WO2018134135A1 - Dried microorganism with excipient - Google Patents
Dried microorganism with excipient Download PDFInfo
- Publication number
- WO2018134135A1 WO2018134135A1 PCT/EP2018/050761 EP2018050761W WO2018134135A1 WO 2018134135 A1 WO2018134135 A1 WO 2018134135A1 EP 2018050761 W EP2018050761 W EP 2018050761W WO 2018134135 A1 WO2018134135 A1 WO 2018134135A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- microorganism
- phosphate salt
- lactobacillus
- probiotic
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/04—Preserving or maintaining viable microorganisms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
Definitions
- the present invention relates to the field of dried microorganisms.
- microorganisms for storage, for example by freeze- or spray- drying.
- dried microorganisms are used in industrial and food uses, for example in the manufacture of cheese and yoghurt, and also as probiotics.
- Probiotics are live microorganisms which are beneficial for human or animal health when administered at appropriate dosages.
- One way of administering probiotics is through ingestion of dried probiotic mixed with excipients and packaged in capsules or sachets.
- dried probiotic cells are not very stable during storage, with the result that live cell counts decrease with time, rendering the treatment less effective. This is particularly true when probiotics are blended with excipients having high humidity content, when container walls are permeable to external atmospheric moisture, and when the probiotic is stored in a high relative humidity environment.
- the invention provides a composition comprising a blend of (a) dried microorganism, and (b) a phosphate salt in powder form.
- the invention provides a unit microbial dose, containing a composition comprising a mixture of (a) dried microorganism, and (b) a phosphate salt in powder form.
- the invention provides a process for the preparation of a composition comprising the steps: (i) providing (a) a dried microorganism, and (b) a phosphate salt in powder form; and
- Figure 3 shows the % survival of Lactobacillus acidophilus as a function of the percentage of K2HPO 4 excipient in a blend under humid conditions (a w 0.4) at 30°C after 6 months.
- Figure 4 shows the % survival of Lactobacillus acidophilus as a function of the percentage of K2HPO 4 excipient in a blend with MCC under humid conditions (a w 0.4) at 30°C after 6 months.
- Figure 5 shows the impact of pH of excipient on the % survival of freeze- dried Lactobacillus acidophilus powder under dry conditions (a w 0.1 ) at 30°C after 1 month and after 3 months.
- KP indicates K2HPO 4 with pH adjusted to the indicated pH
- K2HPO4" indicates K 2 HPO without pH adjustment
- MCC indicates microcrystalline cellulose.
- Figure 6 shows the impact of pH of excipient on the % survival of freeze- dried Lactobacillus acidophilus powder under humid conditions (a w 0.4) at 30°C after 3 months.
- K2HPO4 indicates K 2 HPO with pH adjusted to the indicated pH
- MCC indicates microcrystalline cellulose.
- microorganisms is improved by using a phosphate salt as excipient.
- the effect is particularly remarkable in high water activity (a w ) environments.
- a high water activity is considered to be a w > 0.15.
- microorganism dry powders in particular probiotics
- excipients are blended with excipients to standardize the microorganism concentration.
- MCC microcrystalline cellulose
- the inventors have used MCC as a reference excipient.
- the inventors found that the use of phosphate salts can provide for greater than 60% survival of dried microorganism over 3 months compared to almost 0% survival in MCC excipient. This effect is particularly remarkable in high water activity environments (a w > 0.15, particularly a w > 0.2, more particularly a w > 0.3).
- Water activity is preferably measured by dew point hygrometer.
- Microorganism survival rate is expressed in two different ways.
- composition of the present invention contains a dried microorganism.
- the microorganism in particular a probiotic, may be dried by any means, however, freeze-drying and spray-drying are preferred, with freeze-drying being particularly preferred.
- the expression microorganism is meant to encompass any bacteria or yeast, or mixtures of these, and in particular a probiotic.
- probiotic includes any live microorganisms which are administered to a host with a view to conferring a health benefit on the host.
- it may be a yeast or a bacterium, or mixtures of any of these.
