CN105055457A - Drug for preventing and treating alzheimer's disease as well as preparation method and application of drug - Google Patents
Drug for preventing and treating alzheimer's disease as well as preparation method and application of drug Download PDFInfo
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- CN105055457A CN105055457A CN201510491144.6A CN201510491144A CN105055457A CN 105055457 A CN105055457 A CN 105055457A CN 201510491144 A CN201510491144 A CN 201510491144A CN 105055457 A CN105055457 A CN 105055457A
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Abstract
The invention belongs to the field of life science and relates to an application of clostridium butyricum in preparation of a probiotic preparation for treating and preventing an alzheimer's disease, in particular to a new drug application of probiotic clostridium butyricum in prevention and treatment of the alzheimer's disease. The alzheimer's disease is a progressive nervous system degenerative disease occurring latently and has the clinic characteristics of dysmnesia, aphasia, apraxia, agnosia, view space skill damage, executive dysfunction, personality change, behavior change and other global dementia behaviors. The invention discloses the probiotic preparation which can prevent and treat the alzheimer's disease and doesn't have any toxic or side effects. Intestinal flora is innovatively taken as a therapeutic target, a new mode for preventing and treating the alzheimer's disease is created, the disease symptoms and nerve cell injury are relieved, and the drug has good social and economic benefits and is worth popularization and application.
Description
Technical field
The present invention relates to the purposes of Clostridium butyricum, be specifically related to Clostridium butyricum in preparation prevention and the application in treatment Alzheimer compositions, belong to field of biological pharmacy.
Background technology
Alzheimer (Alzheimer ' sdisease, AD) be a kind of person in middle and old age of betiding drop to main nerve retrograde affection with Progressive symmetric erythrokeratodermia cognitive disorder and memory ability, in clinical main typical characteristic with learning and memory function be Progressive symmetric erythrokeratodermia damage, dull-witted, forgetful, aphasia, attention loss, dysmnesia, aphasia, apraxia, agnosia functional lesion, n-back test obstacle and personality and behavior change etc., be a kind of common complaint among the elderly, serious misery and living burden are brought to sufferers themselves and household.The pathological characteristics of Alzheimer mainly contains brain atrophy, Basal forebrain, Hippocampus and Cortical Neurons and synapse are lost, colloid is too much, inflammation, oxidative damage etc., its typical pathological change is that between neurocyte, appearance is the senile plaque of core in a large number with beta amyloid peptide, occurs neurofibrillary tangles etc. in neuronic cell space.Onset of Alzheimer disease mechanism is complicated, still not fully aware of up to now, current main pathogenesis has: cholinergic theory, infectious disease theory, poisoning by aluminum theory, free radical theory, inflammation, calcium overload theory, metabolism disorder theory, synaptic theory etc.
Treatment of alzheimer also lacks clear and definite effective treatment means, especially centering, late stage dementia patient at present, and late result is more undesirable.The medicine of clinical treatment Alzheimer mainly contains: (1) regulates the medicine of neurotransmitter, as strengthened the medicine of cholinergic nerve function, comprises cholinesterase inhibitor, donepezil; (2) glutamic acid function point analysis preparation, as nmda receptor antagonist.(3) neurodegenerative medicine is alleviated, A β antibody and vaccine, the metalloprotein inhibitors of suppression A beta peptide aggregation, restriction Protein tau Hyperphosphorylationof; (4) antiinflammatory; (5) antioxidant and free radical scavenger; (6) estrogen; (7) neurotrophic factor etc.But these medicines above all can not effective prevention and therapy Alzheimer, and can only alleviate patients with Alzheimer disease symptom, still can not effectively control the development of the Alzheimer state of an illness.At present more without the medicine of desirable control Alzheimer.These medicines can improve the symptom of Alzheimer in a short time above, and they can not cure Alzheimer, and can not obviously change Alzheimer disease process, late result is poor.Their medicines are symptomatic treatment medicine substantially, promote and strengthen do not have impaired or impaired not too serious neuronic function, fundamentally can not stop generation and the development of Alzheimer.
