WO2014199448A1 - 貪食細胞へ物質を送達する担体 - Google Patents
貪食細胞へ物質を送達する担体 Download PDFInfo
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- WO2014199448A1 WO2014199448A1 PCT/JP2013/066108 JP2013066108W WO2014199448A1 WO 2014199448 A1 WO2014199448 A1 WO 2014199448A1 JP 2013066108 W JP2013066108 W JP 2013066108W WO 2014199448 A1 WO2014199448 A1 WO 2014199448A1
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- carrier
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- cells
- lactic acid
- substance
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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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
- C12N1/20—Bacteria; Culture media therefor
Definitions
- the present invention relates to a drug carrier for delivering a substance to phagocytic cells, characterized by containing lactic acid bacteria.
- phagocytic cells in the body play an important role in regulating acquired immunity through antigen processing functions. It is considered. On the other hand, it is also known that an increase in the activity or function of phagocytic cells may cause a pathological state for a living body.
- Diseases resulting from increased phagocytic cell activity or function include atherosclerosis, congestive heart failure, ischemic disease, restenosis, hypertension, fibrotic vascular disorders (diabetes, systemic lupus erythematosus, etc.), neurodegenerative diseases (Eg, Alzheimer's disease, Huntington's disease, Parkinson's disease, spinocerebellar degeneration, amyotrophic lateral sclerosis, etc.), brain injury, cerebrovascular events (eg, stroke, stroke, nerve injury and regeneration within the central nervous system) Etc.), hematopoietic disorder, adult respiratory distress syndrome (ARDS), cancer (especially leukemia including adult T-cell leukemia) and solid cancer, autoimmune disease, infection (eg, HIV infection and AIDS, etc.), fibroproliferative disorder (eg, Psoriasis, etc.), chronic and acute inflammatory diseases (eg, rheumatoid arthritis, Crohn's disease, inflammatory bowel syndrome, etc
- scavenger receptors contributing to foreign body phagocytosis are widely expressed in most phagocytic cells in various living tissues.
- This scavenger receptor has affinity for various negatively charged particles, and mediates the phagocytosis of bacteria and their constituents that have invaded the body, as well as modified LDL modified by oxidation, acetylation and saccharification. It is known (Non-Patent Documents 1 to 3). Since the expression level of the scavenger receptor is not regulated depending on the amount of denatured LDL in phagocytic cells, phagocytic cells take up denatured LDL without limitation. The atherosclerosis is caused by the phagocytic cells in which the degenerated LDL is excessively accumulated foamed in the intima.
- Atherosclerosis is caused by excessive accumulation of denatured LDL in phagocytic cells.
- compounds having an antifoaming action for example, esculeogenin A (Non-patent Document 4), PPAR ⁇ agonist ( Non-patent document 5), adiponectin (non-patent document 6) and the like, or an enzyme responsible for metabolism and degradation of denatured LDL accumulated in phagocytic cells (non-patent document 7) and the like are efficiently delivered to phagocytic cells. Therefore, it is considered that atherosclerosis can be prevented and treated more effectively, and many studies are being conducted today.
- target-directed liposomes require complicated chemical synthesis and purification processes, and there are many problems in industrialization.
- the present invention provides a low-cost and safe carrier for efficiently delivering substances (eg, drugs, drugs, etc.) to phagocytic cells, and for efficiently delivering substances to phagocytic cells. It aims to provide a means.
- substances eg, drugs, drugs, etc.
- the present inventors have surprisingly found that lactic acid bacteria can be efficiently taken up by phagocytic cells, and further research has been conducted, so that lactic acid bacteria can become a scavenger receptor of phagocytic cells.
- the inventors have obtained the knowledge that the efficiency of lactic acid bacteria uptake by phagocytic cells is improved by having high affinity for the phagocytic cells, and have further completed various studies to complete the present invention.
- the present invention relates to the following inventions.
- a carrier for delivering a substance to phagocytic cells comprising lactic acid bacteria and / or an extract thereof.
- the carrier according to (1) above, wherein the lactic acid bacterium is Lactobacillus plantarum L-137.
- the carrier according to (8), wherein the disease involving phagocytic cells is atherosclerosis.
- a composition comprising the carrier according to any one of (1) to (9) and a substance delivered to the phagocytic cell.
- (11) A method for delivering a substance to phagocytic cells, comprising using the carrier according to any one of (1) to (9).
- a carrier for efficiently delivering various desired substances to phagocytic cells can be provided.
- an effective carrier for use in diagnosis, prevention or treatment of a disease involving phagocytic cells for example, atherosclerosis etc.
- a composition comprising the carrier can be provided.
- the lactic acid bacteria used in the present invention have safety according to the present invention from the viewpoints of safety, mass culture and mass acquisition, and relatively easy adaptation of genetic recombination techniques.
- a carrier that is high and has a high delivery effect to phagocytic cells can be produced at low cost.
- the present invention relates to a carrier for delivering a substance to phagocytic cells.
- the carrier of the present invention contains lactic acid bacteria or an extract thereof.
- the carrier contains lactic acid bacteria or an extract thereof, so that the substance delivery efficiency to phagocytic cells is improved.
- the lactic acid bacteria used in the carrier of the present invention are not particularly limited, and known lactic acid bacteria such as Lactobacillus, Streptococcus, Enterococcus, Lactococcus, and Bifidobacterium can be used.
