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WO1997033565A1 - Nucleoside compositions containing paracellular absorption enhancers - Google Patents

Nucleoside compositions containing paracellular absorption enhancers Download PDF

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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
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WO
WIPO (PCT)
Prior art keywords
paracellular
absoφtion
nucleoside analogue
absorption
lamivudine
Prior art date
Application number
PCT/EP1997/001236
Other languages
French (fr)
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.)
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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/en

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    • 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%

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Abstract

A method and pharmaceutical compositions for improving the absorption of nucleoside analogues, especially lamivudine and zidovudine, following oral or intranasal administration using paracellular absorption enhancers.

Description

NUCLEOSIDE COMPOSITIONS CONTAINING PARACELLULAR ABSORPTION ENHANCERS
The present invention relates to a method for improving the absoφtion of nucleoside analogues such as (2R, cisH-amino-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.
The use of lamivudine for the treatment of hepatitis C is described in International patent application no. PCT/EP96/03601.
The use of zidovudine in the treatment of AIDS is described in US Patent No. 4,724,232.
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. 1991; 7:339-364) suggested that manipulation of the paracellular pathway could be used to enhance the oral delivery of small peptides and peptidomimetics. Some in vitro models have suggested that glucose may enhance paracellular absoφtion. However, Nellans (see above) failed to observe any positive effect on absoφtion using lumenal glucose in vivo suggesting that positive in vitro results may be offset in vivo by secretory water flow such that little or no increase in absorption is observed.
International patent application publication no. WO96/08238 discloses the use of paracellular absoφtion enhancers for enhancing the absoφtion of histamine H2 - antagonists.
Studies in intact rats with zidovudine (Fleisher, D. et al. Pharm. Res.. 7, no. 9, Suppl., S154, 1990) suggest that D-glucose may have an effect on the variability of zidovudine absoφtion.
A method of significantly enhancing the absorption of nucleoside analogues such as lamivudine and zidovudine following oral or intranasal administration has now been found.
Thus 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 absoφtion enhancers in the manufacture of medicaments for simultaneous, separate or sequential use for the treatment of viral infection characterised in that the paracellular absoφtion enhancer(s) significantly enhances the absoφtion of the nucleoside analogue.
In a further aspect, 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 absoφtion enhancer significantly enhances the absorption of the nucleoside analogue.
As used herein "physiologically acceptable derivative" means a physiologically acceptable salt, ester or salt of such ester.
The term "paracellular absorption enhancer" as used herein encompasses any compound which enhances paracellular absoφtion. For example, the paracellular absoφtion enhancers are those which occur naturally in nutrients. Paracellular absoφtion 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 absoφtion enhancers include glucose, e.g. D-glucose. A further preferred group of paracellular absoφtion 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.
It will be appreciated that the 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 absoφtion 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. In particular, lamivudine and zidovudine may be used in combination.
It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms. As mentioned hereinbefore, paracellular absorption enhancers have been found to significantly enhance the absoφtion of nucleoside analogues such as lamivudine and zidovudine following oral or intranasal administration. Suφrisingly, both the extent and rate of absoφtion are enhanced.
Thus, according to a further aspect, 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.
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. Preferably, 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.
Thus, according to a further aspect, 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 absoφtion enhancers.
For oral administration, 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). The tablets may be coated by methods well known in the art. 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.
For intra-nasal administration 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.
Particularly suitable pharmaceutical 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 incoφorated 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 absoφtion 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.
The following are illustrations of non-limiting examples of pharmaceutical compositions according to the invention.
Example 1
Tablets for oral administration
Lamivudine or zidovudine 150mg
D-glucose 150mg microcrystalline cellulose 80mg magnesium stearate 5mg sod iun starch glycolate 15mg
Example 2
Capsule
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
Lamivudine or zidovudine 10mg
D-glucose 10OOmg methylparaben 1.2mg propylparaben 0.15mg edetate disodium 0.1mg ethanol 50.8mg propyiene glycol 20mg flavour 1.4mg citric acid . 1.2mg purified water to 1ml
The above formulations are prepared by admixture of the ingredients using conventional pharmaceutical techniques.
Biological Data
Enhancement of the extent and rate of transport of lamivudine and zidovudine by D-glucose was measured in Caco-2 cells using the method set out below.
The results are presented in Table 1.
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 (Transwells™ 12mm diameter, 0.4μm 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 (10μg/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.
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.
The constituents of each buffer are detailed in the table below:
Figure imgf000010_0001
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:
A B C D
Apical side Control Buffer ORS Buffer Control Buffer Control Buffer + compound + compound
Basolateral Control Buffer Control Buffer Control Buffer ORS Buffer side + compound + compound
At 5, 10, 15, 20, 30, 60, 90 and 120 minutes after the start of the experiment, an aliquot from the receptor compartment was removed and added to scintillation fluid prior to liquid scintillation counting. The volume removed was replaced with an equal volume of control buffer. At the end of the experiment the TEER was re-measured.
Aliquots of the receptor compartment at the end of the experiment were analysed by radio-HPLC and compared to an aliquot of the donor compartment at the begining of the experiment to ensure that the compound was transported intact. A further aliquot of the compound in buffer was kept at 37°C for the duration of the experiment and analysed to ensure that the radio-purity of the compound did not deteriorate at this temperature. TABLE 1
Effect of D-Glucose on Transport of Nucleoside Analogues across Caco-2 cells
Compound Rate of Rate of nmols nmols Rate of nmols transport transport transported transported transport transported
30-120 30-120 at 2h at 2h 30-120 at 2h mins mins mins
Control ORS Control ORS ORS as % ORS as % Control Control lamivudine 0.34 1.04 38 166 306% 437%
zidovudine 0.99 1.46 122 169 147% 139%

