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WO1999061481A1 - Derives de polysaccharide amphiphiles - Google Patents

Derives de polysaccharide amphiphiles Download PDF

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Publication number
WO1999061481A1
WO1999061481A1 PCT/KR1999/000242 KR9900242W WO9961481A1 WO 1999061481 A1 WO1999061481 A1 WO 1999061481A1 KR 9900242 W KR9900242 W KR 9900242W WO 9961481 A1 WO9961481 A1 WO 9961481A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
heparin
matter
composition
polysaccharide
Prior art date
Application number
PCT/KR1999/000242
Other languages
English (en)
Inventor
Youngro Byun
Yong Kyu Lee
Original Assignee
Mediplex Corporation, Korea
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from KR1019990014003A external-priority patent/KR100314496B1/ko
Application filed by Mediplex Corporation, Korea filed Critical Mediplex Corporation, Korea
Priority to GB0001794A priority Critical patent/GB2342357B/en
Priority to DE19981169T priority patent/DE19981169B4/de
Priority to JP2000550884A priority patent/JP3541007B2/ja
Priority to AU37358/99A priority patent/AU3735899A/en
Publication of WO1999061481A1 publication Critical patent/WO1999061481A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—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 non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof

Definitions

  • This invention relates to polysaccharide derivatives having increased hydrophobicity as
  • the invention relates to
  • amphiphilic polysaccharide derivatives such as amphiphilic heparin derivatives, wherein the bioactivity of the polysaccharide is preserved. Further, the invention relates to methods of making and using such amphiphilic polysaccharide derivatives.
  • Heparin is a polysaccharide composed of sulfated D-glucosamine and D-glucuronic acid
  • heparin sodium e.g. heparin sodium. It is found in mast cells and can be extracted from many body organs,
  • liver and lungs are especially rich in heparin.
  • the circulating blood contains no heparin except after profound disruption of mast cells.
  • Heparin has many physiological roles, such as blood anticoagulation, inhibition of smooth
  • heparin is a potent anticoagulant agent that
  • heparin is not absorbed efficiently from the GI tract, nasal or buccal mucosal layers, and the like.
  • heparin is soluble in relatively few solvents, it is hard to use for coating surfaces of medical devices or in delivery systems. To improve the properties of heparin, R.J. Linhardt et al., 83 J. Pharm. Sci. 1034-1039
  • One method involves binding heparin to a cationic polymer matrix by ionic bonds. The release of heparin is controlled by an ion exchange mechanism. Another method involves dispersed heparin, where heparin is first physically blended with a polymer, and then the release
  • heparin device is solvent casting. But a solvent casting method cannot be used for preparing the heparin device since heparin is not dissolved in the organic solvent used for dissolving the polymer. If heparin derivatives could be prepared with increased hydrophobicity while maintaining bioactivity, then the heparin derivatives could be simply immobilized in a polymer matrix by a solvent casting procedure.
  • heparin derivative or amphiphilic heparin derivative having high bioactivity would be a
  • hydrophobic heparin derivative could be used in a hydrophobic heparin derivative
  • heparin derivative would greatly extend the medical applications of heparin.
  • composition of matter such as cholesterol, or an alkanoic acid.
  • the polysaccharide is a member selected from the group consisting of heparin, hepa ⁇ n sodium,
  • especially preferred polysaccharide is heparin.
  • heparin has a molecular weight
  • the hydrophobic agent is a member selected from the group consisting of bile acids, sterols, and alkanoic acids.
  • Preferred bile acids include cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid,
  • glycocholic acid taurocholic acid
  • glycodeoxycholic acid glycochenodeoxycholic acid
  • dehydrocholic acid hyocholic acid
  • hyodeoxycholic acid and mixtures thereof.
  • Preferred sterols Preferred sterols
  • cholestanol examples include cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and
  • alkanoic acids comprise about 4 to 20 carbon atoms, such as butyric
  • valeric acid valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid,
  • polysaccharide and the hydrophobic agent are selected from the group consisting of the polysaccharide and the hydrophobic agent.
  • the polysaccharide and the hydrophobic agent are selected from the group consisting of the polysaccharide and the hydrophobic agent.
  • Another aspect of the invention comprises a pharmaceutical composition comprising a
  • composition of matter comprising a polysaccharide
  • pharmaceutically acceptable carrier can be an oral drug carrier, sustained release carrier, carrier
  • sustained release carriers include polymeric matrices such as are well known in the art, including members selected from the group consisting of poly(ethylene oxide)-poly( ⁇ -caprolactone) copolymers, polyurethane polymers, silicone polymers, ethylene vinyl acetate polymers, hydrogels, collagen, gelatin, and mixtures thereof, and the li ke.
  • Still another aspect of the invention comprises a method for inhibiting blood coagulation
  • composition comprising a polymeric matrix intimately admixed with a composition of matter comprising heparin covalently bonded to a hydrophobic agent.
  • the medical device is coated by using a film casting technique such as is well known in the art.
  • FIG. 1 shows bioactivity of hydrophobic heparin as determined by APTT (closed
  • FIG. 2 shows clotting time as a function of time when low molecular weight heparin-
  • DOCA is administered orally.
  • FIG. 3 shows clotting time as a function of time when high molecular weight heparin- DOCA is administered orally.
  • FIG. 4 shows cumulative heparin-DOCA conjugate release from a poly(ethylene oxide)-
  • PEO-PCL poly( ⁇ -caprolactone)
  • heparin-DOCA in the polymeric matrix (v), 5% DOCA; (o), 10% DOCA; ( ⁇ ), 20% DOCA; (D),
  • a bile acid includes a mixture of two or more of such bile acids
  • an alkanoic acid includes reference to one or more of such alkanoic acids
  • a sterol includes reference to a mixture of two or more sterols.
  • Bile acids means natural and synthetic derivatives of the steroid
  • cholanic acid including, without limitation, cholic acid, deoxycholic acid, chenodeoxycholic
  • glycochenodeoxycholic acid dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, and
  • sterols means alcohols structurally related to the steroids including,
  • alkanoic acids means saturated fatty acids of about 4 to 20 carbon
  • alkanoic acids include, without limitation, butyric acid, valeric acid, caproic
