WO2005082377A1 - 抗ヒトTNF-α抗体活性低下抑制剤 - Google Patents
抗ヒトTNF-α抗体活性低下抑制剤 Download PDFInfo
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- WO2005082377A1 WO2005082377A1 PCT/JP2005/003378 JP2005003378W WO2005082377A1 WO 2005082377 A1 WO2005082377 A1 WO 2005082377A1 JP 2005003378 W JP2005003378 W JP 2005003378W WO 2005082377 A1 WO2005082377 A1 WO 2005082377A1
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- antibody
- human tnf
- tnf
- reduction inhibitor
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Classifications
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y10S435/81—Packaged device or kit
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y10S435/00—Chemistry: molecular biology and microbiology
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Definitions
- the present invention relates to a therapeutic agent for inflammatory bowel disease. More specifically, an anti-TNF-a antibody activity decrease inhibitor or immunosuppressant in the treatment of inflammatory bowel disease by repeated administration of an anti-human TNF- ⁇ antibody, an anti-human TNF-a antibody and the protein source, and Z or charcoal. It relates to a kit formulation containing a hydrate source.
- IBD Inflammatory bowel syndrome
- Specific diseases include inflammatory bowel disease and ischemic colitis caused by infection, drugs, chemicals or radiation.
- Nonspecific diseases are also called idiopathic inflammatory bowel disease and are broadly divided into colitis (colitis; in particular, ulcerative colitis (UC)) and Crohn's disease (CD). Is done. Ulcerative colitis is more common in adults under 30 years of age, but it also occurs in children and those over 50 years of age, and there is a mucosal layer of the mucosa of the large intestine! Symptoms can include characteristic findings such as diarrhea, bloody stool, abdominal pain and weight loss.
- Ulcerative colitis has been a relatively rare disease in Japan, but the number of patients has been increasing year by year due to the westernization of dietary life in recent years.
- Various causes such as the theory of intestinal bacterial infection, the theory of dietary allergy, the theory of vascular disorders, the theory of autonomic nervous disorders, and the theory of immune abnormalities, are thought to be the cause, but the details are still unknown and fundamental treatment methods are not yet known. It has not been established yet.
- Crohn's disease is a chronic inflammatory disease mainly observed in young and adult adults, consisting of granulomatous inflammatory disease accompanied by fibrosis and ulceration, and which can occur in any part of the digestive tract. Crohn's disease is classified into stomach / duodenum, small intestine, small intestine large intestine, large intestine, rectum and special types according to the lesion site. It is classified as inactive, active, or very severe according to the activity using the crohn's disease activity index (CDAI) component (by the National Cooperative Crohn's Disease Study Group) as an index. Clinical manifestations include abdominal pain, diarrhea, fever, anal anomalies such as hemorrhoids, and weight loss. Histologically, strong lymphocyte infiltration Lupus and noncaseating epithelioid granulomas are present. The exact cause of Crohn's disease, like ulcerative colitis, has not been clarified.
- CDAI crohn's disease activity index
- steroid hormones and synthetic steroids such as budesonide are administered in hope of a remission-inducing effect.
- steroid administration caused side effects of bone loss, impaired glucose tolerance, hypertension, infection, glaucoma, cataract and gastric ulcer.
- salazosulfaviridine (salazopyrine) is administered with the expectation of an effect on colorectal lesions, but nausea, headache, fever, rash, hemolytic anemia, epidermolysis, granulocytopenia, fibrotic alveolitis Side effects such as headache, knee inflammation and male infertility have been reported.
- TNF- ⁇ Tumor Necrosis Factoi ⁇ a
- Patent Document 1 Since TNF- ⁇ production is enhanced in patients with inflammatory bowel disease, the anti-human TNF- ⁇ antibody, infliximab (genetical recombination) (Patent Document 1), is active in suppressing or neutralizing TNF- ⁇ . Is used as a drug that has the effect of improving Crohn's disease symptoms and closing the defecation in patients with Crohn's disease and patients with fistulas (dementia) (Product name: Remicade (registered trademark) for intravenous drip infusion) 100, Tanabe Seiyaku Co., Ltd.) (Non-Patent Document 2).
- infliximab at 5, 10, 20 mg / kg body weight does not change even if the dosage is changed.
