WO2011128629A2 - Lipid-vectored drug compositions - Google Patents

Lipid-vectored drug compositions Download PDF

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Publication number
WO2011128629A2
WO2011128629A2 PCT/GB2011/000559 GB2011000559W WO2011128629A2 WO 2011128629 A2 WO2011128629 A2 WO 2011128629A2 GB 2011000559 W GB2011000559 W GB 2011000559W WO 2011128629 A2 WO2011128629 A2 WO 2011128629A2
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Prior art keywords
moiety
lipid
oil
targeting
drug substance
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PCT/GB2011/000559
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French (fr)
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WO2011128629A3 (en
Inventor
Kurt Ingar Draget
Stainar Johan Engelsen
Tore Seternes
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Probio Asa
Cockbain, Julian
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Publication of WO2011128629A2 publication Critical patent/WO2011128629A2/en
Publication of WO2011128629A3 publication Critical patent/WO2011128629A3/en

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • 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
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • This invention relates to orally administrable pharmaceutical compositions comprising a lipid-vectored drug substance contained within the oil phase of a physiologically tolerable oil-in-water emulsion.
  • a targeting moiety e.g. at cancerous tissue where the active moiety is cytotoxic or is an imaging agent.
  • the complex may if desired be biodegradable such that the active agent is preferentially released at the target site in the body in which case the complex would be referred to as a prodrug.
  • lipid-targeted drugs can be used in cancer therapy, for example to increase transport into cancerous cells of cytoxic agents.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety.
  • the oil phase containing the drug substance it is meant that the drug substance is within the oil phase or is anchored to the oil phase by the lipid moiety.
  • the bond between the lipid moiety and the active drug moiety may be biodegradable, i.e. the drug substance may be in prodrug form.
  • biodegradable bonds are well known in the pharmaceutical industry, e.g. ester and amide bonds. However ester bonds are preferred, particularly for anti-cancer prodrugs as cancerous cells often have an elevated level of esterases.
  • the lipid moiety is preferably a fatty acid or fatty alcohol, especially one containing 7 to 30 carbons, particularly 12 to 20 carbons, more particularly an unsaturated or polyunsaturated fatty acid or alcohol, in particular a linear acid or alcohol.
  • lipid targeted drug substances usable according to the invention include the compounds desired in WO 2007/067071 , WO 2007/098628 and WO 2008/115069.
  • Such compounds including in particular elacytarabine (the 5'-elaidic acd ester of cytarabine), CP4126 (the 5'-elaidic acid ester of gemcytabine) and CP4200 (a fatty acid ester of azacitidine), are effective for the treatment of cancers and contain a fatty acid linked by an ester bond to an anticancer agent, cytarabine, gemcytarabine or azacitidine.
  • the fatty acid used is typically cis or trans
  • Lipid esters can also be used to taste-mask drugs.
  • clindamycin palmitate is a water-soluble ester of clindamycin [7 (S)-chloro-7-deoxylincomycin] and palmitic acid.
  • the palmitate ester is rapidly hydrolyzed to the microbiologically active clindamycin base after ingestion.
  • Clindamycin palmitate was introduced in place of clindamycin hydrochloride, because of the objectionable taste of the hydrochloride.
  • lipid ester prodrug form of cidofovir is available which is orally available for treatment of infection.
  • the drug substance may typically be included in the compositions of the invention at 10% to 100% of its normal oral daily dose, especially 50% to 100%.
  • the invention provides a method of treatment of a mammalian subject (either human or non-human) by oral administration to said subject of an effective amount of a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety, the improvement comprising administering said drug substance in a physiologically tolerable gelled oil-in-water emulsion.
  • a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety
  • composition comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste- masking moiety, bonded to an active drug moiety, for use in medicine.
  • a drug substance which comprises a lipid moiety, e.g. a targeting or taste- masking moiety, bonded to an active drug moiety, for use in medicine.
  • the invention provides a composition, comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste- masking moiety, bonded to an active drug moiety, for use in treatment by oral administration of a condition responsive to said active drug moiety.
  • a drug substance which comprises a lipid moiety, e.g. a targeting or taste- masking moiety, bonded to an active drug moiety, for use in treatment by oral administration of a condition responsive to said active drug moiety.
