WO1997033565A1 - Compositions nucleosides renfermant des activateurs d'absorption paracellulaire - Google Patents

Compositions nucleosides renfermant des activateurs d'absorption paracellulaire Download PDF

Info

Publication number
WO1997033565A1
WO1997033565A1 PCT/EP1997/001236 EP9701236W WO9733565A1 WO 1997033565 A1 WO1997033565 A1 WO 1997033565A1 EP 9701236 W EP9701236 W EP 9701236W WO 9733565 A1 WO9733565 A1 WO 9733565A1
Authority
WO
WIPO (PCT)
Prior art keywords
paracellular
absoφtion
nucleoside analogue
absorption
lamivudine
Prior art date
Application number
PCT/EP1997/001236
Other languages
English (en)
Inventor
Laurence Francis Lacey
Original Assignee
Glaxo Group Limited
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
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU21552/97A priority Critical patent/AU2155297A/en
Publication of WO1997033565A1 publication Critical patent/WO1997033565A1/fr

Links

Classifications

    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to a method for improving the abso ⁇ tion of nucleoside analogues such as (2R, cisH- a mi n o-1-(2-hydroxymethyl-1 ,3- oxathiolan-5-yl) -(1H)- pyridmidin-2-one, also known as lamivudine, and 3'-azido- 3'-deoxythymidine, also known as zidovudine.
  • nucleoside analogues such as (2R, cisH- a mi n o-1-(2-hydroxymethyl-1 ,3- oxathiolan-5-yl) -(1H)- pyridmidin-2-one, also known as lamivudine, and 3'-azido- 3'-deoxythymidine, also known as zidovudine.
  • Lamivudine and zidovudine are reverse transcriptase inhibitors useful in the treatment of viral infections.
  • PCT patent application publication number WO 91/17159 describes the compound (2R, cis)-4-amino-1-(2-hydroxymethyl-1 ,3-oxathiolane-5-yl)-(1 H)- pyrimidin-2-one (also known as lamivudine) and its use in the treatment of HIV infections.
  • Lamivudine is the (-)-enantiomer of one of the compounds (BCH-189) described in EPA 0382526.
  • PCT patent application publication number WO92/11852 describes the use of BCH-189 and its individual enantiomers, including lamivudine, for the treatment of hepatitis B.
  • Nucleoside analogues such as lamivudine and zidovudine may be administered orally or intranasally and, following oral or intranasal administration, are absorbed paracellularly (i.e. through the tight junctions between cells of the intestinal mucosa). Enhancement of drug absorption is in general advantageous since this it enables lower doses to be effective (enhanced extent of absorption) and provides more rapid relief from symptoms (enhanced rate of absorption). It has been reported that certain monosaccharides and amino acids stimulate cytoskeleton contraction to open up paracellular spaces to a sufficient size to pass molecules of a high molecular weight. Thus, Nellans (Nellans, H.N., Adv. Drug Delivery.
  • nucleoside analogues such as lamivudine and zidovudine following oral or intranasal administration
  • the present invention provides, in one aspect, the use of nucleoside analogues such as lamivudine and zidovudine or physiologically acceptable derivatives thereof and one or more paracellular abso ⁇ tion enhancers in the manufacture of medicaments for simultaneous, separate or sequential use for the treatment of viral infection characterised in that the paracellular abso ⁇ tion enhancer(s) significantly enhances the abso ⁇ tion of the nucleoside analogue.
  • the invention provides a method of treatment of viral infection comprising orally or intranasally administering to a mammalian subject an effective amount of a pharmaceutical composition comprising a nucleoside analogue such as lamivudine or zidovudine or a physiologically acceptable derivative thereof and one or more paracellular absorption enhancers, wherein the paracellular abso ⁇ tion enhancer significantly enhances the absorption of the nucleoside analogue.
  • a nucleoside analogue such as lamivudine or zidovudine or a physiologically acceptable derivative thereof
  • paracellular absorption enhancers significantly enhances the absorption of the nucleoside analogue.