" probiotic bacteria " is active microorganism, effectively can improve intestinal microflora, suppresses pathogen, produces good health effect, be prepared into the probiotics preparations such as medicine, health product or beverage at present.Regulate by improving intestinal microbial population and treat the common recognition that general disease more and more becomes scientific circles now, a lot of nervous system disease is found in clinical practice, as infantile autism, depression, all there is close contacting with enteric flora disturbance, there is close relationship with the brain-gut axis of human body, even have and to palliate a disease the successful examples of symptom by drinking Yoghourt.Brain-gut axis is one and is present in central nervous system and unifies the bi-direction interactive system of the complexity between intestinal microbial population, more and more known by people.But, have no relevant report both at home and abroad by probiotic bacteria regulating intestinal canal flora control Alzheimer.
Clostridium butyricum belongs to (Clostridiumbutyricum) as important probiotic bacteria, previously should be used for prevention and therapy enteritis, constipation and other diseases widely.Clostridium butyricum belongs to and is generally present in soil, in the intestinal of animal and human's body, it is Gram-positive anaerobic bacillus(cillus anaerobicus), gastric acid can be tolerated and enter intestinal, the regeneration of secretion intestinal mucosa and the important nutrient butyric acid (butanoic acid) repaired, the intestinal mucosa of repairing damage, diminish inflammation, nutrition intestinal, enterobacterial infection is comprised to a variety of causes, chemotherapy of tumors, intestinal tract disease caused by surgical operation etc. has good curative effect, people are to Alzheimer and micro-ecological in intestines understanding deficiency, scientist is also few to the research of this respect, up to the present, there is not yet the research application report of Clostridium butyricum control Alzheimer.
Summary of the invention
The object of the invention is to the defect and the deficiency that overcome prior art, inventive application Clostridium butyricum in the control of Alzheimer, and then develops the probiotics preparation of prevention or treatment Alzheimer.The object of this invention is to provide a kind of Clostridium butyricum bacterial strain that is safe, effectively preventing Alzheimer and probiotics preparation and preparation method.
The invention provides Clostridium butyricum (Clostridiumbutyricum) the WZMC1018 bacterial strain that a strain has control Alzheimer.
Clostridium butyricum of the present invention is Clostridium butyricum (Clostridiumbutyricum) WZMC1018 bacterial strain, on October 22nd, 2014 at China Committee for Culture Collection of Microorganisms's common micro-organisms center, it is referred to as CGMCC (address: No. 3, Yard 1, BeiChen xi Road, Chaoyang District, Beijing City, Institute of Microorganism, Academia Sinica, postcode 100101) preservation, deposit number is CGMCCNo.9830.
Clostridium butyricum of the present invention (Clostridiumbutyricum) WZMC1018 has following biological property:
(1) colonial morphology: be creamy white, circle is slightly convex, and edge is irregular, diameter 1 ~ 3mm, and surface is gloss slightly, has bubble to produce in fluid medium;
(2) individual morphology: be G
+bacillus cereus, thalline is in straight or knee shape, and 0.6 ~ 1.2 × 3.0 ~ 7.0 μm, end is round, single, paired, short chain, accidental long filament shape thalline;
(3) physiological and biochemical property: maltose (+); Mannitol (+); Raffinose (+); Lactose (+); Ribose (+); Starch (+).
Cultivate optimal condition: well-grown under anaerobism, does not grow in aerobic environment.Optimum growth temperature 35 ~ 40 DEG C; Minimum growth temperature 25 ~ 28 DEG C; The highest 43 ~ 45 DEG C; Growth optimum pH 6.5 ~ 7.0; PH4.5 ~ 5.0 or 8.0 ~ 8.5 do not grow.
Another object of the present invention is to provide a kind of new pharmaceutical applications of Clostridium butyricum, i.e. the application of Clostridium butyricum in preparation control Alzheimer probiotics preparation compositions, said composition can be medicine, health product and beverage etc.
The present invention is using the Clostridium butyricum WZMC1018 bacterial strain of effective dose as medicament active composition, according to certain preparation process, add the conventional adjuvant such as excipient, nutrient, make any one and be suitable for treatment and prevention Alzheimer probiotics preparation, the dosage form used clinically can be granule, powder, oral liquid, enema etc.
Indication effective dose of the present invention refers to can not lower than 1 × 10 according to total viable count that the solid live bacteria preparation made as active ingredient alone or in combination described in above comprises using Clostridium butyricum
7cFU/g.
