CN100508993C - Enterobacteria containing tablet - Google Patents
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- CN100508993C CN100508993C CNB031037267A CN03103726A CN100508993C CN 100508993 C CN100508993 C CN 100508993C CN B031037267 A CNB031037267 A CN B031037267A CN 03103726 A CN03103726 A CN 03103726A CN 100508993 C CN100508993 C CN 100508993C
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Abstract
The present invention provides a tablet preparation containing intraintestinal bacteria, and said tablet can effectively uptake intraintestinal bacteria and can be stored for a long period of time.
Description
Technical field
The present invention relates to contain the tablet of intestinal bacterium.
Background technology
In recent years, bacillus bifidus is that main intestinal bacterium extensively is applied to medicine, quasi drug, food etc.But, the easy inactivation of a variety of causes such as suppress when intestinal bacterium Yin Wendu, humidity, light, pH value and film-making, so about a lot of problems of preparation existence.Particularly, for tablet, suppressing and the survival rate of viable bacteria descended during known because film-making.And, the intestinal bacterium in the tablet, easy inactivation in long preservation.
Summary of the invention
The present inventor overcomes the above-mentioned problem that in the past existed, and has successfully developed the tablet that contains intestinal bacterium, and the thalline survival rate during film-making is more than 20%, and the stability preserve 6 months under 40 ℃, 75%RH (relative humidity) condition after is more than 20%.And then the present inventor, finished the present invention by concentrating on studies.
That is, the present invention relates to
(1) a kind of tablet that contains intestinal bacterium is characterized in that, the thalline survival rate during film-making is more than 20%, and the stability of preserving after 6 months under 40 ℃, 75%RH condition is more than 20%.
According to aforementioned (1) described tablet, it is characterized in that (2) viable count is 1.0 * 10
5～2.0 * 10
11CFU/g.
According to aforementioned (1) described tablet, it is characterized in that (3) hardness is 30～300N.
According to aforementioned (1) described tablet, it is characterized in that (4) intestinal bacterium is for by the antibacterial of selecting in bacillus bifidus, lactobacillus, lactic acid coccus and the group that has the spore lactobacillus to constitute.
The specific embodiment
The intestinal bacterium that contains in the tablet of the present invention is the general name in the antibacterial class of enteral existence, specifically, for example can exemplify bacillus acidophilus (Lactobacillus acidophilus), lactobacillus casei (Lactobacillus casei), Lactobacillus gasseri (Lactobacillus gasseri), Lactobacillus plantarum (Lactobacillus plantarum), lactobacillus delbruockii subspecies bulgaricus (Lactobacillus delbrueckii subsp bulgaricus), Lactobacillus delbrueckii subsp. lactis lactobacilluss (Lactobacillus) such as (Lactobacillus delbrueckii subsplactis) belongs to; For example, lactobacillus helveticus (Leuconostoc mesenteroides), excrement chain (intestinal) coccus (Streptococcus (Enterococcus) faecalis), dung chain (intestinal) coccus (Streptococcus (Enterococcus) faecium), Hai Shi chain (intestinal) coccus (Streptococcus (Enterococcus) hirae), lactobacillus lactis (Lactobacillus lactis), streptococcus thermophilus lactic acid coccuses such as (Streptococcus thermophilus); Bifidobacterium bifidum (Bifidobacterium bifidum), long bifidus bacillus (Bifidobacterium Longum), short bifidus bacillus (Bifidobacterium breve), bifidobacterium adolescentis (Bifidobacteriumadolescentis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium pseudolongum (Bifidobacterium pseudolongum), thermophilic bifidus bacillus bifidus bacilluss (Bifidobacterium) such as (Bifidobacteriumthermophirum) belongs to (being also referred to as bacillus bifidus); For example, the bacillus (Bacillus coagulans) etc. that condenses has the spore lactobacillus; For example, bacteroids (Bacteroides) such as bacteroides fragilis (fragilis) bacterium or bacteroides melanogenicus belong to; For example, Eubacterium (Eubacterium) such as エ ア ロ Off ア シ エ Application ス belongs to; For example, peptostreptococcus anaerobius peptostreptococcuses (Peptstreptcoccus) such as (P.anaerobius) belongs to; For example, enterococcus faecalis enterococcus (Enterococcus) such as (E.faecalis) belongs to; For example, clostridium perfringen enterobacterias (Enterobacter) such as (E E.aerogenes) belongs to; Propionibacterium propionibacteriums (Propionibacterium) such as (P.acnes) belongs to; For example, Streptococcus mutans streptococcus (Streptococcus) such as (S.mutans) belongs to; For example, ミ Star オ ケ ラ (Mitsuokella) such as マ Le チ ア シ ダ bacterium belongs to; For example, sarcina (Sarcina) such as Sarcina lutea belongs to; For example, Block ロ-cud bacterium (Ruminococcus) such as ミ bacterium belong to; For example, veillonella parvula Wei Rong Shi coccuses (Veillonella) such as (Veillonella parvula) belongs to; For example, the microorganism of Erichsen megacoccus megacoccus (Megasphaera) such as (エ Le ス デ ニ) genus.
