CN101173228A - Novel lactic acid bacillus mycopremna, pharmaceutical composition and uses thereof, and production method - Google Patents
Novel lactic acid bacillus mycopremna, pharmaceutical composition and uses thereof, and production method Download PDFInfo
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- CN101173228A CN101173228A CNA2006101178257A CN200610117825A CN101173228A CN 101173228 A CN101173228 A CN 101173228A CN A2006101178257 A CNA2006101178257 A CN A2006101178257A CN 200610117825 A CN200610117825 A CN 200610117825A CN 101173228 A CN101173228 A CN 101173228A
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- lactic acid
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- acid bacteria
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- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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Abstract
The invention provides a lactobacillus rhamnosus strain SLR0406, which can survive for 30-60 days at 37 degrees Celsius. The invention also provides a drug combination with the lactobacillus rhamnosus strain SLR0406. The lactobacillus rhamnosus strain SLR0406 CCTCC-M206023 can be stored for long time and can effectively treat diarrhea and related symptoms caused by antibiotics and chemotherapy drugs.
Description
Technical field
The diarrhoea that the present invention relates to new lactobacillus (L.rhamnosus) bacterial strain, its preparation method and cause in treatment microbiotic and chemotherapy and the new purposes of associated conditions thereof.
Background technology
Under the normal circumstances, intestinal microflora, host and outside atmosphere are set up a dynamic eubiosis, and this eubiosis plays an important role to the health of human body.But, at present owing to multiple reason (as medical measure and environmental factorss such as antibiotic unreasonable use, long-term chronic, wound or operation, immunosuppressor, hormone, chemotherapeutic, radiotherapies) has been destroyed this eubiosis, thereby cause flora disorderly and cause symptom such as diarrhoea.
In above-mentioned reason, the use of microbiotic and chemotherapeutic becomes increasingly conspicuous at present.Along with antibiotic widespread use, antibiotic-associated diarrhea (AAD) receives publicity day by day.Microbiotic also can damage normal microflora simultaneously in inhibition or kill pathogenic organisms, enterococcus bacteria or fungi then can hypertrophy.Nearly all microbiotic (comprising vancomycin and metronidazole) all can bring out AAD, and the most common with penbritin, secondly is clindamycin, cynnematin, aminoglycosides etc.Antineoplastic in addition chemotherapeutics also can cause the intestinal microflora disorder, thereby causes diarrhoea.
Studies show that, clinical prolonged application Broad spectrum antibiotics and chemotherapeutics can cause alteration of intestinal flora, intestinal mucosa morphological change and gut barrier function infringement, thereby make a large amount of bacteriums and intracellular toxin thereof in the enteric cavity enter internal organs and body circulation, cause severe infections such as microbemia, pyemia by mesenteric lymph nodes.This enterogenic infection relies on conventional antibiotic therapy not only to be difficult to cure, and can cause the deterioration of the state of an illness and spread.In case fungi infestation causes diarrhoea, because power and water is separated the matter disorder, the case fatality rate height.
The diarrhoea and the related indication control that microbiotic and chemotherapy cause that be applied as of the rise of microecology and little ecological therapy in recent years provides new approaches.The probiotics probiotic bacterium is that a group to the bacterium that the host plays prebiotic effect, mainly contains lactobacillus, streptococcus acidi lactici, bifidus bacillus etc. by improving the intestinal microflora balance.These bacteriums are healthy HE normal microfloras.The importance of lactobacillus in intestinal microflora is confirmed in many different researchs.Through finding a large amount of oral health that Mammals helps to keep and promote this animal that award of rhamnose lactic acid bacteria.After the absorption, the temporary transient field planting of lactobacillus rhamnosus meeting is on intestinal mucosa, and growths such as inhibition pathogenic bacterium and rotavirus, suppresses anaphylaxis, thus the alleviating diarrhoea symptom.
Safety evaluation about lactobacillus rhamnosus has had many reports in addition, Safetyassessment of potential probiotic lactic acid bacterial strains Lactobacillusrhamnosus HN001 for example, Lb.acidophilus HN017, with Bifidobacterium lactis HN019 inBALB/c mice, International Journal of Microbiology 56:87-96.
But the stability of the probiotics of report can not be satisfactory at present.Therefore, the probiotics that needs a kind of energy prolonged preservation at present.
Summary of the invention
The object of the present invention is to provide a kind of new rhamnose lactic acid bacteria strain, its can prolonged preservation and can effectively treat microbiotic and diarrhoea and related symptoms that chemotherapeutics causes.
Rhamnose lactic acid bacteria strain of the present invention was named as SLR0406, had been preserved in the Chinese typical culture collection center in Wuhan on March 17th, 2006, and its preserving number is CCTCC-M206023.
The invention provides a kind of rhamnose lactic acid bacteria strain SLR0406, it was 37 ℃ of survivals 30-60 days, and the sugar-fermenting feature is as follows:
The close cotton mouse nuclear of breast wheat rhizoma nardostachyos sea, Ah Xian fruit half Portugal seven
Draw the sugared newborn grape sugar bud of dimension to reveal three or two sub-Lee's sugar algae leaves
The spirit of the sugared sugar alcohol sugar of uncle sugar sugar sugar sugar
Sugar
- + + + + + ± + + - - + + + +
In a preferred embodiment of the present invention, described rhamnose lactic acid bacteria strain SLR0406 is the bacterial strain or the inactivated strain of living.