  • physiologically acceptable derivative means a physiologically acceptable salt, ester or salt of such ester.
  • paracellular absorption enhancer encompasses any compound which enhances paracellular abso ⁇ tion.
  • the paracellular abso ⁇ tion enhancers are those which occur naturally in nutrients.
  • Paracellular abso ⁇ tion enhancers include carbohydrates such as monosaccharides, e.g. glucose, galactose, mannose, 3-0-methyl glucose, xylose, ribose, arabinose, ribulose, fructose and sorbose.
  • the monosaccharides may be employed in either their D- or L- forms. Where the monosaccharide is naturally occurring, the naturally occurring form is preferred.
  • Preferred paracellular abso ⁇ tion enhancers include glucose, e.g. D-glucose.
  • a further preferred group of paracellular abso ⁇ tion enhancers includes galactose, e.g. D-galactose, mannose, e.g. D-mannose, 3-0-methyl glucose, e.g. 3-0- methyl D-glucose, xylose, e.g. D-xylose.
  • paracellular absorption enhancer(s) employed in the instant invention will be of the reversible type i.e. one whose absorption enhancement effect rapidly diminishes when it is no longer present at the site of action. All of the paracellular abso ⁇ tion enhancers specifically mentioned above are of the reversible type.
  • the paracellular absorption enhancers may be used alone or in combination.
  • Nucleoside analogues may be used alone or in combination in the compositions, methods and uses of the invention.
  • lamivudine and zidovudine may be used in combination.
  • reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
  • paracellular absorption enhancers have been found to significantly enhance the abso ⁇ tion of nucleoside analogues such as lamivudine and zidovudine following oral or intranasal administration. Su ⁇ risingly, both the extent and rate of abso ⁇ tion are enhanced.
  • the present invention provides a method of significantly enhancing the rate of absorption of a nucleoside analogue such as lamivudine and zidovudine following oral or intranasal administration by simultaneous, separate or sequential administration of a nucleoside analogue such as lamivudine and zidovudine with one or more paracellular absorption enhancers.
  • a nucleoside analogue such as lamivudine and zidovudine following oral or intranasal administration by simultaneous, separate or sequential administration of a nucleoside analogue such as lamivudine and zidovudine with one or more paracellular absorption enhancers.
  • Nucleoside analogues such as lamivudine and zidovudine or physiologically acceptable derivatives thereof and one or more paracellular absorption enhancers may be co-administered in the form of separate pharmaceutical compositions for simultaneous and/or sequential use.
  • a nucleoside analogue such as lamivudine or zidovudine and paracellular absorption enhancer(s) are administered as a single pharmaceutical composition for oral or intranasal use comprising effective amounts of the active ingredient.
  • the invention provides a pharmaceutical composition for oral use comprising a nucleoside analogue such as lamivudine or zidovudine or a physiologically acceptable derivative thereof and one or more paracellular abso ⁇ tion enhancers.
  • a nucleoside analogue such as lamivudine or zidovudine or a physiologically acceptable derivative thereof and one or more paracellular abso ⁇ tion enhancers.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); a glidant (e.g. corn starch, colloidal silicon dioxide), lubricants (e.g. magnesium stearate, talc sodium sterol fumarate or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • a glidant e.g. corn starch, coll
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl- p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one more more dispersing agents, soiubilising agents or suspending agents.
  • Liquid sprays are conveniently delivered from pressurised packs.
  • Dispersible powder formulations typically comprise a powder mix of the active ingredient(s) and a suitable powder base such as lactose or starch.