- the dried microorganism in particular a probiotic
- the dried microorganism, in particular a probiotic may be provided in form of granules or powder.
- the microorganism, in particular a probiotic is in powder form.
- composition of the present invention may contain one species of
- composition of the present invention contains one species of microorganism, in particular a probiotic and, optionally, one strain of microorganism, in particular a probiotic. In one aspect the composition of the present invention contains a mixture of strains of microorganism, in particular a probiotic. In one aspect the composition of the present invention contains a mixture of species of
- microorganisms in particular probiotics.
- the microorganism in particular a probiotic, is selected from lactobacilli, bifidobacteria, saccharomyces and mixtures thereof.
- the microorganism, in particular a probiotic is selected from species selected from Bacillus coagulans, Bifidobacterium longum subsp. infantis, Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus johnsonii, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus reuteri protectis, Lactobacillus reuteri prodentis, Saccharomyces boulardii, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus paracasei and mixtures thereof.
- the microorganism, in particular a probiotic is selected from species selected from Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium lactis, and mixtures thereof.
- the microorganism in particular a probiotic, is selected from probiotics of the strains Lactobacillus acidophilus (NCFM strain), Lactobacillus Casei (LPC37 strain), Bifidobacterium Lactis (HN0019) and mixtures thereof.
- NCFM strain Lactobacillus acidophilus
- LPC37 strain Lactobacillus Casei
- HN0019 Bifidobacterium Lactis
- the microorganism in particular a probiotic, may be present in any suitable amount to deliver the required amount of microorganism, in particular a probiotic.
- the 'concentration' of the microorganism, in particular a probiotic in colony forming units (CFU) of microorganism per gram of the composition may also be selected by one skilled in the art.
- the microorganism, in particular a probiotic is present in an amount of at least 1 x 10 8 CFU per gram of the composition.
- the microorganism, in particular a probiotic is present in an amount of at least 1 x 10 9 CFU per gram of the composition.
- the microorganism, in particular a probiotic is present in an amount of at least 1 x 10 10 CFU per gram of the composition. In one aspect the microorganism, in particular a probiotic, is present in an amount of from 1 x 10 9 to 5 x 10 9 CFU per gram of the composition.
- the dose contains any desired amount of probiotic.
- a typical unit dose will contain 10 8 to 10 14 CFU per dose, more preferably 10 9 to 10 12 CFU per dose, particularly preferably 10 9 to 10 1 1 CFU.
- the microorganism, in particular a probiotic is in dried form, preferably spray- dried or freeze-dried, in particular freeze-dried.
- the dried microorganism, in particular a probiotic has a water activity of no greater than 0.4, more preferably no greater than 0.3, particularly preferably no greater than 0.2. More particularly preferably, the dried microorganism, in particular a probiotic has a water activity of no greater than 0.1 .
- the composition of the present invention contains a phosphate salt.
- a phosphate salt is any salt of phosphoric acid (HsPO 4 ), and includes salts based on dihydrogen phosphate (H 2 PO 4 ⁇ ), hydrogen phosphate (HPO 4 2 ⁇ ), and phosphate (PO 4 3 ⁇ ).
- the composition of the present invention contains a salt of hydrogen phosphate (HPO 4 2 ⁇ ), or a mixture of hydrogen phosphate (HPO 4 2 ⁇ ) and dihydrogen phosphate (H 2 PO 4 ⁇ ). Both hydrated and anhydrous phosphate salts can be used.
- the cation of the phosphate salt is not particularly limited.
- the cation of the phosphate salt is selected from sodium,
- phosphate salts include K 2 HPO 4 , KH 2 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , MgHPO 4 , Mg[H 2 PO 4 ] 2 , CaHPO 4 , Ca[H 2 PO 4 ] 2 .
- the phosphate salt is a potassium phosphate salt.
- the phosphate salt is dipotassium phosphate (K 2 HPO 4 ), or a mixture of dipotassium phosphate (K 2 HPO 4 ) and potassium dihydrogen phosphate (KH 2 PO 4 ).