The present invention also provides a kind of pharmaceutical composition, and it comprises rhamnose lactic acid bacteria strain SLR0406 of the present invention, protective material and pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, the formulation of described pharmaceutical composition is selected from oral liquid, tablet, capsule and other oral solid formulation and freeze-dried powder preparation.
In a preferred embodiment of the present invention, the content of described rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 is the 0.1-99.9 weight part, is preferably the 10-80 weight part, more preferably the 20-70 weight part, most preferably be the 40-60 weight part; Described protectant consumption is the 0.1-99.9 weight part, is preferably the 20-90 weight part, and more preferably the 30-80 weight part most preferably is the 40-60 weight part.
In a preferred embodiment of the present invention; described protective material comprises skim-milk 10～20 weight parts; sodium alginate 10～20 weight parts; neolactose 10～20 weight parts; starch 6～20 weight parts; Sodium Glutamate 0.01～2 weight part; vitamins C-sodium 0.01～0.2 weight part, preferably, described protective material contains skim-milk 12～18 weight parts; neolactose 12～18 weight parts; starch 10～16 weight parts, Sodium Glutamate 0.05～1.5 weight part, vitamins C-sodium 0.05～0.15 weight part; more preferably; described skim-milk 14～16 weight parts that contain, neolactose 14～16 weight parts, starch 12～14 weight parts; Sodium Glutamate 0.5～1.0 weight part, vitamins C-sodium 0.1～0.12 weight part.
The present invention also provides a kind of method for preparing freeze-dried powder preparation of the present invention, and described method comprises:
(a) preparation substratum and sterilization;
(b) step (a) gained substratum is placed fermentor tank inoculation rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206030, and fermentation;
(c) the fermentation products therefrom carries out the centrifugal bacterium mud that obtains;
(d) in gained bacterium mud, add protective material, and carry out lyophilize and get lyophilized powder;
(e) add vehicle in step (d) obtained freeze-drying powder, sieving obtains freeze-dried powder preparation.
The present invention also provide described rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 in that treatment microbiotic and chemotherapy cause diarrhoea and particularly intestinal microflora disorder of associated conditions, hepatopathy assisting therapy and reduce in the ammonia concentration in purposes.
In a preferred embodiment of the present invention, described associated conditions comprises acute diarrhea, chronic diarrhoea, irritable bowel syndrome and constipation.
Rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 of the present invention can prolonged preservation, and can treat diarrhoea and related symptoms that microbiotic and chemotherapeutics cause, particularly intestinal microflora disorder effectively.
Embodiment
Rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 of the present invention obtains by the following method:
(a) with commercially available many strains lactobacillus rhamnosus bacterial strain (available from China Committee for Culture Collection of Microorganisms common micro-organisms center) be under 4.0～7.0 the condition aerobic fermentation 12-36 hour, be placed in the triangular flask at 37 ℃, pH, and 0 ℃ of-50 ℃ of preservation;
(b) bacterial strain in the triangular flask is coated with the dull and stereotyped colony number of surveying every day, and carry out microscopy and observe, carry out sterility test simultaneously, treat that colony number is reduced to 20 bacterium colonies and whole bacterium colonies is chosen to the recovery of kitchen meat pipe when following, carry out Physiology and biochemistry and identify, qualification result meets the amplification rejuvenation of its physio-biochemical characteristics (being following sugar-fermenting index) back;
(c) obtained strains in the step (b) is repeated step (a)-(b), up to obtaining at 30-60 days bacterial strain of 37 ℃ of survivals, i.e. rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023.
Cultural characteristic and the thalli morphology of rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 of the present invention are as follows:
Facultative anaerobe, optimum growth temperature is 37 ℃～40 ℃, optimum pH is 5.5～7.0, on the MRS substratum, cultivate and grew the oyster white bacterium colony in 48 hours, the bacterium colony rounded protuberance is smooth, Gram-positive, no gemma, nothing folder film, atrichia, thalline is quarter butt, the club shape of two terminal circle, single or double row.
Rhamnose lactic acid bacteria strain SLR0406 of the present invention can be 37 ℃ of survivals at least 30 days, and for example 30-60 days, 30-50 days, 30-40 days.
Use API 50CHL test kit (available from BioMerieux, Lyon, France) by the test kit specification sheets rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 of the present invention and commercially available rhamnose lactic acid bacteria (available from common micro-organisms center, Beijing) are carried out fermentation mode mensuration, the result is as follows:
| Pectinose | Fibres sugars | Fructose | Semi-lactosi | Glucose | Lactose | Maltose | N.F,USP MANNITOL | Melizitose | Close disaccharides | Raffinose | Rhamnosyl | Ribose | Trehalose | Polychrom | |
| Commercially available bacterial strain | - | - | + | + | + | + | ( d) | + | + | - | - | + | + | + | + |
| SLR0406 CCTCC-M206030 | - | + | + | + | + | + | ± | + | + | - | - | + | + | + | + |
The sugar-fermenting experimental result shows that only fibres sugars fermentation result is variant before and after the domestication, so rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 meets the lactobacillus rhamnosus feature.
Genetics is identified: carry out the 16SrDNA sequential analysis of SLR0406 by Beijing institute of microbiology, institute's calling sequence is shown in SEQ ID NO:1.The result shows SLR0406 CCTCC-M206023 and other lactobacillus rhamnosus height homology, and similarity surpasses 99%.
Rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 of the present invention can this area in regular dosage form carry out administration.For example, above-mentioned rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 can make oral liquid, tablet, capsule and other oral solid formulation and freeze-dried powder preparation etc.In a preferred embodiment of the present invention, described rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 can make freeze-dried powder preparation.
The present invention also provides a kind of freeze-dried powder preparation, and it comprises rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 lyophilize bacterium powder and protective material.
In above-mentioned preparation, the content of described rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 is conventional, as long as can play desired result.In a preferred embodiment of the present invention, the consumption of described rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 is the 0.1-99.9 weight part, is preferably the 10-80 weight part, more preferably the 20-70 weight part, most preferably be the 40-60 weight part.
In above-mentioned preparation, described protective material is the GPF (General Protection False agent in this area.In a preferred embodiment of the present invention; described protective material comprises skim-milk 10～20 weight parts, sodium alginate 10～20 weight parts, neolactose 10～20 weight parts, starch 6～20 weight parts; Sodium Glutamate 0.01～2 weight part, vitamins C-sodium 0.01～0.2 weight part.In another preferred embodiment of the present invention, described protective material contains skim-milk 12～18 weight parts, neolactose 12～18 weight parts, starch 10～16 weight parts, Sodium Glutamate 0.05～1.5 weight part, vitamins C-sodium 0.05～0.15 weight part.Also have in the preferred embodiment described skim-milk 14～16 weight parts that contain, neolactose 14～16 weight parts, starch 12～14 weight parts, Sodium Glutamate 0.5～1.0 weight part, vitamins C-sodium 0.1～0.12 weight part of the present invention.
In above-mentioned preparation, described protectant consumption is conventional.In a preferred embodiment of the present invention, described protectant consumption is the 0.1-99.9 weight part, is preferably the 20-90 weight part, and more preferably the 30-80 weight part most preferably is the 40-60 weight part.
In above-mentioned freeze-dried powder preparation, also can comprise pharmaceutically acceptable carrier.Described pharmaceutically acceptable carrier is conventional in the art, and it can be for example acceptable filler of pharmacy, vehicle, seasonings etc.
The present invention also provides the preparation method of above-mentioned freeze-dried powder preparation, and this method comprises the following step:
(a) preparation substratum and sterilization;
(b) step (a) gained substratum is placed fermentor tank inoculation rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023, and fermentation;
(c) the fermentation products therefrom carries out the centrifugal bacterium mud that obtains;
(d) in gained bacterium mud, add protective material, and carry out lyophilize and get lyophilized powder;
(e) add vehicle in step (d) obtained freeze-drying powder, sieving obtains freeze-dried powder preparation.
In aforesaid method, described substratum is conventional in the art, and which substratum those of ordinary skill in the art can directly obtain in conjunction with its expertise on reading basis of the present invention can be used for of the present invention.In a preferred embodiment of the present invention, described substratum comprises nitrogenous source, carbon source and special composition.In another preferred embodiment of the present invention, described nitrogenous source is selected from skim-milk, peptone, tryptone, ammonium salt, extractum carnis and/or plant trunk; Described carbon source is selected from glucose, lactose, neolactose, semi-lactosi, glycerine, sorbyl alcohol, trehalose and/or maltose; Described special composition is selected from yeast powder, Tomato juice, kimchi juice, halfcystine and/or soil temperature 80.
At aforesaid method, described preparation substratum and to carry out the disinfectant step be conventional in the art, how those of ordinary skill in the art can directly be prepared substratum in conjunction with its expertise on the basis of the present invention and carried out disinfection reading.In a preferred embodiment of the present invention, described preparation substratum also carries out the disinfectant step and comprises and fully be dissolved in skim-milk, glucose and yeast extract paste in the water, and the pH value is adjusted to 6.5-7.5, and obtained aqueous solution places in the pressure kettle in 100-200 ℃ of sterilization 5-60 minute, is cooled to 37～38 ℃ subsequently.
In aforesaid method, described inoculation rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 and the step of fermenting are conventional in the art, only use rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 of the present invention to replace other conventional bacterial strain, so how those of ordinary skill in the art can directly inoculate and ferment again in conjunction with its expertise according to description of the invention.In a preferred embodiment of the present invention, described inoculation rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 and the step of fermenting comprise: place step (a) products therefrom in the fermentor tank and under aseptic condition the rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 of inoculation 5-30 volume % (with the volumeter of step (a) products therefrom), pressing in 37～38 ℃, jars then is to feed sterile air under the condition of 0.3～0.6 kg/cm to ferment 12 hours～24 hours.
In aforesaid method, the step that described lyophilize obtains lyophilized powder is conventional in the art, and those of ordinary skill in the art can directly learn how to carry out lyophilize in conjunction with its expertise again according to description of the invention.In a preferred embodiment of the present invention, the step that described lyophilize obtains lyophilized powder comprises: in the weight of gained bacterium mud, add the protective material of 5-30 weight % in bacterium mud, and carry out lyophilize, get lyophilized powder.
At above-mentioned preparation substratum and carry out in the disinfectant step, do not have concrete restriction for the consumption of skim-milk, glucose and yeast extract paste, can form the substratum of inoculating rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 as long as form.In an example of the present invention, the consumption of described skim-milk is the 5-15 kilogram, is preferably the 6-10 kilogram, more preferably the 7-9 kilogram.In an example of the present invention, the consumption of described glucose is the 0.5-5 kilogram, is preferably the 1-3 kilogram, and more preferably the 1.2-2 kilogram most preferably is the 1.3-1.8 kilogram.In an example of the present invention, the consumption of described yeast extract paste is the 0.5-5 kilogram, is preferably the 0.6-3 kilogram, and more preferably the 0.7-2 kilogram most preferably is the 0.8-1.5 kilogram.
