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WO2004071496A1 - Forme d'administration orale contenant de l'acide liponique destinee a la liberation d'agent actif specifique au colon - Google Patents

Forme d'administration orale contenant de l'acide liponique destinee a la liberation d'agent actif specifique au colon Download PDF

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Publication number
WO2004071496A1
WO2004071496A1 PCT/EP2004/001079 EP2004001079W WO2004071496A1 WO 2004071496 A1 WO2004071496 A1 WO 2004071496A1 EP 2004001079 W EP2004001079 W EP 2004001079W WO 2004071496 A1 WO2004071496 A1 WO 2004071496A1
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WO
WIPO (PCT)
Prior art keywords
acid
component
composition according
lipoic acid
colon
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2004/001079
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German (de)
English (en)
Inventor
Andreas Bernkop-Schnürch
Hans Schuhbauer
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Evonik Operations GmbH
Original Assignee
Degussa GmbH
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Filing date
Publication date
Application filed by Degussa GmbH filed Critical Degussa GmbH
Publication of WO2004071496A1 publication Critical patent/WO2004071496A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention relates to a pharmaceutical composition as a dosage form for the colon-specific active ingredient release of ⁇ -lipoic acid (derivatives) and their use.
  • ⁇ -Lipoic acid (thioctic acid, 1, 2-dithiolane-3-pentanoic acid) occurs in small concentrations in the form of its R enantiomer in plant and animal cells as a natural product.
  • the ⁇ -lipoic acid originally discovered as a growth factor acts physiologically in hydrophilic and lipophilic media as a coenzyme in the oxidative decarboxylation of ⁇ -ketocarboxylic acids, e.g. Pyruvates, and as an antioxidant.
  • ⁇ -lipoic acid is used to regenerate vitamin C, vitamin E, glutathione and coenzyme Q10.
  • ⁇ -Lipoic acid increases glucose metabolism and has been used for some time to treat diabetic polyneuropathy (D. Ziegler, M. Hanefeld, KJ Ruhnau, HP Meissner, M. Lobisch, K. Schutte, FA Gries, Treatment of symptomatic diabetic peripheral neuropathy with the antioxidant ⁇ -lipoic acid: A 3-week multicentre randomized controlled trial (ALADIN study), Diabetologia 38 (1995) 1425-1433).
  • ⁇ -Lipoic acid is also an excellent radical scavenger, which shows an anti-inflammatory effect in inflammatory diseases (RW Egan, PH Gale, GC Beveridge, GB Phillips, LJ Marnett, Radical scavenging as the mechanism for Stimulation of prostaglandin cyclooxygenase and depression of inflammation by lipoic acid and sodium iodide. Prostaglandins. 1978 Dec; 16 (6): 861-9). Inflammation of the colon, such as ulcerative colitis, bowel disease or Crohn's disease, is a special form of such inflammatory diseases.
  • ⁇ -lipoic acid Due to its antioxidant and radical scavenger properties, ⁇ -lipoic acid, which is also used as a dietary supplement, could be a positive one Show effect on the course or the healing process of such inflammatory diseases of the colon. When administered orally, however, ⁇ -lipoic acid is already completely absorbed in the stomach and small intestine, so that the active ingredient does not reach the colon as the actual target site.
  • Tozaki et al. H. Tozaki, T. Fujita, T. Odoriba, A. Terabe, T. Suzuki, C. Tanaka, S. Okabe, S. Muranishi, A.
  • Yamamoto Colon-specific delivery of R68070, a new thromboxane synthase inhibitor, using chitosan capsules: therapeutic effects against 2,4,6-trinitrobenzene sulfonic acid-induced ulcerative colitis in rats, Life Sei. 64 (1999) 1155-1162; H. Tozaki, J. Komoike, C. Tada, T. Maruyama, A. Terabe, T. Suzuki, A. Yamamoto, S. Muranishi, Chitosan capsules for colon-specific drug delivery: improvement of insulin absorption from the rat colon, J. Pharm. Sei.
  • DE 100 45 904 A1 describes an extended-release formulation containing ⁇ -lipoic acid and chitosan, which, in addition to the lipoic acid component, consists of at least one cationogenic polymer and at least one acid different from the lipoic acid component, and which contains the active ingredient ⁇ -lipoic acid in in vitro controlled release studies over 8 hours.
  • ⁇ -lipoic acid is largely released in the small intestine after oral administration (Andreas Bemkop-Schnürch, Elisabeth Reich-Rohrwig, Michaela Martent, Hans Schuhbauer, Martin Kratzel; not yet published).