  • caprylic acid caprylic acid
  • capric acid lauric acid
  • myristic acid palmitic acid
  • stearic acid and mixtures
  • hydrophobic heparin derivative and “amphiphilic heparin derivative” are used interchangeably.
  • Heparin is a very hydrophilic material. Increasing the hydrophobicity of heparin by bonding a hydrophobic agent thereto results in what is termed herein an amphiphilic heparin derivative or hydrophobic heparin derivative. Either term is believed proper
  • heparin derivative has increased hydrophobicity as compared to native heparin and
  • the heparin derivative has a hydrophilic portion and a hydrophobic portion and is, thus,
  • heparin is used as an antithrombogenic agent to prevent blood
  • Heparin is highly hydrophilic because of a high density of negative charges such as are provided by sulfonic and carboxylic groups. Due to this hydrophilicity, heparin is usually
  • Heparin derivatives with slightly hydrophobic properties or amphiphilic properties and with high bioactivity are described herein.
  • Hydrophobic agents such as bile acids, e.g. deoxycholic acid (DOCA); sterols, e.g. cholesterol;
  • bile acids e.g. deoxycholic acid (DOCA)
  • sterols e.g. cholesterol
  • alkanoic acids e.g. lauric acid and palmitic acid
  • deoxycholic acid and cholesterol are non-toxic since they are naturally occurring compounds
  • hydrophobic moieties to the amine groups of hepann had little or no effect on hepa ⁇ n bioactivity
  • the yield of the coupling reaction was about 70 to 80% and was not significantly changed by changing the hydrophobic agents or feed molar ratios.
  • the amount of DOCA in the conjugate was also increased.
  • the weight % of DOCA in heparin-DOCA was 24% when the feed molar ratio of
  • heparin to DOCA was 1:200. This molar ratio was very high compared to the ratio of amine
  • hydrophobic hepa ⁇ n denvatives would have many
  • the hydrophobic hepa ⁇ n can be administered orally.
  • the oral administration of hepa ⁇ n can extend greatly the usage of hepa ⁇ n as an oral anti -coagulant drug.
  • the hepa ⁇ n de ⁇ vative is formulated with a pharmaceutically acceptable earner such as is
  • hydrophobic hepann denvatives can be used
  • hydrophobic hepa ⁇ n de ⁇ vative is typically mixed with a earner, and then coated on the surface of the medical device by a film casting technique such as is well known in the art
  • hydrophobic heparin can be obtained by conjugating a bile acid, sterol, or alkanoic acid to heparin.
  • solubility tests polar solvents or organic solvents were suitable to dissolve the heparin-hydrophobic agent conjugates.
  • the heparin-deoxycholic acid conjugate showed good solubility in 65% acetone
  • hydrophobic agent conjugated to heparin was studied with respect to two biological activities of
  • amine groups of heparin had little effect on its bioactivity.
  • the bioactivity of heparin in heparin- hydrophobic agent conjugates exhibited a progressive reduction, however, when the amount of hydrophobic agent in the conjugate exceeded 20 wt. %. At less than 20 wt. % of hydrophobic
  • the bioactivity of the conjugates was greater than 80% of the bioactivity
  • the proof of the heparin derivatives is the amide bond produced by the coupling of an amine group of heparin with a carboxyl group of the hydrophobic
  • Heparin-DOCA Conjugate Heparin can be dissolved in relatively few solvents, such as water and formamide.
  • the heparin derivatives of the present invention have a slightly hydrophobic property, thus it was anticipated that such derivatives would be soluble in additional solvents. This was tested in the present example by assessing solubility in mixtures of
  • solubility of the heparin-DOCA conjugate in the solvent was increased as the acetone content of the solvent was increased.
  • the solubility of heparin-DOCA (24%) in the solvent was maximized at 50:50 volume ratio of acetone and water.
  • Sepharose® CL-4B was used for removing the unreacted heparin from heparin-DOCA, heparin-
  • hydrophobic heparin (5 mg) in the same phosphate buffer (5 ml) was loaded on the column, and eluted with the gradient solvent respectively.
  • the flow rate was 1 ml/min, and each 2-ml fraction was collected by fraction collector. After elution on the column, the column was washed with
  • Heparin-DOCA conjugate was not eluted in PBS but was eluted in ammonium sulfate solution. As the concentration of ammonium sulfate in the eluent increased, the hydrophobicity of the eluted
  • heparin conjugates also increased.
  • the heparin-DOCA conjugate was completely eluted in 1.3
  • heparin used in these experiments had a potency of 140 units per mg.
  • the bioactivities of all of the heparin derivatives prepared in this study was above 70% compared to the bioactivity of unmodified heparin. There was no difference in the bioactivities of the conjugates with respect to the hydrophobic agents used for making the conjugates.
  • the bioactivities of heparin derivatives decreased slightly, however, with increasing amounts of hydrophobic agent in the
  • Example 7 Heparin Oral Delivery. Six rats, housed in the animal care facility at the Korea Animal Center were fasted for 12 hours before dosing. Groups of rats weighing 250-300 g were administered a single oral dose of heparin, high molecular weight heparin-DOCA, or low molecular weight heparin-DOCA. Blood samples (0.5 ml) were collected serially by heparin coated capillary mixed with 3.8% sodium citrate. Samples were collected prior to administration of heparin or heparin derivatives and for 10 hours thereafter at hourly intervals. Plasma was harvested by centrifugation and was frozen at below -20 °C. Plasma heparin activity in each sample was determined by APTT assays. The APTT bioassay was performed according to the procedure of Example 6. Plasma APTT units were determined from clotting time, which was
  • PEO/PCL is a multiblock copolymer composed of alternating blocks of
  • poly(ethylene oxide) (MW about 2,000) and poly( ⁇ -caprolactone) (MW about 2,000), wherein
  • the total molecular weight of the copolymer is about 30,000.
  • the heparin derivative was mixed with the polymer, dissolved in acetone/water, cast on the polyethylene discs, and then the solvent
  • copolymer film was calculated by summation of the cumulative amount released over 40 days, and the amount remaining in the disc at 40 days. This was compared with the initial amount calculated from the drug loading. The cumulative amount of heparin derivative released was plotted against time and the percentages released were used in statistical comparisons performed by repeated measures analysis of variance.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Botany (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
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Abstract