At above-mentioned preparation substratum and carry out in the disinfectant step, described sterilising temp is preferably 110-150 ℃, more preferably 120-130 ℃.
At above-mentioned preparation substratum and carry out in the disinfectant step, described sterilization time is preferably 6-40 minute, more preferably 7-20 minute, most preferably is 8-15 minute.
At above-mentioned inoculation rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 and in fermenting, the consumption of rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206030 is preferably 6-20 volume %, more preferably 7-15 volume % most preferably is 8-12 volume %.
At above-mentioned inoculation rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 and in fermenting, press in the fermentor tank and be preferably the 0.4-0.5 kg/cm.
Obtain in the step of lyophilized powder in above-mentioned lyophilize, described protectant consumption is preferably 6-20 weight %, and more preferably 7-15 weight % most preferably is 8-12 weight %.
Obtain in the step of lyophilized powder in above-mentioned lyophilize, described lyophilize is preferably carried out at-50 ℃ to 30 ℃, more preferably carries out to 10 ℃ at-40 ℃.In above-mentioned steps (e), described vehicle is preferably starch or pregelatinized Starch.
Rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 of the present invention uses simple, for example can carry out administration by oral.
Rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 of the present invention can prolonged preservation, and can treat diarrhoea and related symptoms that microbiotic and chemotherapeutics cause effectively.
Describe bright the present invention in detail below in conjunction with embodiment, these embodiment are presented for purposes of illustration, do not limit the scope of the invention.
Embodiment 1: preparation rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023
Be prepared as follows rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023:
(a) with commercially available many strains lactobacillus rhamnosus bacterial strain (available from China Committee for Culture Collection of Microorganisms common micro-organisms center) aerobic fermentation 24 hours under 37 ℃ condition, be placed in the triangular flask, and 37 ℃ of preservations, the initial pH that ferments is 7.0, and pH is 3.8～4.2 during end;
(b) the bacterium liquid in the triangular flask is coated with the dull and stereotyped colony number of surveying every day, and carry out microscopy and observe, carry out sterility test simultaneously, treat that colony number is reduced to 20 bacterium colonies and whole bacterium colonies is chosen to the recovery of kitchen meat pipe when following, carry out Physiology and biochemistry and identify, qualification result meets the amplification rejuvenation of its physio-biochemical characteristics (sugar-fermenting index as herein described) back;
(c) obtained strains in the step (b) is repeated step (a)-(b), up to the bacterial strain that obtains to survive 30-60 days, i.e. rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 at 37 ℃.
Embodiment 2-5
Prepare rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023 as embodiment 1 identical method, the storage temperature of step (a) that different is is respectively 4 ℃, 25 ℃, 40 ℃ and 45 ℃.
Embodiment 6: preparation lyophilized powder capsule
In the 500L fermentor tank, add 8 kilograms of skim-milks (New Zealand's import skim-milk) respectively, 1.5 kilograms of glucose (glucose sugar refinery, Shanghai), 1 kilogram of yeast powder (Britain OXOID.LTD) fully is dissolved in the 350L water, with 40% sodium hydroxide solution with pH regulator to 7.0.Obtained aqueous solution was sterilized 10 minutes in pressure kettle in 121 ℃, obtained aseptic product.
Inoculum size by 10 volume % (with the volumeter of above-mentioned aseptic product) in above-mentioned aseptic product is inoculated embodiment 1 gained lactobacillus rhamnosus SLR0406 CCTCC-M206023, and under aerobic, 37 ℃ of conditions, cultivate 20 hours postcooling, centrifugal 3 kilograms in the bacterium mud that gets.
In above-mentioned bacterium mud, add 3 kilograms of protective material mixings,, get 2 kilograms in bacterium powder-40 ℃ of lyophilizes.
In above-mentioned bacterium powder, add 8 kilograms of pregelatinized Starchs, cross 40 mesh sieves, directly the can capsule.
Protective material prescription: 2 kilograms of skim-milks (New Zealand's import skim-milk); 2.5 kilograms of neolactoses, 0.4 kilogram of Sodium Glutamate (Guangzhou monosodium glutamate food factory), 0.05 kilogram in vitamins C-sodium (Jiangsu Jingjiang pharmaceutical factory); said components is dissolved in 12 kg water, and in 121 ℃ of sterilizations 15 minutes.
Embodiment 7: preparation lyophilized powder capsule
In the 500L fermentor tank, add 8 kilograms of skim-milks (New Zealand's import skim-milk) respectively, 1.5 kilograms of glucose (glucose sugar refinery, Shanghai), 1 kilogram of yeast powder (Britain OXOID.LTD) fully is dissolved in the 350L water, with 40% sodium hydroxide solution with pH regulator to 7.0.Obtained aqueous solution was sterilized 10 minutes in pressure kettle in 121 ℃, obtained aseptic product.
Inoculum size by 10 volume % (with the volumeter of above-mentioned aseptic product) in above-mentioned aseptic product is inoculated embodiment 2 gained lactobacillus rhamnosus SLR0406 CCTCC-M206023, and under aerobic, 37 ℃ of conditions, cultivate 20 hours postcooling, centrifugal 3 kilograms in the bacterium mud that gets.