The intestinal bacterium that contains in the tablet of the present invention preferably has the intestinal bacterium of whole intestinal effect.Specifically, preference is as bacillus bifiduses such as, bifidobacterium bifidum, long bifidus bacillus, short bifidus bacillus, bifidobacterium adolescentis, bifidobacterium infantis, false bacillus bifidus, thermophilic bifidus bacilluss; For example, Lactobacilluss such as bacillus acidophilus, lactobacillus casei, Lactobacillus gasseri, Lactobacillus plantarum, lactobacillus delbruockii subspecies bulgaricus, Deshi Lactobacillus subspecies; For example, lactic acid coccuses such as lactobacillus helveticus, excrement chain (intestinal) coccus, dung chain (intestinal) coccus, Hai Shi chain (intestinal) coccus, lactobacillus lactis, streptococcus thermophilus; For example, the bacillus that condenses etc. has the spore lactobacillus, preferred especially bifidobacterium bifidum.
Tablet of the present invention is characterized in that, the thalline survival rate during film-making is about more than 20%.Thalline survival rate during film-making is preferably approximately 20～95%, is more preferably 30～95%, is preferably about 50～95% especially.At this moment, the thalline survival rate during film-making, can be by down facial 1: calculate thalline survival rate (%)=(viable count in the viable count in the 1g tablet/1g film-making raw material) * 100.The mensuration of " viable count in the 1g tablet " is with the powdered in small, broken bits at once of the tablet after the film-making in the preceding formula, measures the viable count in this powder." viable count in the 1g film-making raw material " is to try to achieve by the viable count of the film-making raw material before the mensuration film-making.As for the mensuration of viable count, if in the tablet in the mensuration of viable count and the film-making raw material mensuration of viable count undertaken by same procedure, then there is no particular limitation.The mensuration of aforementioned viable count is according to the kind of thalline and difference, for example can easily measure by the quantitative approach of the various thalline put down in writing in the outer drug ingredient specification of Japanese Pharmacopoeia.
Tablet of the present invention is characterized in that, the stability preserve 6 months under 40 ℃, the condition of 75%RH after is about more than 20%.It is about 20～95% that storage stability is preferably, and is more preferably approximately 30～95%, is preferably about 50～95% especially.At this moment, according to the viable count in the tablet after the film-making, and under 40 ℃, the condition of 75%RH, preserve 6 months after viable count in the tablet, by following formula 2: storage stability is calculated in storage stability (%)=(viable count in the tablet after the viable count/1g film-making in the tablet after 1g preserves) * 100.As for the mensuration of viable count,, then there is not special qualification as long as the mensuration of the viable count in the tablet after mensuration of the viable count in the tablet after preserving and the film-making is undertaken by same procedure.As mentioned above can be by the quantitative approach put down in writing in the outer drug ingredient specification of Japanese Pharmacopoeia for example etc., measure viable count according to the kind of thalline.
Tablet of the present invention, preferred viable count is about 1.0 * 10
5～be about 2.0 * 10
11CFU/g.Being more preferably viable count is about 1.0 * 10
6～1.0 * 10
11CFU/g is preferably about 1.0 * 10 especially
7～1.0 * 10
11CFU/g.Viable count in the tablet is measured by the quantitative approach of putting down in writing in the outer drug ingredient specification of Japanese Pharmacopoeia according to the thalline kind.
Tablet of the present invention except intestinal bacterium, also can further contain various additives such as normally used excipient, binding agent, disintegrating agent, lubricant, anticoagulant in the preparation technique field as required.As aforementioned excipients, can exemplify saccharides such as white sugar, lactose, mannitol or glucose; The starch based such as starch of corn starch, potato starch or part αization; Crystalline cellulose; Calcium hydrogen phosphate; Other can be used as various antacids that excipient uses etc. calcium phosphate etc.As the aforementioned adhesion agent, can exemplify saccharide or sugar alcohols such as white sugar, glucose, maltose alcohol; Dextrin, starch, sodium alginate, carrageenin, the polysaccharides such as skin ulcer natural gum, Radix Acaciae senegalis or agar of healing; Natural polymer subclasses such as Tragacanth, gelatin or glutelin; Cellulose derivatives such as hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose or sodium carboxymethyl cellulose; Synthetic macromolecular compounds such as polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, Polyethylene Glycol, polyacrylic acid, polymethylacrylic acid or vinylite etc.As disintegrating agent, can exemplify starch, low degree of substitution hydroxypropyl cellulose, polyvinyl pyrrolidone or the cross-linking sodium carboxymethyl cellulose etc. of carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, corn starch, hydroxypropyl starch, part αization.As lubricant, anticoagulant, can exemplify Talcum, magnesium stearate, calcium stearate, silica gel, hard ester acid, light anhydrous silicic acid, sucrose fatty acid ester, wax class, fixed oil, Polyethylene Glycol or sodium benzoate etc.Above-mentioned content of additive is so long as then be fit in the usual range use in the preparation technique field.The content of excipient is preferably about 10～99 weight %, and the content of binding agent is preferably about 1～30 weight %, and the content of disintegrating agent is preferably about 0～20 weight %, and the content of lubricant, anticoagulant is preferably about 0.5～10 weight %.