- a study is needed to maintain the effect for a long time at a low dose.
- it is necessary to remit acute inflammatory diseases in a short period of time and to maintain the effects while suppressing the occurrence of side effects for a long period of time.
- Inflammatory bowel disease has no serious side effects and it is difficult to control its inflammation for a long time, and there have been many clinical cases of relapse or recurrence.
- Patent Document 1 International Publication No. W092 / 16553
- Non-Patent Document 1 Present, D.H. et al, N Engl J Med., 340 (18): 1398-1405, 1999 Disclosure of the invention
- the present inventors have made intensive studies to solve the above-mentioned therapeutic problems in the administration of the anti-human TNF-a antibody, and have completed the present invention.
- An anti-human TNF-a antibody activity reduction inhibitor in repeated administration of an anti-TNF-a antibody in the treatment of inflammatory bowel disease which comprises a protein source and a Z or carbohydrate source.
- Anti-human TNF-a antibody for the treatment of inflammatory bowel disease comprising a protein source and a Z or carbohydrate source, resulting in reduced immunity in repeated administration of the anti-TNF-a antibody Suppressive and Z or infectious disease preventive agents
- the protein source which is the active ingredient of the anti-TNF-a antibody activity reduction inhibitor of the present invention may be any animal or plant protein that is good for nutritional supply.
- milk protein is preferable, and particularly, low-lactose milk protein, casein and the like are preferable.
- the vegetable protein isolated soybean protein and the like are preferable. Two or more proteins may be blended.
- the protein source may be a peptide of a hydrolyzed protein.
- an amino acid is more preferable.
- the amino acid is not particularly limited as long as it is an amino acid usually used for the purpose of supplying nutrition such as infusion or enteral nutrition, but it is preferably a crystalline amino acid.
- the amino acid may be any of D-form, L-form and DL-form, but L-form is preferable. Specifically, L-isoleucine, L-leucine, L-parin, L-lysine, L-methionine, L-phenyalanine, L-threon, L-tryptophan, L-alanine, L-arginine, L-aspartic acid, L-cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine, glycine and the like can be mentioned. These amino acids can be used (combined) alone or in combination of two or more.
- the protein source is an amino acid
- the protein source preferably contains at least the following amino acids by dry weight. L- 2.0-8.0 W / W%
- Each amino acid need not always be used as a free amino acid, and may be used in the form of an inorganic acid salt, an organic acid salt, an ester hydrolyzable in a living body, or the like. Further, they may be used in the form of dipeptides in which the same or different amino acids are peptide-bonded. It is preferable to contain at least one of milk protein, vegetable protein, and amino acid as a protein source. In particular, by containing an amino acid as a protein source, it is possible to preferably exert an effect of suppressing the decrease in activity in repeated administration of an anti-human TNF- ⁇ antibody. Therefore, it is preferred that only amino acids be included as a protein source.
- Examples of the carbohydrate source which is an active ingredient of the anti-TNF- ⁇ antibody activity decrease inhibitor of the present invention include monosaccharides, disaccharides, and polysaccharides, which are preferred by saccharides, and more specifically, glucose. , Fructose, mannose, galactose, sucrose, sugar (or refined sucrose), maltose, lactose, dextrin, maltodextrin, starch, corn starch, soybean oligosaccharide, sugar alcohols and the like. These two or more saccharides may be blended.
- the anti-human TNF-a antibody is repeatedly administered by repeatedly containing at least one selected saccharide as a carbohydrate source. Demonstrates a reduction control effect
- the anti-TNF-a antibody activity reduction inhibitor of the present invention may contain a protein source and a carbohydrate source alone, or may contain a combination thereof.
- the anti-TNF-a antibody activity reduction inhibitor of the present invention can further contain a lipid source in addition to the protein source and the Z or carbohydrate source.
- the lipid source is preferable because it can suitably exert an activity reduction suppressing effect.
- the lipid source is not particularly limited, but is preferably a vegetable oil or an animal oil. Vegetable oils include soybean oil, perilla oil, corn oil and the like, with soybean oil being preferred. Egoma oil may be contained as an oil or fat containing a large amount of ⁇ 3 fatty acid. As an animal oil, a fish oil containing an ⁇ 3 fatty acid such as eicosapentaenoic acid or docosahexaenoic acid is preferable.