  • ⁇ -lipoic acid / chitosan formulations are suitable as sustained release forms for releasing the active substance ⁇ -lipoic acid over a prolonged period and thus keeping it at a high concentration level in the plasma for a longer period of time, but such formulations are only suitable to a limited extent in order to achieve specific drug release.
  • the object of the present invention is to provide a pharmaceutical composition which, in particular, has an improved release and thus bioavailability of the ⁇ -lipoic acid and / or its suitable derivatives in the colon -Area and ensures that the ⁇ -lipoic acid plasma level remains constant for several hours in order to significantly improve the therapeutic effect of ⁇ -lipoic acid (derivatives).
  • the new drug release system was primarily intended to ensure the controlled drug release of ⁇ -lipoic acid or its suitable derivatives in the colon.
  • (d) contains at least one synthetic polymeric auxiliary different from component (a).
  • ⁇ -lipoic acid when ⁇ -lipoic acid is combined with, for example, chitosan as component (a), the desired release of active ingredient does not actually occur until the active ingredient (b) and the polymer (a) are in a preferred ratio to one another, but always with the addition of certain auxiliaries, such as Acetic acid, as component (c) and synthetic polymers, such as suitable hydrogel formers, can be used as component (d).
  • auxiliaries such as Acetic acid
  • synthetic polymers such as suitable hydrogel formers
  • Chitosan so decisively influenced that the swelling process actually begins only when the formulation has already reached the last section of the small intestine.
  • this swelling process which therefore only starts fully in the colon, there is a controlled colon-specific release of active ingredient, which is caused by the enzymatic degradation of the cationogenic polymer, e.g. Chitosan, is additionally reinforced in the colon.
  • the present invention thus represents a colon-specific dosage form with which release systems are made available by combining an anionogenic active substance such as ⁇ -lipoic acid with a special cationogenic carrier matrix and auxiliary substances, which release the active substance with a time delay due to predominantly ionic interactions between the components and after a certain passage distance, the majority only release in the colon.
  • an anionogenic active substance such as ⁇ -lipoic acid
  • auxiliary substances which release the active substance with a time delay due to predominantly ionic interactions between the components and after a certain passage distance, the majority only release in the colon.
  • an increased serum ⁇ -lipoic acid concentration of 500 ng / ml or higher is preferably only detectable after at least 2 hours, particularly preferably only after at least 3 hours.
  • the release of the active ingredient is preferably delayed in vitro under the conditions described in Example 1.4 such that a cumulative active ingredient release of 50% and a differential active ingredient release of at least 5 mg / h each occur over a period of more than 4 hours.
  • the cationogenic polymer (a) is preferably selected from chitosan (poly-D-glucosamine), a chitosan salt (such as, for example, chitosan hydrochloride, acetate or glutamate), cationogenic polypeptides (such as poly-L-lysine), basic Lectins (glycoproteins, e.g. from extracts such as phytohemagglutinins or other basic polypeptides), basic polysaccharides (such as hexosamine sugar) or basic biopolymers of plant, animal or synthetic origin as well as any mixtures thereof.
  • chitosan poly-D-glucosamine
  • a chitosan salt such as, for example, chitosan hydrochloride, acetate or glutamate
  • cationogenic polypeptides such as poly-L-lysine
  • basic Lectins glycoproteins, e.g. from extracts such as phytohe
  • racemic and enantiomerically pure R - (+) - ⁇ -lipoic acid or S- (-) - ⁇ -lipoic acid or salts thereof or any mixtures thereof have proven particularly useful for the administration system according to the invention. It is also possible to use racemic dihydroliponic acid (6,8-dimercaptooctanoic acid) or enantiomerically pure S - (+) - dihydroliponic acid or R - (-) - dihydroliponic acid or salts thereof or any mixtures thereof.
  • component (a) anionogenic ⁇ -lipoic acid
  • component (b) anionogenic ⁇ -lipoic acid
  • component (c) anion A ⁇
  • auxiliary component ( d) auxiliary component
  • the chitosan preferred as a cationogenic polymer can be obtained from chitin (poly-N-acetyl-D-glucosamine) by chemical conversion (deacetylation).
  • the natural sources of chitosan include krill and the shells of crabs, lobsters, lobsters and other representatives of the crustaceans.
  • High molecular weight chitosan with a molecular weight of 50 to 500 kilodaltons and a degree of deacetylation of 80 to 95% is particularly suitable for use in cosmetic formulations and in food supplements.
  • the lipoic acid component is used entirely or partially in the form of its salts as an anionogenic component. Salts which contain cations from the series of alkali metals (such as sodium or potassium) or alkaline earth metals (such as calcium or magnesium) are particularly suitable.
