CN1554355A - Bite spiramycin and its use in anti inflammatory disease - Google Patents

Bite spiramycin and its use in anti inflammatory disease Download PDF

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Publication number
CN1554355A
CN1554355A CNA2003101224209A CN200310122420A CN1554355A CN 1554355 A CN1554355 A CN 1554355A CN A2003101224209 A CNA2003101224209 A CN A2003101224209A CN 200310122420 A CN200310122420 A CN 200310122420A CN 1554355 A CN1554355 A CN 1554355A
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spiramycin
bitsoft
iii
pharmaceutical composition
tablet
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CN1237976C (en
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王以光
金文藻
佟祖铭
慈家元
杨生武
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Shenyang Tonglian Group Co Ltd
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Beijing Shouke Group Co
Shenyang Tonglian Group Co Ltd
Institute of Medicinal Biotechnology of CAMS
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Abstract

The present invention relates to bite spiramycin composition and its application in resisting inflammatory diseases. The composition has total content of active component isovaleryl spiramycin not less than 50% and 4''-amino spiramycin not less than 80% as well as one or several pharmaceutically acceptable carrier. The intracorporeal and extracorporeal pharmacodynamic tests show that the medicine composition has excellent activity on most G+ bacteria and certain effect on G- bacteria. Especially, the composition has obvious effect on pulmonitis mycoplasma, so the present invention provides scientific basis on the treatment of relevant diseases.

Description

Bitsoft's spiramycin and the application in anti-infectious disease thereof
Technical field:
The present invention relates to a kind of Macrolide genetic engineering antibiotics, particularly 4 "-acidylated spiramycin pharmaceutical composition and the application in anti-infectious disease thereof.
Background technology:
Macrolide antibiotics occupies critical role clinically, because of it has good active to gram positive bacteria and mycoplasma, the part gram negative bacteria also there is effect, and unmanageable pathogen such as some popular day by day toxoplasmas, legionella there are good antibacterial activity and tissue permeability, oral absorption is fast, untoward reaction is few, liver, renal function there is not influence substantially, also have potential immunoregulation effect, the nineties is considered to will compete with Beta-lactam medicine in treatment adult respiratory tract infection.In recent years, make progress by the new derivant of chemical improvement development to fourteen-ring erythromycin molecular structure in countries in the world.Transformation to erythromycin mainly is to adopt chemical semisynthesis at present, and reaction obtains Roxithromycin through two steps as erythromycin, and four-step reaction obtains clarithromycin, and the reaction of five steps obtains azithromycin etc.Improved erythromycin series antibiotic is all improving significantly aspect antibacterial activity, blood drug level, half-life, absolute acid stability and the untoward reaction.But, generally speaking still must be prepared by tunning and semi-synthetic two links of chemistry, not only need to solve, and also have the report of 2.3-4.1% untoward reaction in the problem aspect production cost, the three wastes processing.
Studies show that of 16 yuan of ring macrolide antibiotics structure activity relationships; 2,6-didesoxy-3-C-methyl-L-ribo-hexose 4 " cytotropic infiltration plays an important role for molecule in the close ester acyl group in position group; adopt technique for gene engineering at 2,6-didesoxy-3-C-methyl-L-ribo-hexose 4 " position connects the long acyl carbochain, can improve its lipotropy and strengthen its activity in vivo.Based on above-mentioned thinking, this laboratory is planned thematic project " antibiotic resistance gene engineering research " (project number: under support 102-19-8) in country " 863 ", carried out this work from nineteen ninety, successfully Deltamycin A4 is produced bacterium 4 "-the isovaleryl transferase gene carried out clonal expression in spiramycin-producing strain; obtained to produce with the isovaleryl spiramycin be main constituent strain plasmid-type genetic engineering spiramycin streptomyces (Streptomyces spiramyceticus) p66B-F21 (deposit number: CGMCC No.0304), and applied for the shengjimycin process patent (application number: 97104440.6); Subsequently; keeping 4 "-isovaleryl transferase gene integration state under; by means such as mutation, natural separation; improve the ability that integrated original strain WSJ-1 fermentation produces Bitsoft's spiramycin (original name shengjimycin); obtain superior strain WSJ-195 (deposit number: CGMCC No.0801), and applied for integrated genetic engineering strain patent (application number: 02148771.5) the same year.