Tablet of the present invention except above-mentioned additive, can suitably contain multiplicaiton factor, times powder, flavoring agent, spice, dyestuff of intestinal bacterium for example etc.As the multiplicaiton factor of intestinal bacterium, particularly bacillus bifidus, can exemplify oligosaccharides such as lactulose, oligomeric lactulose or oligomeric isomaltose.As a times powder, can exemplify Saccharum Sinensis Roxb., glucose, dextrin, starch, defat starch, lactoprotein or natural goods and extract class etc.; As flavoring agent, can exemplify ascorbic acid or citric acid; As spice, can exemplify 1-menthol, sour milk powder spice or Fructus Citri Limoniae powder spice etc.; As dyestuff, can exemplify natural pigment etc.There is no particular limitation for the content of these materials, can suitably select.
Tablet of the present invention also can contain lactobacillus other pharmacological components in addition.As other pharmacological components, there is no particular limitation, can exemplify the composition that (a) have whole intestinal effect (for example dietary fiber etc.), (b) the gastric acid inhibitory secretion or in and gastric acid and prevent to make composition (for example, the antacid such as sodium bicarbonate, magnesium oxide of intestinal bacterium inactivation because of gastric acid; Cholilytic drugs such as timepidium bromide (timepidium bromide) or methylsulfuric acid N-methyl scopolamine; Anti-gastric juice agent such as ulcerlmin; H such as cimetidine, ranitidine or famotidine
2Receptor antagonist; Proton pump inhibitors such as omeprazole etc.), (c) relevant intestinal diseases (for example, inflammatory enteritis such as ulcerative colitis or segmental enteritis, Anaphylaxis enteritis etc.) the treatment preventive drug, (d) anti-allergic agent such as sodium cromoglicate, (e) hyperlipemia agent such as pravastatin sodium, (f) anticarcinogen such as ftorafur, (g) Remedies for diabetes such as voglibose etc.
There is no particular limitation for the form of tablet of the present invention.For example, tablet of the present invention can be a nude film, can be thin membrane coated tablet, chewable tablet also, nuclear sheet, foaming sheet or multilayer tablet arranged.
As aforementioned coated tablet, can exemplify coated tablet or enteric coatel tablets etc.By such coating, the inactivation of the intestinal bacterium that gastric acid causes after can preventing to take.As aforementioned enteric coatel tablets, can exemplify the tablet that forms the thin film that constitutes by the enteric solubility macromolecular compound in die surfaces.Aforementioned enteric solubility macromolecular compound, so long as be dissolved in the above water of pH5, and be insoluble to thin film formation property macromolecular compound of the acid solution of not enough pH5, then there is no particular limitation, can use and use macromolecular compound usually in the art.Enteric solubility macromolecular compound as such can exemplify cellulose derivative, polythene derivative, maleic acid-ethylenic copolymer or acrylic acid series copolymer.Concrete example as the plain derivant of aforementioned fibers has carboxymethylethylcellulose, cellulose acetate-phthalate, succinic acid cellulose acetate, O-phthalic acid methyl cellulose, phthalic acid hydroxymethyl ethyl cellulose, Hydroxypropyl Methylcellulose Phathalate, succinic acid acetic acid hydroxypropyl emthylcellulose etc.As the concrete example of aforementioned polythene derivative, polyvinyl alcohol phthalic acid ester, poly-vinyl butyrate phthalic acid ester, polyvinyl acyl group acetal phthalic acid ester (Port リ PVC ニ Le ア セ ト ア セ -Le Off レ-ト) etc. are arranged.In addition, as the concrete example of aforementioned maleic acid-ethylenic copolymer, vinyl acetate-copolymer-maleic anhydride, vinyl butyl ether-copolymer-maleic anhydride, styrene-maleic acid monoester copolymer etc. are arranged.As the concrete example of aforementioned acrylic acid series copolymer, acrylic acid methyl ester .-methacrylic acid copolymer, styrene-propene acid copolymer, acrylic acid methyl ester .-methacrylic acid-1-Octyl acrylate copolymer, methacrylic acid-methylmethacrylate copolymer (for example オ イ De ラ ギ Star ト (trade name, レ-system Off ア-マ company make)) etc. are arranged.Wherein, as the enteric solubility macromolecular compound, preferred オ イ De ラ ギ Star ト.These enteric solubility macromolecular compounds can be used alone, and also can make up two or more uses.
Aforementioned chewable tablet is a kind of at dissolved in oral cavity or chew and the preparation taken.In the aforementioned chewable tablet, be also included within disintegrate rapidly in the oral cavity, the preparation of disintegrate within preferred about 60 seconds.Aforementioned chewable tablet preferably contains at least a above additive that is selected from water-soluble binder, water solublity excipient and disintegrating agent.As aforementioned water-soluble binder, cellulose-based or the ethylene base system macromolecular compound of preferred use has polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinyl alcohol, methylcellulose, pullulan, agar, gelatin or sodium alginate etc. specifically.As water soluble excipient, sugar alcohol or sugar etc. are arranged.As sugar alcohol, can exemplify erythritol, xylitol or mannitol etc.; As sugar, can exemplify lactose or glucose etc.As disintegrating agent, can exemplify aforesaid material.Disintegrating agent also can use with the disintegrate auxiliary agent.As the disintegrate auxiliary agent, preferred volatile substances, Camphora, urethane, carbamide, ammonium bicarbonate or the benzoic acid etc. that for example have distillation character.Above-mentioned content of additive has no particular limits in chewable tablet, suitably selects in the scope that can use in this technical field.