  • compositions according to the present invention are tablets and liquid syrups or suspensions for oral administration
  • Suitable methods of formulation are known in the art and include those methods described in WO 91/17159 and US Patent No. 4,724,232, which are inco ⁇ orated herein by reference.
  • the paracellular absorption enhancer(s) may be incorporated into the above- mentioned formulations according to conventional procedures.
  • Nucleoside analogues and paracellular absorption enhancer(s) may, if desired, be administered in combination with one or more other therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art.
  • the ratio of nucleoside analogue to paracellular absorption enhancer(s) used in the method or compositions according to the invention may be in the range of 1:1 to 1:1000 (by weight), such as 1:1 to 1:50 or 1:150 (by weight), for example 1 : 5 (by weight).
  • the amount of paracellular abso ⁇ tion enhancer used in the oral formulations according to the instant invention is in the range of 10 to 3000mg, e.g. 20 to 1000mg, per dosage unit.
  • the amount of the nucleoside analogue used in the oral formulations according to the instant invention is preferably in the range of 5 to 800mg per dosage unit. For example, 20mg to 700mg per dosage unit.
  • the unit dose (for example contained in one tablet according to the invention) may be administered for example, 1 to 4 times a day.
  • Example The formulation of Example is filled into two part gelatine capsules.
  • the formulation of Example is filled into two part gelatine capsules.
  • Solution for oral administration is
  • the above formulations are prepared by admixture of the ingredients using conventional pharmaceutical techniques.
  • Caco-2 cells originating from a human colorectal carcinoma, were obtained from Porton Down (ECACC No: 86010202). Cells were allowed to grow and differentiate on polycarbonate membrane culture plate inserts (TranswellsTM 12mm diameter, 0.4 ⁇ m pore size; Costar UK Ltd, High Wycombe, Bucks). The cells were maintained in minimum essential medium (Eagle's) containing 10% bovine calf serum (Gibco BRL), 1% non-essential amino acids, penicillin (100U/ml), streptomycin (10 ⁇ g/ml) and L-glutamine (2mM). All tissue culture media (except where stated) were obtained from Hycione Europe Ltd. The medium was changed three times a week.
  • Eagle's containing 10% bovine calf serum (Gibco BRL), 1% non-essential amino acids, penicillin (100U/ml), streptomycin (10 ⁇ g/ml) and L-glutamine (2mM). All tissue culture media (except where stated) were obtained from Hy
  • the medium used for carrying out the transport studies was a glucose buffer formula based on Kreb's bicarbonate solution.
  • Termed ORS buffer this contained a high concentration of glucose compared to the control buffer.
  • Transport rates were measured on compounds in both the control and ORS buffers to determine the effect of a high concentration of glucose.
  • the pH of both buffers was approximately 6.4.
  • a solution of each compound at a concentration of 1 mM was prepared in both the control and ORS buffers. Each solution was spiked with a small amount of the respective radiolabelled compound to facilitate detection.
  • Cell transport studies were performed at 37°C in a water bath with gentle shaking. The cells used had been grown for a period of 21 to 26 days. The cells were acclimatised for 30 to 60 minutes in control buffer prior to the start of the experiment. During this time, the trans-epithelial electrical resistance (TEER) across the cells was measured with a volt-ohmmeter. This is used as a measure of tight junction integrity. Transport rates were measured in the apical (AP) to basolateral (BL) direction in both control and ORS buffer, and also in the BL to AP direction. Studies were initiated by adding the correct buffer/ compound concentration as presented below:
  • Control ORS Control ORS ORS as % ORS as % Control Control lamivudine 0.34 1.04 38 166 306% 437%

