WO1999061481A1 - Amphiphilic polysaccharide derivatives - Google Patents
Amphiphilic polysaccharide derivatives Download PDFInfo
- 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
Links
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.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Biochemistry (AREA)
- Botany (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU37358/99A AU3735899A (en) | 1998-05-28 | 1999-05-14 | Amphiphilic polysaccharide 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 |
GB0001794A GB2342357B (en) | 1998-05-28 | 1999-05-14 | Amphiphilic heparin derivatives |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1998/19469 | 1998-05-28 | ||
KR19980019469 | 1998-05-28 | ||
KR1999/14003 | 1999-04-20 | ||
KR1019990014003A KR100314496B1 (ko) | 1998-05-28 | 1999-04-20 | 항혈전성이 있는 헤파린 유도체, 그의 제조방법 및 용도 |
US09/300,173 | 1999-04-27 | ||
US09/300,173 US6245753B1 (en) | 1998-05-28 | 1999-04-27 | Amphiphilic polysaccharide derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999061481A1 true WO1999061481A1 (en) | 1999-12-02 |
Family
ID=27349744
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR1999/000242 WO1999061481A1 (en) | 1998-05-28 | 1999-05-14 | Amphiphilic polysaccharide derivatives |
Country Status (5)
Country | Link |
---|---|
JP (1) | JP3541007B2 (de) |
AU (1) | AU3735899A (de) |
DE (1) | DE19981169B4 (de) |
GB (1) | GB2342357B (de) |
WO (1) | WO1999061481A1 (de) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1333871A1 (de) * | 2000-10-24 | 2003-08-13 | Mediplex Corporation, Korea | Hydrophobe mehrkomponenten-heparinkonjugate, ein verfahren zur ihrer herstellung und verwendung |
EP1383518A1 (de) * | 2001-04-30 | 2004-01-28 | Mediplex Corporation | Orale abgabe von makromolekülen |
EP1385530A1 (de) * | 2001-05-09 | 2004-02-04 | Mediplex Corporation | Formulierung aus amphiphilen heparinderivativen zur verbesserung der schleimhautabsorption |
FR2864091A1 (fr) * | 2003-12-19 | 2005-06-24 | Ethypharm Sa | Derive amphiphile d'heparine forme par couplage de l'heparine avec un acide biliaire |
US7303768B2 (en) | 1998-07-24 | 2007-12-04 | Seo Hong Yoo | Preparation of aqueous clear solution dosage forms with bile acids |
WO2009092151A1 (en) * | 2007-12-05 | 2009-07-30 | Xiao-Xia Zhu | Amphiphilic polymers having a cholane core |
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)
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 (en) * | 1993-11-01 | 1995-05-11 | Alpha-Beta Technology, Inc. | Derivatized polysaccharide bile acid sequestrant for reducing cholesterol |
JPH07206903A (ja) * | 1994-01-24 | 1995-08-08 | Takeda Chem Ind Ltd | 超分子構造型集合体 |
-
1999
- 1999-05-14 WO PCT/KR1999/000242 patent/WO1999061481A1/en active Application Filing
- 1999-05-14 JP JP2000550884A patent/JP3541007B2/ja not_active Expired - Fee Related
- 1999-05-14 DE DE19981169T patent/DE19981169B4/de not_active Expired - Fee Related
- 1999-05-14 GB GB0001794A patent/GB2342357B/en not_active Expired - Fee Related
- 1999-05-14 AU AU37358/99A patent/AU3735899A/en not_active Abandoned
Patent Citations (4)
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 (en) * | 1993-11-01 | 1995-05-11 | Alpha-Beta Technology, Inc. | Derivatized polysaccharide bile acid sequestrant for reducing 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)
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 (18)
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 (de) * | 2000-10-24 | 2004-07-07 | Mediplex Corp Korea | Hydrophobe mehrkomponenten-heparinkonjugate, ein verfahren zur ihrer herstellung und verwendung |