- Lactobacillus plantarum Lactobacillus acidophilus
- Lactobacillus brevis Lactobacillus casei
- Lactobacillus fermentum Lactobacillus fermentum (Lactobacillus fermentum)
- Lactobacillus paracasei Lactobacillus paracasei, Lactobacillus buchneri, Lactobacillus delbrueckii, Lactobacillus rhamnosus, octo Streptococcus Enterococcus faecalis
- Enterococcus faecium Lactococcus lactis
- Lactococcus plan examples include Talam (Lactococcus plantarum), Bifidobacterium thermophilum, Bif
- Lactobacillus plantarum L-137 strain (Institute of Biotechnology, Institute of Industrial Science and Technology, accession number FERM on November 30, 1995) P-15317, deposited as Microtechnical Bacterium No. 15317), Lactobacillus plantarum JCM 1149 reference strain, and Lactobacillus plantarum L-051 strain (Microtechnological Bacteria No. 11912) Particularly preferred is Lactobacillus plantarum L-137 strain and the like.
- the lactic acid bacteria used in the present invention may be any of those cultured in a medium such as a natural medium, a synthetic medium, and a semi-synthetic medium.
- the culture of lactic acid bacteria may be performed according to a known method, a method known per se, or a method analogous thereto.
- the medium is not particularly limited, and for example, a medium containing a nitrogen source and / or a carbon source is preferably used.
- the nitrogen source is not particularly limited, and examples thereof include meat extract, peptone, gluten, casein, yeast extract, amino acid and the like.
- the carbon source is not particularly limited, and examples thereof include glucose, xylose, fructose, inositol, maltose, water candy, soup, starch, bagasse, bran, molasses, and glycerin. These may be used alone or in combination of two or more.
- the medium may further contain an inorganic substance.
- the inorganic material is not particularly limited, and examples thereof include ammonium sulfate, potassium phosphate, magnesium chloride, salt, iron, manganese, molybdenum, and various vitamins. These may be used alone or in combination of two or more. May be.
- the culture temperature and culture time of the lactic acid bacteria are not particularly limited as long as the culture can be carried out efficiently.
- the culture temperature is usually about 25 to 40 ° C., preferably about 27 to 35 ° C., for example.
- the culture time may be, for example, about 12 to 48 hours.
- the lactic acid bacteria may be cultured by aeration shaking.
- the pH of the medium is not particularly limited, but in one embodiment of the present invention, it may be generally about pH 3 to 6, preferably about pH 4 to 6.
- the lactic acid bacterial cells used in the present invention may be live or dead cells, and are not particularly limited. From the viewpoints of stability and ease of handling, dead cells are used. It is preferable.
- a method for preparing dead cells of the lactic acid bacteria will be specifically described.
- the method for preparing the dead cells is not particularly limited as long as the effects of the present invention are not lost.
- (I) after culturing the lactic acid bacteria from the culture solution after completion of the culture, A method of sterilizing bacterial cells to make them dead cells, (II) sterilizing viable bacterial cells of lactic acid bacteria in a culture solution to make dead cells, and then removing the dead cells from the culture solution You may prepare by any methods, such as the method of isolate
- separating As a method for separating the cells from the culture solution, various methods usually used in this field may be adopted, and there is no particular limitation.
- a method of separating the culture solution and the bacterial cells by removing the supernatant by means such as centrifugation after adding distilled water to the culture solution is adopted. May be. In this embodiment, after removing the supernatant after adding distilled water to the culture and centrifuging, if necessary, further adding distilled water to the residue from which the supernatant has been removed and centrifuging. May be repeated several times. In one embodiment of the present invention, a filtration step may be included as a separation operation.
- the sterilization treatment method is not particularly limited, and examples thereof include heating, ultraviolet irradiation, and formalin treatment.
- the sterilization treatment may be performed on the collected live cells or may be performed on a culture solution containing the live cells.
- the heating temperature is not particularly limited.
- the heating temperature is usually about 60 ° C. to 100 ° C., preferably about 70 to 90 ° C.
- a heating means a known method can be used, and is not particularly limited.
- means such as a heater may be used.
- the heating time is not particularly limited as long as the sterilization treatment can be sufficiently completed.
- the heating time may be usually about 5 to 40 minutes, preferably about 10 to 30 minutes after reaching a desired temperature.
- the dead cells obtained as described above may be further subjected to grinding, crushing, or freeze-drying treatment, etc. to obtain a treated product of dead cells.
- the treated product of dead cells can also be suitably used as dead cells.
- an extract of lactic acid bacteria may be used instead of or together with lactic acid bacteria.
- the extraction method of the said extract is not specifically limited, You may carry out according to a well-known method, itself well-known method, or a method according to them. Specifically, for example, (i) a method of extracting lactic acid bacteria live cells or dead cells with immersion or stirring under normal pressure or under pressure in an extraction solvent heated at room temperature or (ii) ) A method of extraction while refluxing in an extraction solvent may be mentioned. For the extraction temperature and extraction time, the type of extraction solvent to be used may be appropriately selected depending on the extraction conditions.
- the extraction solvent is not particularly limited, and for example, water, an organic solvent, or a mixed solvent in any ratio thereof may be used.
- the organic solvent is not particularly limited, and examples thereof include lower alcohols (for example, methanol, ethanol, n-propanol, isopropanol and n-butanol), polyhydric alcohols (for example, 1,3-butylene glycol, propylene glycol, Alcohols that are liquid at room temperature, such as glycerin; ethers (eg, diethyl ether, propyl ether, etc.); esters (eg, ethyl acetate, butyl acetate, etc.); ketones (eg, acetone, ethyl methyl ketone, etc.) ); Hydrocarbons (eg, hexane, xylene, toluene, etc.); chloroform and the like.
- lower alcohols for example, methanol, ethanol, n-propanol,
- alcohols that are liquid at room temperature for example, lower alcohols having 1 to 4 carbon atoms, are preferably used from the viewpoints of operability and environmental impact, and from the viewpoint of safety due to residual solvents. More preferably, ethanol is used.
- the mixture containing the extract obtained by the extraction operation and the residue is subjected to filtration or centrifugation, if desired, and the extract obtained by removing the solid component as the residue is used as it is for the carrier of the present invention. It may be used for preparation, or the extract may be dried and powdered by a method such as concentration, lyophilization or spray drying.