Bitsoft's spiramycin is the mixture based on isovaleryl spiramycin III, isovaleryl spiramycin II, three components of isovaleryl Spiramycin I, contain a certain amount of (different) butyryl, propionyl, acetylspiramycin III and (different) butyryl, propionyl, acetylspiramycin II, its chemical constitution and component are as follows:
Isovaleryl spiramycin (isv-) III R=COCH 2CH 3R '=COCH 2CH (CH 3) 2
Isovaleryl spiramycin II R=COCH 3R '=COCH 2CH (CH 3) 2
Isovaleryl Spiramycin I R=H R '=COCH 2CH (CH 3) 2
Isobutyryl spiramycin (iBu-) III R=COCH 2CH 3R '=COCH (CH 3) 2
Isobutyryl spiramycin II R=COCH 3R '=COCH (CH 3) 2
Butyryl spiramycin (Bu-) III R=COCH 2CH 3R '=COCH 2CH 2CH 3
Butyryl spiramycin II R=COCH 3R '=COCH 2CH 2CH 3
Propionylspiramycin (Pr-) III R=COCH 2CH 3R '=COCH 2CH 3
Propionylspiramycin II R=COCH 3R '=COCH 2CH 3
Acetylspiramycin (Ac-) III R=COCH 2CH 3R '=COCH 3
Acetylspiramycin II R=COCH 3R '=COCH 3
At present, Bitsoft's spiramycin has been finished whole preclinical pharmacology tests and I phase clinical research.In order to ensure clinical application safety and reliability, provide that a kind of component is stable, quality controllable Bitsoft's spiramycin preparation (pharmaceutical composition) is very necessary.
Summary of the invention:
The invention provides 4 "-application of acidylated spiramycin in pharmacy.
It is a kind of with 4 that the present invention also provides "-acidylated spiramycin is the pharmaceutical composition of active constituents of medicine.
The said pharmaceutical composition of the present invention, be meant contain safety and the treatment effective dose 4 "-acidylated spiramycin and pharmaceutically acceptable carrier.
Term used herein " safety and treatment effective dose " is meant can alleviate or reverse or treat human body or other mammiferous disease and the medicine of being taken or medicament there is no medicine, chemical compound, compositions, product or the medicament of grievous injury to mammiferous tissue enough consumptions.
Term used herein " pharmaceutically acceptable carrier " is meant the pharmaceutical carrier of pharmaceutical field routine, as diluent, excipient such as water etc., filler such as starch, sucrose etc.; Binding agent such as cellulose derivative, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerol; Disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Surfactant such as hexadecanol; Absorption carrier such as Kaolin and soap clay; Lubricant such as Pulvis Talci, calcium stearate and magnesium and Polyethylene Glycol etc.In addition, can also in compositions, add other adjuvant such as flavouring agent, sweeting agent etc.
The present invention said 4 "-acidylated spiramycin is based on the mixture of isovaleryl spiramycin III, isovaleryl spiramycin II, three components of isovaleryl Spiramycin I, contains a certain amount of isobutyryl spiramycin III, isobutyryl spiramycin II, butyryl spiramycin III, butyryl spiramycin II, propionylspiramycin III, propionylspiramycin II, acetylspiramycin III and acetylspiramycin II.Wherein, isovaleryl spiramycin total content (I+II+III) should be not less than 50%; 4 "-total content of acidylated spiramycin should be not less than 80%.
Compositions of the present invention can be chosen this area pharmaceutical carrier commonly used of diluent, disintegrating agent, lubricant, filler, binding agent, wetting agent, absorption enhancer, surfactant, excipient or any other safe and effective amount of safe in utilization and effective dose wantonly.
Compositions of the present invention exists to be fit to medicinal dosage form, and these dosage forms are: tablet, plain tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, granule, injection, injectable powder, lyophilized injectable powder, sterile powder injection etc.