Des polysaccharides qui sont largement utilisés en tant que médicaments anticoagulants, en particulier l'héparine, sont administrés cliniquement seulement par injection intraveineuse ou sous-cutanée car ils présentent un fort caractère hydrophile et une charge négative élevée. Des dérivés d'héparine amphiphiles ont été synthétisés par conjugaison avec, respectivement, des acides biliaires, des stérols et des acides alcanoïques. Le caractère hydrophile des dérivés d'héparine dépend du rapport molaire de l'héparine à l'agent hydrophobe. Les dérivés d'héparine obtenus ont montré un caractère faiblement hydrophobe et une bonne solubilité dans un solvant acéto-aqueux, ainsi que dans l'eau. Les dérivés d'héparine ont une activé anticoagulante élevée. Ces dérivés d'héparine faiblement hydrophobes peuvent être absorbés dans le tractus gastro-intestinal et administrés en doses orales. Ainsi, ces dérivés d'héparine peuvent être utilisés pour une modification superficielle destinée à empêcher la coagulation, pour des dispositifs médicaux, tels que des dispositifs extracorporels et des dispositifs implantés.
PCT/KR1999/000242 1998-05-28 1999-05-14 Derives de polysaccharide amphiphiles WO1999061481A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB0001794A GB2342357B (en) 1998-05-28 1999-05-14 Amphiphilic heparin derivatives
DE19981169T DE19981169B4 (de) 1998-05-28 1999-05-14 Kovalent an Gallensäuren oder Sterine gebundenes Heparin, dessen Verwendung und diese enthaltende pharmazeutische Zusammensetzung
JP2000550884A JP3541007B2 (ja) 1998-05-28 1999-05-14 両親媒性ポリサッカリド誘導体
AU37358/99A AU3735899A (en) 1998-05-28 1999-05-14 Amphiphilic polysaccharide derivatives