Clostridium butyricum of the present invention refers to the form of living cells, and total viable count that probiotics preparation compositions comprises can not lower than 1 × 10
7cFU/g, generally 1 × 10
8more than CFU/g, can reach 1 × 10
12cFU/g or 1 × 10
12more than CFU/g.
The preferred preparation process of the present invention is, the preparation of Clostridium butyricum preparation: by Clostridium butyricum WZMC1018 bacterial strain seed liquor by weight 1% inoculum concentration access after sterilizing containing weight peptone 1%, Carnis Bovis seu Bubali cream 1%, yeast extract 0.5%, glucose 2%, K
2hPO
40.2%, MgSO
47H
2o0.05%, MnSO
44H
2o0.02%; oligofructose 0.3%; in dibasic ammonium citrate 0.2% fluid medium; after 36 DEG C ~ 38 DEG C anaerobic fermentations, centrifugalize thalline, adds in sodium glutamate containing weight 5% and 5% greasiness milk powder frozen-dried protective liquid by thalline; clostridium butyricum active bacteria mycopowder can be obtained after mixed freezing drying; the dry mycopowder of gained, mixes with pharmaceutical carrier, namely obtains described final dosage form probiotic composition.Preparation process is not limited to of the present invention, and other known preparation process is all passable.Pharmaceutical carrier can be oligofructose, glucose, trehalose etc.
Because the present invention makes public for the first time with Clostridium butyricum WZMC1018 bacterial strain as medicament active composition is in preparation treatment and the application in prevention Alzheimer disease drugs; therefore; with Clostridium butyricum WZMC1018 bacterial strain for active ingredient and auxiliary material combination make medicament; as long as this medicament is used for the treatment of and prevention Alzheimer, all belong to protection scope of the present invention.
Effective dose refers to can not lower than 1 × 10 according to total viable count that the solid live bacteria preparation made as active ingredient alone or in combination described in above comprises using Clostridium butyricum
7cFU/g.
The total viable count of Clostridium butyricum that Clostridium butyricum preparation compositions of the present invention comprises can not lower than 1 × 10
7cFU/g, generally 1 × 10
8more than CFU/g, can reach 1 × 10
12cFU/g or 1 × 10
12more than CFU/g.
The present invention selects Clostridium butyricum WZMC1018 bacterial strain to prevent and treat Alzheimer, evident in efficacy, and with the increase of dosage, curative effect is strengthened, and does not find any toxic and side effects.
Advantage of the present invention and effect:
The present invention discloses the purposes of Clostridium butyricum WZMC1018 bacterial strain at control Alzheimer first, and provides the preparation method of Clostridium butyricum preparation compositions.The Clostridium butyricum WZMC1018 bacterium source that the present invention selects is in human body, and through screening, domestication and checking, safety is high, has good ecological mutual aid.The present invention obviously can improve the alteration of intestinal flora caused by Alzheimer, and the present invention can improve cerebral tissue activities of antioxidant enzymes, anti-neuronal apoptosis, improving studing ability.The metabolite of Clostridium butyricum has the short-chain fatty acid such as butanoic acid, by blood brain barrier, also can play the nerve injury effect of anti-Alzheimer disease in brain.Therefore, Clostridium butyricum preparation compositions of the present invention can as the medicine of control Alzheimer, have no side effect, easy to use, can be used as the auxiliary treatment that nutritional preparation and other nutrients one are used from clinical patients, allow patient just can complete auxiliary treatment in the process of diet at ordinary times, can greatly alleviate patients with Alzheimer disease misery.
Detailed description of the invention
Clostridium butyricum mycopowder is first prepared in the preparation of Clostridium butyricum preparation compositions, then dose corresponding adjuvant as required and make corresponding dosage form, the present invention is specifically prepared as example with oral clostridium butyricum active bacteria powder, the preparation method of probiotic bacteria is described, the preparation method of other dosage form is omitted, illustrate no longer one by one, concrete preparation dosage form is not limited to method described below.If do not specialize, the conventional means that technological means used in embodiment is well known to those skilled in the art.
The Isolation and ldentification of embodiment 1 Clostridium butyricum (Clostridiumbutyricum) WZMC1018 bacterial strain
Using the feces of a healthy young people as sample separation, on modified MRS agar culture medium, under 37 DEG C of anaerobic conditions, 48h is coated with separation and Culture, obtain Clostridium butyricum of the present invention (Clostridiumbutyricum) WZMC1018, be accredited as Clostridium butyricum and belong to.