- lipids Two or more of the above-mentioned lipids may be blended.
- a fat containing at least one ⁇ 3 fatty acid selected from the group consisting of ⁇ -linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid may be contained. More preferred.
- each component is 5-30 WZW% (more preferably 8-20 WZW%) for the protein source, 40-90 WZW% (more preferably 70-85 WZW%) for the carbohydrate source, and 0- 30 WZW% (preferably 0.01-25 WZW%, more preferably 0.1-1 WZW%).
- a preferred first form of the anti-human TNF- ⁇ antibody activity decrease inhibitor of the present invention is a nutritional composition for oral or enteral administration.
- each component of the present composition is good as long as it is within the range shown above.
- the protein source is 110 WZV%
- the carbohydrate source is 5-30 WZV%
- the lipid source is 0.5-20 WZV%.
- a nutritional composition having such a component content may be in the form of an enteral nutritional supplement, such as a liquid diet.
- the amount of each amino acid in the composition is preferably the following in terms of dry weight.
- dextrin is used as a carbohydrate source and soybean oil is used as a lipid. More specifically, Elental (registered trademark) which has the composition shown in Tables 1 and 2 and is commercially available as an enteral nutritional agent can be mentioned.
- composition for oral or enteral administration of the present invention is prepared in an appropriate dosage form such as powders, fine granules, granules and tablets. , Capsules, liquid preparations and the like. Since it is preferably liquid at the time of administration, it is preferably a liquid or a dosage form which can be dissolved in an appropriate amount of water at the time of use. In order to make it easy for even the elderly and children to take the above dosage forms, it is preferable to prepare them into flavored and flavored preparations. To make it liquid, it is preferable to dilute it with water so that it becomes about 1 kcal per lcc.
- Additives to be added to powders, fine granules, granules, tablets, capsules, etc. include excipients (eg, lactose, glucose, D-mantol, starch, crystalline cellulose, calcium carbonate, calcium phosphate, light powder) Cyanic anhydride, trehalose, etc.), binders (eg, starch paste solution, gelatin solution, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, etc.), disintegrants (eg, starch, gelatin powder, carboxymethyl) Cellulose, carboxymethylcellulose calcium salt, etc.), lubricants (eg, magnesium stearate, talc, etc.), coating agents (eg, hydroxypropyl cenorellose, hydroxypropinolemethinoresenorelose, acetinoresenorelose, sucrose, acid) Dani titanium etc.) Yes, and other additives such as a coloring agent and
- Additives added to the liquid for internal use include preservatives (eg, benzoic acid, Benzoic acid esters, sodium dehydroacetate, etc.), suspending or emulsifying agents (eg, arabia gum, tragacanth, carboxymethylcellulose sodium salt, methylcellulose, egg yolk, surfactants, etc.), sweetening and souring agents (eg, trehalose, quinic acid) And the like, and if necessary, a coloring agent, a stabilizer and the like are added.
- a solvent used for these mainly purified water such as ethanol, glycerin and propylene glycol can be used.
- each active ingredient is used as it is, or mixed and granulated with a pharmaceutically or pharmaceutically acceptable additive according to each dosage form, or dissolved in an appropriate solvent.
- a pharmaceutically or pharmaceutically acceptable additive according to each dosage form, or dissolved in an appropriate solvent.
- It can be prepared by a conventional method, for example, by emulsifying or suspending and further mixing with an appropriate base.
- the dosage is preferably 80 to 640 g (300 to 2400 kcal) per day for adults and more preferably around 1200 kcal, but can be adjusted according to age, body weight and symptoms. is there.
- Examples of the administration method include a method of injecting into nasal cavity, gastric fistula, or intestinal fistula into the duodenum or jejunum, or orally.
- the administration period is not particularly limited as long as the patient is suffering from an inflammatory disease, but is preferably administered at least during the anti-human TNF-a antibody treatment period.
- the anti-human TNF-a antibody may be administered before the start of the therapy, or the anti-human TNF-a antibody may be continuously administered after the end of the therapy! It is more preferable to administer the anti-human TNF- ⁇ antibody continuously every day during the administration period of the anti-human TNF- ⁇ antibody from the start of repeated administration.