- the phosphate salt is pH adjusted to between pH 6 and pH 9, preferably between pH 6.5 and 8, more particularly preferably pH 6.8 to 7.2.
- pH of the salt is meant the pH of a solution when the salt is dissolved in water. The pH may be adjusted by using blends of
- HPO 4 2" and H 2 PO 4 " salts are used.
- the relative amounts of these salts to yield a desired pH is well known.
- a molar ratio of 61 .5/38.5 HPO 4 2 7H 2 PO 4 - gives a pH of 7.
- pH adjusted salts may be prepared by titrating solutions of salts of PO 4 3" and/or HPO 4 2" with an acid or base to the desired pH and then drying the resulting solution, for example, by spray drying.
- the phosphate salt may be present in the composition of the invention in any suitable amount to provide the desired stabilisation of the dried microorganism, in particular a probiotic.
- the wt%'s are given with respect to the total weight of microorganism, in particular a probiotic and phosphate salt.
- the phosphate salt is present in an amount of at least 10% by weight of the composition.
- the phosphate salt is present in an amount of at least 20% by weight of the composition.
- the phosphate salt is present in an amount of at least 30% by weight of the composition.
- the phosphate salt is present in an amount of at least 40% by weight of the composition.
- the phosphate salt is present in an amount of at least 50% by weight of the composition. In one aspect, the phosphate salt is present in an amount of at least 60% by weight of the composition. In one aspect, the phosphate salt is present in an amount of at least 70% by weight of the
- the phosphate salt is present in an amount of at least 80% by weight of the composition.
- the phosphate salt is present in an amount of from 10 to 90% by weight of the composition. In one aspect, the phosphate salt is present in an amount of from 20 to 90% by weight of the composition. In one aspect, the phosphate salt is present in an amount of from 30 to 90% by weight of the composition. In one aspect, the phosphate salt is present in an amount of from 40 to 90% by weight of the composition, more preferably 50 to 80 % by weight. In one aspect, the phosphate salt is present in an amount of from 50 to 90% by weight of the composition. In one aspect, the phosphate salt is present in an amount of from 60 to 90% by weight of the composition. In one aspect, the phosphate salt is present in an amount of from 70 to 90% by weight of the composition. In one aspect, the phosphate salt is present in an amount of from 80 to 90% by weight of the composition. In the present context, the wt%'s are given with respect to the total weight of microorganism, in particular a probiotic and phosphate salt.
- the phosphate salt is present in an amount of at least 10% by weight of the total composition. In one aspect, the phosphate salt is present in an amount of at least 20% by weight of the total composition. In one aspect, the phosphate salt is present in an amount of at least 30% by weight of the total composition. In one aspect, the phosphate salt is present in an amount of at least 40% by weight of the total composition. In one aspect, the phosphate salt is present in an amount of at least 50% by weight of the total composition. In one aspect, the phosphate salt is present in an amount of at least 59%, or 60% by weight of the total composition. In one aspect, the phosphate salt is present in an amount of at least 70% by weight of the total composition. In one aspect, the phosphate salt is present in an amount of at least 80% by weight of the total composition.
- a suitable mixture is 80 wt% phosphate salt and 20 wt% microorganism, in particular a probiotic.
- the phosphate salt is preferably in the form of a powder.
- the particle size distribution has a D10 value in microns of 5-120 (more preferably 5-90), a D50 value in microns of 70-180 (more preferably 80-140), and a D90 value in microns of 160-400 (more preferably 180-350).
- the survival rate of microorganism, in particular a probiotic is particularly increased under high water activity (a w > 0.15, preferably a w > 0.2, more preferably a w > 0.3) conditions.
- composition of the invention preferably increases the survival of
- microorganism in particular a probiotic by at least 30% as compared to microorganism alone, more preferably by at least 40%, particularly preferably more than 60%.
- composition of the invention preferably increases the survival of microorganism, in particular a probiotic under humid conditions (a w > 0.15, preferably > 0.2, more preferably > 0.3) by at least 1 % to 30% as compared to microorganism alone, more preferably by at least 20%, particularly preferably more than 30%.