  • the content of the lipoic acid component (b) in the release system can be varied within wide limits. However, it has proven to be particularly advantageous to set the proportion by weight of the lipoic acid component, based on the total weight of the active ingredient release system, between 0.1 and 90% by weight, in particular between 20 and 70% by weight. Analogously, the proportion by weight of the cationogenic polymer component (a) should preferably be between 0.1 and 90% by weight and in particular between 10 and 75% by weight.
  • the proportions of the organic acid component (c) can also be varied widely. According to the invention, portions of 0.001 to 80% by weight are preferably provided, but portions of 0.1 to 50% by weight and in particular portions of 0.1 to 25% by weight, again based on the total weight of the delivery system , are to be preferred.
  • organic or inorganic Bronsted acids such as acetic acid, hydrochloric acid, (modified) polymethacrylic acid and glutamic acid
  • organic or inorganic Lewis acids from their range carbon dioxide, Ca 2+ and Fe 2+ are particularly suitable.
  • Physiologically acceptable acids are expediently used.
  • the invention thus takes into account any mixtures of individual acid forms with one another but also between the individual acid forms.
  • the polymeric adjuvant according to component (d) is a substance which at least partially inhibits the release in the stomach and / or small intestine.
  • preferred representatives of component (d), the synthetic, polymeric auxiliary are hydrogel formers, such as polyvinylpyrrolidone, optionally modified polymethacrylates, such as polyhydroxyethyl methacrylate (PHEMA), or acrylates, such as poly (N-isopropylacrylamide) and polyurethanes, or polysaccharides, such as Sodium alginate.
  • hydrogel formation can also be carried out by suitable freeze-drying measures and / or the addition of porosinogens, e.g.
  • component (d) Water, micronized sucrose, lactose, dextrin, sodium chloride and / or polyethylene glycols (PEG) with a typical molecular weight of approx. 40,000 daltons.
  • proportions are to be regarded as particularly suitable which, based on the total weight of the system, are between 0.1 and 80% by weight and in particular between 1.0 and 10% by weight.
  • the present invention prefers a dosage form which, in addition to the components (a) to (d) which are essential to the invention, also contains a polyvalent anion, for example a sulfate, in particular Na 2 SO 4 and / or K 2 SO 4 , as a result of which the swelling behavior of the cationogenic polymeric carrier (for example chitosan) can be influenced by the polyvalent anion in a particularly advantageous manner for the user.
  • a polyvalent anion for example a sulfate, in particular Na 2 SO 4 and / or K 2 SO 4
  • proportions are to be regarded as particularly suitable which, based on the total weight of the system at max. 30% by weight and in particular between 0.5% and 5% by weight.
  • the preparation of the dosage form according to the invention is not restricted to any special process, but because of its simplicity, a procedure is recommended in which the cationogenic polymer (for example chitosan) is swollen in water with the addition of an acid, such as glacial acetic acid, and then this approach with the lipoic acid Component and the auxiliary is homogenized. Finally, the system can be assembled accordingly.
  • the cationogenic polymer for example chitosan
  • the lipoic acid homogenized with chitosan or another suitable cationogenic polymer according to the invention and components (c) and (d) can also be produced by any other suitable method. It is of primary importance here whether the lipoic acid component was produced, for example, by recrystallization with an organic solvent or solvent mixture, or whether the crude ⁇ -lipoic acid is used without any organic solvent.
  • customary formulation aids can be used as additional optional components of the agent. Fillers, lubricants, flow aids, mold release agents, plasticizers, blowing agents, stabilizers, dyes, extenders, binders, disintegrants, wetting agents, flow agents or counter-adhesives are particularly suitable for this purpose.
  • the present invention also relates to its use, in particular for producing an agent for the treatment and / or prevention of inflammatory diseases of the colon, disease forms such as colitis, enterocolitis, gastrocolitis, gastroenteritis or enteritis being particularly suitable according to the invention.
  • disease forms such as colitis, enterocolitis, gastrocolitis, gastroenteritis or enteritis being particularly suitable according to the invention.
  • preparation of an agent for the treatment of irritable bowel syndrome or Crohn's disease, particularly persistent forms of disease is also provided.
  • the use of special dosage forms of the agent that are suitable for oral administration such as tablets (for example enteric-coated film tablets), dragées, micro- and nanoparticles, has proven itself, the latter two forms also in the tablets and dragées or another Means can be included.
  • the average size of the micro or nanoparticles is preferably in the range from 50 nm to 200 ⁇ m.