- the viscosity of the solution is preferably 5 mPa's or less, so long as it is within this viscosity range. It can be easily administered enterally in the stomach and intestine.
- bedridden patients have the problem that, when the low-viscosity solution is administered, the esophagus is refluxed and vomiting is caused, and it causes reflux pneumonia.
- a thickener it is preferable to add to the composition of the present invention to increase the solution viscosity.
- the thickener it is preferable to use sodium alginate, alginic acid and carrageenans. The thickener is preferably added so that the solution viscosity can be adjusted to 300 mPa's or more.
- the anti-human TNF-a antibody activity decrease inhibitor of the present invention includes dietary fiber, for example, a water-soluble diet. It is also possible to add artificial fiber or insoluble dietary fiber. The amount of dietary fiber added
- the daily dose is preferably 1 to 30 g, more preferably 5 to 15 g, particularly preferably 3 to 8 g.
- Dietary fibers include pectin, methoxy pectin, galatatomannan, arginic acid and its salts, agar extracted from seaweeds containing galactans such as tenguza and ogonori, carboxymethylcellulose and its salts as water-soluble dietary fibers. I can list them.
- the insoluble fibers include plant-derived fibers such as apple fiber, corn fiber, and non-fiber, dried vegetables such as broccoli, cauliflower, cabbage, and spinach, cellulose, hemicellulose, carrageenan, and lignin.
- the ingredients include soybean and wheat bran.
- a preferred U-second form of the anti-human TNF-a antibody activity decrease inhibitor of the present invention is that it is prepared into a preparation for administration into the central vein.
- the content of each active ingredient can be arbitrarily prepared as an infusion component with reference to a preparation for oral or enteral administration. The same applies to the dose.
- PENTUSIN registered trademark which has the composition shown in Table 3 below and is commercially available as a high-calorie infusion solution.
- Lithium dihydrogen phosphate 2.176
- kits product in which the suppression of the decrease in the activity of the anti-human TNF-a antibody of the present invention is integrally packaged with the anti-human TNF-a antibody is also good.
- the anti-human TNF-a antibody is prepared as a lyophilized product
- the lyophilized anti-human TNF- ⁇ antibody is placed in a plastic container in order to demonstrate the convenience of administration and the usefulness of aseptic preparation.
- it may be in the form of a kit preparation in which the infusion is separated and housed in a communicable manner.
- the present invention can be expected to have an effect of suppressing the decrease in activity by repeated administration of an anti-human TNF-a antibody to patients with Crohn's disease among inflammatory bowel diseases.
- Crohn's disease has a more favorable effect in the active phase and in patients with Z or deafness.
- the anti-human TNF-a antibody activity reduction inhibitor of the present invention has an effect of reducing the side effects of antibody administration in combination with immunosuppression.
- an antibody having high affinity for TNF- ⁇ in a human body and having an action of neutralizing the activity can be used.
- the affinity for human TNF-alpha, of at least 10 8 Micromax _1 in the Ka preferably has a 10 9 Micromax affinity _1 even without more preferably less.
- strong in vivo human TNF- ⁇ blocking ability or neutralization ability for example, the ability to neutralize the cytotoxic activity of human TNF- ⁇ , the ability to block TNF-induced IL-6 secretion, (Eg, the ability to block procoagulant activity).
- Those having high specificity for human TNF- ⁇ are preferred.
- the anti-human TNF-a antibody used in the present invention a monoclonal antibody or a part thereof can be used.
- examples of such antibodies include chimeric antibodies, humanized antibodies, humanized antibodies, primatized antibodies, surface-reprocessed antibodies, single-chain antibodies, and TNF receptor-IgG-Fc fusion proteins. It is desirable that these antibodies have low immunogenicity and toxicity in vivo.
- a chimeric antibody is an immunoglobulin molecule characterized by the binding of two or more moieties from different animal species.
- the variable region of a chimeric antibody is derived from a non-human mammal antibody (eg, a mouse monoclonal antibody) and is combined with its immunoglobulin constant regions.
- Chimeric antibodies include monovalent, divalent or polyvalent immunoglobulins. Chimeric antibodies and methods for producing them are described in EP1714961, EP173494, WO86 / 01533, EP184187, WO87 / 02671, WO910996, W092 / 11383, and the like. Further, infliximab can be mentioned as a preferred drug.