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR1998/19469 1998-05-28
KR19980019469 1998-05-28
KR1019990014003A KR100314496B1 (ko) 1998-05-28 1999-04-20 항혈전성이 있는 헤파린 유도체, 그의 제조방법 및 용도
KR1999/14003 1999-04-20
US09/300,173 US6245753B1 (en) 1998-05-28 1999-04-27 Amphiphilic polysaccharide derivatives
US09/300,173 1999-04-27

Publications (1)

Publication Number Publication Date
WO1999061481A1 true WO1999061481A1 (fr) 1999-12-02

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PCT/KR1999/000242 WO1999061481A1 (fr) 1998-05-28 1999-05-14 Derives de polysaccharide amphiphiles

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JP (1) JP3541007B2 (fr)
AU (1) AU3735899A (fr)
DE (1) DE19981169B4 (fr)
GB (1) GB2342357B (fr)
WO (1) WO1999061481A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1333871A4 (fr) * 2000-10-24 2004-07-07 Mediplex Corp Korea Conjugues d'heparine composites hydrophobes, ainsi que procede de preparation et utilisation de ceux-ci
FR2864091A1 (fr) * 2003-12-19 2005-06-24 Ethypharm Sa Derive amphiphile d'heparine forme par couplage de l'heparine avec un acide biliaire
EP1385530A4 (fr) * 2001-05-09 2005-11-09 Mediplex Corp Formulation de derives d'heparine amphiphiles servant a ameliorer l'absorption par les muqueuses
EP1383518A4 (fr) * 2001-04-30 2005-11-09 Mediplex Corp Administration orale de macromolecules
US7303768B2 (en) 1998-07-24 2007-12-04 Seo Hong Yoo Preparation of aqueous clear solution dosage forms with bile acids
WO2009092151A1 (fr) * 2007-12-05 2009-07-30 Xiao-Xia Zhu Polymères amphiphiles à noyau cholane
US7772220B2 (en) 2004-10-15 2010-08-10 Seo Hong Yoo Methods and compositions for reducing toxicity of a pharmaceutical compound
US7932243B2 (en) 1998-07-24 2011-04-26 Seo Hong Yoo Bile preparations for gastrointestinal disorders
US8173627B2 (en) 2004-08-30 2012-05-08 Seo Hong Yoo Neuroprotective effect of solubilized UDCA in focal ischemic model
US8759322B2 (en) 2008-11-05 2014-06-24 National University Corporation Tokyo Medical And Dental University Hyaluronic acid derivative and pharmaceutical composition thereof
US8772691B2 (en) 2003-06-23 2014-07-08 Abl Ip Holding Llc Optical integrating cavity lighting system using multiple LED light sources
CN105233294A (zh) * 2007-02-08 2016-01-13 爱密斯菲尔科技公司 苯烷基羧酸输送剂