  • Illustration 1
  • component (a) anionogenic ⁇ -lipoic acid
  • component (b) anionogenic ⁇ -lipoic acid
  • component (c) anion A
  • polymeric auxiliary (d) " PH-
  • This mixture was dried at 37 ° C. and granulated (ERWEKA, Briquette breaker).
  • the granules were comminuted again with a roller crusher and pressed into tablets with a eccentric press to form a diameter of 10 mm, a height of 3.5 mm and a weight of 3.3 g ⁇ 0.2 g.
  • the tablets were then coated with a gastric juice resistant coating.
  • a gastric juice resistant coating For this purpose, 1.08 g of Eudragit L100-55 were dissolved in 10 ml of acetone which contained 1 mg of NaOH. Then 0.54 g of talc and color pigment (q.s.) were added. After the addition of 120 ⁇ l of triethyl citrate, the tablets were coated uniformly with this suspension and dried for at least 3 days. Yellow was chosen as the color pigment according to the Lüscher color theory, since this color is to be regarded as the most suitable for gastrointestinal disorders for psychological reasons.
  • the release profile of the tablets was determined using the leaf stirring method in a dissolution tester. 800 ml of 0.08 M HCl served as the release medium in the first two hours, and a phosphate buffer pH 6.7 served as the release medium for the rest of the period. With a water bath was warmed to 37 ° C. The speed of the stirrer was 50 revolutions per minute. Aliquots of 1 ml were taken at certain intervals and analyzed by HPLC as described above. The release showed no active ingredient release in the artificial gastric juice (0.08 M HCI). However, a controlled release of the active ingredient was achieved by a pH shift to pH 6.7. The results of this study are summarized in Figure 2. In order to obtain an in vitro / in vivo correlation, the hourly "differential" drug release in mg has been shown graphically (Figure 3).
  • a test person male; 36 years was given four ⁇ -lipoic acid tablets (330 mg per tablet), which were produced as described in Example 1, orally and the concentration of ⁇ -lipoic acid in the blood was determined at 30 minute intervals. It was shown that the active ingredient is released completely in the colon. The average length of time in the stomach when fasted is between 30 and 90 minutes, that in the small intestine between 150 and 200 minutes (Coupe, Davies, Wilding, quote, see below). Since the active ingredient ⁇ -lipoic acid is absorbed immediately after its release and thus enters the blood without delay (R. Hermann, G.
  • the same subject showed an increased concentration of ⁇ -lipoic acid in the blood after 15 minutes after taking DE-OS 100 45 904 unmodified ⁇ -lipoic acid / chitosan tablets.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un système de libération d'agent actif spécifique au colon, contenant un acide liponique, caractérisé en ce qu'il est composé (a) d'au moins un polymère cationogène ; (b) d'un dérivé d'acide alpha -liponique ; (c) d'au moins un acide organique différent du composant d'acide liponique (b) ; et, (d) d'au moins un agent auxiliaire polymère synthétique, différent du composant polymère (a). Etonnamment, le système de libération d'agent actif selon l'invention permet d'obtenir une libération d'agent actif contrôlée plus longue dans le colon. Par conséquent, la concentration en acide liponique est augmentée de façon forcée dans le colon, ce qui présente un intérêt médical et commercial dans le traitement de diverses maladies spécifiques au colon. Il est par ailleurs possible de répondre de façon avantageuse à des exigences techniques d'application par utilisation supplémentaire d'un composant sulfate facultatif.