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un procédé et des compositions pharmaceutiques permettant d'améliorer l'absorption d'analogues nucléosidiques, notamment la lamivudine et la zidovudine, après administration par voie orale ou intranasale au moyen d'activateurs de l'absorption paracellulaire.
PCT/EP1997/001236 1996-03-13 1997-03-12 Compositions nucleosides renfermant des activateurs d'absorption paracellulaire WO1997033565A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU21552/97A AU2155297A (en) 1996-03-13 1997-03-12 Nucleoside compositions containing paracellular absorption enhancers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9605293.1 1996-03-13
GBGB9605293.1A GB9605293D0 (en) 1996-03-13 1996-03-13 Medicaments

Publications (1)

Publication Number Publication Date
WO1997033565A1 true WO1997033565A1 (fr) 1997-09-18

Family

ID=10790327

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/001236 WO1997033565A1 (fr) 1996-03-13 1997-03-12 Compositions nucleosides renfermant des activateurs d'absorption paracellulaire

Country Status (3)

Country Link
AU (1) AU2155297A (fr)
GB (1) GB9605293D0 (fr)
WO (1) WO1997033565A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6004968A (en) * 1997-03-24 1999-12-21 Glaxo Wellcome Inc. Pharmaceutical compositions containing lamivudine
US6113920A (en) * 1996-10-31 2000-09-05 Glaxo Wellcome Inc. Pharmaceutical compositions
GB2470494B (en) * 2008-01-17 2012-08-08 Univ Holy Ghost Duquesne Antiretroviral drug formulations for treatment of children exposed to HIV/AIDS
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
CN103908466A (zh) * 2012-12-29 2014-07-09 安徽贝克生物制药有限公司 齐多夫定、拉米夫定胶囊剂及其制备方法
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
RU2587782C1 (ru) * 2015-01-19 2016-06-20 Общество с ограниченной ответственностью "Трейдсервис" Стабильная фармацевтическая композиция ламивудина
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0382526A2 (fr) * 1989-02-08 1990-08-16 Biochem Pharma Inc 1,3-oxathiolanes substitués doués de propriétés antivirales
EP0397211A2 (fr) * 1989-05-12 1990-11-14 NELSON-SUMISHO Co., Ltd. Administration percutanée de la 3'-azido-3'-déoxythymidine
WO1991017159A1 (fr) * 1990-05-02 1991-11-14 Iaf Biochem International Inc. Analogues de nucleosides de 1,3-oxathiolane
WO1992011852A1 (fr) * 1991-01-03 1992-07-23 Biochem Pharma Inc. Utilisation d'analogues de nucleoside 1,3-oxathiolane dans le traitement de l'hepatite b
WO1992016236A1 (fr) * 1991-03-19 1992-10-01 Rajadhyaksha Vithal J Compositions et procede relatifs a des composes heterocycliques contenant deux heteroatomes a titre de promoteurs de penetration de membranes
WO1993011775A1 (fr) * 1991-12-13 1993-06-24 G.D. Searle & Co. Azidothymidine transdermique
WO1996008238A1 (fr) * 1994-09-14 1996-03-21 Glaxo Group Limited Utilisation d'agents d'accroissement paracellulaires tels que le glucose pour accroitre l'absorption d'antagonistes du recepteur h2 de l'histamine
WO1997006804A1 (fr) * 1995-08-19 1997-02-27 Glaxo Group Limited Analogues de nucleosides 1,3-oxathiolane utilises dans le traitement de l'hepatite c

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0382526A2 (fr) * 1989-02-08 1990-08-16 Biochem Pharma Inc 1,3-oxathiolanes substitués doués de propriétés antivirales
EP0397211A2 (fr) * 1989-05-12 1990-11-14 NELSON-SUMISHO Co., Ltd. Administration percutanée de la 3'-azido-3'-déoxythymidine
WO1991017159A1 (fr) * 1990-05-02 1991-11-14 Iaf Biochem International Inc. Analogues de nucleosides de 1,3-oxathiolane
WO1992011852A1 (fr) * 1991-01-03 1992-07-23 Biochem Pharma Inc. Utilisation d'analogues de nucleoside 1,3-oxathiolane dans le traitement de l'hepatite b
WO1992016236A1 (fr) * 1991-03-19 1992-10-01 Rajadhyaksha Vithal J Compositions et procede relatifs a des composes heterocycliques contenant deux heteroatomes a titre de promoteurs de penetration de membranes
WO1993011775A1 (fr) * 1991-12-13 1993-06-24 G.D. Searle & Co. Azidothymidine transdermique
WO1996008238A1 (fr) * 1994-09-14 1996-03-21 Glaxo Group Limited Utilisation d'agents d'accroissement paracellulaires tels que le glucose pour accroitre l'absorption d'antagonistes du recepteur h2 de l'histamine
WO1997006804A1 (fr) * 1995-08-19 1997-02-27 Glaxo Group Limited Analogues de nucleosides 1,3-oxathiolane utilises dans le traitement de l'hepatite c