In above-mentioned bacterium mud, add 3 kilograms of protective material mixings,, get 2 kilograms in bacterium powder-40 ℃ of lyophilizes.
In above-mentioned bacterium powder, add 8 kilograms of pregelatinized Starchs, cross 40 mesh sieves, directly the can capsule.
Protective material prescription: 2 kilograms of skim-milks (New Zealand's import skim-milk); 2.5 kilograms of neolactoses, 0.4 kilogram of Sodium Glutamate (Guangzhou monosodium glutamate food factory), 0.05 kilogram in vitamins C-sodium (Jiangsu Jingjiang pharmaceutical factory); said components is dissolved in 12 kg water, and in 121 ℃ of sterilizations 15 minutes.
Embodiment 8: preparation lyophilized powder capsule
In the 500L fermentor tank, add 8 kilograms of skim-milks (New Zealand's import skim-milk) respectively, 1.5 kilograms of glucose (glucose sugar refinery, Shanghai), 1 kilogram of yeast powder (Britain OXOID.LTD) fully is dissolved in the 350L water, with 40% sodium hydroxide solution with pH regulator to 7.0.Obtained aqueous solution was sterilized 10 minutes in pressure kettle in 121 ℃, obtained aseptic product.
Inoculum size by 10 volume % (with the volumeter of above-mentioned aseptic product) in above-mentioned aseptic product is inoculated embodiment 3 gained lactobacillus rhamnosus SLR0406 CCTCC-M206023, and under aerobic, 37 ℃ of conditions, cultivate 20 hours postcooling, centrifugal 3 kilograms in the bacterium mud that gets.
In above-mentioned bacterium mud, add 3 kilograms of protective material mixings,, get 2 kilograms in bacterium powder-40 ℃ of lyophilizes.
In above-mentioned bacterium powder, add 8 kilograms of pregelatinized Starchs, cross 40 mesh sieves, directly the can capsule.
Protective material prescription: 2 kilograms of skim-milks (New Zealand's import skim-milk); 2.5 kilograms of neolactoses, 0.4 kilogram of Sodium Glutamate (Guangzhou monosodium glutamate food factory), 0.05 kilogram in vitamins C-sodium (Jiangsu Jingjiang pharmaceutical factory); said components is dissolved in 12 kg water, and in 121 ℃ of sterilizations 15 minutes.
Embodiment 9: preparation lyophilized powder capsule
In the 500L fermentor tank, add 8 kilograms of skim-milks (New Zealand's import skim-milk) respectively, 1.5 kilograms of glucose (glucose sugar refinery, Shanghai), 1 kilogram of yeast powder (Britain OXOID.LTD) fully is dissolved in the 350L water, with 40% sodium hydroxide solution with pH regulator to 7.0.Obtained aqueous solution was sterilized 10 minutes in pressure kettle in 121 ℃, obtained aseptic product.
Inoculum size by 10 volume % (with the volumeter of above-mentioned aseptic product) in above-mentioned aseptic product is inoculated embodiment 4 gained lactobacillus rhamnosus SLR0406 CCTCC-M206023, and under aerobic, 37 ℃ of conditions, cultivate 20 hours postcooling, centrifugal 3 kilograms in the bacterium mud that gets.
In above-mentioned bacterium mud, add 3 kilograms of protective material mixings,, get 2 kilograms in bacterium powder-40 ℃ of lyophilizes.
In above-mentioned bacterium powder, add 8 kilograms of pregelatinized Starchs, cross 40 mesh sieves, directly the can capsule.
Protective material prescription: 2 kilograms of skim-milks (New Zealand's import skim-milk); 2.5 kilograms of neolactoses, 0.4 kilogram of Sodium Glutamate (Guangzhou monosodium glutamate food factory), 0.05 kilogram in vitamins C-sodium (Jiangsu Jingjiang pharmaceutical factory); said components is dissolved in 12 kg water, and in 121 ℃ of sterilizations 15 minutes.
Embodiment 10: preparation lyophilized powder capsule
In the 500L fermentor tank, add 8 kilograms of skim-milks (New Zealand's import skim-milk) respectively, 1.5 kilograms of glucose (glucose sugar refinery, Shanghai), 1 kilogram of yeast powder (Britain OXOID.LTD) fully is dissolved in the 350L water, with 40% sodium hydroxide solution with pH regulator to 7.0.Obtained aqueous solution was sterilized 10 minutes in pressure kettle in 121 ℃, obtained aseptic product.
Inoculum size by 10 volume % (with the volumeter of above-mentioned aseptic product) in above-mentioned aseptic product is inoculated embodiment 5 gained lactobacillus rhamnosus SLR0406 CCTCC-M206023, and under aerobic, 37 ℃ of conditions, cultivate 20 hours postcooling, centrifugal 3 kilograms in the bacterium mud that gets.
In above-mentioned bacterium mud, add 3 kilograms of protective material mixings,, get 2 kilograms in bacterium powder-40 ℃ of lyophilizes.
In above-mentioned bacterium powder, add 8 kilograms of pregelatinized Starchs, cross 40 mesh sieves, directly encapsulated.