- the carrier of the present invention contains the fungus body or the extract so that it can be incorporated into phagocytic cells with high efficiency. Therefore, the carrier of the present invention is a very suitable carrier as a carrier for efficiently delivering a desired substance to phagocytic cells.
- phagocytic cells are not particularly limited, but preferably contain macrophages, monocytes, polynuclear leukocytes, dendritic cells, and the like.
- the substance delivered to phagocytic cells by the carrier of the present invention is not particularly limited, and examples thereof include functional substances.
- the functional substance is preferably a substance having a function that exerts some effect by being delivered to a phagocytic cell.
- the “some effect” is not particularly limited, and may be a preferable or useful effect, or may be an effect that causes a harmful effect.
- the “detrimental effect” can be used for testing and research, and when there are phagocytic cells that exert an undesirable effect on the living body, they can be used for suppressing or extinguishing their functions. Can do. That is, the functional substance may be selected according to the purpose of using the carrier of the present invention.
- the functional substance includes, for example, a compound having an antifoaming action on macrophages (for example, esculeogenin A, PPAR ⁇ agonist, adiponectin, etc.); Enzymes responsible for metabolism and degradation of accumulated cholesterol (eg, cholesterol oxidase ChoA); inflammatory cytokines (eg, IL-1 ⁇ , etc.) that contribute to phagocytic cell activation; and to detect and identify cells
- Useful fluorescent dyes for example, fluorescein isothiocyanate (FITC) etc.
- the functional substance is a substance used for diagnosis, prevention and / or treatment of a disease involving phagocytic cells.
- the disease involving the phagocytic cell is not particularly limited, and examples thereof include atherosclerosis, congestive heart failure, ischemic disease, restenosis, hypertension, fibrotic vascular disorder (diabetes, systemic lupus erythematosus, etc.), nerve Degenerative diseases (eg, Alzheimer's disease, Huntington's disease, Parkinson's disease, spinocerebellar degeneration, amyotrophic lateral sclerosis, etc.), brain injury, cerebrovascular events (eg, stroke, seizures, nerve injury and internal nervous system) Regeneration), hematopoietic disorder, adult respiratory distress syndrome (ARDS), cancer (particularly leukemia including adult T-cell leukemia) and solid cancer, autoimmune disease, infection (for example, HIV infection and AIDS, etc.), fibroproliferative disorder ( Eg psoriasis), chronic and acute inflammatory diseases (eg rheumatoid arthritis, Crohn's disease, inflammatory bowel syndrome etc.), glomerular
- the substance used for diagnosis, prevention and / or treatment of a disease involving phagocytic cells for example, for the purpose of preventing or improving atherosclerosis, esculeogenin A, PPAR ⁇ agonist, Examples include adiponectin and ChoA.
- the substance delivered to the phagocytic cell may be carried on the carrier of the present invention, or the substance to be delivered to the phagocytic cell and the carrier of the present invention may be used in combination.
- a method for supporting the substance to be delivered to the phagocytic cell on the carrier of the present invention will be described.
- the supporting method is not particularly limited as long as the effects of the present invention are not lost.
- the substance to be delivered to the phagocytic cell is bound to the surface of the lactic acid bacterium and / or inside the microbial cell or to the lactic acid bacterium extract. May be.
- the bonding method is not particularly limited, but includes, for example, a chemical bond including covalent bond, polar covalent bond, ionic bond, electrostatic bond, coordinate covalent bond, aromatic bond, hydrogen bond, dipole or van der Waals interaction. Bonding may be employed.
- a substance to be delivered to the phagocytic cell may be supported on the microbial cells by expressing and producing on the microbial cell surface and / or inside the microbial cells by genetic engineering.
- the lactic acid bacterium when the lactic acid bacterium is loaded with a fluorescent labeling agent (for example, FITC isomer-I (manufactured by Dojindo)), the lactic acid bacterium and the fluorescent labeling agent are reacted under light shielding,
- the fluorescent labeling agent can be supported on the surface.
- the reaction conditions may be, for example, about 30 ° C. to 45 ° C. for about 10 minutes to 120 minutes.
- the plasmid pWK7 prepared by arbitrarily fusing the lactic acid bacterium-derived plasmid and the E. coli-derived plasmid introduced with the choA gene (for example, , J Biosci Bioeng. 2001; 92 (5): 459-65.) Is introduced into lactic acid bacteria by electroporation or the like, and transformed to allow the lactic acid bacteria to carry cholesterol oxidase ChoA. Also good.
- adiponectin for example, see Atherosclerosis. 2013; 228 (1): 124-35.
- IL-1 ⁇ for example, Clin Vaccine Immunol. 2010; 17 (1 ): See 43-8.
- the carrier of the present invention may contain components other than lactic acid bacteria in addition to the lactic acid bacteria and / or the extract.
- the component is not particularly limited as long as the effects of the present invention are not lost, and for example, any component known in the fields of medicine, pharmacy, food and the like can be used.
- the components other than the lactic acid bacteria are those having a high affinity with the lactic acid bacteria and / or the extract, or those capable of binding to the lactic acid bacteria and / or the extract. Is preferred. Examples of such components include lipids, sterols, vegetable oils, mineral oils, lecithins and the like.
- the carrier of the present invention may contain a substance that promotes uptake into phagocytic cells such as a targeting agent.
- a targeting agent preferably refers to a compound showing selectivity for a specific target organ or tissue.
- various compounds usually used in this field may be used, and are not particularly limited. Examples thereof include retinoids.
- the content of the lactic acid bacteria and / or the extract is not particularly limited as long as the effect of the present invention is exhibited, but in 100% by mass of the drug carrier, for example, about 1% by mass. It may be in the range of ⁇ 100% by weight.
