CN1032675C - Concentrated water solution containing spiramycin depressor for intravenous injection after dilution - Google Patents
Concentrated water solution containing spiramycin depressor for intravenous injection after dilution Download PDFInfo
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- CN1032675C CN1032675C CN 93110508 CN93110508A CN1032675C CN 1032675 C CN1032675 C CN 1032675C CN 93110508 CN93110508 CN 93110508 CN 93110508 A CN93110508 A CN 93110508A CN 1032675 C CN1032675 C CN 1032675C
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Abstract
The present invention relates to a concentrated water solution containing a gyrase depressor for intravenous injection after dilution. The concentrated water solution is mainly prepared from a gyrase depressor, water, a certain amount of acid allowed by physiology, and proper auxiliary materials of a medicinal formula. The concentrated water solution is characterized in that the gyrase depressor is 9-fluorine-2, 3-dihydrogen-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxygen-7-hydrogen-pyridine (1, 2, 3-relief) (1, 4) benzoxazine-6-carboxylic acid, and each milliliter of concentrated water solution contains 0.1 to 0.2 gram of active compounds. The acid comprises acetic acid, hydrochloric acid, a mixture of the acetic acid and other kinds of acid, and a mixture of the hydrochloric acid and other kinds of acid. The concentrated solution can be used for treating the diseases of human bodies or animals after dilution.
Description
The present invention relates to a kind of intravenous fluid, the reactive compound that wherein contains is a rotatory enzyme inhibitor.
Up to now, the preparation of the injection for intravenous of quinolones rotatory enzyme inhibitor have the bigger infusion solution [concentration is the transfusion of the 50ml or the 100ml of 0.1% or 0.2% (W/V)] of the volume of using ciprofloxacin that patent DE3333719, DE3537761 make and norfloxacin and concentrated solution thereof [concentration is the 10ml injection of 1% or 2% (W/V)).Because volume is bigger, correspondingly increased the consumption of all kinds of solvents, adjuvant and packaging material, improved cost, and produce, transportation, storage have inconvenience more.Still do not have a kind of 5% concentration that surpasses at present, dosage form is 2ml ampoule or bottle, holds seance dosage (the spissated aqueous solution of injection for intravenous after 0.2～0.4g) the dilution.This is because known carbostyril compound water solublity is lower, even pass through proper method, resemble narrate among the patent DE3333719 improve the water solublity of this compounds and add excessive lactic acid with lactic acid to guarantee not produce precipitation, owing to added excessive lactic acid in this aqueous solution, the acidity of solution is higher, easily cause phlebitis during intravenous injection, nor can make the concentrated aqueous solution of the high concentration of gratifying dilution back injection for intravenous.
The object of the present invention is to provide a kind of rota-enzyme restrainer that contains rotatory enzyme inhibitor of high concentration.
Technical scheme of the present invention is:
The rota-enzyme restrainer that contains rotatory enzyme inhibitor that the present invention relates to, mainly acid and an amount of medicinal formula adjuvant that is allowed by rotatory enzyme inhibitor, water, a certain amount of physiology formed; Described rotatory enzyme inhibitor is a 9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen-7-hydrogen-pyrido [1,2,3-takes off] [1,4] benzoxazine-6-carboxylic acid [is racemic modification ofloxacin (English name ofloxacin) or left-handed S shape isomer Lay Flucloxacillin (English name: levofloxacin or DR-3355), be reactive compound], every milliliter of concentrated aqueous solution contains the described reactive compound of 0.1～0.2 gram, described acid comprises acetic acid, hydrochloric acid, acetic acid and other sour mixture, hydrochloric acid and other sour mixture, the mixture of described acid or acid should be enough to make the reactive compound dissolving and make solution keep stable.
The present invention compared with prior art, patent DE3333719 has related to the preparation of the Lactated intravenous fluid of reactive compound ofloxacin, according to this patent, when the lactic acid of molal quantity such as containing in the aqueous solution of reactive compound, the solution instability, easily precipitate, must add excessive lactic acid and not produce precipitation, so its solution pH value is adjusted between 3.5～4.5 with assurance.And the present invention is when using acetic acid to improve the water solublity of reactive compound, needn't add excessive acetic acid, aqueous solution with approximate acetic acid (hydrochloric acid) that waits molal quantity and reactive compound formation is very stable, though in concentration up to 20% (W/V), still satisfactory when reserve temperature is low to moderate 5 ℃.And the pH value of the rota-enzyme restrainer of the reactive compound that the present invention relates to remains between 4.5～6.0, more near the normal physiological PH value scope of human body (about pH value 7.4), acid-base balance influence to human body is littler, and is also littler to the zest of human body.