- the composition of the invention preferably increases the survival of probiotic by at least 30% as compared to probiotic with MCC as excipient, more preferably by at least 40%, particularly preferably more than 60%.
- the composition of the invention preferably increases the survival of probiotic under humid conditions (a w > 0.15, preferably > 0.2, more preferably > 0.3) by at least 30% as compared to probiotic with MCC as excipient, more preferably by at least 40%, particularly preferably more than 60%. Additional Components
- composition of the present invention may contain only probiotic and phosphate salt or it may contain one or more additional components.
- composition further comprises additional excipients such as maltodextrin, microcrystalline cellulose (MCC), prebiotics such as inulin, fructooligosaccharides, galactooligosaccharides, polydextrose, flow aid agents such silica, magnesium stearate.
- excipients such as maltodextrin, microcrystalline cellulose (MCC), prebiotics such as inulin, fructooligosaccharides, galactooligosaccharides, polydextrose, flow aid agents such silica, magnesium stearate.
- additional components preferably they constitute less than 20 wt% of the total composition, more preferably less than 10 wt%.
- composition of the invention may be used for administration to a human or animal as a probiotic, or it may be used for industrial or food applications.
- Typical food applications include the production of cheese, yoghourt, fermented soy products (such as miso, natto, etc.), sauerkraut, comestible alcohol products, etc.
- Typical industrial applications include the production of raw or finished materials by fermentation such as industrial alcohol production.
- composition of the invention may be in the form of a bulk powder mix, for example for storage or transport before food or industrial use or before administration to a human or animal, and/or before division into suitable dosage forms.
- the invention provides a unit microbial dose for administration to a human or animal.
- the unit microbial dose comprises a suitable amount of the composition of the invention, which may be packaged, for example, in sachets, capsules or tablets.
- a typical unit dose will contain 10 8 to 10 14 CFU per dose, more preferably 10 10 to 10 12 CFU per dose.
- the invention provides a process for the preparation of the composition of the invention comprising (i) providing (a) a dried microorganism, and (b) a phosphate salt in powder form; (ii) mixing the dried microorganism, and the phosphate salt in powder form, to provide the composition.
- the microorganism is freeze-dried.
- the mixing can be performed by any method that does not damage the microorganism. For example, rotation or shaking in a suitable container, and/or mixing with a mixing implement, such as a paddle.
- Lactobacillus acidophilus (NCFM strain), Lactobacillus casei (LPC37 strain), Bifidobacterium lactis (BBi), Bifidobacterium lactis (BBL), and
- Microcrystalline cellulose was supplied by Mingtai Chemical Company, and the di-potassium phosphate was obtained from BK Glulhi Gmbh Company.
- Capsules used were Vcaps, size 0, CS, hypromellose from Capsugel cie.
- Silica was Sipernat 50s, obtained from Evonik industries AG.
- Magnesium stearate was obtained from Aceto corporation.
- Maltodextrin (IT6) was obtained from Roquette.
- the cell count method used is the method from quality control laboratory according to the strain. The results were given in colony forming unit per gram of product (CFU/g).
- the various probiotic species were blended with MCC to obtain a CFU between 1 .5 X 10 10 and 3 X 10 10 CFU/g.
- the blends were mixed by rotation (about 60tr/min) in a plastic bottle for 20 min. Then, the capsules were filled with the blends.
- the preparation of the samples was made in a clean room at 40% RH and 25 deg. C.
- Maltodextrin was exposed to an atmosphere at 40% RH until equilibrium was reached. As a consequence, the a w of the maltodextrin was close to 0.4. The same method was used to obtain maltodextrin equilibrated at a w 's of 0.3 and 0.1 .
- probiotic (20 wt%)-MCC (80 wt%) blend probiotic (20 wt%)-MCC (80 wt%) blend
- the capsules were stored in an environmental chamber at 30°C for 6 months.
- CFU and a w were measured at time 0 months, 1 months, and 3 months to evaluate the impact of excipient type on stability performance.