- Infliximab (generic name: Infliximab, trade name: Remicade (registered trademark)) is a chimeric monoclonal comprising the antigen-binding variable region of mouse anti-human TNF- ⁇ mouse IgGl antibody and the constant region of human HgGl kappa immunoglobulin. Antibodies. Infliximab can be produced by the production method described in International Publication WO092 / 16553. [0023] Humanization and surface treatment of antibodies are described in US5225539, EP239400, EP519596, and EP592106.
- the anti-TNF-antibody of the present invention is more preferably used in the treatment of rheumatism in the same manner as infliximab. Is acceptable.
- the anti-TNF-a antibody activity inhibitor of the present invention makes it possible to use an anti-human TNF-a antibody, which is an excellent therapeutic agent, in drug therapy for patients with inflammatory bowel disease, for the treatment of inflammatory bowel disease.
- an anti-human TNF-a antibody which is an excellent therapeutic agent
- a decrease in the activity of the anti-human TNF-a antibody when repeatedly administered can be effectively suppressed.
- the anti-TNF-a antibody which is an excellent therapeutic agent in pharmacotherapy for patients with inflammatory bowel disease
- it can suppress immune decline and prevent Z or infectious diseases when repeatedly administered.
- the patient was a 31-year-old man who was a small intestine / colon type Crohn's disease patient who developed at the age of 25. By August 2002, he had three hospitalizations with repeated recurrence of Crohn's disease.
- infliximab (Remicade (registered trademark) for intravenous infusion 100) was administered enterally with 1200 kcal of Elental (registered trademark). 5 mg / kg was administered.
- the pre-dose clinical activity index for Crohn's disease was 186 (more than 150 active), but dropped to 67 two weeks after treatment. During this time, open longitudinal ulcers in the transverse and sigmoid colons became scarred. After that, she was treated with home enteral nutrition therapy, but the symptoms recurred in February 2003 and the CDAI rose to 230.
- infliximab stimulates antibody production, and its effect is diminished by repeated administration, but it is presumed that in the above case, the effect of infliximab could be maintained by the combined use of Elental (registered trademark). .
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Abstract
Description
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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JP2006510518A JP5554466B2 (ja) | 2004-03-01 | 2005-03-01 | 抗ヒトTNF−α抗体活性低下抑制剤 |
US11/514,225 US7638335B2 (en) | 2004-03-01 | 2006-09-01 | Kit comprising antihuman TNF-α antibody and antihuman TNF-α antibody activity lowering inhibitor |
US12/562,728 US7871631B2 (en) | 2004-03-01 | 2009-09-18 | Methods of inhibiting the lowering of antihuman TNF-α antibody |
US12/620,191 US20100061999A1 (en) | 2004-03-01 | 2009-11-17 | Antihuman tnf-alpha antibody activity lowering inhibitor |
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JP2004-056343 | 2004-03-01 | ||
JP2004056343 | 2004-03-01 |
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US11/514,225 Continuation US7638335B2 (en) | 2004-03-01 | 2006-09-01 | Kit comprising antihuman TNF-α antibody and antihuman TNF-α antibody activity lowering inhibitor |
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WO2005082377A1 true WO2005082377A1 (ja) | 2005-09-09 |
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JP2014530254A (ja) * | 2011-10-18 | 2014-11-17 | コヒラス・バイオサイエンシズ・インコーポレイテッド | アミノ酸によって安定化されたエタネルセプト製剤 |
JP2016132622A (ja) * | 2015-01-16 | 2016-07-25 | イーエヌ大塚製薬株式会社 | 敗血症治療又は予防用栄養組成物 |
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JPWO2005082377A1 (ja) | 2007-10-25 |
US20060292148A1 (en) | 2006-12-28 |
US20100008916A1 (en) | 2010-01-14 |
JP5554466B2 (ja) | 2014-07-23 |
JP2012184249A (ja) | 2012-09-27 |
JP5672264B2 (ja) | 2015-02-18 |
US20100061999A1 (en) | 2010-03-11 |
US7871631B2 (en) | 2011-01-18 |
US7638335B2 (en) | 2009-12-29 |
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