Those skilled in the art know that usually the amount that is used for the treatment of required active component will change with various factors, comprise character and the patient's age and the state of an illness of the disease for the treatment of, and are finally judged by the doctor in charge.The said compositions of the present invention is during with the unit dosage forms administration, what contain the 25～600mg that has an appointment in each unit dosage form must active component Bitsoft spiramycin, preferably be about 50～400mg, be more preferably 100mg, with every day needed dosage with the form administration of single dose or divided dose.
The inside and outside pharmacodynamics test proves, its active component Bitsoft spiramycin has infection effect preferably in the compositions provided by the invention, not only to gram positive bacteria, the golden Portugal bacterium of especially anti-erythromycin, anti-beta-lactamase, streptococcus pneumoniae, micrococcus scarlatinae have better antibacterial activity, and also effective to part negative bacterium such as micrococcus catarrhalis, gonococcus, hemophilus influenza and part legionella and anaerobe, significantly active to mycoplasma pneumoniae especially.
The invention effect:
The present invention is carrying out in chemical extraction and the purge process superior strain WSJ-195 fermentation liquid; adopt HPLC quantitative analysis means to detect the content of Bitsoft's spiramycin; determined in Bitsoft's spiramycin 4 "-the controlled extraction process route of each component ratio of acidylated spiramycin, for preparation Bitsoft's spiramycin crude drug and carrier compositions thereof have been established the scientific and reliable basis.
Implement example:
Below listed embodiment can help those skilled in the art more fully to understand the present invention, but do not limit the present invention in any way.
Embodiment 1: The preparation of Bitsoft's spiramycin
The method for preparing Bitsoft's spiramycin from fermentation liquid is to add filter aid such as 1% aluminum sulfate in fermentation liquid, filters.Filtrate is regulated pH to 8.5-9.0 with NaOH, extracts Bitsoft's spiramycin in the fermentation liquid with butyl acetate, the butyl ester extracting solution with salt-free water washing after, 1% phosphate (NaH of reuse 1/4 volume 2PO 4) washing (1-3 time), the ratio of Bitsoft's each component of spiramycin in the HPLC Detection and Extraction liquid is to determine with 1% phosphate (NaH 2PO 4) washing times.HPLC detects total isovaleryl spiramycin content and was not less than 50% o'clock, and the salt-free washing of reuse once changes Bitsoft's spiramycin over to the 0.7%NaH of pH2.0 then 2PO 4Sour water is removed the butyl acetate in the sour water, changes in the aqueous alkali of pH to 8.5～9.0 to precipitate again, and drying obtains Bitsoft's spiramycin finished product.The detailed extraction flow chart 1 of Bitsoft's spiramycin.
Embodiment 2: The HPLC method for quantitatively determining of Bitsoft's spiramycin
Use Tianjin, island LC-10A high performance liquid chromatograph, Tianjin, island SPD-6A detector; Chromatographic column: Sweden Kromasil C18 post, 5 μ m, 0.46 * 15cm; Mobile phase: acetonitrile-0.2mol/L ammonium phosphate-water (53: 20: 27) (pH=7.0), every 100ml 7 TBAH of addition that flow; Detect wavelength 231nm, flow velocity: 1.0ml/min.
In the 8mg/ml-0.2mg/ml concentration range, concentration and response value are linear to native system for Bitsoft's spiramycin.Lowest detectable limit reaches 1 * 10 -4Mg/ml.Adopt external standard method; with 94 in the standard substance "-acidylated spiramycin gross area integration, calculate the response value of every microgram Bitsoft spiramycin, and will examine in the product 94 "-gross area integration of acidylated spiramycin; compare with standard substance, calculate the content of Bitsoft's spiramycin in the inspection product.The HPLC collection of illustrative plates of Bitsoft's spiramycin standard substance is shown in (Fig. 2).
Embodiment 3: The HPLC of Bitsoft's spiramycin finished product component detects
The Bitsoft's spiramycin that provides by embodiment 1 extracts the HPLC quantitative detecting method that flow process and embodiment 2 provide, and 8 batches of fermentation liquids of Bitsoft's ferment of spiramycin are extracted, and the HPLC detection case of the product compositions that obtains is as shown in table 1.