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6113920A (en) * 1996-10-31 2000-09-05 Glaxo Wellcome Inc. Pharmaceutical compositions
US6004968A (en) * 1997-03-24 1999-12-21 Glaxo Wellcome Inc. Pharmaceutical compositions containing lamivudine
GB2470494B (en) * 2008-01-17 2012-08-08 Univ Holy Ghost Duquesne Antiretroviral drug formulations for treatment of children exposed to HIV/AIDS
US8685984B2 (en) 2011-10-21 2014-04-01 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8680106B2 (en) 2011-10-21 2014-03-25 AbbVic Inc. Methods for treating HCV
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
US8969357B2 (en) 2011-10-21 2015-03-03 Abbvie Inc. Methods for treating HCV
US8993578B2 (en) 2011-10-21 2015-03-31 Abbvie Inc. Methods for treating HCV
US9452194B2 (en) 2011-10-21 2016-09-27 Abbvie Inc. Methods for treating HCV
CN103908466A (zh) * 2012-12-29 2014-07-09 安徽贝克生物制药有限公司 齐多夫定、拉米夫定胶囊剂及其制备方法
RU2587782C1 (ru) * 2015-01-19 2016-06-20 Общество с ограниченной ответственностью "Трейдсервис" Стабильная фармацевтическая композиция ламивудина
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

Also Published As

Publication number Publication date
AU2155297A (en) 1997-10-01
GB9605293D0 (en) 1996-05-15

Similar Documents

Publication Publication Date Title
CA2637774C (fr) Nucleosides avec activite virale anti-hepatite b
US6521609B1 (en) Use of CGRP antagonists and CGRP release inhibitors for combating menopausal hot flushes
AU715213B2 (en) Synergistic combinations of zidovudine, 1592U89 and 3TC or FTC
CN101330909B (zh) A3腺苷受体激动剂在制备治疗骨关节炎的药物中的应用
DE60018273T2 (de) Pegyliertes interferon alpha in kombination mit einem ccr5 antagonisten für eine hiv-therapie
WO1997033565A1 (fr) Compositions nucleosides renfermant des activateurs d'absorption paracellulaire
NZ517367A (en) Use of CGRP antagonists and CGRP release inhibitors for combating menopausal hot flashes
ES2307593T3 (es) Antagonistas del receptor a2a de adenosina para el tratamiento y la prevencion de la fibrosis hepatica, la cirrosis y la esteatosis hepatica.
DE60123042T2 (de) L-fmau zur behandlung von hepatitis-delta-virus-infizierung
KR101037095B1 (ko) 건성안 장애의 치료를 위한 아데노신 ａ3 수용체 아고니스트
AU728461B2 (en) Pharmaceutical compositions
IL105090A (en) Acid N) phosphonoacetyl (Aspartic L in a broad spectrum antiviral agent
WO2022174269A1 (fr) Agents de dégradation d'irak4 et leurs utilisations
Wagner et al. Antiviral nucleoside drug delivery via amino acid phosphoramidates
JP2000507211A (ja) 単純ヘルペス感染症の組合せ治療におけるヌクレオシド類似体
EP0979650A1 (fr) Agents antiviraux
WO1997033579A1 (fr) Medicaments comprenant des agonistes du recepteur de type 5ht1 presentant une meilleure absorption
CA2250844C (fr) Composition anti-vih contenant un derive d'imidazole
JP2933229B2 (ja) エイズウイルスの増殖抑制剤
JP2004530700A (ja) Ａ１アデノシン及びｐ２ｘプリン受容体拮抗薬を使用する方法及び製剤
KR20160090312A (ko) 조산 조건의 치료에서 사용을 위한 용량 단위의 조합
AP1150A (en) Compositions comprising an HIV protease inhibitor such as Vx 478 and a water soluble vitamin E compound such as vitamin E-TPGS.
IL297014A (en) Pharmaceutical formulations of polyethylene glycol-based drug matrices of adrenomedullin and use
IT202100024668A1 (it) Composizioni e metodi per la terapia antivirale combinata
MXPA99008690A (en) Pharmaceutical compositions

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN YU AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97532281

Format of ref document f/p: F