As aforementioned multilayer tablet, can exemplify the tablet that made up the different layer of disintegrative, have the tablet that contains different intestinal bacteriums, have the layer that contains intestinal bacterium with contain composition beyond the intestinal bacterium layer tablet etc.As the tablet that has made up the different layer of disintegrative, can exemplify the tablet that made up slow-releasing layer and rapid release layer etc.Aforementioned slow-releasing layer can utilize the known method manufacturing, for example with the intestinal bacterium micro encapsulation, or as above-mentioned will layer around implement coating and obtain.In addition, aforementioned rapid release layer also can utilize the known method manufacturing, can obtain by reducing film-making pressure.And, aforementioned rapid release layer, the same during with the above-mentioned chewable tablet of manufacturing, also can make by kind or the content selecting to add additives such as water-soluble binder, water solublity excipient or disintegrating agent.In having layer that contains intestinal bacterium and the tablet that contains the layer of composition beyond the intestinal bacterium, there is no particular limitation as the composition beyond the intestinal bacterium.Can exemplify (a) vitamins (for example, vitamin A, vitamin B
1, vitamin B
2, vitamin B
6, vitamin B
12Vitamin C, vitamin D, vitamin E, vitamin K, nicotinic acid, pantothenic acid, folic acid, biotin etc.), (b) minerals (for example, sodium, potassium, calcium, magnesium, iodine, chlorine, phosphorus, ferrum, copper, manganese, selenium, zinc, chromium, molybdenum etc.), (c) aminoacid (for example, tryptophan, methionine, lysine, phenylalanine, leucine, isoleucine, valine, threonine, glutamine, glutamic acid, the L-cysteine, tyrosine, glycine, alanine, agedoite, aspartic acid, proline, arginine, histidine or serine etc.) or (d) dietary fiber (for example, cellulose, hemicellulose, glucosan, insoluble dietary fiber such as lignin or Keratin; Water solublity dietary fiber such as dextrin (indigestibility), pectic substance, guar gum, xanthan gum or mannan) etc. the material that has nutritive value.As the composition beyond the intestinal bacterium, can exemplify as other above-mentioned pharmacological components or as the multiplicaiton factor of above-mentioned intestinal bacterium etc.
Manufacture method as tablet of the present invention, for example, with additive pelletizes in advance such as appropriate excipients, binding agent, anticoagulant, coloring agent, flavouring agent, sweeting agents, additives such as the viable bacteria powder of adding and mixing intestinal bacterium, lubricant in the pelletize thing that obtains, the indirect method of tableting that the mixture that obtains is carried out film-making by pelleter.In addition, also have additives such as the viable bacteria powder of intestinal bacterium and required suitable vehicle, binding agent, anticoagulant, coloring agent, flavouring agent, sweeting agent are mixed, this mixture is carried out the direct method of tableting of film-making by known pelleter.
Below, discuss each step in detail.
The viable bacteria powder of intestinal bacterium can be made by spray drying, lyophilization, fluid bed drying.Wherein, in the present invention, the viable bacteria powder of intestinal bacterium is preferably made by spray drying.
As utilizing spray drying to make the method for the viable bacteria powder of intestinal bacterium, can exemplify and to contain the solution of intestinal bacterium or the suspension also exsiccant method of in warm braw, spray.At the aforementioned solvent that uses in the solution of intestinal bacterium that contains, can use known solvent in this technical field, but preferably make water.Also can add ethanol as required.At the aforementioned outstanding turbid medium that uses in the suspension of intestinal bacterium that contains, also can use known outstanding turbid medium in this technical field, but preferably make water or added the aqueous solution of ethanol etc.Outstanding when turbid, also can use suspension.As suspension, can use for example known material such as sodium alginate or methylcellulose.In the above-mentioned solution or suspension that contains intestinal bacterium, also can add protective agent.Protective agent can use material commonly used in this technical field, for example, and vitaminss such as ascorbic acid; For example, aminoacid such as glutamine, glutamic acid, L-cysteine, glycine, phenylalanine, serine or threonine; For example, saccharide or sugar alcohols such as glucose, fructose, sucrose, maltose, mannitol or maltose alcohol; For example, polysaccharides such as oligosaccharides such as lactulose or oligomeric lactulose, cyclodextrin or dextrin; For example, the higher fatty acids class fat that obtains from Semen Allii Tuberosi, Semen sojae atricolor or Semen arachidis hypogaeae etc.; For example, protein decomposition product such as the protein that obtains from milk or Semen sojae atricolor etc. or peptide; For example, mineral-type such as magnesium sulfate; Or in addition, for example, sucrose fatty acid ester, malic acid, nucleic acid class, yeast extract, defatted milk powder, peptone, gelatin or tannic acid etc.This protective agent can use above-mentioned substance separately, also can the two or more uses of combination in any.And this protectant addition is approximately about 0.1～5.0 times of wet thallus weight, preferred about 0.5～3.0 times.In the above-mentioned solution or suspension that contains intestinal bacterium, also can be further for example add normally used additive in these technical fields such as excipient, binding agent, disintegrating agent or antistatic agent with common cooperation ratio.