EP1333871A1 (de) * | 2000-10-24 | 2003-08-13 | Mediplex Corporation, Korea | Hydrophobe mehrkomponenten-heparinkonjugate, ein verfahren zur ihrer herstellung und verwendung |
EP1383518A1 (de) * | 2001-04-30 | 2004-01-28 | Mediplex Corporation | Orale abgabe von makromolekülen |
EP1383518A4 (de) * | 2001-04-30 | 2005-11-09 | Mediplex Corp | Orale abgabe von makromolekülen |
EP1385530A1 (de) * | 2001-05-09 | 2004-02-04 | Mediplex Corporation | Formulierung aus amphiphilen heparinderivativen zur verbesserung der schleimhautabsorption |
EP1385530A4 (de) * | 2001-05-09 | 2005-11-09 | Mediplex Corp | Formulierung aus amphiphilen heparinderivativen zur verbesserung der schleimhautabsorption |
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 (en) * | 2007-12-05 | 2009-07-30 | Xiao-Xia Zhu | Amphiphilic polymers having a cholane core |
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 |
---|---|
GB0001794D0 (en) | 2000-03-22 |
JP2002516355A (ja) | 2002-06-04 |
GB2342357A (en) | 2000-04-12 |
GB2342357B (en) | 2002-03-27 |
DE19981169B4 (de) | 2007-09-13 |
JP3541007B2 (ja) | 2004-07-07 |
DE19981169T1 (de) | 2000-11-16 |
AU3735899A (en) | 1999-12-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6245753B1 (en) | Amphiphilic polysaccharide derivatives | |
US6656922B2 (en) | Oral delivery of macromolecules | |
EP0640622B1 (de) | Polysaccharidderivat und wirkstoffträger | |
JP4332507B2 (ja) | 医薬組成物 | |
CA2157410C (en) | Enhanced circulation effector composition and method | |
AU692389B2 (en) | Cyclodextrin compounds and methods of making and use thereof | |
US5846951A (en) | Pharmaceutical compositions | |
DE69636813T2 (de) | Heparine-proteine kovalente Konjugate, die eine Alpha-Carbonyl-Amin enthalten und Verfahren für deren Produktion | |
EP1619210A1 (de) | DDS-Verbindungen und Methoden ihrer Prüfung | |
WO1993005793A1 (en) | A novel conjugate, its preparation and use and a substrate prepared with the conjugate | |
JP2004522712A (ja) | ヒドロキシアパタイト標的化ポリ(エチレングリコール)および関連重合体 | |
WO2016168710A1 (en) | Antithrombin-heparin compositions and methods | |
JPH01503548A (ja) | ヘパリン誘導体 | |
WO1997046261A1 (en) | Process for producing drug complexes | |
WO1999061481A1 (en) | Amphiphilic polysaccharide derivatives | |
WO2003089010A1 (en) | Glycodendrimers having biological activity | |
Lee et al. | Preparation of slightly hydrophobic heparin derivatives which can be used for solvent casting in polymeric formulation | |
WO1999026984A1 (fr) | Modification de l'heparine de faible masse moleculaire et remede contre l'ulcere de la peau | |
JP2003504312A (ja) | 生物学的に活性な材料 | |
AU2016274868B2 (en) | Medical devices, systems, and methods utilizing antithrombin-heparin compositions | |
WO1994008595A1 (en) | Use of non-anticoagulant heparin for treating ischemia/reperfusion injury | |
EP4245764A1 (de) | Neue kohlenhydratderivate als mimetika der antigene der blutgruppen a und b | |
Stehle et al. | Altered pharmacokinetic properties of a lipophilically derivatized low-molecular-weight heparin in rats | |
KR101528476B1 (ko) | 향상된 메소글리칸 약물 전달 제형 | |
CA2231989A1 (en) | Therapy for tissue membrane insufficiency |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AT AU BR CA CH CN DE DK ES FI GB HU ID IN JP KP KZ MN MX NO NZ PL PT RO RU SD SE SG TR UA ZA |
|
ENP | Entry into the national phase |
Ref document number: 200001794 Country of ref document: GB Kind code of ref document: A |
|
RET | De translation (de og part 6b) |
Ref document number: 19981169 Country of ref document: DE Date of ref document: 20001116 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 19981169 Country of ref document: DE |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8607 |