- Probiotic survival rate was expressed in two different ways.
- MCC represents the case where the probiotic was mixed with MCC
- K2HPO 4 represents the case where the probiotics were mixed with K2HPO 4
- freeze- dried probiotic represents the case where the probiotic powder alone was used.
- FIG. 1 shows the same results in graphic form.
- MCC represents the case where the probiotic was mixed with MCC
- K2HPO 4 represents the case where the probiotics were mixed with K2HPO 4
- "freeze-dried probiotic” represents the case where the probiotic powder alone was used.
- Table 1 and Figure 1 show that the impact of K2HPO 4 on stability varies as a function of strain. Survival is always higher with K2HPO 4 as excipient than with MCC or probiotic alone. It is clear that the use of K2HPO 4 as excipient improves the stability (survival) of the strains, and in particular in humid conditions.
- Percent survival of Lactobacillus acidophilus after three months at 30°C as a function of a w and excipient is shown in Table 2.
- MCC represents the case where the probiotic was mixed with MCC
- K2HPO 4 represents the case where the probiotics were mixed with K2HPO 4 .
- FIG. 2 shows the same results in graphic form.
- MCC represents the case where the probiotic was mixed with MCC
- K2HPO 4 represents the case where the probiotics were mixed with K2HPO 4 .
- This example looks at stability of probiotics in a humid environment as a function of K2HPO 4 concentration. Sipernat 50s and magnesium stearate were added as flow aids to have a sample composition similar to a commercial blend composition. For this example, freeze-dried Lactobacillus acidophilus powder was used. The example was prepared in two steps. In Part 1 , the probiotic was mixed with K2HPO 4 only. In Part 2, the probiotic was mixed with K2HPO 4 and MCC.
- Blends consisting of freeze-dried Lactobacillus acidophilus powder, K2HPO 4 , Sipernat 50s, and Magnesium Stearate were prepared. Ten samples were made in which the concentration of freeze-dried Lactobacillus acidophilus was gradually increased and the concentration of K2HPO 4 gradually decreased while the concentrations of Sipernat 50s and Stearate Magnesium were kept constant. The table below shows the description of the different samples for Part 1 .
- Part 2 Probiotics mixed with K 2 HP0 4 and MCC
- Blends consisting of freeze-dhed Lactobacillus acidophilus powder, and K2HPO 4 , MCC, Sipernat 50s, and Magnesium Stearate were prepared.
- K2HPO 4 concentration of K2HPO 4 was gradually increased and the concentration of MCC gradually decreased, while the concentrations of the Lactobacillus acidophilus powder, Sipernat 50s and Stearate Magnesium were kept constant.
- the table below shows the description of the different samples for Part 2.
- FIG. 3 shows the same results in graphic form.
- Table 5 and Figure 3 show that the survival varies as a function of the amount of K2HPO 4 .
- the results show that above 50 wt% K2HPO 4 the survival is significantly increased. Above 80 wt% K2HPO 4 survival is still significantly better than without K2HPO 4 , although less than at 80 wt%.
- Figure 4 shows the same results in graphic form.
- Table 6 and Figure 4 show that the survival varies as a function of the K2HPO 4 percentage, and above 40 wt% K2HPO 4 is significantly better than without K 2 HPO .
- K2HPO 4 was blended in dry form with various amounts of KH2PO 4 calculated to give the desired pH.
- Part 1 Impact of pH of excipient on survival under dry conditions:
- Freeze-dried Lactobacillus acidophilus powder was blended with the different excipients at various pH's.
- the composition of each blend was 80% of excipient K2HPO 4 powder and 20% freeze-dried probiotic powder.
- the blends were mixed by rotation (about 60tr/min) in plastic bottles for 20 min. Sachets were filled with the blends.
- the preparation of the samples was made in a clean room at 40% RH and 25°C. During testing the sachets were stored at 30°C in dry humidity (a w ⁇ 0.1 ) for 3 months.
- Part 2 Impact of pH of excipient on survival under humid conditions:
- Freeze-dried Lactobacillus acidophilus powder was blended with the different K2HPO 4 powders at different pH's and MCC.