Protective material prescription: 2 kilograms of skim-milks (New Zealand's import skim-milk); 2.5 kilograms of neolactoses, 0.4 kilogram of Sodium Glutamate (Guangzhou monosodium glutamate food factory), 0.05 kilogram in vitamins C-sodium (Jiangsu Jingjiang pharmaceutical factory); said components is dissolved in 12 kg water, and in 121 ℃ of sterilizations 15 minutes.
Embodiment 11-15: preparation viable bacteria tablet
Obtain 2 kilograms of bacterium powder as embodiment 6-10, and add 0.5 kilogram of beta-cyclodextrin therein respectively, pulverize and obtain powder.Add 8 kilograms of pregelatinized Starchs and 1 kilogram of lactose at the gained powder, cross 24 mesh sieves behind the thorough mixing, and obtain tablet with tabletting machine (Far East, Shanghai pharmaceutical machine factory) compressing tablet.
Embodiment 16: acute toxicity test
Select Wistar rat and beagle dog as research object, the toxicity of gained viable bacteria tablet among the research embodiment 11-15.Select 60 of Wistar rats (male and female half and half), 10 of beagle dogs (male and female half and half).10 of Wistar rats (male and female half and half) are added 2 of beagle dogs (male and female half and half) be divided into 1 group (experimental group 1-5), 10 of independent Wistar rats (male and female half and half) are divided into one group (control group)
The 500mg tablet that embodiment 11-15 is made is dispersed in the 12.5ml stroke-physiological saline solution and is diluted to suspension, with the standards of 2 gram tablet/kg body weight disposable clothes experimental group 1-5 respectively.Observe the reaction that animal occurs, observed continuously 14 days.The general index of experimental group and control animals (animal appearance, behavior, movement etc.) is all normal, and the intoxicating phenomenon and the phenomena of mortality do not take place the body weight no significant difference.
Embodiment 17: acute toxicity test
Select 60 of Kunming small white mouses, be divided into 10 one group (experimental group 1-5 and control group).
The 500mg tablet of embodiment 11-15 gained is dispersed in the 12.5ml stroke-physiological saline solution is diluted to suspension, with gained suspension abdominal injection in the animal of experimental group 1-5,0.5 milliliter every.0.5 milliliter of control group intraperitoneal injection of saline.Observe the reaction that animal occurs, observed continuously 14 days.The general index of experimental group and control animals (animal appearance, behavior, movement etc.) is all normal, and the intoxicating phenomenon and the phenomena of mortality do not take place the body weight no significant difference.
Embodiment 18: long term toxicity test
Experimentize as embodiment 17, different is that the successive administration time is 3 months, and animal freely ingests, drinks water during the administration.Observe animal during the administration.According to the observation, administration group and control group behavior are normal, the normal and no significant difference of body weight gain, and abnormal change does not all appear in every biochemistry and pathological index.
The result of embodiment 16-18 shows that the preparation of being made by lactobacillus rhamnosus SLR0406CCTCC-M206023 of the present invention does not have acute toxicity and cumulative toxicity to Wistar rat, Kunming small white mouse and beagle dog, can use by safety clothes.
Embodiment 19
The BALB/c mouse of selection female SPF (18g ± 2g) 30, and be divided into 2 groups, model group is 20, control group is 10.As the modeling medicine, adopt the mode of drinking-water+stomach that model group is carried out modeling with the microbiotic ampicillin.Ampicillin stomach dosage 300 mg/day.The ampicillin treatment time is 3 days, observes ight soil and changes and record.
Have or not diarrhoea rare just (it is standard that free from smutting during is arranged on the filter paper) judgement to occur.
1. the number of animals of passage of loose stools in diarrhea rate=group/this treated animal sum
2. the rare just level of the index=loose stool rate * that suffers from diarrhoea, wherein the rare of loose stool rate=every animal just counts/always just counts; The rare degree just of rare just level expression is with rare size deciding grade and level of just polluting filter paper formation stain area.Be divided into 4 grades, standard is as follows:
Progression 1234
Stain diameter (cm)＜1 1-1.9 2-3＞3
Model group was carried out administration in ampicillin 300mg/ days, cause mouse watery stool to occur, all suffer from diarrhoea, promptly diarrhea rate is 100%, and the diarrhoea index is 0.93 ± 0.12, and control group is normally taken food, and 2 indexs of gained are 0.
Control group and model group mouse intestinal flora average be (log value) relatively
To be divided into 60 mouse of microbiotic ampicillin such as above-mentioned processing 6 groups (experimental group 1-5 and control group).With embodiment 11-15 gained tablet with every day 10
8The dosage of CFU oral stomach is respectively given experimental group 1-5, the reference substance physiological saline of the no viable bacteria of natural recovering group clothes.Clothes are 7 days continuously, put to death mouse on the 8th day, and dissect under aseptic condition, carry out live bacterial count after the enteron aisle sampling thing of each mouse is cultivated.
Each is organized experiment mice and handles 1 all rear intestinal flora quantitative analysis results (log value)
Annotate: the numerical value of experimental group is averaged
The result causes diarrhea of mouse after showing continuous clothes microbiotic, after this obeys product of the present invention continuously, compares the test group symptom of diarrhea with natural recovering group and obviously improves, and beneficial bacteria of intestinal tract quantity returns to normal level rapidly.
Embodiment 20: stability in storage
Gained lactobacillus rhamnosus among the embodiment 1-5 (being SLR0406 CCTCC-M206023) and original strain (available from China Committee for Culture Collection of Microorganisms common micro-organisms center) fermented liquid are stored under 37 ℃ of conditions, relatively its stability.By following table as can be seen under identical preservation condition the viable count of naturalized strain than the high order of magnitude of original strain, therefore more stable through the bacterial strain of domestication.