The HPLC detection case of 8 jars of Pi Bitsofts of table 1 spiramycin finished product component
??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 On average
??isv-III ??34.86 ??36.22 ??33.84 ??37.03 ??34.19 ??37.76 ??35.37 ??39.79 ??36.13
??isv-II ??24.67 ??24.93 ??24.36 ??24.85 ??20.02 ??25.85 ??25.19 ??24.18 ??24.27
??isv-I ??13.79 ??14.89 ??13.42 ??14.02 ??15.86 ??15.34 ??13.33 ??12.38 ??14.13
??Bu-III ??iBu-III ??3.56 ??3.45 ??3.54 ??3.56 ??3.22 ??3.16 ??3.04 ??2.62 ??3.27
??Bu-II ??iBu-II ??0.77 ??0.27 ??0.22 ??0.57 ??0.33 ??0.24 ??0.26 ??0.27 ??0.37
??Pr-III ??5.11 ??5.48 ??5.70 ??5.23 ??6.73 ??4.76 ??5.13 ??5.32 ??5.43
??Pr-II ??0.85 ??0.82 ??0.86 ??0.89 ??0.30 ??0.17 ??0.28 ??0.26 ??0.33
??Ac-III ??8.13 ??5.74 ??7.43 ??7.16 ??7.43 ??5.68 ??7.37 ??7.36 ??7.04
??Ac-II ??2.84 ??1.92 ??3.05 ??3.08 ??3.47 ??1.89 ??3.18 ??3.09 ??2.82
Total isv ??73.32 ??76.04 ??71.62 ??75.9 ??70.07 ??78.95 ??73.89 ??76.35 ??74.53
Total 4 " acidylate ??94.58 ??93.72 ??92.42 ??96.39 ??91.55 ??94.85 ??93.15 ??95.27 ??93.79
Embodiment 4: The preparation of pharmaceutical preparation
The various dosage forms of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Active component is mixed with one or more carriers, be made into required dosage form then.
It is 0.1～99.5% active component that pharmaceutical composition of the present invention preferably contains weight ratio, most preferably contains weight ratio and be 0.5～95% active component.
A, the plain sheet of Bitsoft's spiramycin (by 10000 calculating)
Prescription: moisture the tiring of the former powder 1000g of Bitsoft's spiramycin ÷ (u/mg)
Low-substituted hydroxypropyl cellulose (5%) 92.5g
Carboxymethyl starch sodium (3%) 55.5g
Magnesium stearate (1%) 18.5g
Starch gross weight-other supplementary material weight
Gross weight 1850g
Concrete processing step: take by weighing appropriate amount of starch, be diluted with water to 15% concentration, be heated to pasty state, make binding agent; Major ingredient Bitsoft spiramycin, supplementary product starch, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, magnesium stearate are crossed 100 mesh sieves respectively, press recipe quantity, take by weighing required major ingredient and adjuvant; Behind Bitsoft's spiramycin, starch, the abundant mix homogeneously of low-substituted hydroxypropyl cellulose, make soft material with the gelatinized corn starch of 15% starch concentration, 14 mesh sieves are granulated, 50-60 ℃ of drying, moisture content is controlled at 3-5%, 14 mesh sieve granulate, add carboxymethyl starch sodium, magnesium stearate is mixed, and measures granule content; According to granule content, it is heavy to calculate sheet, and tabletting (Φ 9mm scrobicula drift) detects tablet weight variation; Through packing after the assay was approved.
B. Bitsoft's spiramycin capsule (by 10000 calculating)
Prescription: moisture the tiring of the former powder 1000g of Bitsoft's spiramycin ÷ (u/mg)
The former grain weight amount of starch (medicinal) 1080g-Bitsoft's spiramycin
10000 of medicinal No. 3 capsules
White oil 50ml
Concrete processing step: after major ingredient Bitsoft spiramycin, adjuvant medical starch taken by weighing respectively by the technical recipe amount, the fully mixed back of the blender of packing into 1.5-2 hour; Sampling detection level gained data should with gross data basically identical (weight that every capsules is adorned is about 0.105g), medicinal No. 3 capsules through being up to the standards are reached mixed good raw material to be installed by the requirement of fully-automatic capsule machine operation, inserting loader respectively fills, populated capsule is carried out difference test (in ± 10%,＜0.3g), check disintegration in 30 minutes, to check the satisfactory capsule in back, put into glazing machines adding white oil and carry out 15-20 minute polishing, take out then and carry out finished product packing and check.