- the amount of the substance delivered to the phagocytic cell to be carried on or mixed with the carrier of the present invention is not particularly limited as long as the effect of the present invention is not hindered, but 100 parts by mass of the carrier of the present invention On the other hand, for example, it may be about 10 to 300 parts by mass.
- compositions comprising the carrier of the present invention and a substance to be delivered to the phagocytic cell.
- the substance delivered to the phagocytic cell is preferably a functional substance as described above.
- the composition in this aspect is not specifically limited, For example, a pharmaceutical, food-drinks, feed, food additive, feed additive, etc. may be sufficient, Preferably it is a pharmaceutical etc.
- the use of the carrier of the present invention for the manufacture of a medicine is also encompassed by the present invention.
- the said pharmaceutical of this invention is demonstrated.
- the route of administration of the pharmaceutical is not particularly limited, and for example, it may be administered to a mammal by either oral or parenteral route.
- the pharmaceutical dosage form is not particularly limited, and may be selected according to the administration route.
- any form of an oral preparation and a parenteral preparation may be used.
- the oral preparation include granules, powders, tablets (including sugar-coated tablets), pills, capsules, syrups, emulsions, suspensions and the like.
- parenteral agent for example, injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection etc.), instillation, external preparation (for example, nasal administration) Preparations, transdermal preparations, ointments, etc.), suppositories (for example, rectal suppositories, vaginal suppositories, etc.).
- the pharmaceutical product of the present invention may be produced by a method commonly used in this field.
- the pharmaceutical may include, for example, a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier include excipients, binders, diluents, additives, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, Examples include preservatives.
- examples of the pharmaceutically acceptable carrier include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and a low-melting wax. , Cocoa butter and the like, and these may be used alone or in combination of two or more.
- the oral preparation may be a solid preparation (eg, tablet, pill, capsule, powder, granule, etc.).
- the solid preparation may be formulated according to a conventional method by mixing an active ingredient with an excipient, a binder, a disintegrant, a lubricant, a stabilizer, a solubilizing agent and the like.
- the excipient include lactose, mannitol, glucose, microcrystalline cellulose, starch and the like.
- the binder include hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesium aluminate metasilicate, and the like.
- the disintegrant include fibrin calcium glycolate.
- the lubricant include magnesium stearate.
- solubilizer examples include glutamic acid and aspartic acid. If desired, it may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), and the coating may be two or more layers.
- a coating agent for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
- the oral preparation may be a liquid (for example, a solution, suspension, emulsion, syrup, elixir, etc.).
- the liquid preparation may be formulated by dissolving the active ingredient in a commonly used diluent (for example, purified water, ethanol or a mixture thereof) and suspending or emulsifying it.
- this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
- the injection includes, for example, a solution, suspension, emulsion, and solid injection used by dissolving or suspending in a solvent at the time of use.
- the injection may be formulated, for example, by dissolving, suspending or emulsifying the active ingredient in a solvent.
- the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, and alcohols such as ethanol, and these may be used alone or in combination of two or more. .
- the injection includes a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like. Also good.
- the injection may further include sterilization or aseptic operation in the final step.
- a sterile solid preparation such as a freeze-dried product may be produced and used by dissolving in sterile distilled water for injection or other solvent before use.
- the dose of the pharmaceutical product of the present invention is not particularly limited, and may be appropriately selected depending on the purpose.
- the dosage is the type and degree of the disease; the administration route; the administration subject; the age, sex, state, etc. of the administration subject; or the type of the functional substance supported on or mixed with the carrier of the present invention, and other conditions. You may set according to.
- the subject of administration of the pharmaceutical product of the present invention is not particularly limited, and includes any animal such as mammals (human, mouse, rat, horse, dog, cat, rabbit, pig, cow, etc.).
- the food and drink of the present invention are generally used as food additives such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, coloring agents, bleaching agents, fungicides, and gum bases.
- sweeteners such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, coloring agents, bleaching agents, fungicides, and gum bases.
- One or more of bitterings, enzymes, brighteners, acidulants, seasonings, emulsifiers, reinforcing agents, production agents, fragrances, spice extracts and the like may be added.
- the food and drink of the present invention includes health food, functional food, food for specified health use, food for infants, food for infants, food for pregnant women, and food for the sick.
- the form of the food or drink of the present invention is not particularly limited. Specific examples include tablets, granules, powders, and drinks as so-called dietary supplements (supplements). Other than this, for example, beverages such as tea drinks, soft drinks, carbonated drinks, nutrition drinks, fruit drinks, lactic acid drinks, noodles such as buckwheat, udon, Chinese noodles, instant noodles, strawberries, candy, gum, chocolate, snacks, Biscuits, jelly, jam, cream, baked confectionery, confectionery such as bread, marine products such as kamaboko, ham, sausage, processed food, dairy products such as processed milk, fermented milk, salad oil, tempura oil, margarine, mayonnaise , Shortening, whipped cream, dressing and other fats and oils processed foods, sauces, seasonings such as sauce, curry, stew, rice cakes, rice cakes, miscellaneous cooking retort pouch foods, ice cream, sorbet, shaved ice, etc. Can be mentioned.
- beverages such as tea drinks, soft drinks, carbonated
- the intake of the food / beverage product of the present invention is not particularly limited, and the form of the food / beverage product; the age, sex, state, etc. of the subject ingesting the food / beverage product; or the carrier or the carrier of the present invention mixed with the carrier You may set according to the kind of functional substance, and other conditions.
- the scavenger receptor is not particularly limited, but is preferably a class A scavenger receptor.
- the class A scavenger receptor include AI and AII (CD204 antigen receptor recognized by monoclonal antibody Clone2F8).
- the present invention also includes a method of delivering a substance to phagocytic cells using the carrier of the present invention.
- the substance to be delivered to the phagocytic cell may be as described above, and the delivery may be via the scavenger receptor.