Below by embodiment technical scheme of the present invention is further described:
Medicinal formula adjuvant described in the technical scheme mainly comprises: antioxidant, anti-photodissociation agent, chelating agent, PH regulator.Described antioxidant can be selected for use from sodium pyrosulfite, sodium sulfite, anhydrous sodium sulfite, anti-photodissociation agent can be selected for use from guanosine, inosine, L-cysteine, and chelating agent can be selected for use from disodiumedetate, calcio-disodium edetate.The PH regulator can be selected for use from sodium hydroxide solution, sodium carbonate liquor.Described medicinal formula adjuvant can also comprise cosolvent, and described cosolvent can be selected for use from following material: ethanol, propylene glycol, Polyethylene Glycol, glycerol, mannitol, fatty acid esters of sorbitan class (spans), polyethylene fatty acid esters of sorbitan class (Tweens), polyoxyethylene fatty acid ester class (wheat pool class), oxygen ethylene oxy acrylic polymers class (pluronic).Acid described in the technical scheme or sour mixture can be selected for use from following one group of inorganic or organic acid: hydrochloric acid, acetic acid, methanesulfonic acid, citric acid, propanoic acid, succinic acid, 1,3-propanedicarboxylic acid, fumaric acid, maleic acid, tartaric acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid, ascorbic acid, phosphoric acid, nitric acid, malic acid, L-aspartic acid.Every milliliter of concentrated aqueous solution contains 0.1～0.2 gram reactive compound and described acid, the consumption of acid is relevant with the reactive compound molar concentration, with respect to 1 mole of reactive compound, add 0.5～1.5 mole of acid, 0.8～1.2 moles better, need to prove that Suan amount has comprised dissociated and last dissociated acid here, with the pH value of above-mentioned PH regulator regulator solution.The pH value of concentrated solution is 4.5～6.0.The dosage form of described solution can prepare and is divided in ampoule bottle or the low capacity vial, and its bodge can be 1～10 milliliter, preferably 1～2 milliliter.
Enumerate the prescription example of the concentrated aqueous solution of some reactive compounds that the present invention relates to below:
(1). ofloxacin 100.0g
Glacial acetic acid 16.7g
Disodiumedetate 0.2g
L-cysteine hydrochloride 0.5g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (2). ofloxacin 100.0g
Concentrated hydrochloric acid 28.1g
Disodiumedetate 0.2g
L-cysteine hydrochloride 0.5g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (3). ofloxacin 200.0g
Glacial acetic acid 33.3g
Methanesulfonic acid 5.0g
Disodiumedetate 0.2g
Tween 80 2.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (4). ofloxacin 200.0g
Glacial acetic acid 33.3g
Propanoic acid 10.0g
Disodiumedetate 0.3g
Tween 80 1.5g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (5). ofloxacin 200.0g
Glacial acetic acid 33.3g
Succinic acid 12.0g
Disodiumedetate 0.2g
Propylene glycol 100.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (6). ofloxacin 200.0g
Glacial acetic acid 33.3g
Disodiumedetate 0.2g
Propylene glycol 200.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (7). ofloxacin 200.0g
Glacial acetic acid 33.3g
Sodium pyrosulfite 1.0g
Propylene glycol 100.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (8). ofloxacin 200.0g
Glacial acetic acid 33.3g
Sodium pyrosulfite 1.0g
PEG400 200.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (9). ofloxacin 200.0g
Glacial acetic acid 33.3g
Disodiumedetate 0.2g
PEG400 150.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (10). ofloxacin 200.0g
Glacial acetic acid 33.3g
Disodiumedetate 0.2g
Pluronic 5.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (11). ofloxacin 200.0g
Glacial acetic acid 33.3g
L-cysteine hydrochloride 0.5g
Pluronic 4.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (12). ofloxacin 100.0g
Glacial acetic acid 16.7g
Sodium pyrosulfite 0.5g
Pluronic 2.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (13). ofloxacin 100.0g
Glacial acetic acid 16.7g
Disodiumedetate 0.2g
Mannitol 50.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (14). ofloxacin 100.0g
Glacial acetic acid 16.7g
Sodium pyrosulfite 1.0g
Mannitol 50.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (15). ofloxacin 200.0g
Glacial acetic acid 33.3g
Disodiumedetate 0.2g
Mannitol 100.0g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (16). ofloxacin 100.0g
Glacial acetic acid 16.7g
Tween 80 2.0g
L-cysteine hydrochloride 0.5g
10% sodium hydroxide solution is an amount of
Water for injection is an amount of
Total amount 1000.0ml (17). Lay Flucloxacillin (Levofloxacin) 100.0g
Glacial acetic acid 16.7g
Water for injection is an amount of
Total amount 1000.0ml (18). Lay Flucloxacillin (Levofloxacin) 200.0g
Glacial acetic acid 33.3g
Water for injection is an amount of