C. Bitsoft's spiramycin coated tablet (by 10000 calculating)
Prescription: with reference to embodiment A.
Concrete processing step: operate according to the embodiment A method, the sheet heart is after the assay was approved put into coating pan, the syrup (concentration is 65-70%) for preparing is slowly added in the pot, temperature is risen to about 40 ℃ then, add an amount of Pulvis Talci, forced air drying 25-30 minute sub-coat Bao Pinghou several times repeatedly, carry out carrying out in sugarcoating layer 15-20 minute the sugarcoating layer coating again, treat that sugarcoating layer Bao Pinghou carries out the coatings coating of required tone, putting into syrup after mill base mixed up stirs evenly and pours pot into, each about 15-20 minute, stir several times respectively.
D. Bitsoft's spiramycin dry syrup (by 10000 bags of calculating)
Prescription: moisture the tiring of the former powder 1250g of Bitsoft's spiramycin ÷ (u/mg)
Citric acid (0.5%) (citric acid) 15g
Sucrose gross weight-other supplementary material
The about 500g of gross weight
The about 1g of pigment (curcumin)
Concrete processing step: the former powder of Bitsoft's spiramycin, citric acid, sucrose are ground into granule 85% by 300 orders with the high velocity air pulverizer respectively, 15% by 180 orders, and the fine powder after will pulverizing then took by weighing the back fully mixed 1-1.5 hour by recipe quantity, surveyed its content, calculate loading amount (theoretical loading amount is every bag of 500mg), then mixed material is packed in the packing machine, install aluminium platinum paper, by racking machine operation requirement packing, content uniformity in ± 5%, the qualified back outer package of testing after installing.
E. Bitsoft's spiramycin enteric coatel tablets (by 10000 calculating)
Prescription: with reference to embodiment A.
Concrete processing step: the preparation of the sheet heart is by the embodiment A operation, the satisfactory heart put into coating pan, syrup and Pulvis Talci with 60-70% concentration carry out three layers of end clothing layer coatings, carry out the sealing coat coating then, add 10% Yu Mi ?alcoholic solution, dried up reuse diethyl phthalate, acetone, cellulose acetate phthalate, alcoholic solution in rollover 10-15 minute, be that the enteric drop adds in the pot, dried up 2-3 time in rollover 10-15 minute.After the assay was approved, carry out the sugar-coat coating by Embodiment C.
F. Bitsoft's spiramycin gastric soluble tablet (by 10000 calculating)
Prescription: with reference to embodiment A.
Concrete processing step: the preparation of the sheet heart is by the embodiment A operation, the satisfactory heart put into high-efficiency coating machine, then standard compliant coating powder (comprising fat-soluble and water solublity) is mixed with coating solution on request, again coating solution is put into colloid mill and pulverized, filter stand-by.To install the high-efficiency coating pot preheating of the sheet heart, rotating speed is controlled at 5-10 rev/min, and temperature is controlled at 45-60 ℃, with aerosol shower nozzle (＞300 order) coating hole liquid is sprayed in the pot, dry then 25-35 minute, carry out 8-12 time repeatedly, even until bag, dry packing after the assay was approved.
G. Bitsoft's spiramycin granule (by 10000 bags of calculating)
Prescription: moisture the tiring of the former powder 1250g of Bitsoft's spiramycin ÷ (u/mg)
Icing Sugar 20000g
Dextrin 9000g
5%PVP-K30 is an amount of
Concrete processing step: the former powder of Bitsoft's spiramycin, Icing Sugar, dextrin are crossed 120 mesh sieves; take by weighing Bitsoft's spiramycin, Icing Sugar, dextrin mix homogeneously by recipe quantity; the above-mentioned material of mix homogeneously is made soft material with the 5%PVP-K30 rubber cement; 70 ℃ of dryings of oscillating granulator granulation, granulate are inspected qualified back packing by ready samples.