- Lactobacillus plantarum L-137 (accession number FERMBP-08607) strain was inoculated on a MRS (de Man, Rogosa, Sharpe) liquid medium and cultured at 32 ° C. for 24 hours. After culture, the culture was centrifuged at 4200 ⁇ g, 4 ° C. for 10 minutes to collect the cells. The obtained cells were well dispersed in physiological saline and centrifuged at 4200 ⁇ g, 4 ° C. for 10 minutes, and then the supernatant was removed to collect the cells. Furthermore, the operation of dispersing the collected cells in physiological saline and centrifuging under the above conditions was repeated three times.
- MRS de Man, Rogosa, Sharpe
- Example product 1 The obtained bacterial cells were dispersed in ion-exchanged water and heated at 80 ° C. for 20 minutes. The precipitate was freeze-dried by centrifugation at 4200 ⁇ g, 4 ° C. for 10 minutes to obtain a heated dead cell (Example product 1).
- Example 2 A heat-killed cell was obtained in the same manner as in Example 1 except that the Lactobacillus plantarum JCM1149 strain was used instead of the Lactobacillus plantarum L-137 strain (Example product 2).
- Example products 1 and 2 were suspended in 1 mL of 50 mM sodium carbonate buffer (pH 9.6) at a concentration of 5 mg / mL.
- Fluorescein isothiocyanate (FITC) isomer-I (Dojindo Laboratories) was added to the cell suspension to a final concentration of 5 ⁇ g / mL, and reacted at 37 ° C. for 60 minutes under light shielding.
- Labeled with The cells labeled with FITC were centrifuged at 19000 ⁇ g and 4 ° C. for 10 minutes, and the precipitate was suspended in 1 mL of phosphate buffer and centrifuged under the same conditions as described above. After repeating the operations of suspending in phosphate buffer and centrifuging three times, the residue obtained by centrifugation was suspended in 1 mL of phosphate buffer and diluted 500-fold with RPMI 1640 medium containing 10% FBS. .
- Phagocytic cells were derived from mouse spleen. Spleens were removed from mice (BALB / c, female, 6-12 weeks old) and crushed in RPMI 1640 medium containing 10% FBS. With a solution prepared by adding ammonium chloride to 0.017M Tris buffer (pH 7.65) to a final concentration of 0.75%, the resulting cell population is treated at 4 ° C for 5 minutes to destroy erythrocytes. Thereafter, it was passed through a # 200 mesh to obtain a spleen cell suspension. The number of cells in the spleen cell suspension was measured using an automatic blood cell counter (CDA-500, manufactured by Sysmex Corporation).
- CDA-500 automatic blood cell counter
- spleen cells As the concentration of spleen cells is 1 ⁇ 10 7 (cell number) / mL, were suspended above spleen cell suspension in 10% FBS-containing RPMI1640 medium was added in 1mL 24-well culture plate, 5% The cells were cultured at 37 ° C. for 90 minutes in a carbon dioxide incubator. Thereafter, the culture solution was pipetted, and the culture solution containing non-adherent cells was carefully removed to obtain an adherent cell population rich in phagocytic cells. After removing the culture solution, 500 ⁇ L of 10% FBS-containing RPMI1640 medium was added.
- Example 1 FITC-labeled bacteria of Example Product 1 and Example Product 2 prepared at a concentration of 10 ⁇ g / mL in RPMI1640 medium containing 10% FBS to 500 ⁇ L of adherent cell population containing a large number of phagocytes obtained in the above (preparation of phagocytic cells) 500 ⁇ L of the body (samples 1 and 2) or a control sample (sample 3) prepared only with 10% FBS-containing RPMI1640 medium without microbial cells was added to 500 ⁇ L of the adherent cell population rich in phagocytic cells. Samples 1 to 3 were cultured in a 5% carbon dioxide incubator at 37 ° C.
- Example 2 4 ⁇ g of monoclonal antibody IgG2b (clone RTK4530, hereinafter referred to as anti-scavenger A antibody) against the A type scavenger receptor was added to 500 ⁇ L of the adherent cell population containing a large amount of phagocytic cells obtained in the above (preparation of phagocytic cells) (sample) 4).
- a sample to which 4 ⁇ g of isotype control antibody was added instead of the anti-scavenger A antibody was also prepared (Sample 5). After culturing at 37 ° C.
- Example Product 1 500 ⁇ L of the FITC-labeled bacterial cell of Example Product 1 prepared to a concentration of 10 ⁇ g / mL in RPMI 1640 medium containing 10% FBS was added for 4 hours or 24 hours. Incubate for hours. After 4 hours or 24 hours, phagocytic cells are collected, and the ratio of phagocytic cells incorporating FITC-labeled cells in the collected phagocytic cells is detected using a flow cytometer, and the percentage of phagocytic cells incorporating bacteria. Was calculated. The results are shown in Table 2.
- various desired substances can be efficiently delivered to phagocytic cells.
- a drug for a disease involving phagocytic cells as a functional substance, diseases involving phagocytic cells.
- An effective carrier or a composition containing the carrier for use in diagnosis, prevention or treatment of eg, atherosclerosis
- the present invention has been widely used in the fields of foods and pharmaceuticals because it is safe, can be mass-cultured and mass-acquired, and is relatively easy to apply genetic recombination techniques. Since the lactic acid bacteria and / or extract thereof are used, according to the present invention, a carrier with high safety and high delivery effect to phagocytic cells can be produced at low cost.