Annotate: the experimental result of SLR0406 CCTCC-M206023 is averaged
Embodiment 21
With gained lactobacillus rhamnosus among the embodiment 1 (being SLR0406 CCTCC-M206023), fermented liquid stores under 37 ℃ of conditions, measures viable count with the 5th day, the 10th day, the 30th day and the 40th day respectively, and the result is as follows:
| Store fate (d) | 0 | 5 | 10 | 30 | 40 |
| Viable count | 2.90×10 8 | 2.13×10 8 | 1.16×10 8 | 8.54×10 4 | 4.03×10 2 |
As seen from the above table, gained lactobacillus rhamnosus of the present invention can stably preserve 30 days at least at 37 ℃.And, gained lactobacillus rhamnosus among the embodiment 1 was saved in the 60th day, the viable count of its survival also can reach about 100.
Sequence table
＜110〉Xinyi Pharmaceutical Factory
＜120〉new lactic bacilli strains, medical composition and its use and manufacture method
<130>060350
<160>1
<170>PatentIn version 3.3
<210>1
<211>1426
<212>DNA
＜213〉16SrDNA of rhamnose lactic acid bacteria SLR0406
<400>1
gctccctaaa agggttacgc caccggcttc gggtgttaca aactctcatg gtgtgacggg 60
cggtgtgtac aaggcccggg aacgtattca ccgcggcgtg ctgatccgcg attactagcg 120
attccgactt cgtgtaggcg agttgcagcc tacagtccga actgagaatg gctttaagag 180
attagcttga cctcgcggtc tcgcaactcg ttgtaccatc cattgtagca cgtgtgtagc 240
ccaggtcata aggggcatga tgatttgacg tcatccccac cttcctccgg tttgtcaccg 300
gcagtcttac tagagtgccc aactaaatgc tggcaactag tcataagggt tgcgctcgtt 360
gcgggactta acccaacatc tcacgacacg agctgacgac aaccatgcac cacctgtcat 420
tttgcccccg aaggggaaac ctgatctctc aggtgatcaa aagatgtcaa gacctggtaa 480
ggttcttcgc gttgcttcga attaaaccac atgctccacc gcttgtgcgg gcccccgtca 540
attcctttga gtttcaacct tgcggtcgta ctccccaggc ggaatgctta atgcgttagc 600
tgcggcactg aagggcggaa accctccaac acctagcatt catcgtttac ggcatggact 660
accagggtat ctaatcctgt tcgctaccca tgctttcgag cctcagcgtc agttacagac 720
cagacagccg ccttcgccac tggtgttctt ccatatatct acgcatttca ccgctacaca 780
tggagttcca ctgtcctctt ctgcactcaa gtttcccagt ttccgatgca cttcctcggt 840
taagccgagg gctttcacat cagacttaaa aaaccgcctg cgctcgcttt acgcccaata 900
aatccggata acgcttgcca cctacgtatt accgcggctg ctggcacgta gttagccgtg 960
gctttctggt tggataccgt cacgccgaca acagttactc tgccgaccat tcttctccaa 1020
caacagagtt ttacgacccg aaagccttct tcactcacgc ggcgttgctc catcagactt 1080
gcgtccattg tggaagattc cctactgctg cctcccgtag gagtttgggc cgtgtctcag 1140
tcccaatgtg gccgatcaac ctctcagttc ggctacgtat cattgccttg gtgagccgtt 1200
acctcaccaa ctagctaata cgccgcgggt ccatccaaaa gcgatagctt acgccatctt 1260
tcagccaaga accatgcggt tcttggattt atgcggtatt agcatctgtt tccaaatgtt 1320
atcccccact taagggcagg ttacccacgt gttactcacc cgtccgccac tcgttcaaaa 1380
ttaaatcaag atgcaagcac ctttcaataa tcagaactcg ttcgac 1426
(SEQ ID NO：1)
Claims (10)
1. rhamnose lactic acid bacteria strain SLR0406, it was 37 ℃ of survivals 30-60 days, and the sugar-fermenting feature is as follows:
The close cotton mouse nuclear of breast wheat rhizoma nardostachyos sea, Ah Xian fruit half Portugal seven
Draw the sugared newborn grape sugar bud of dimension to reveal three or two sub-Lee's sugar algae leaves
The spirit of the sugared sugar alcohol sugar of uncle sugar sugar sugar sugar
Sugar
- + + + + + ±+ + - - + + + +
2. rhamnose lactic acid bacteria strain SLR0406 as claimed in claim 1, its preserving number are CCTCC-M206023.
3. rhamnose lactic acid bacteria strain SLR0406 as claimed in claim 1 is characterized in that it is the bacterial strain or the inactivated strain of living.
4. pharmaceutical composition, it comprises the described rhamnose lactic acid bacteria strain SLR0406 of claim 1, protective material and pharmaceutically acceptable carrier.
5. pharmaceutical composition as claimed in claim 4 is characterized in that the formulation of described pharmaceutical composition is selected from oral liquid, tablet, capsule and other oral solid formulation and freeze-dried powder preparation.