When the above-mentioned solution that contains intestinal bacterium or suspension are carried out spray drying, as the spray-drying installation that uses in this spray drying, the preferred spray-drying installation that possesses the micro-granulating device that can form single micron order spray droplet that uses.The particle diameter of spray droplet very hour, the surface area of per unit weight spray droplet increases, and effectively contacts with dry wind, can effectively suppress the dead or damage of bacterium that the heat of dry wind causes.At this, so-called single micron-sized spray droplet, the particle diameter that is meant spray droplet behind arithmetic point one be 1～10 μ m after rounding up.As spray-drying installation, specifically, can exemplify, its micro-granulating device is for utilizing the double-channel nozzle of rotary atomizer (rotating circular disk), pressurized nozzles or compressed gas forces or the spray-drying installation of four runner nozzles.In the present invention,, but consider the preferred spray-drying installation that uses with four runner nozzles from the angle that can obtain small spray droplet no matter its form can be used above-mentioned any spray-drying installation.This sprayer unit can be known device (for example, the device of record in the Japan Patent 2797080).In spray-drying installation with four runner nozzles, as four runner structure of nozzle, for example, when making gas flow and flow channel for liquids become a system, this system is symmetrical arranged two systems at nozzle edge, and is arranged on nozzle edge as the inclined-plane of fluid flow face.
The spray droplet of the intestinal bacterium of spraying from above-mentioned micro-granulating device by the warm braw drying, can obtain the viable bacteria powder of intestinal bacterium in the hothouse of spray-drying installation.The temperature (hereinafter referred to as " inlet temperature ") of the hothouse inlet of dry wind is about 2～400 ℃, is preferably about 5～250 ℃, is more preferably about 5～150 ℃.Even inlet temperature is about 200～400 ℃ high temperature, because the heat of gasification of water evaporates, it is so high that the temperature of the thing that is dried can not become.And, by shortening the holdup time in hothouse, can effectively suppress the dead or damage of viable bacteria.In addition, the hothouse outlet temperature of dry wind (hereinafter referred to as " outlet temperature ") is about 0～120 ℃, is preferably about 5～90 ℃, is more preferably about 5～70 ℃.And hothouse also can reduce pressure.By decompression, can improve drying efficiency, shorten drying time.The post-decompression pressure of hothouse is different because of the size of spray droplet, so cannot treat different things as the same, for example the pressure of coarse vacuum scope specifically, can exemplify about 1.0 * 10
3～7.0 * 10
3Pa.
As utilizing fluid bed drying to make the method for the viable bacteria powder of intestinal bacterium, can exemplify, in fluid bed with warm braw powder body flown upward on one side, will contain the solution spray of intestinal bacterium on one side, bag is attached to the method on the powder body.The powder body that becomes nuclear that use this moment is called base material.As base material, there is no particular limitation, can exemplify Semen Maydis grit, Semen sojae atricolor powder (bloom), skimmed milk (defatted milk powder of pelletize), rice flour (go up new powder, comprise glutinous rice flour), wheat flour, vitamins or amino acids etc., wherein preferred vitamin class or amino acids.In containing the solution of intestinal bacterium, can add the protective agent that is used to protect intestinal bacterium.As protective agent, the identical material of protective agent that uses in the time of can using with spray drying, but preferred saccharide.As saccharide, can exemplify sucrose, maltose or lactose etc.As the protective agent that uses in the present invention, preferably use the sucrose of 10～20 weight %.
As concrete manufacture method, at first drop into base material to fluid bed dryer.Adjust micro-granulating device this moment simultaneously.Supply with warm braw from the batch can below of fluid bed dryer, base material is flowed.The temperature of warm braw is preferably about 40～60 ℃, is more preferably about 50～55 ℃.The solution that will contain intestinal bacterium carries out micronize in micro-granulating device, spray is attached on the interior base material of fluid bed.Spray droplet is attached on the base material time, and the water evaporates of spray droplet is formed with the thin layer that intestinal bacterium and protective agent as required constitute, thereby obtains the viable bacteria powder on substrate surface.
As utilizing lyophilization to make the method for the viable bacteria powder of intestinal bacterium, can with contain the solution of lactobacillus or suspension in 0.008～0.8 holder, carry out drying under-20～-60 ℃ the low temperature approximately and make.In this manufacture method,, preferably in solution that contains lactobacillus or suspension, add protective agent in order to prevent drying or the thalline death of when dissolving.As aforementioned protective agent; can use known material; for example, partial hydrolysate of the polysaccharide that contains in skimmed milk, sodium glutamate, gelatin and sucrose, phenylalanine, histidine, citric acid, succinic acid, tartaric acid and carbonic acid alkali, glucose, trehalose, defatted milk powder, the sodium ascorbate, Rhizoma amorphophalli powder etc.