The formula of modified MRS culture medium: peptone 10g, Carnis Bovis seu Bubali cream 10g, yeast extract 5g, glucose 20g, K
2hPO
42g, MgSO
47H
2o0.5g, MnSO
4.4H
2o0.2g, oligofructose 3g, dibasic ammonium citrate 2g, agar 15g, distilled water 1L, adjust pH to 7.0,115 DEG C of sterilizings 15 minutes.
Clostridium butyricum of the present invention (Clostridiumbutyricum) WZMC1018 has following microbial characteristic:
(1) colonial morphology: be creamy white, circle is slightly convex, and edge is irregular, diameter 1 ~ 3mm, and surface is gloss slightly, has bubble to produce in fluid medium.
(2) individual morphology: be G
+bacillus cereus, thalline is in straight or knee shape, and 0.6 ~ 1.2 × 3.0 ~ 7.0 μm, end is round, single, paired, short chain, accidental long filament shape thalline.
(3) physiological and biochemical property: maltose (+); Mannitol (+); Raffinose (+); Lactose (+); Ribose (+); Starch (+).
Cultivate optimal condition: well-grown under anaerobism, does not grow in aerobic environment.Optimum growth temperature 35 ~ 40 DEG C; Minimum growth temperature 25 ~ 28 DEG C; The highest 43 ~ 45 DEG C; Growth optimum pH 6.5 ~ 7.0; PH4.5 ~ 5.0 or 8.0 ~ 8.5 do not grow.
Clostridium butyricum of the present invention (Clostridiumbutyricum) WZMC1018, on October 22nd, 2014 at China Committee for Culture Collection of Microorganisms's common micro-organisms center, it is referred to as CGMCC (address: No. 3, Yard 1, BeiChen xi Road, Chaoyang District, Beijing City, Institute of Microorganism, Academia Sinica, postcode 100101) preservation, Classification And Nomenclature is that Clostridium butyricum belongs to, and deposit number is CGMCCNo.9830.
The preparation of embodiment 2 Clostridium butyricum (Clostridiumbutyricum) WZMC1018 probiotics preparation compositions
1. seed liquor preparation: the mono-bacterium colony of picking Clostridium butyricum (Clostridiumbutyricum) WZMC1018, is inoculated in 50mL MRS liquid culture medium, and pH is 7.0 ± 0.5,37 DEG C, and Anaerobic culturel 24h, is seed liquor;
The formula of modified MRS culture medium: peptone 10g, Carnis Bovis seu Bubali cream 10g, yeast extract 5g, glucose 20g, sodium acetate 5g, K
2hPO
42g, MgSO
47H
2o0.5g, MnSO
44H
2o0.2g, oligofructose 3g, dibasic ammonium citrate 2g, distilled water 1L, adjust pH to 7.0,115 DEG C of sterilizing 15min.
2. fermentation culture: the seed liquor of getting step 1, is seeded in new modified MRS culture medium with 1% inoculum concentration, 37 DEG C, Anaerobic culturel 24h, terminates to cultivate;
3. collect thalline: get step 2 fermentation liquid, with 12,000rpm, 10min condition, remove fermented supernatant fluid, centrifugalize goes out thalline;
4. mycopowder preparation: get thalline that step 3 collects and add in sodium glutamate containing weight 5% and 5% greasiness milk powder frozen-dried protective liquid and can obtain Clostridium butyricum mycopowder after mixed freezing drying.
5. finished product preparation: get the dry mycopowder of step 4 gained, according to the viable count of Clostridium butyricum, mix with pharmaceutical carrier (oligofructose, glucose, trehalose etc.) in proportion, prepare Clostridium butyricum preparation compositions finished product, the viable count of finished product is not less than 1 × 10
7cFU/g or 1 × 10
7cFU/mL.
Embodiment 3 prevents and treats the animal experiment study of Alzheimer
Object: observe the impact of Clostridium butyricum preparation of the present invention on the learning and memory of Alzheimer mice, intracerebral oxidation index and neurocyte morphological change.
One, materials and methods:
1. medicine: Clostridium butyricum (Clostridiumbutyricum) WZMC1018 mycopowder is 1 × 10 containing viable count
8cFU/g, concrete preparation method detailed in Example 2.
2. Clostridium butyricum laboratory animal: ICR mice is male, body weight 18-22g is male, is provided by school experiment animal center.