- the composition of each blend was 80% of excipient and 20% of freeze dry probiotic powder.
- the blends were mixed by rotation (about 60tr/min) in plastic bottles for 20 min.
- the preparation of the samples was made in a clean room at 40% RH and 25°C.
- Capsules were filled with the blends and the capsules were introduced into a glass bottle. Maltodextrin at an a w of approximately 0.4 was then added on top and the bottle was shaken.
- the bottles were stored at 30°C for 3 months.
- Figure 5 shows the same results in graphic form.
- Table 7 and Figure 5 show that survival/stability under dry conditions varies as a function of pH, but in all cases is better than survival with MCC as sole excipient. Stability was impacted by the pH of excipient. For stability under dry conditions, the optimal pH of K2HPO 4 is between 6.9 and 7.1 . Other species evaluated included Bifidobacterium lactis and Lactobacillus casei.
- Figure 6 shows the same results in graphic form.
- Table 8 and Figure 6 show that the stability varies as function of pH value.
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Abstract
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
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US16/479,342 US20190338239A1 (en) | 2017-01-19 | 2018-01-12 | Dried microorganism with excipient |
PL18702616.6T PL3571287T3 (en) | 2017-01-19 | 2018-01-12 | Dried microorganism with excipient |
KR1020197023565A KR20190104395A (en) | 2017-01-19 | 2018-01-12 | Dried microorganisms with excipients |
BR112019013357A BR112019013357A2 (en) | 2017-01-19 | 2018-01-12 | composition, unit microbial dose and process for preparing the composition |
JP2019538674A JP7181879B2 (en) | 2017-01-19 | 2018-01-12 | Dried microorganisms with excipients |
EP18702616.6A EP3571287B8 (en) | 2017-01-19 | 2018-01-12 | Dried microorganism with excipient |
AU2018209083A AU2018209083B2 (en) | 2017-01-19 | 2018-01-12 | Dried microorganism with excipient |
CN201880007706.7A CN110214177A (en) | 2017-01-19 | 2018-01-12 | Dried microorganism with excipient |
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US201762448066P | 2017-01-19 | 2017-01-19 | |
US62/448,066 | 2017-01-19 | ||
EP17159494.8 | 2017-03-07 | ||
EP17159494 | 2017-03-07 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US4621058A (en) * | 1983-04-11 | 1986-11-04 | Mid-America Dairymen, Inc. | Method of preparing cheese starter media |
WO2009061222A2 (en) * | 2007-11-07 | 2009-05-14 | Encoate Holdings Limited | Stabilisation of dried biological material |
WO2011018547A1 (en) * | 2009-08-12 | 2011-02-17 | Vetcare Oy | Probiotic preparation for the prevention or treatment of canine gastrointestinal disorders |
WO2011018509A1 (en) * | 2009-08-14 | 2011-02-17 | Danisco A/S | Coated dehydrated microorganisms with enhanced stability and viability |
CN103431318A (en) * | 2013-07-18 | 2013-12-11 | 浙江劲膳美生物科技有限公司 | Special diet edible for female color-spot patients |
-
2018
- 2018-01-12 WO PCT/EP2018/050761 patent/WO2018134135A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4621058A (en) * | 1983-04-11 | 1986-11-04 | Mid-America Dairymen, Inc. | Method of preparing cheese starter media |
WO2009061222A2 (en) * | 2007-11-07 | 2009-05-14 | Encoate Holdings Limited | Stabilisation of dried biological material |
WO2011018547A1 (en) * | 2009-08-12 | 2011-02-17 | Vetcare Oy | Probiotic preparation for the prevention or treatment of canine gastrointestinal disorders |
WO2011018509A1 (en) * | 2009-08-14 | 2011-02-17 | Danisco A/S | Coated dehydrated microorganisms with enhanced stability and viability |
CN103431318A (en) * | 2013-07-18 | 2013-12-11 | 浙江劲膳美生物科技有限公司 | Special diet edible for female color-spot patients |
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