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Abstract
Description
(1)乳酸菌及び/又はその抽出物を含有することを特徴とする、貪食細胞へ物質を送達するための担体。
(2)前記乳酸菌がラクトバチルス(Lactobacillus)属に属することを特徴とする前記(1)に記載の担体。
(3)前記乳酸菌がラクトバチルス・プランタラム(Lactobacillus plantarum)に属することを特徴とする前記(1)に記載の担体。
(4)前記乳酸菌がラクトバチルス・プランタラムL-137株(Lactobacillus plantarum L-137)であることを特徴とする前記(1)に記載の担体。
(5)前記乳酸菌が死菌体であることを特徴とする前記(1)~(4)のいずれかに記載の薬物担体。
(6)貪食細胞への物質の送達が、貪食細胞のスカベンジャー受容体を介することを特徴とする前記(1)~(5)のいずれかに記載の担体。
(7)前記スカベンジャー受容体がクラスAのスカベンジャー受容体であることを特徴とする前記(6)に記載の担体。
(8)前記物質が、貪食細胞が関与する疾患の診断、予防及び/又は治療に用いる物質であることを特徴とする前記(1)~(7)のいずれかに記載の担体。
(9)前記貪食細胞が関与する疾患が、アテローム性動脈硬化症であることを特徴とする前記(8)に記載の担体。
(10)前記(1)~(9)のいずれかに記載の担体と、前記貪食細胞に送達する物質とを含有する組成物。
(11)前記(1)~(9)のいずれかに記載の担体を用いることを特徴とする貪食細胞への物質の送達方法。
また、本発明に用いる乳酸菌は、安全性である点、大量培養及び大量取得が可能である点、遺伝子組み換え技術の適応が比較的容易である点などから、本発明によれば、安全性が高く、貪食細胞への送達効果が高い担体を、安価に製造することができる。
培養液から菌体を分離する方法としては、この分野で通常用いられる種々の方法を採用してもよく、特に限定されない。本発明のひとつの態様において、具体的には、例えば、培養液に蒸留水を加えた後に遠心分離等の手段によって上清を除くことによって、培養液と菌体とを分離する方法等を採用してもよい。なお、この態様においては、培養液に蒸留水を加えて遠心分離を行った後に上清を除去した後、所望により、上清を除去した残留物にさらに蒸留水を加えて遠心分離を行う操作を何度か繰り返してもよい。本発明のひとつの態様において、分離操作として濾過工程を含んでいてもよい。
前記担持方法は、本発明の効果を失しない限り、特に限定されないが、例えば、前記貪食細胞に送達する物質を、前記乳酸菌の菌体表面及び/又は菌体内部あるいは前記乳酸菌抽出物に結合させてもよい。前記結合方法としては、特に限定されないが、例えば、共有結合、極性共有結合、イオン結合、静電結合、配位共有結合、芳香族結合、水素結合、双極子又はファンデルワールス相互作用を含む化学結合を採用してもよい。また、遺伝子工学的に、前記菌体表面及び/又は菌体内部に発現、産生させることで、前記貪食細胞に送達する物質を菌体に担持させてもよい。
遺伝子工学的な技術を応用することで、例えば、アディポネクチン(例えば、Atherosclerosis. 2013; 228(1): 124-35.を参照。)やIL-1β(例えば、Clin Vaccine Immunol. 2010; 17(1): 43-8.を参照。)を、乳酸菌に担持させることができる。
また、本発明の前記担体の医薬製造への使用も本発明に包含される。
前記医薬品の投与経路は、特に限定されず、例えば、経口または非経口のいずれかの経路で哺乳動物に投与してもよい。
前記経口剤としては、顆粒剤、散剤、錠剤(糖衣錠を含む)、丸剤、カプセル剤、シロップ剤、乳剤、懸濁剤などが挙げられる。非経口剤としては、特に限定されないが、例えば、注射剤(例えば、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤等)、点滴剤、外用剤(例えば、経鼻投与製剤、経皮製剤、軟膏剤等)、坐剤(例えば、直腸坐剤、膣坐剤等)などが挙げられる。
また、無菌の固形剤、例えば凍結乾燥品を製造し、その使用前に無菌の注射用蒸留水又は他の溶剤に溶解して使用してもよい。
本発明の前記飲食品は、一般的に飲食品に用いられる食品添加剤、例えば甘味料、着色料、保存料、増粘安定剤、酸化防止剤、発色料、漂白料、防かび剤、ガムベース、苦味料、酵素、光沢剤、酸味料、調味料、乳化剤、強化剤、製造用剤、香料、香辛料抽出物等の一種以上が添加されてもよい。なお、本発明の前記飲食品には、健康食品、機能性食品、特定保健用食品、乳児用食品、幼児用食品、妊産婦用食品、病者用食品が含まれる。
本発明の前記担体の貪食細胞への物質の送達は、スカベンジャー受容体を介することが好ましい。該スカベンジャー受容体は、特に限定されないが、クラスAのスカベンジャー受容体であることが好ましい。該クラスAのスカベンジャー受容体としては、AI及びAII(モノクローナル抗体Clone2F8によって認識されるCD204抗原受容体)等が挙げられる。
MRS(de Man, Rogosa, Sharpe)液体培地にラクトバチルス・プランタラムL-137(受託番号FERMBP-08607)株を播種し、32℃で24時間培養した。培養後、培養液を4200×g、4℃、10分間遠心分離し菌体を集めた。得られた菌体を生理食塩水によく分散し、4200×g、4℃、10分間遠心分離した後、上清を除き、菌体を集めた。さらに、集めた菌体に生理食塩水によく分散させ、上記条件にて遠心分離をする操作を3回繰り返した。その後、得られた菌体をイオン交換水に分散し、80℃で20分間加熱した。4200×g、4℃、10分間遠心分離して沈殿を凍結乾燥することにより、加熱死菌体を得た(実施例品1)。
前記ラクトバチルス・プランタラムL-137株の代わりにラクトバチルス・プランタラムJCM1149株を用いた以外は、実施例1と同様にして、加熱死菌体を得た(実施例品2)。
実施例品1及び2を、50mM炭酸ナトリウム緩衝液(pH9.6)1mLに5mg/mLの濃度で懸濁した。菌体懸濁液に終濃度が5μg/mLになるようにフルオレセインイソチオシアネート(FITC)isomer-I(同仁化学)を添加し、37℃で60分間、遮光下で反応させて、菌体をFITCで標識した。FITCで標識した菌体を19000×g、4℃の条件で10分間遠心分離し、沈殿を1mLのリン酸緩衝液に懸濁後、上記と同条件で遠心分離した。リン酸緩衝液への懸濁と遠心分離の操作を3回繰り返した後、遠心分離で得られた残留物を1mLのリン酸緩衝液に懸濁し、10%FBS含有RPMI1640培地で500倍希釈した。
貪食細胞は、マウス脾臓由来のものを用いた。