Total amount 1000.0ml (19). Lay Flucloxacillin (Levofloxacin) 100.0g
Glacial acetic acid 13.3g
Disodiumedetate 0.2g
Water for injection is an amount of
Total amount 1000.0ml (20). Lay Flucloxacillin (Levofloxacin) 200.0g
Glacial acetic acid 20.0g
Pluronic 2.0g
Water for injection is an amount of
Total amount 1000.0ml (21). Lay Flucloxacillin (Levofloxacin) 100.0g
Glacial acetic acid 13.3g
L-cysteine hydrochloride 0.5g
Water for injection is an amount of
Total amount 1000.0ml (22). ofloxacin 100.0g
Glacial acetic acid 10.0g
Concentrated hydrochloric acid 11.2g
L-cysteine hydrochloride 0.5g
Water for injection is an amount of
Total amount 1000.0ml (23). ofloxacin 100.0g
Concentrated hydrochloric acid 28.1g
Methanesulfonic acid 12.0g
Disodiumedetate 0.2g
L-cysteine hydrochloride 0.5g
Water for injection is an amount of
Total amount 1000.0ml (24). ofloxacin 100.0g
Concentrated hydrochloric acid 28.1g
Propanoic acid 17.0g
Disodiumedetate 0.2g
L-cysteine hydrochloride 0.5g
Water for injection is an amount of
Total amount 1000.0ml (25). ofloxacin 100.0g
Concentrated hydrochloric acid 28.1g
Succinic acid 10.0g
Disodiumedetate 0.2g
L-cysteine hydrochloride 0.5g
Water for injection is an amount of
Total amount 1000.0ml
It is to be noted, racemic modification ofloxacin (English name ofloxac in, all be called for short ofloxacin above) and left-handed S type isomer (English name Levofloxacin, also claim DR-3355, all be called for short the Lay Flucloxacillin above) have an identical molecular formula, identical molecular structural formula and identical chemical name, just difference is arranged owing to the different three-dimensional configuration of the two molecule shows optical activity (optical activity), so can use chemical name " 9-fluoro-2; 3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen-7-hydrogen-pyrido [1; 2; 3-takes off] [1,4] benzoxazine-6-carboxylic acid " to be referred to as the two.
The preparation of aqueous solution of the present invention can be adopted the cold filter method of thermosol: reactive compound, acid, water for injection (or organic solvent) and suitable pharmaceutic adjuvant are heated to 40～80 ℃, be stirred to dissolving fully, add proper amount of active carbon, be incubated 1～4 hour, filter, filtrate is cooled to 5～10 ℃ with ice bath, leaves standstill 10～48 hours, is filtered to clear and bright once more.This technology can guarantee the preparation storage-stable, is particularly conducive to prevent sedimentary generation.
The concentrated aqueous solution of the reactive compound that the present invention relates to can be diluted in the multiple venous transfusions such as sodium chloride injection, ringer's solution, glucose injection, Dextrose and Sodium Chloride Inj., metronidazole injection, formula mannitol injection liquid, adopt the method for intravenous drip or intravenous injection, be applied to the prevention and the treatment of human body or the multiple infection of animal body.
The concentrated aqueous solution of the reactive compound that the present invention relates to has has a broad antifungal spectrum, antibacterial activity is strong and toxicity is little characteristics.For Gram-positive and gram negative bacteria, especially enterobacteria belongs to all inhibitory action, more outstanding is to be responsive for drug-fast those antibacterials of multiple antimicrobial drug (as penicillin, cephamycin class, aminoglycosides, sulfonamides) to the concentrated aqueous solution of reactive compound of the present invention.Or various diseases that mixed infection cause simple by above-mentioned various pathogenic bacterium can reach prevention by the concentrated aqueous solution of reactive compound of the present invention, alleviate and the purpose of healing.
The concentrated aqueous solution of the reactive compound that the present invention relates to is effective especially for the inhibition of multiple microorganisms such as antibacterial, mycoplasma, chlamydia, antibacterial mechanisms is for suppressing the DNA gyrase in the synthetic system of DNA of bacteria, antibacterial action is an antibacterial type, thereby is specially adapted to human body or the part of animal body and the prevention and the treatment of systemic infection that these pathogenic microorganism cause.
For example: for being effective: gram-positive cocci such as staphylococcus and Streptococcus, Gram-negative coccus (gonococcus) and gram negative bacilli such as escherichia coli, pneumobacillus, hemophilus influenza, Citrobacter, Serratia, Proteus, bacillus pyocyaneus etc. by one or more parts that cause of following pathogenic bacterium or the prevention and the treatment of systemic infection.Antimicrobial spectrum also comprises anaerobe, Mycobacterium (tubercule bacillus), mycoplasma (multiple pathogenic microorganism such as mycoplasma hominis, mycoplasma pneumoniae, chlamydia.