Embodiment 5: antibacterial activity in vitro
A, anti-mycoplasma pneumoniae effect
The cultivation of mycoplasma (Mp) culture medium that contains glucose G-PPLO (Difco company): G-PPLO 3g, yeast leachate 0.5g, three distilled water 70ml, 0.4% phenol red liquid 1.0ml, autoclaving (121 ℃, 15min).In this culture medium, add rabbit anteserum 20ml, yeast extract 10ml, 50% Glucose Liquid 2ml, (0.5ml of 200,000 units/ml) transfers pH7.8 to the penicillin sodium saline solution.Mycoplasma pneumoniae employing type strain Mp-1 (Mp-FH, ATCC-15531), local strain (Mp-2,3,4).With the Mp strain of lyophilization or stored frozen, secondary with G-PPLO fluid medium biography, measure mycoplasma concentration (〉=10 8CFU/ml).Take by weighing Bitsoft's spiramycin in volumetric flask, add dehydrated alcohol and fully dissolve, add tri-distilled water again and make 100 micrograms/ml stock solution.Adopt the test tube doubling dilution to measure minimum inhibitory concentration (MIC), Bitsoft's spiramycin stock solution is made the series concentration medicinal liquid, it is 2 * 10 that every pipe 1.8ml, every pipe add 0.2ml bacterium amount 6The Mp bacterium liquid of CFU/ml, 37 ℃ of incubators are cultivated, every day observed and recorded Mp growing state, until three weeks.With the minimum liquor strength that can suppress Mp growth MIC as the anti-mycoplasma pneumoniae of Bitsoft's spiramycin.The results are shown in Table 2.
The minimum inhibitory concentration of the anti-mycoplasma pneumoniae of table 2.
Mp Experiment number Bitsoft's spiramycin
Mp-1 ????8 ?0.06-0.125
Mp-2 ????3 ?0.06
Mp-3 ????3 ?0.03-0.125
Mp-4 ????3 ?0.03-0.125
B, antibacterial action
Test organisms is by clinical separation pathogenic bacterium, Quality Control bacterium and reference culture.Culture medium is MH (a Difco company).Each test organisms is 37 ℃ of cultivation 18h in 2mlMH liquid, are diluted to 10 with MH liquid 6CFU/ml is as test organisms liquid.Adopt the doubling dilution dilute liquid medicine, add 10 6CFU/ml test organisms liquid 0.1ml in 37 ℃ of cultivation 20h, observes growing state, determines the MIC (table 3) of Bitsoft's spiramycin to each test organisms.
Table 3. Bitsoft spiramycin is to the MIC of each test organisms
Bacterial strain MIC microgram/ml
Streptococcus pneumoniae 31108 ????0.12
Streptococcus pneumoniae 9757 ????0.25
Streptococcus pneumoniae 9618 ????0.06
Streptococcus pneumoniae 50 ????0.06
Micrococcus scarlatinae A12 ????0.5
Micrococcus scarlatinae 3008 ????0.5
Micrococcus scarlatinae 772 ????0.25
Micrococcus scarlatinae 97129 ????0.25
The gold bacterium ATCC25923 of Portugal ????1.00
The gold bacterium 209p of Portugal ????1.00
Gold Portugal bacterium 15 ????0.5
Gold Portugal bacterium 9776 ????1.00
Form staph 26069 ????1.00
Form staph 9760 ????0.5
Form staph 32 ????0.25
Form staph 9784 ????0.5
Hemophilus influenza 58530 ????0.06
Hemophilus influenza 11 ????0.25
Embodiment 6: infection effect in the body
A, anti-mycoplasma pneumoniae effect
With mycoplasma pneumoniae reference culture Mp-FH, ATCC-15531 infects Golden Hamster, infective dose is Mp600 ten thousand bacterium amounts, infects back oral administration Bitsoft spiramycin, once a day; connect continuous Give medicine 12 days, put to death animal on the 14th day in infecting the back, lung tissue Mp cultivates, and the result shows, lung tissue Mp cultivates obviously the be negative reaction and the anti-mycoplasma pneumoniae effect relevant with dosage (table 4) of Bitsoft's spiramycin after the medication.
