add sodium sulfite and Cys stirring and dissolving; Phosphorate acid for adjusting pH to 5.2-5.5, and add the activated carbon adsorption 30 minutes of 0.2%, decarburization, injects water to formula full dose; By 0.45um filtering with microporous membrane, then by the aseptic filtration of 0.22um microporous filter membrane, be dispensed in ampoule bottle, rush nitrogen, sealing by fusing ampoule bottle, 100 DEG C of flowing steam sterilizations 30 minutes, to obtain final product.This mensiso adopts the form of injection to use, and preparation method is comparatively simple, but impurity content is more, and stability is not enough.
Summary of the invention
The invention provides a kind of mensiso freeze-dried powder and preparation method thereof, this mensiso freeze-dried powder outward appearance is full, uniform color, and moisture content is lower, and drug content is high and related substance is few, and unexpected obtain product and draw moist little, require low to envionmental humidity; This preparation method operation is simple, quality controllable and be suitable for suitability for industrialized production.
A kind of mensiso freeze-dried powder, is made up of mensiso, mannitol, Polyethylene Glycol and pH adjusting agent;
The pH value of the described pH adjusting agent hierarchy of control is 6.0 ~ 6.5.
By adding specific adjuvant, making that the mensiso outward appearance that obtains is full, uniform color, being less likely to occur to collapse and spray a bottle phenomenon, have higher drug content and lower draw moist, and dissolution velocity is fast, and the particulate matter in its solution is little; Meanwhile, by strict control ph, effectively improve the stability of product.
As preferably, described pH adjusting agent is sodium hydroxide solution, and concentration is 1mol/L, sodium hydroxide low price, for producing adverse influence to human body during adjust ph.
The ratio regular meeting of mensiso, mannitol and Polyethylene Glycol is on the outward appearance of product and draw the larger impact of moist generation, and as preferably, the weight ratio of mensiso, mannitol and Polyethylene Glycol is 1:1 ~ 2:2 ~ 3.
As most preferably, the prescription of every 1000 bottles of freeze-dried powders consists of:
Present invention also offers a kind of preparation method of described mensiso freeze-dried powder, comprise the following steps:
(1) mensiso, mannitol, Polyethylene Glycol are dissolved in water for injection, stir and make it dissolve, then use sodium hydroxide solution adjust ph to 5.5 ~ 6.5, obtain mixed solution;
(2) add active carbon in the mixed solution prepared in step (1), stir, filtering decarbonization, obtains filtrate;
(3) filtrate that step (2) obtains carries out lyophilization, obtains described mensiso freeze-dried powder.
As preferably, the addition of step (2) described active carbon is 0.05 ~ 0.5% of liquor capacity, more preferably 0.02 ~ 0.15%, and mixing time is 30 minutes.Now there is adsorption hardly to principal agent mensiso in active carbon, after filtration, solution colour is achromaticity and clarification liquid, mensiso after activated carbon adsorption carries out the detection of related substance, and its total impurities is below 5.0%, and bacterial endotoxin conforms with the regulations.
As preferably, the freeze-drying process described in step (3) is: filtrate is cooled to-40 ~-45 DEG C, pre-freeze 1 ~ 2 hour, evacuation, be warming up to 25 ~ 30 DEG C with the speed of 5.4 ~ 6.0 DEG C/h, then be incubated 1 ~ 2 hour, obtain mensiso freeze-dried powder.The method technique is simple, only need it is freezing after, with the programming rate of 5.4 ~ 6.0 DEG C/h, is warming up to 25 ~ 30 DEG C, does not need separately to establish two sections of temperature-rise periods again, and the mensiso profile obtained is loose, full.
The present invention compared with the prior art, not only prepares survival processes simple, easily operates, so greatly saved the production cost of prior art; And the product of preparation there has been qualitative leap in stability side, be conducive to producing in enormous quantities, be convenient to store and market sale.
Detailed description of the invention
Embodiment 1
Prescription composition (specification: 7.5 ten thousand units/prop up) 1000 bottles:
Preparation method:
(1) first the mensiso of recipe quantity, mannitol, Polyethylene Glycol are dissolved in water for injection, stir and make it dissolve, with 1mol/L sodium hydroxide solution adjust ph to 6.0 ~ 6.5;
(2) add the active carbon of preparating liquid total amount 0.1% in the solution prepared in above-mentioned steps (1), stir 30 minutes, coarse filtration and 0.22 μm of microporous filter membrane aseptic filtration process, gained filtrate is semi-finished product stock solution.
(3) the semi-finished product stock solution that step (2) obtains is cooled to-42 DEG C, pre-freeze 2 hours, and evacuation, is warming up to 30 DEG C with the speed of 5.5 DEG C/h, then is incubated 1 hour, namely obtains mensiso freeze-dried powder.
Embodiment 2
Prescription composition (specification: 7.5 ten thousand units/prop up) 1000 bottles:
Preparation method:
(1) first the mensiso of recipe quantity, mannitol, Polyethylene Glycol are dissolved in water for injection, stir and make it dissolve, with 1mol/L sodium hydroxide solution adjust ph to 6.0 ~ 6.5;
(2) add the active carbon of preparating liquid total amount 0.1% in the solution prepared in above-mentioned steps (1), stir 30 minutes, coarse filtration and 0.22 μm of microporous filter membrane aseptic filtration process, gained filtrate is semi-finished product stock solution.
(3) the semi-finished product stock solution that step (2) obtains is cooled to-42 DEG C, pre-freeze 2 hours, and evacuation, is warming up to 25 DEG C with the speed of 5.5 DEG C/h, then is incubated 2 hours, namely obtains mensiso freeze-dried powder.
Comparative example 1
Except not adding mannitol, all the other steps are with embodiment 1.
Comparative example 2
Except not adding Polyethylene Glycol, all the other steps are with embodiment 1.
Comparative example 3
Except not adding mannitol and Polyethylene Glycol, all the other steps are with embodiment 1.
Comparative example 4
Except lyophilizing is carried out according to the following steps, all the other steps are with embodiment 1.
Point semi-finished product stock solution of good dress is put into freeze drying box, and temperature controls to keep-40 DEG C time 2 hours; Be evacuated to be less than 14Pa start distillation, products temperature be warming up to 0 DEG C ~-10 DEG C and keep, until ice crystal disappear after keep 3 hours again; After sublimation drying terminates, carry out being warming up to 25 DEG C and keep 3 hours in this temperature range, the qualified rear sealing of finished product, packaging warehouse-in.
Comparative example 5
Other steps are identical with embodiment 1, and the operation of step (1) is as follows:
(1) first the mensiso of recipe quantity, mannitol, Polyethylene Glycol are dissolved in water for injection, stir and make it dissolve, with 1mol/L sodium hydroxide solution adjust ph to 5.2 ~ 5.5.
Quality testing in long-term 9 months is carried out respectively to mensiso freeze-dried powder prepared by the mensiso freeze-dried powder prepared by embodiment 1 ~ 2 and comparative example 1 ~ 5, concrete detection method all according to Pharmacopoeia of the People's Republic of China version in 2005 second, the results are shown in Table 1:
Table 1 mensiso quality measurements
Visible, the indices of the injection mensiso that the present invention obtains conforms with the regulations, and when the one do not added in mannitol and Polyethylene Glycol or two kinds, occurs collapsing, not full and spray bottle phenomenon, and drug content and solubility obviously decline; When lyophilizing routine change, drug content and solubility obviously decline, but to outward appearance without too much influence; When pH value changes, initial character is better, but less stable, and after placing a period of time, drug content and solubility obviously decline.