When utilizing direct method of tableting, in the viable bacteria powder of the intestinal bacterium that passes through to make as mentioned above, can mix appropriate excipients, binding agent, lubricant as required, solidify additives such as preventing agent, coloring agent, flavouring agent, sweeting agent, utilize known pelleter that this mixture is carried out film-making.There is no particular limitation as pelleter, but preferably have the rotation pelleter or the single-shot formula pelleter of good productivity ratio.Film-making pressure during film-making is about 1～100kN/cm
2, be preferably about 5～50kN/cm
2, be more preferably about 10～40kN/cm
2In said method, the viable bacteria powder of lubricant and intestinal bacterium does not mix, and can add lubricant in dashing of using of film-making and punch die as an alternative and carry out film-making.
When utilizing indirect method of tableting, add additive such as appropriate excipients, binding agent, anticoagulant, coloring agent, flavouring agent, sweeting agent and carry out pelletize, make the pelletize thing that film-making is used.The manufacturing of pelletize thing can be undertaken by known method, for example can use known comminutors such as fluidized bed prilling, stirring-granulating, rotating granulation, rotating fluidized bed pelletize, extruder grain or dry type pelletize easily to carry out.In the pelletize thing that the film-making that obtains is used, interpolation mixes by additives such as the viable bacteria powder of the intestinal bacterium of above-mentioned manufacture method manufacturing, lubricants, utilizes pelleter that the mixture that obtains is carried out film-making.There is no particular limitation as pelleter, but the rotation pelleter or the single-shot formula pelleter that preferably have good productivity ratio.Film-making pressure during film-making is about 1～100kN/cm
2, be preferably about 5～50kN/cm
2, be more preferably about 10～40kN/cm
2In the method, the viable bacteria powder of lubricant and intestinal bacterium does not mix, work carry out film-making can in dashing of using of film-making and punch die, adding lubricant.
When tablet of the present invention is the form of chewable tablet, except utilizing the usual method manufacturing, can be by following method manufacturing.Can exemplify the suspension of saccharides such as in the bubble-cap of PTP (push-through packs), injecting intestinal bacterium, mannitol and the agent of agar isogel, remove moisture, in bubble-cap, form the method for tablet by lyophilization or drying under reduced pressure.Can exemplify the powder body that in the viable bacteria powder of intestinal bacterium, to have added based on the additive of the water-soluble binder of saccharide, after low pressure condition lower compression is shaped, tablet is placed on to add makes its moistening, as to be dried again method in the wet environment.In the viable bacteria powder of intestinal bacterium, add the powder body of Polyethylene Glycol water solublity meltbility binding agents such as (Port リ エ リ レ Application グ リ コ-Le), after the low pressure compression molding, under than the high temperature conditions of the fusing point of water solublity meltbility binding agent, dissolve the aforementioned adhesion agent, afterwards the method that water solublity meltbility binding agent is solidified once more.
Tablet of the present invention can be by following method manufacturing during as the form of multilayer tablet.As first method, have the film-making raw material stratiform that constitutes each layer overlappingly, this material film-making is formed the method for multilamellar tablet.Film-making this moment pressure is preferably about 5～50kN/cm
2As second method, have and to constitute the film-making raw material of each layer in advance at low film-making pressure (5～30kN/cm
2) when carrying out film-making under the condition, each layer of tablet shape that obtains carried out lamination, compared with first high low film-making pressure (10～50kN/cm
2) carry out film-making under the condition and form the method for multilamellar tablet.In order to reduce influence when the film-making, preferred back one method to intestinal bacterium.Multilayer tablet is more than three layers the time, and the layer that preferably contains intestinal bacterium is present in the tablet outside.
The tablet that contains intestinal bacterium among the present invention, its purposes is unqualified, can use in wide scope.For example, tablet of the present invention can be used as medicine, food or feedstuff use.And, also can be used as fertilizer of crops or pesticide.
For example, lactic acid bacteria class by known, has significant impact for health as one of useful intestinal bacterium.Particularly many reports have appearred in the physiologic meaning for bacillus bifidus, lactic acid coccus or lactobacillus, clear and definite produce organic acid such as lactic acid or acetic acid at enteral and suppress the effect of harmful bacterium, the tax activation of the generation of vitamin and immunity etc.Thereby tablet of the present invention can be used as with the health maintenance of people, livestock animals or pet animals etc. and strengthens or the prevention of disease or medicine, food or the feedstuff use that treatment is purpose.