The anti-mycoplasma pneumoniae effect of table 4. Bitsoft spiramycin
Group (mg/kg) Number of animals (only) Mp growing state in the animal number of elements
????-????+????+
????200 ????10 ????8????2????0
????40 ????10 ????3????2????5
????20 ????10 ????0????1????9
Infect contrast ????10 ????1????1????8
-Mp cultivates negative, and ± Mp cultivates suspicious, and+Mp cultivates positive
B, vivo bacteria corrosion action
Test organisms is cultivated 18h for 37 ℃ in the 2mlMH culture fluid, with 5% gastric Mucin dilution bacterium liquid, makes mouse infection 100% cause death the bacterium number as infectious bacteria liquid.Every deadly bacterium amount of injected in mice 0.5ml; after the infection respectively at every mice various dose of 0.5-6h Guan Wei Give medicine 0.2ml; each dosage number of animals is 10, observes the animal dead number, calculates the median protective dose (EDED) of Bitsoft's spiramycin after to infection animal respectively.The results are shown in Table 5.
Table 5. Bitsoft spiramycin is to the protective effect of mouse infection
Infectious bacteria Dosage mg/kg Mortality rate % ??ED 50mg/kg
Streptococcus pneumoniae ????22 ????10 ????11.72
????17 ????30
????12 ????50
????7 ????80
Micrococcus scarlatinae ????74 ????0 ????28.69
????52 ????30
????30 ????60
????8 ????90
Gold Portugal bacterium ????75 ????0 ????32.06
????53 ????40
????31 ????60
????9 ????90
Description of drawings:
Fig. 1-Bitsoft's spiramycin extracts flow process
The HPLC collection of illustrative plates of Fig. 2-Bitsoft's spiramycin standard substance
Wherein: 1.-the isovaleryl spiramycin III
2.-the isovaleryl spiramycin II
3.-the isovaleryl Spiramycin I
4.-the isobutyryl spiramycin III
5.-the isobutyryl spiramycin II
6.-propionylspiramycin III
7.-propionylspiramycin II
8.-acetylspiramycin III
9.-acetylspiramycin II
10.-spiramycin III

Claims (8)

1, a kind of pharmaceutical composition is characterized in that said compositions contains treatment effective amount of actives Bitsoft's spiramycin and pharmaceutically acceptable carrier.
2, pharmaceutical composition according to claim 1; the Bitsoft's spiramycin that it is characterized in that treating effective dose is the mixture based on isovaleryl spiramycin III, II, three components of I; contain a certain amount of (different) butyryl spiramycin III, II; butyryl spiramycin III, II; propionylspiramycin III, II and acetylspiramycin III, II; wherein; isovaleryl spiramycin total content (I+II+III) should be not less than 50%, 4 "-total content of acidylated spiramycin should be not less than 80%.
3, pharmaceutical composition according to claim 1 and 2, it is characterized in that said composition exists to be fit to medicinal dosage form, these dosage forms are: tablet, plain tablet, sugar coated tablet, film coated tablet, enteric coated tablet, gastric solubleness tablet, capsule, hard capsule, granule, dry syrup, injection, injectable powder, lyophilized injectable powder and sterile powder injection.
4, according to each pharmaceutical composition in the claim 1～3, wherein the consumption of Bitsoft's spiramycin is preferably the about 25～600mg of per unit dosage form.
5, pharmaceutical composition according to claim 4, the wherein consumption of the Bitsoft's spiramycin about 50～400mg of per unit dosage form more preferably.
6, pharmaceutical composition according to claim 5, wherein the consumption of Bitsoft's spiramycin most preferably is per unit dosage form 100mg.
7, a kind of preparation of drug combination method, it is characterized in that butyl acetate extracting solution with Bitsoft's spiramycin is with salt-free water washing after, need utilize the ratio of Bitsoft's each component of spiramycin in the HPLC Detection and Extraction liquid, to determine with 1% phosphate (NaH 2PO 4) washing times, when wherein total isovaleryl spiramycin content was not less than 50%, the salt-free washing of reuse once precipitated then, and drying obtains Bitsoft's spiramycin finished product.
8, the application of Bitsoft's spiramycin pharmaceutical composition in the preparation anti-infectives.
CN 200310122420 2003-12-23 2003-12-23 Bite spiramycin and its use in anti inflammatory disease Expired - Lifetime CN1237976C (en)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102060894A (en) * 2010-12-08 2011-05-18 华东理工大学 High-speed countercurrent chromatography for preparing isovalerylspiramycin III
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