3. model preparation and animal grouping: D-galactose induction Alzheimer mouse model: every day presses the D-galactose of 150mg/kg subcutaneous injection 3% to Alzheimer disease model group and treatment group mice, every day 1 time, continuous 6 weeks, prepare Alzheimer mouse model; The isopyknic normal saline of negative control group mice subcutaneous injection every day.From the 4th week, Clostridium butyricum treatment group mice pressed concentration 1 × 10 every day
9cFU/mL, volume 0.2mL, every day 1 time, continuous 4 weeks; The normal saline of negative control group and model group mouse stomach equivalent.Before per injection, carry out strict sterilization to injection site and syringe needle, in case mouse infection, whole mice all gives standard mouse food routine feeding.Experiment terminates the last week and carries out the test of water maze neuroethology to whole mice, and after neuroethology test terminates, fast fetching cecal content and Hippocampus of Mice, cerebral tissue carries out the mensuration of SOD enzyme activity, MDA content.Another part mice carries out perfusion and fixes, and the pathology of HE dyeing, TUNEL dyeing detect.
4. ability of learning and memory test
Adopt Morris water maze to carry out ability of learning and memory test, comprise constant-bearing navigation and space exploration experiment.Experimental facilities is made up of video acquisition system, data analysis system and four ring tanks resembling line, the Spatial learning ability of test experience animal and spatial memory capacity.
A) constant-bearing navigation experiment: mice is put into water from 4 place of entry respectively towards pool wall, record mice finds platform required time, i.e. escape latency (escapelatency), follow-on test 5d.
B) space exploration experiment: remove platform on the 6th day, measures mice and resembles the line time of staying in target.
5. the SOD enzyme activity of cerebral tissue and MDA assay: after the test of Morris water maze neuroethology terminates, each group of mice is often organized execution, on ice fast fetching Hippocampus, homogenate, the centrifugal 10min of 2000rpm/min, gets supernatant.SOD activity and MDA assay are undertaken by the description of test kit.
6. the active and Glu assay of the AChE of pair cerebral tissue: detect the active and Glu content of cerebral tissue AChE, operate by test kit description.
7. pathologic examination: the paraformaldehyde with 4% carries out cardiac perfusion to be fixed, and gets brain, paraffin embedding, section, for HE dyeing and TUNEL staining examine.
7.1HE dyes: paraffin section is carried out conventional H E dyeing, and the dewaxing of paraffin section routine comes downwards in distilled water to be waited to contaminate; Haematoxylin dyeing 5min is put in section, and tap water washes away unnecessary dyestuff; Cut into slices in hydrochloride alcohol and break up the several seconds; Tap water fully washes section; 5min in 1% Yihong aqueous solution, washes away unnecessary Yihong; Gradient alcohol dehydration, mounting.
7.2TUNEL dyes: TUNEL dying operation by specification carries out, and TUNEL positive cell core dyes brown color.
8. apply the change of PCR-DGGE technical measurement intestinal microbial population, calculate species abundance index, Shannon-Wiener index, species evenness index.After performance testing, by sacrifice, take out cecal content rapidly.Fresh specimens is transferred to ice chest laboratory immediately and is stored in-80 DEG C and analyzing preparation 15 minutes further.Then, the genomic DNA of antibacterial is extracted in the fecal specimens of DNA extraction agent box.
9. statistical analysis: experimental data represents with mean ± standard deviation, SPSS18.0 statistical software is adopted to carry out one factor analysis of variance (One-WayANOVA) statistical analysis, group difference adopts q inspection, and p < 0.05 indicates significant difference.
Two, experimental result:
1. the ability of learning and memory of Alzheimer mice is affected
Neuroethology result shows: the decline of obvious ability of learning and memory and judgement appears in Alzheimer disease model mice; Clostridium butyricum treatment group obviously improves the learning memory disorder of Alzheimer disease model mice, and constant-bearing navigation achievement (escape latency) obviously shortens, and has significant difference (p < 0.01) with model group ratio.Above result shows that Clostridium butyricum tool of the present invention has clear improvement the learning and memory function of Alzheimer mice.Experimental result is in table 1.