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB891554A (en) * 1959-10-19 1962-03-14 Applic Chimiques D Etudes Et D Galenic suppository containing salts of heparin
GB1157754A (en) * 1966-06-29 1969-07-09 Canada Packers Ltd Orally Active Heparin and method of making and using same
WO1995012620A1 (fr) * 1993-11-01 1995-05-11 Alpha-Beta Technology, Inc. Sequestrant d'acide biliaire polyosidique transforme en derive utilise pour abaisser le taux de cholesterol
JPH07206903A (ja) * 1994-01-24 1995-08-08 Takeda Chem Ind Ltd 超分子構造型集合体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB891554A (en) * 1959-10-19 1962-03-14 Applic Chimiques D Etudes Et D Galenic suppository containing salts of heparin
GB1157754A (en) * 1966-06-29 1969-07-09 Canada Packers Ltd Orally Active Heparin and method of making and using same
WO1995012620A1 (fr) * 1993-11-01 1995-05-11 Alpha-Beta Technology, Inc. Sequestrant d'acide biliaire polyosidique transforme en derive utilise pour abaisser le taux de cholesterol
JPH07206903A (ja) * 1994-01-24 1995-08-08 Takeda Chem Ind Ltd 超分子構造型集合体

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Database WPIL on EPO, week 95-40, London; Derwent Publications Ltd., 1995-309101, & JP 07206903 A (Takeda Chem. Ind. Ltd.) 08.08.95. *
Journal of Pharmaceutical Sciences, Vol. 83, No. 7, July 1994, Pages 1034-1039, J. LIU et al.: "New approaches for the preparation of hydrophobic hydrophobic heparin derivatives". *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932243B2 (en) 1998-07-24 2011-04-26 Seo Hong Yoo Bile preparations for gastrointestinal disorders
US7303768B2 (en) 1998-07-24 2007-12-04 Seo Hong Yoo Preparation of aqueous clear solution dosage forms with bile acids
EP1333871A4 (fr) * 2000-10-24 2004-07-07 Mediplex Corp Korea Conjugues d'heparine composites hydrophobes, ainsi que procede de preparation et utilisation de ceux-ci
EP1383518A4 (fr) * 2001-04-30 2005-11-09 Mediplex Corp Administration orale de macromolecules
EP1385530A4 (fr) * 2001-05-09 2005-11-09 Mediplex Corp Formulation de derives d'heparine amphiphiles servant a ameliorer l'absorption par les muqueuses
US8772691B2 (en) 2003-06-23 2014-07-08 Abl Ip Holding Llc Optical integrating cavity lighting system using multiple LED light sources
FR2864091A1 (fr) * 2003-12-19 2005-06-24 Ethypharm Sa Derive amphiphile d'heparine forme par couplage de l'heparine avec un acide biliaire
WO2005061552A1 (fr) * 2003-12-19 2005-07-07 Ethypharm Derive amphiphile d’heparine forme par couplage de l’heparine avec un acide biliaire
US8173627B2 (en) 2004-08-30 2012-05-08 Seo Hong Yoo Neuroprotective effect of solubilized UDCA in focal ischemic model
US7772220B2 (en) 2004-10-15 2010-08-10 Seo Hong Yoo Methods and compositions for reducing toxicity of a pharmaceutical compound
CN105233294A (zh) * 2007-02-08 2016-01-13 爱密斯菲尔科技公司 苯烷基羧酸输送剂
US10456472B2 (en) 2007-02-08 2019-10-29 Emisphere Technologies, Inc. Phenylalkylcarboxylic acid delivery agents
US11253596B2 (en) 2007-02-08 2022-02-22 Novo Nordisk North America Operations A/S Phenylalkylcarboxylic acid delivery agents
WO2009092151A1 (fr) * 2007-12-05 2009-07-30 Xiao-Xia Zhu Polymères amphiphiles à noyau cholane
US8759322B2 (en) 2008-11-05 2014-06-24 National University Corporation Tokyo Medical And Dental University Hyaluronic acid derivative and pharmaceutical composition thereof

Also Published As

Publication number Publication date
JP2002516355A (ja) 2002-06-04
DE19981169T1 (de) 2000-11-16
GB2342357B (en) 2002-03-27
GB0001794D0 (en) 2000-03-22
AU3735899A (en) 1999-12-13
DE19981169B4 (de) 2007-09-13
JP3541007B2 (ja) 2004-07-07
GB2342357A (en) 2000-04-12

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