マウス(BALB/c、雌性、6~12週齢)から脾臓を摘出し、10%FBS含有RPMI1640培地中で押しつぶした。0.017Mのトリス緩衝液(pH7.65)に最終濃度0.75%となるように塩化アンモニウムを加えて作製した溶液で、得られた細胞集団を4℃、5分間処理して赤血球を破壊後、#200メッシュに通して、脾臓細胞浮遊液を得た。脾臓細胞浮遊液中の細胞数は自動血球計測装置(CDA-500、シスメックス社製)を用いて測定した。脾臓細胞の濃度が1×107(細胞数)/mLとなるように、10%FBS含有RPMI1640培地に上記の脾臓細胞浮遊液を懸濁後、24穴培養プレートに1mLずつ添加し、5%炭酸ガス培養器内で37℃、90分間培養した。その後、培養液をピペッティングし、非接着細胞を含む培養液を丁寧に除去して、貪食細胞を多く含む接着細胞集団を得た。培養液を除去後、10%FBS含有RPMI1640培地を500μL添加した。
上記(貪食細胞の調製)で得た貪食細胞を多く含む接着細胞集団500μLに、10%FBS含有RPMI1640培地で10μg/mLの濃度に調製された実施例品1及び実施例品2のFITC標識菌体(試料1及び2)、あるいは、菌体を含まず10%FBS含有RPMI1640培地のみで調製された対照試料(試料3)500μLを、貪食細胞を多く含む接着細胞集団500μLに添加した。上記試料1~3を5%炭酸ガス培養器内で37℃、4時間あるいは24時間培養し、その後、貪食細胞を回収した。回収した貪食細胞中のFITC標識菌体を取り込んだ貪食細胞の割合を、フローサイトメーター(ベックマンコールター)を用いて検出し、貪食細胞が菌を取り込んだ割合を算出した。結果を表1に示す。
上記(貪食細胞の調製)で得た貪食細胞を多く含む接着細胞集団500μLに、Aタイプのスカベンジャー受容体に対するモノクローナル抗体IgG2b(clone RTK4530、以下、抗スカベンジャーA抗体という。)を4μg添加した(試料4)。また、抗スカベンジャーA抗体に替えてアイソタイプコントロール抗体4μgを添加した試料も調製した(試料5)。5%炭酸ガス培養器内で37℃、1時間培養後、10%FBS含有RPMI1640培地で10μg/mLの濃度に調製された実施例品1のFITC標識菌体500μLを添加し、4時間あるいは24時間培養した。4時間後、あるいは24時間後に貪食細胞を回収し、回収した貪食細胞中のFITC標識菌体を取り込んだ貪食細胞の割合を、フローサイトメーターを用いて検出し、貪食細胞が菌を取り込んだ割合を算出した。結果を表2に示す。
また、試験例2の結果から、スカベンジャーA受容体を不活性化させた貪食細胞(試料4を添加した細胞)においては、乳酸菌菌体の取り込み率が顕著に低くなることが分かる。すなわち、本発明の担体は、主に貪食細胞のスカベンジャー受容体を介して取り込まれることが示された。
Claims (11)
- 乳酸菌及び/又はその抽出物を含有することを特徴とする、貪食細胞へ物質を送達するための担体。
- 前記乳酸菌がラクトバチルス(Lactobacillus)属に属することを特徴とする請求項1に記載の担体。
- 前記乳酸菌がラクトバチルス・プランタラム(Lactobacillus plantarum)に属することを特徴とする請求項1に記載の担体。
- 前記乳酸菌がラクトバチルス・プランタラムL-137株(Lactobacillus plantarum L-137)であることを特徴とする請求項1に記載の担体。
- 前記乳酸菌が死菌体であることを特徴とする請求項1~4のいずれかに記載の薬物担体。
- 貪食細胞への物質の送達が、貪食細胞のスカベンジャー受容体を介することを特徴とする請求項1~5のいずれかに記載の担体。
- 前記スカベンジャー受容体がクラスAのスカベンジャー受容体であることを特徴とする請求項6に記載の担体。
- 前記物質が、貪食細胞が関与する疾患の診断、予防及び/又は治療に用いる物質であることを特徴とする請求項1~7のいずれかに記載の担体。
- 前記貪食細胞が関与する疾患が、アテローム性動脈硬化症であることを特徴とする請求項8に記載の担体。
- 請求項1~9のいずれかに記載の担体と、前記貪食細胞に送達する物質とを含有する組成物。
- 請求項1~9のいずれかに記載の担体を用いることを特徴とする貪食細胞への物質の送達方法。
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EP13886888.0A EP3009149B1 (en) | 2013-06-11 | 2013-06-11 | Carrier for transporting substance to macrophages |
KR1020167000210A KR102143856B1 (ko) | 2013-06-11 | 2013-06-11 | 대식세포에 물질을 송달하는 담체 |
US14/897,722 US10314916B2 (en) | 2013-06-11 | 2013-06-11 | Carrier for delivery of substance to phagocytes |
CN201380077352.0A CN105431173B (zh) | 2013-06-11 | 2013-06-11 | 向吞噬细胞运输物质的载体 |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000508162A (ja) * | 1995-10-20 | 2000-07-04 | ケンブリッジ ユニバーシティ テクニカル サービセス リミテッド | 生物学的に活性のあるポリペプチドのデリバリー |
JP2001064174A (ja) * | 1999-08-23 | 2001-03-13 | Takeda Food Products Ltd | 免疫賦活効果を相乗的に増強した製剤 |
JP2005068092A (ja) * | 2003-08-26 | 2005-03-17 | Ala:Kk | 免疫促進用組成物 |
JP2006519014A (ja) * | 2003-01-30 | 2006-08-24 | バイオガイア・エイビー | 乳酸菌からの抗炎症活性 |
JP2010095465A (ja) * | 2008-10-16 | 2010-04-30 | House Wellness Foods Kk | 乳酸菌含有免疫賦活用組成物 |
JP2010523144A (ja) * | 2007-04-11 | 2010-07-15 | バイオガイア・エイビー | アテローム性動脈硬化症を軽減するための、選択された乳酸菌の使用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1084709A1 (en) * | 1999-09-17 | 2001-03-21 | Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno | Oral recombinant lactobacilli vaccines |
JP4667568B2 (ja) * | 2000-09-01 | 2011-04-13 | ハウスウェルネスフーズ株式会社 | 免疫増強組成物 |