The pathogenic bacterium of listing above just are illustrated as an example, never are to only limit to this.Provide the example of the disease of some or mixed infections simple by above-mentioned pathogenic bacterium below: the multiple of human body catches, as pneumonia, chronic bronchitis, diffuse panbronchiolitis, bronchiectasis (during infection), the superinfection of chronic respiratory, pharyngolaryngitis, tonsillitis, acute bronchitis, pyelonephritis, cystitis, prostatitis, epididymis inflammation, urethritis, folliculitis, cellulitis, lymphatic vessel (knot) inflammation, hidradenitis, the skin ulcer cellulitis, Subcutaneous tumor, acne agminata, infectious sebaceous cyst, skin ulcer, furuncle and phyma disease, suppurative cellulites around the anus, intrauterine infection, uterus appendages inflammation, bartholinitis, mastitis, typhoid fever, cholecystitis, cholangitis, otitis media, the paranasal sinus inflammation, the eyelash inflammation, hordeolum, dacryocystisis, corneal ulcer, bacillary dysentery, enteritis, periodontal tissue's inflammation, surrounding inflammation of corona, the jaw inflammation.
The same with human body, effective too to the bacterial infection of other animal, be exemplified below:
Pig: escherichia coli diarrhoea, intestinal viral disease, septicemia, dysentery, salmonellosis.
Cattle: diarrhoea, septicemia, bronchopneumonia, salmonellosis, Pasteur bar disease, mycoplasma and genital infection.
Horse: bronchopneumonia, arthrosis, puerperium and puerperal infection and salmonellosis.
Certainly, just enumerated the example of some diseases above, the concentrated aqueous solution of the reactive compound that the present invention relates to can prevent and (or) treatment disease also never only refer to these.
Claims (4)
1. a rota-enzyme restrainer that contains rotatory enzyme inhibitor mainly is made up of the sour and an amount of medicinal formula adjuvant that reactive compound rotatory enzyme inhibitor, water, physiology allow; It is characterized in that: described reactive compound rotatory enzyme inhibitor is a 9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen-7-hydrogen-pyrido [1,2,3-takes off] [1,4] benzoxazine-6-carboxylic acid, every milliliter of concentrated aqueous solution contains the described reactive compound of 0.1～0.2 gram, and described acid is acetic acid, and the consumption of described acetic acid should be enough to make this reactive compound dissolving and make this solution keep stable.
2. the rota-enzyme restrainer that contains rotatory enzyme inhibitor according to claim 1 is characterized in that: the consumption of described acid is relevant with the reactive compound molar concentration, with respect to 1 mole of reactive compound, adds 0.5～1.5 mole of acetic acid.
3. the rota-enzyme restrainer that contains rotatory enzyme inhibitor according to claim 2 is characterized in that: the consumption of acetic acid adds 0.8～1.2 mole acetic acid with respect to 1 mole of reactive compound in the described solution.
4. the rota-enzyme restrainer that contains rotatory enzyme inhibitor according to claim 1 is characterized in that: the pH value of this solution is 4.5～6.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93110508 CN1032675C (en) | 1993-01-01 | 1993-01-01 | Concentrated water solution containing spiramycin depressor for intravenous injection after dilution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93110508 CN1032675C (en) | 1993-01-01 | 1993-01-01 | Concentrated water solution containing spiramycin depressor for intravenous injection after dilution |
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| Publication Number | Publication Date |
|---|---|
| CN1074604A CN1074604A (en) | 1993-07-28 |
| CN1032675C true CN1032675C (en) | 1996-09-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 93110508 Expired - Lifetime CN1032675C (en) | 1993-01-01 | 1993-01-01 | Concentrated water solution containing spiramycin depressor for intravenous injection after dilution |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101693008B (en) * | 2009-10-16 | 2011-12-14 | 安徽丰原淮海制药有限公司 | Ofloxacin injection and preparation process thereof |
| CN111317713B (en) * | 2020-04-28 | 2022-04-12 | 湖北潜江制药股份有限公司 | Preparation method of ofloxacin injection |
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- 1993-01-01 CN CN 93110508 patent/CN1032675C/en not_active Expired - Lifetime
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Owner name: JIANGSU WUZHONG INDUSTRY CO.,LTD. Free format text: FORMER OWNER: SUZHOU CHANGZHENG PHARMACEUTICAL FACTORY Effective date: 20021101 |
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Effective date of registration: 20021101 Address after: Wuzhong District Bridge East Road Suzhou city Jiangsu province 215128 No. 388 Patentee after: Jiangsu Wuzhong industrial Limited by Share Ltd Address before: 215007 No. 9-3, inner outer gate, South Gate, Suzhou, Jiangsu Patentee before: Chngzheng Pharmaceutic Factory, Suzhou |
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Expiration termination date: 20130104 Granted publication date: 19960904 |