Claims (8)

1. a mensiso freeze-dried powder, is characterized in that, is made up of mensiso, mannitol, Polyethylene Glycol and pH adjusting agent;
The pH value of the described pH adjusting agent hierarchy of control is 6.0 ~ 6.5.
2. mensiso freeze-dried powder according to claim 1, is characterized in that, described pH adjusting agent is sodium hydroxide solution.
3. mensiso freeze-dried powder according to claim 1, is characterized in that, the weight ratio of mensiso, mannitol and Polyethylene Glycol is 1:1 ~ 2:2 ~ 3.
4. mensiso freeze-dried powder according to claim 1, is characterized in that, the prescription of every 1000 bottles of freeze-dried powders consists of:
5. a preparation method for the mensiso freeze-dried powder as described in any one of Claims 1 to 4, is characterized in that, comprise the following steps:
(1) mensiso, mannitol, Polyethylene Glycol are dissolved in water for injection, stir and make it dissolve, then use sodium hydroxide solution adjust ph to 5.5 ~ 6.5, obtain mixed solution;
(2) add active carbon in the mixed solution prepared in step (1), stir, filtering decarbonization, obtains filtrate;
(3) filtrate that step (2) obtains carries out lyophilization, obtains described mensiso freeze-dried powder.
6. the preparation method of mensiso freeze-dried powder according to claim 5, is characterized in that, the addition of step (2) described active carbon is 0.05 ~ 0.5% of liquor capacity.
7. the preparation method of mensiso freeze-dried powder according to claim 6, is characterized in that, the addition of step (2) described active carbon is 0.02 ~ 0.15% of liquor capacity.
8. the preparation method of mensiso freeze-dried powder according to claim 5, it is characterized in that, freeze-drying process described in step (3) is: filtrate is cooled to-40 ~-45 DEG C, pre-freeze 1 ~ 2 hour, evacuation, be warming up to 25 ~ 30 DEG C with the speed of 5.4 ~ 6.0 DEG C/h, then be incubated 1 ~ 2 hour, obtain mensiso freeze-dried powder.
CN201510776798.3A 2015-11-13 2015-11-13 A kind of mensiso freeze-dried powder and preparation method thereof Active CN105362236B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113209029A (en) * 2021-04-26 2021-08-06 海南通用康力制药有限公司 Preparation method of sisomicin sulfate sterile powder injection for injection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07165586A (en) * 1993-12-13 1995-06-27 Shionogi & Co Ltd Steroid ointment for external use
CN101874789A (en) * 2007-08-23 2010-11-03 姚俊华 Lansoprazole-contained freeze-dried powder injection
CN102552179A (en) * 2012-01-13 2012-07-11 山东罗欣药业股份有限公司 Rabeprazole sodium composite lyophilized injectable powder and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07165586A (en) * 1993-12-13 1995-06-27 Shionogi & Co Ltd Steroid ointment for external use
CN101874789A (en) * 2007-08-23 2010-11-03 姚俊华 Lansoprazole-contained freeze-dried powder injection
CN102552179A (en) * 2012-01-13 2012-07-11 山东罗欣药业股份有限公司 Rabeprazole sodium composite lyophilized injectable powder and preparation method thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113209029A (en) * 2021-04-26 2021-08-06 海南通用康力制药有限公司 Preparation method of sisomicin sulfate sterile powder injection for injection
WO2022227115A1 (en) * 2021-04-26 2022-11-03 海南通用康力制药有限公司 Preparation method for sisomicin sulfate sterile powder injection for injection

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