PCT/EP2004/001079 2003-02-12 2004-02-05 Forme d'administration orale contenant de l'acide liponique destinee a la liberation d'agent actif specifique au colon Ceased WO2004071496A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10305661.0 2003-02-12
DE10305661A DE10305661A1 (de) 2003-02-12 2003-02-12 Darreichungsform zur Kolon-spezifischen Wirkstofffreisetzung

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008006890A3 (fr) * 2006-07-14 2008-04-17 Fabio Conteduca matériau biocompatible de synthèse à résistance à l'oxydation accrue, procédé de préparation dudit matériau et articles prothétiques produits avec ledit matériau
US8476233B2 (en) 2003-08-29 2013-07-02 Therapeutic Research, Llc Methods for treatment for ulcerative colitis in mammals
US8916546B2 (en) 2003-08-29 2014-12-23 Therapeutic Research Llc Materials and methods for treatment and diagnosis of disorders associated with oxidative stress
CN106188168A (zh) * 2016-07-18 2016-12-07 山东师范大学 利用生产谷氨酸的菌渣制备盐酸氨基葡萄糖的方法
CN106905478A (zh) * 2017-04-19 2017-06-30 贵州大学 一种α‑硫辛酸分子印迹聚合物及其制备方法
FR3122573A1 (fr) * 2021-05-10 2022-11-11 Hydro Fill Technology Compositions de conjugués poly-lysine et de micelles et/ou de copolymères de poly-lysine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117229429B (zh) * 2023-08-17 2024-03-15 江西师范大学 一种壳寡糖硫酸盐及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4317646A1 (de) * 1993-05-27 1994-12-01 Asta Medica Ag Tabletten mit Thioctsäure und mindestens einer basischen Komponente
WO2000053176A1 (fr) * 1999-03-05 2000-09-14 Uni-Ci S.R.L. Compositions pharmaceutiques, dietetiques et cosmetiques a base d'acide alpha-lipoique et de cysteine
DE19938098A1 (de) * 1999-08-12 2001-02-15 Woerwag Pharma Gmbh & Co Feste Arzneimittelformulierung mit hohem Gehalt an Thioctsäure (alpha-Liponsäure)
DE10045904A1 (de) * 1999-10-01 2001-11-15 Sueddeutsche Kalkstickstoff alpha-Liponsäure(-Derivate) enthaltende Retardform
US20020102301A1 (en) * 2000-01-13 2002-08-01 Joseph Schwarz Pharmaceutical solid self-emulsifying composition for sustained delivery of biologically active compounds and the process for preparation thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4317646A1 (de) * 1993-05-27 1994-12-01 Asta Medica Ag Tabletten mit Thioctsäure und mindestens einer basischen Komponente
WO2000053176A1 (fr) * 1999-03-05 2000-09-14 Uni-Ci S.R.L. Compositions pharmaceutiques, dietetiques et cosmetiques a base d'acide alpha-lipoique et de cysteine
DE19938098A1 (de) * 1999-08-12 2001-02-15 Woerwag Pharma Gmbh & Co Feste Arzneimittelformulierung mit hohem Gehalt an Thioctsäure (alpha-Liponsäure)
DE10045904A1 (de) * 1999-10-01 2001-11-15 Sueddeutsche Kalkstickstoff alpha-Liponsäure(-Derivate) enthaltende Retardform
US20020102301A1 (en) * 2000-01-13 2002-08-01 Joseph Schwarz Pharmaceutical solid self-emulsifying composition for sustained delivery of biologically active compounds and the process for preparation thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TOZYKI-H. FUJITA-T. ODORIBA-T. TERABE-A. SUZUKI-T. TANAKA-C. OKABE-S. MURANISHI-S. YAMAMOTO-A.: "Colon-Specific Delivery of R68070, a New Thromboxane Synthase Inhibitor, Using Chitosan Capsules: Therapeutic Effects against 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Ulcerative Colitis in Rats.", LIFE SCIENCES, vol. 64, no. 13, 1999, pages 1155 - 1162, XP001182415 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8476233B2 (en) 2003-08-29 2013-07-02 Therapeutic Research, Llc Methods for treatment for ulcerative colitis in mammals
US8916546B2 (en) 2003-08-29 2014-12-23 Therapeutic Research Llc Materials and methods for treatment and diagnosis of disorders associated with oxidative stress
US10064877B2 (en) 2003-08-29 2018-09-04 Therapeutic Research, Llc Materials and methods for treatment and diagnosis of disorders associated with oxidative stress
WO2008006890A3 (fr) * 2006-07-14 2008-04-17 Fabio Conteduca matériau biocompatible de synthèse à résistance à l'oxydation accrue, procédé de préparation dudit matériau et articles prothétiques produits avec ledit matériau
US7989518B2 (en) 2006-07-14 2011-08-02 Fabio Conteduca Synthetic biocompatible material having an improved oxidation resistance, process for preparing the same and prosthetic articles obtained therefrom
CN106188168A (zh) * 2016-07-18 2016-12-07 山东师范大学 利用生产谷氨酸的菌渣制备盐酸氨基葡萄糖的方法
CN106905478A (zh) * 2017-04-19 2017-06-30 贵州大学 一种α‑硫辛酸分子印迹聚合物及其制备方法
FR3122573A1 (fr) * 2021-05-10 2022-11-11 Hydro Fill Technology Compositions de conjugués poly-lysine et de micelles et/ou de copolymères de poly-lysine
WO2022238400A1 (fr) * 2021-05-10 2022-11-17 Hydro Fill Technology Compositions de conjugues poly-lysine et de micelles et/ou de copolymeres de poly-lysine

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