Table 1 is on the impact of mice constant-bearing navigation achievement (escape latency)
2. on the Hippocampus SOD enzyme activity of Alzheimer mice and the impact of MDA content
Alzheimer disease model hippocampus of mice SOD enzyme activity obviously reduces, and MDA content obviously raises; Clostridium butyricum treatment group significantly improves SOD enzyme activity in hippocampus of mice, and significantly reduces MDA content (p < 0.05), and above result shows that Clostridium butyricum of the present invention has obvious antioxidation, and experimental result is in table 2.
Table 2 is on the impact of Mice brain tissues SOD vigor and MDA content
3. on the impact of Alzheimer mice Glu content and AchE activity
Alzheimer disease model mice Glu content and the active obviously rising of AchE; Clostridium butyricum treatment group obviously reduces Glu content and AchE activity (p < 0.05), and experimental result is in table 2.
Table 3 is on the impact of mice Glu content and AchE activity
The 4.HE Alzheimer disease model group mouse Nerve cell arrangement that dyes is loose, structural fuzzy, has the impaired signs such as karyopycnosis, and Clostridium butyricum treatment group mouse Nerve cell level improves, damage comparatively Alzheimer disease model group mice obviously alleviates.
5.TUNEL coloration result: TUNEL coloration result shows: in Alzheimer disease model group hippocampus of mice neurocyte core, visible a large amount of dark brown yellow particle (TUNEL is positive) cell number increases; The dyeing of Clostridium butyricum treatment group neurocyte is more shallow, and cellularity is better, and positive cell number reduces, and above result shows that Clostridium butyricum of the present invention has obvious Anti-G value.
6. the intestinal microbial population of Alzheimer is affected
Clostridium butyricum treatment group significance on intestinal microbial population abundance index, Shannon-Wiener index (H ') and species evenness index is better than Alzheimer disease model mice.
Conclusion:
Compared with prior art, the present invention is creatively therapy target with intestinal microbial population, start the new model of control Alzheimer, the medicine of control Alzheimer have developed a kind of good effect, having no side effect, proves through animal experiment study, obviously improves the ability of learning and memory of Alzheimer mice, effective reduction Glu content and AchE activity, promote SOD vigor, effectively reduce MDA content, alleviate apoptotic pathological change.
The present invention selects Clostridium butyricum WZMC1018 bacterial strain to prevent and treat Alzheimer, evident in efficacy, and with the increase of dosage, curative effect is strengthened, and do not find any toxic and side effects, and easy to use, can be used as the auxiliary treatment that nutritional preparation and other nutrients one are used from clinical patients, allow patient just can complete auxiliary treatment in the process of diet at ordinary times, can greatly alleviate patients with Alzheimer disease misery.
Claims (6)
1. the application of Clostridium butyricum in preparation control Alzheimer compositions, is characterised in that described compositions comprises medicine, health product and oral liquid.
2. apply according to claim 1, it is characterized in that Clostridium butyricum is Clostridium butyricum WZMC1018 bacterial strain, this bacterial strain is deposited in China Committee for Culture Collection of Microorganisms's common micro-organisms center, deposit number: CGMCCNo.9830 on October 22nd, 2014.
3. apply according to claim 1, it is characterized in that described Clostridium butyricum is form of viable cells.
4. apply according to claim 1, it is characterized in that compositions is the compositions made using Clostridium butyricum as active ingredient.
5. apply according to claim 1, it is characterized in that the viable count that described compositions comprises Clostridium butyricum is not less than 1 × 10
7cFU/g.
6. Clostridium butyricum is in the preparation method of control Alzheimer compositions, comprise the steps: by Clostridium butyricum WZMC1018 bacterial strain seed liquor by weight 1% inoculum concentration access after sterilizing containing weight peptone 1%, Carnis Bovis seu Bubali cream 1%, yeast extract 0.5%, glucose 2%, K
2hPO
40.2%, MgSO
47H
2o0.05%, MnSO
4.4H
2o0.02%; oligofructose 0.3%; in dibasic ammonium citrate 0.2% fluid medium; after 36 DEG C ~ 38 DEG C anaerobic fermentations, centrifugalize thalline, adds in sodium glutamate containing weight 5% and 5% greasiness milk powder frozen-dried protective liquid by thalline; clostridium butyricum active bacteria mycopowder can be obtained after mixed freezing drying; the dry mycopowder of gained, mixes with pharmaceutical carrier, namely obtains described final dosage form probiotic composition.
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