NZ549139A (en) * | 2004-02-02 | 2009-11-27 | Engeneic Molecular Delivery Pty Ltd | Compositions and methods for targeted in vitro and in vivo drug delivery to mammalian cells via bacterially derived intact minicells |
JP5088817B2 (ja) * | 2007-09-03 | 2012-12-05 | ハウスウェルネスフーズ株式会社 | 乳酸菌とシソ科の植物とを含む組成物 |
CN102481322A (zh) * | 2009-05-01 | 2012-05-30 | 微制药有限公司 | 预防和治疗退化性疾病的细菌组合物 |
WO2011150127A2 (en) | 2010-05-25 | 2011-12-01 | The Board Of Trustees Of The University Of Illinois | Novel systems, vectors, and methods for delivery of biomolecules to eukaryotic cells |
US20130052171A1 (en) * | 2011-08-30 | 2013-02-28 | Chia Nan University Of Pharmacy And Science | Immunomodulatory isolated lactobacillus strainand application thereof |
-
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000508162A (ja) * | 1995-10-20 | 2000-07-04 | ケンブリッジ ユニバーシティ テクニカル サービセス リミテッド | 生物学的に活性のあるポリペプチドのデリバリー |
JP2001064174A (ja) * | 1999-08-23 | 2001-03-13 | Takeda Food Products Ltd | 免疫賦活効果を相乗的に増強した製剤 |
JP2006519014A (ja) * | 2003-01-30 | 2006-08-24 | バイオガイア・エイビー | 乳酸菌からの抗炎症活性 |
JP2005068092A (ja) * | 2003-08-26 | 2005-03-17 | Ala:Kk | 免疫促進用組成物 |
JP2010523144A (ja) * | 2007-04-11 | 2010-07-15 | バイオガイア・エイビー | アテローム性動脈硬化症を軽減するための、選択された乳酸菌の使用 |
JP2010095465A (ja) * | 2008-10-16 | 2010-04-30 | House Wellness Foods Kk | 乳酸菌含有免疫賦活用組成物 |
Non-Patent Citations (12)
Title |
---|
ARTERIOSCLER THROMB VASC BIOL, vol. 27, no. 11, November 2007 (2007-11-01), pages 2400 - 6 |
ATHEROSCLEROSIS, vol. 228, no. 1, 2013, pages 124 - 35 |
CELL MICROBIOL., vol. 11, no. 8, August 2009 (2009-08-01), pages 1160 - 9 |
CLIN VACCINE IMMUNOL., vol. 17, no. 1, 2010, pages 43 - 8 |
J BIOL CHEM., vol. 286, no. 6, 11 February 2011 (2011-02-11), pages 4854 - 70 |
J BIOSCI BIOENG., vol. 92, no. 5, 2001, pages 459 - 65 |
JAPANESE JOURNAL OF LACTIC ACID BACTERIA, vol. 14, no. 2, 2003, pages 72 - 79 |
NAT MED., vol. 7, no. L, 2001, pages 48 - 52 |
NATURE, vol. 386, no. 6622, 20 March 1997 (1997-03-20), pages 292 - 6 |
See also references of EP3009149A4 * |
TAKAHIRO OKUNO ET AL.: "cholera tokin B Bunpitsu Nyusankin o Mochiita 2 Step Chokan Nai DDS no Kaihatsu", ABSTRACTS OF ANNUAL MEETING OF PHARMACEUTICAL SOCIETY OF JAPAN, vol. 129 TH, no. 3, 5 March 2009 (2009-03-05), pages 172, XP008180982 * |
TOSHIFUMI HIBI ET AL.: "Bio Iyaku ni yoru Targeting Chiryo Enshosei Cho Shikkan ni Okeru DDS", DRUG DELIV SYST, vol. 19, no. 2, 10 March 2004 (2004-03-10), pages 84 - 89, XP008180975 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11571447B2 (en) | 2017-05-26 | 2023-02-07 | House Wellness Foods Corporation | Composition for preventing, ameliorating or treating metabolic syndrome |
Also Published As
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JPWO2014199448A1 (ja) | 2017-02-23 |
US10314916B2 (en) | 2019-06-11 |
CN105431173B (zh) | 2020-12-22 |
EP3009149B1 (en) | 2021-10-20 |
HK1222581A1 (zh) | 2017-07-07 |
KR20160037879A (ko) | 2016-04-06 |
CN105431173A (zh) | 2016-03-23 |
EP3009149A4 (en) | 2017-02-15 |
US20160144041A1 (en) | 2016-05-26 |
JP6088648B2 (ja) | 2017-03-01 |
KR102143856B1 (ko) | 2020-08-12 |
EP3009149A1 (en) | 2016-04-20 |
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