6. pharmaceutical composition as claimed in claim 4, the content that it is characterized in that described rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 is the 0.1-99.9 weight part, be preferably the 10-80 weight part, more preferably the 20-70 weight part, most preferably be the 40-60 weight part; Described protectant consumption is the 0.1-99.9 weight part, is preferably the 20-90 weight part, and more preferably the 30-80 weight part most preferably is the 40-60 weight part.
7. pharmaceutical composition as claimed in claim 6; it is characterized in that described protective material comprises skim-milk 10～20 weight parts; sodium alginate 10～20 weight parts; neolactose 10～20 weight parts; starch 6～20 weight parts; Sodium Glutamate 0.01～2 weight part; vitamins C-sodium 0.01～0.2 weight part, preferably, described protective material contains skim-milk 12～18 weight parts; neolactose 12～18 weight parts; starch 10～16 weight parts, Sodium Glutamate 0.05～1.5 weight part, vitamins C-sodium 0.05～0.15 weight part; more preferably; described skim-milk 14～16 weight parts that contain, neolactose 14～16 weight parts, starch 12～14 weight parts; Sodium Glutamate 0.5～1.0 weight part, vitamins C-sodium 0.1～0.12 weight part.
8. method for preparing the described freeze-dried powder preparation of claim 4, described method comprises:
(a) preparation substratum and sterilization;
(b) step (a) gained substratum is placed fermentor tank inoculation rhamnose lactic acid bacteria strain SLR0406CCTCC-M206023, and fermentation;
(c) the fermentation products therefrom carries out the centrifugal bacterium mud that obtains;
(d) in gained bacterium mud, add protective material, and carry out lyophilize and get lyophilized powder;
(e) add vehicle in step (d) obtained freeze-drying powder, sieving obtains freeze-dried powder preparation.
9. the diarrhoea and particularly intestinal microflora disorder of associated conditions, the hepatopathy assisting therapy that cause in treatment microbiotic and chemotherapy of rhamnose lactic acid bacteria strain SLR0406 CCTCC-M206023 and reduce purposes in the ammonia concentration.
10. purposes as claimed in claim 9 is characterized in that described associated conditions comprises acute diarrhea, chronic diarrhoea, irritable bowel syndrome and constipation.
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| PCT/CN2007/070962 WO2008052468A1 (en) | 2006-11-01 | 2007-10-26 | New lactobacillus rhamnosus strain, its pharmaceutical composition and the uses thereof, and the method for preparation |
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Cited By (4)
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| CN108813262A (en) * | 2018-07-02 | 2018-11-16 | 杭州相生相成科技有限公司 | A kind of compound probiotic solid beverage containing DHA algal oil |
| CN110121353A (en) * | 2016-06-21 | 2019-08-13 | Yun股份有限公司 | Dermatological preparations for the skin microbial group that maintains and/or get well |
| CN110846229A (en) * | 2019-12-19 | 2020-02-28 | 广州傲农生物科技有限公司 | Preservation method and preservative for improving survival rate of bacillus coagulans |
| CN115025133A (en) * | 2022-06-14 | 2022-09-09 | 山东省农业科学院 | Lactic acid bacteria oral liquid and application thereof in relieving and treating diarrhea |
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| CN111743875B (en) * | 2019-09-17 | 2022-07-29 | 河南金百合生物科技股份有限公司 | Preparation method of clostridium butyricum microencapsulated viable bacteria preparation |
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| CN114128882A (en) * | 2020-09-03 | 2022-03-04 | 香港科技大学深圳研究院 | Cistanche probiotic chewable tablet with laxative properties and preparation method and application thereof |
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| SE511524C2 (en) * | 1997-06-02 | 1999-10-11 | Essum Ab | Lactobacillus casei rhamnosus strain and pharmaceutical preparation for the control of pathogenic intestinal bacteria |
| CN1160451C (en) * | 2000-10-16 | 2004-08-04 | 鼎健生物科技食品股份有限公司 | Rhamnose lactic acid bacteria strain and its use |
| SG97174A1 (en) * | 2000-12-19 | 2003-07-18 | Cell Biotechnology Food Co Ltd | Lactobacillus rhamnosus strain and uses thereof |
| CN100396770C (en) * | 2004-03-19 | 2008-06-25 | 景岳生物科技股份有限公司 | Novel microorganism Lactobacillus rhamnosus GM-020 and application thereof in treating obesity |
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| CN110121353A (en) * | 2016-06-21 | 2019-08-13 | Yun股份有限公司 | Dermatological preparations for the skin microbial group that maintains and/or get well |
| CN110121353B (en) * | 2016-06-21 | 2024-03-12 | Yun股份有限公司 | Dermatological preparations for maintaining and/or restoring healthy skin microbiota |
| CN108813262A (en) * | 2018-07-02 | 2018-11-16 | 杭州相生相成科技有限公司 | A kind of compound probiotic solid beverage containing DHA algal oil |
| CN110846229A (en) * | 2019-12-19 | 2020-02-28 | 广州傲农生物科技有限公司 | Preservation method and preservative for improving survival rate of bacillus coagulans |
| CN115025133A (en) * | 2022-06-14 | 2022-09-09 | 山东省农业科学院 | Lactic acid bacteria oral liquid and application thereof in relieving and treating diarrhea |
| CN115025133B (en) * | 2022-06-14 | 2023-08-04 | 山东省农业科学院 | Lactic acid bacteria oral liquid and application thereof in relieving and treating diarrhea |
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| CN101173228B (en) | 2011-08-17 |
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