Claims

Claims
1. A pharmaceutical composition for oral or intranasal use comprising a nucleoside analogue, or a physiologically acceptable derivative thereof, and one or more paracellular absoφtion enhancers.
2. A composition according to claim 1 wherein the nucleoside analogue is zidovudine or a physiologically acceptable derivative thereof.
3. A composition according to claim 1 wherein the nucleoside analogue is lamivudine or a physiologically acceptable derivative thereof.
4. A composition according to any one of claims 1 to 3 wherein the paracellular absorption enhancer is glucose.
5. A composition according to any one of claims 1 to 3 wherein the paracellular absoφtion enhancer is selected from galactose, mannose, 3-0- methyl glucose, xylose, ribose, arabinose, ribulose, fructose and sorbose.
6. The use of a pharmaceutical composition as defined in any one of claims
1 to 5 for the manufacture of a medicament for the treatment of viral infection, characterised in that the paracellular absorption enhancer(s) significantly enhances the absorption of the nucleoside analogue.
7. The use as claimed in claim 6 wherein the viral infection is HIV , hepatitis
B or hepatitis C.
8. A method of treatment of viral infection comprising orally or intranasally administering to a sufferer an effective amount of a pharmaceutical composition as claimed in any one of claims 1 to 5 wherein the paracellular absorption enhancer significantly enhances the absorption of the nucleoside analogue.
9. The method as claimed in claim 8 wherein the viral infection is HIV , hepatitis B or hepatitis C.
10. The use of a nucleoside analogue, or a physiologically acceptable derivative thereof, and one or more paracellular absoφtion enhancers in the manufacture of medicaments for simultaneous, separate or sequential use in the treatment of gastrointestinal disorders, characterised in that the paracellular absoφtion enhancer(s) significantly enhances the absoφtion of the nucleoside analogue.
PCT/EP1997/001236 1996-03-13 1997-03-12 Nucleoside compositions containing paracellular absorption enhancers WO1997033565A1 (en)

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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 (en) * 2012-12-29 2014-07-09 安徽贝克生物制药有限公司 Zidovudine and lamivudine capsule and preparation method thereof
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 (en) * 2015-01-19 2016-06-20 Общество с ограниченной ответственностью "Трейдсервис" Stable pharmaceutical composition lamivudine
WO2017189978A1 (en) 2016-04-28 2017-11-02 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

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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
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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 (en) * 2012-12-29 2014-07-09 安徽贝克生物制药有限公司 Zidovudine and lamivudine capsule and preparation method thereof
RU2587782C1 (en) * 2015-01-19 2016-06-20 Общество с ограниченной ответственностью "Трейдсервис" Stable pharmaceutical composition lamivudine
WO2017189978A1 (en) 2016-04-28 2017-11-02 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

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