Tablet of the present invention has the recovery intestinal mucosa, or the enzyme current potential of intestinal tube has the effect of regulating this current potential when changing under stress state.And, can make the function normalization of intestinal bacteria, promote vitamin and proteinic synthetic, digestion process or enzyme process and absorption process, prevent pathogenic microbes group's formation, also have the effect that immune stimulatory is replied.Therefore, tablet of the present invention for example can be used for the treatment or the prevention of diarrhoea, constipation, hypercholesterolemia, hepatopathy, immunity degradation disease, enteritis (for example, gastroenteritis or colitis etc.); Food, medicament, chemical drugs or physics medicament cause after the imbalance, or the recovery of the intestinal after surgery intrusion, chemotherapy or the contact infection disease; The obstruction that absorbs for endotoxin reaches the antagonism that the endogenous poisonous substance is generated.When in aforementioned applications, using, preferably contain lactobacillus or bacillus bifidus in the tablet of the present invention.
Tablet of the present invention can be used as snack categories and directly absorbs, and also can be added in milk product such as yoghourt or cheese, snack categories or the beverage class etc.And lactic acid bacteria class is significant for local flavor or keeping of conservatory raising or quality in the manufacturing process of food such as bean sauce, soy sauce, brined vegetable or Janpanese sake.Therefore, tablet of the present invention can be used for the manufacturing of aforementioned food.
Embodiment
[embodiment 1] contains the manufacturing of intestinal bacterium tablet
[cultivation of thalline]
To utilize GAM culture medium (day water Pharmaceutical Co., Ltd makes) to increase the culture fluid of the bifidobacterium bifidum of bacterium in advance,, under 37 ℃ of conditions, cultivate 16 hours with a kind of inoculation of medium 0.1 weight %.With its centrifugalize, the precipitate that obtains is as wet thallus.
[making of bacterium suspension]
In the synthetic aqueous solution of concentration with mannitol 0.5M, sodium glutamate 0.5M, arginine 0.1M, sodium succinate 0.1M, magnesium sulfate 0.01M, add in the synthetic disperse medium of dextrin with the standard that reaches 35 weight %, the wet thallus that obtains is outstanding turbid.
[utilizing spray drying to make the bacterium end]
Will be as the bacterium suspension of above-mentioned manufacturing, the spray dryer that use has four runner nozzles (as No. 2797080 records of Japan Patent) carries out spray drying.That is to say, to supply with the bacterium suspension with the speed of 8mL/ branch (4mL/ branch/1mm nozzle) from two flow channel for liquids, spray droplet from two gas flows produce with the speed supply Compressed Gas of 40NL/ branch (value that converts under 20 ℃ of conditions) carries out drying by dry wind, makes the bacterium end.Wherein, the inlet temperature of dry wind is 100 ℃, with 1.0m
3/ minute ratio supply with to hothouse, outlet temperature is 67 ℃.
[manufacturing of tablet]
In lactose pelletize thing, mix bacterium end and the magnesium stearate that obtains by above-mentioned spray drying, as the film-making raw material.With respect to film-making raw material total amount, the part by weight at bacterium end is 1 weight %, and the part by weight of magnesium stearate is 0.5 weight %.This film-making raw material is used D51 type pelleter (Kikusui Seisakusho Ltd.'s manufacturing), with 10kN/cm
2Film-making pressure carry out film-making.The diameter that makes tablet is 9mm, and weight is 300mg, and hardness is 49～68.6N (5～7kgf).
The mensuration of the viable count in [embodiment 2] film-making raw material and the tablet
Viable count in film-making raw material and the tablet is measured by the following method.For tablet, be broken into powder gently, and uniform mixing.With the film-making raw material and become pulverous tablet and accurately measure 10.0g separately, and add diluent, make total amount reach 100mL.Vibration mixes strongly afterwards, and about insulation is vibrated once more after 30 minutes and mixed under 35～37 ℃ of conditions.Accurately measure 1mL, repeat to join in addition the operation among the accurate diluent 9mL of separatory, will reach contain 20～200 left and right sides viable bacteria concentration among the 1mL solution as test solution.Accompany for respectively adding the 1mL test solution in (petri) formula culture dish at three, wherein add the agar culture medium 20mL of the quantitative usefulness of bacillus bifidus that keeps 45～48 ℃ separately and mix rapidly, solidify.Anaerobic was cultivated 48～72 hours under 35～37 ℃ of conditions, and the group that statistics occurs tries to achieve average group's number.Viable count among each 1g of film-making raw material and tablet calculates by following formula.
Viable count (CFU/g)=average group's number * dilution ratio
At this moment, the agar culture medium of the quantitative usefulness of bacillus bifidus dissolves by the composition that heats beyond the horse blood in the following composition, and being adjusted to pH is 7.2, after utilizing autoclave sterilizer to heat under 115 ℃ of conditions to sterilize in 20 minutes, be cooled to 50 ℃, and the adding horse blood is made.
Cattle liver leachate 150mL
Animal flesh system peptone 10g
Casein system peptone 5g
Yeast extract 5g
Meat extract 3g
Semen sojae atricolor system peptone 3g
Glucose 10g
Potassium hydrogen phosphate 1g
Potassium dihydrogen phosphate 1g
Starch 0.5g
L-cysteine hydrochloride 0.5g
Magnesium sulfate 0.2g
Sodium chloride 0.01g
Ferrous sulfate 0.01g
Manganese sulfate 7mg
Polysorbate80 1g
Agar 15g
Horse blood 50mL
Purified Water 790mL
pH?7.1～7.3
In addition, above-mentioned diluent is by mixing following composition, utilizes autoclave sterilizer to heat under 121 ℃ of conditions to sterilize in 15 minutes and modulates.
Anhydrous phosphoric acid hydrogen sodium 6.0g
Potassium dihydrogen phosphate 4.5g
Polysorbate80 0.5g
L-cysteine hydrochloride 0.5g
Agar 1.0g
Purified Water 1000mL
pH?6.8～7.0
The mensuration of survival rate during [embodiment 3] film-making
Calculating formula is calculated below survival rate utilization during film-making.
Viable count * 100 in viable count in survival rate during film-making (%)=1g tablet/1g film-making raw material
In addition, the hardness of tablet utilizes tablet breaking strength measuring device (manufacturing of TH-203RP Fushan Mountain Industry Co., Ltd) to measure.
Table 1
| For the first time | For the second time | For the third time | On average | |
| The average hardness of tablet (N) | 53.9 | 55.86 | 62.72 | 57.526 |
| Viable count (* 10 in the film-making raw material 6CFU/g) | 54 | 58 | 51 | 54.3 |
| Viable count (* 10 in the tablet 6CFU/g) | 32 | 41 | 38 | 37 |
| Survival rate during film-making (%) | 59 | 71 | 75 | 68.1 |
The mensuration of [embodiment 4] storage stability
The tablet made among the embodiment 1 is preserved under 40 ℃, the condition of 75%RH, measured through the viable count after specified time limit.Viable count in the tablet is measured by the following method.Get the tablet more than 50, accurately measure its quality, try to achieve average quality.Afterwards, try to achieve average group's number by the method identical with embodiment 2.According to the value that obtains, obtained viable count in the tablet 9 slices by following formula.
Viable count (CFU/g) in 9 in the tablet=average group number * dilution ratio * (average weight (g) * 10/ test solution collection capacity (g)) * 9
According to the viable count that obtains, calculate stability (%) by following formula.
Stability (%)={ viable count (9 in CFU/ tablet) during through the viable count (9 in CFU/ tablet) in the tablet after specified time limit/on-test in the tablet } * 100
Table 2
Industrial applicibility
Granule, powder or granula subtilis can produce sense of discomfort rough or that get stuck between the teeth for the user. Capsule can be out of shape when transportation, or destroyed possibility is higher. But the tablet form can not produce foregoing problems, can provide medicine or the food that is very easy to processing for the user. That is, tablet of the present invention is taken easily, can be out of shape in the time of also needn't worrying to transport or destroyed.
And then tablet of the present invention is because the thalline survival rate during film-making is about more than 20%, so can effectively absorb intestinal bacterium. And, tablet of the present invention, the stability of preserving 6 months under 40 ℃, 75%RH condition is more than 20%, so have can long preservation advantage.
Claims (4)
1. a tablet that contains intestinal bacterium is characterized in that, by at 1～100kN/cm
2Film-making pressure under the viable bacteria powder by intestinal bacterium that intestinal bacterium spray drying, lyophilization or fluid bed drying are obtained carried out film-making obtain, and the thalline survival rate during film-making is more than 20%, and the stability of preserving after 6 months under 40 ℃, 75%RH condition is about more than 20%.
2. tablet according to claim 1 is characterized in that, viable count is 1.0 * 10
5～2.0 * 10
11CFU/g.
3. tablet according to claim 1 is characterized in that, hardness is 30～300N.
4. tablet according to claim 1 is characterized in that, intestinal bacterium is for by the bacterium of selecting in bacillus bifidus, lactobacillus, lactic acid coccus and the group that has the spore lactobacillus to constitute.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031037267A CN100508993C (en) | 2003-02-17 | 2003-02-17 | Enterobacteria containing tablet |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031037267A CN100508993C (en) | 2003-02-17 | 2003-02-17 | Enterobacteria containing tablet |
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| Publication Number | Publication Date |
|---|---|
| CN1522711A CN1522711A (en) | 2004-08-25 |
| CN100508993C true CN100508993C (en) | 2009-07-08 |
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|---|---|---|---|
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| CN103518980B (en) * | 2013-05-21 | 2015-01-28 | 南京农业大学 | Preparation method for microecologics for laying hen feeds and application of microecologics |
| CN106819365A (en) * | 2016-12-28 | 2017-06-13 | 新昌县赛因斯生物科技有限公司 | Promote production and use domestic animal feed additive |
| CN106879832A (en) * | 2016-12-30 | 2017-06-23 | 新昌县赛因斯生物科技有限公司 | Improve the feed addictive and its preparation method of Funiu White Goat speed of weight increment and immunity |
| PT3891267T (en) * | 2018-11-05 | 2024-07-04 | Marvelbiome Inc | Microbial compositions comprising ellagitannin and methods of use |
| CN110607262B (en) * | 2019-09-25 | 2022-03-25 | 君维安(武汉)生命科技有限公司 | Probiotic composition for intervening inflammatory enteritis and screening method and application thereof |
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| CN1522711A (en) | 2004-08-25 |
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