  • the invention provides the use of a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety for the manufacture of a medicament for use by oral administration in the treatment of a condition responsive to said active drug moiety.
  • a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety for the manufacture of a medicament for use by oral administration in the treatment of a condition responsive to said active drug moiety.
  • compositions of the invention may contain further components such as nutrients, e.g. lipids, (especially triglycerides and
  • phospholipids typically of plant or marine animal origin
  • vitamins, minerals, and folic acid pH modifiers, viscosity modifiers, flavours, aromas, sweeteners, colorants, antioxidants, etc.
  • the gelled emulsion compositions of the invention will preferably be in dose unit form, with each dose unit having a weight of 50 to 3000 mg, especially 100 to 1500 mg, particularly 400 to 000 mg.
  • the dose units of the gelled emulsion may be formed for example by moulding, extrusion or cutting or the like.
  • the dose units are preferably in tablet or lozenge form; however for child use they may conveniently be presented in child- friendly form, e.g. geometric shapes such as rods, strips and tubes, or animal, doll, or vehicle shapes, for example the shape of a popular cartoon character.
  • composition of the invention will preferably be uncoated, i.e. not within a capsule or shell-coating. Accordingly, to avoid water loss during storage, the dose units will conveniently be individually packaged, e.g. in foil wrappers or in the blisters of a blister pack.
  • the oil phase of the oil-in-water emulsion may be any physiologically tolerable lipid, e.g. fatty acid esters such as triglycerides and phospholipids, for example plant or animal oils, especially plant and marine animal oils. Particularly preferably an oil is used which is high in omega-3, omega-6 or omega-9 essential fatty acids, especially omega-3 essential fatty acids, more especially EPA and DHA. In this way the oil phase itself is a highly bioavailable source of nutrient lipids.
  • physiologically tolerable lipid e.g. fatty acid esters such as triglycerides and phospholipids
  • plant or animal oils especially plant and marine animal oils.
  • Particularly preferably an oil is used which is high in omega-3, omega-6 or omega-9 essential fatty acids, especially omega-3 essential fatty acids, more especially EPA and DHA.
  • omega-3, omega-6 or omega-9 essential fatty acids especially omega-3 essential fatty acids, more especially EPA and DHA.
  • the physiologically tolerable lipid is not an omega-3 acid
  • the lipid phase preferably also comprises an omega-3 acid.
  • omega-3 acids in addition to lipophilic prodrugs in the oil phase gives the added advantage of high uptake of the nutritionally valuable omega-3 oils.
  • omega-3 acids examples include a-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA),
  • ALA a-linolenic acid
  • SDA stearidonic acid
  • ETE eicosatrienoic acid
  • ETA eicosatetraenoic acid
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • DHA docosahexaenoic acid
  • omega-6 acids include linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo- gamma-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid, docosapentaenoic acid, and calendic acid.
  • omega-9 acids include oleic acid, eicosenoic acid, mead acid, erucic acid and nervonic acid.
  • compositions according to the invention contain a citrus flavour (e.g. orange or lemon oil) in order to mask any remaining oil taste on chewing. It is also particularly preferred that the compositions according to the invention contain xylitol, e.g. as 0.5 to 50% wt., preferably 1 to 40% wt., e.g. 15 to 40% wt., in order to mask both taste and mouth feel. These may be in the aqueous phase or the oil phase (e.g. as a water-in-oil-in water emulsion), or both; however inclusion in the aqueous phase will generally be sufficient.
  • a citrus flavour e.g. orange or lemon oil
  • xylitol e.g. as 0.5 to 50% wt., preferably 1 to 40% wt., e.g. 15 to 40% wt.
  • the essential fatty acids may form part or the whole of the oil phase in the gelled emulsion, preferably at least 10% wt, more especially at least 50% wt, particularly at least 80% wt. of that phase. They may be used as single compounds or as compound mixtures, e.g. plant or marine oils.
  • the oil phase of the oil-in-water emulsion may also contain solubilisers in order to increase the solubility of the drug substance in the oil phase.
  • solubilisers would be known to a person skilled in the art and include Chremophor ELTM, castor oil, Tween 80TM, SolutolTM HS15, LutrolTM and Olestra.
  • the aqueous phase of the gelled emulsion will contain water and a physiologically tolerable gelling agent, e.g. a hydrocolloid such as gelatin, alginate, carrageenan or a pectin.
  • a physiologically tolerable gelling agent e.g. a hydrocolloid such as gelatin, alginate, carrageenan or a pectin.
  • a physiologically tolerable gelling agent e.g. a hydrocolloid such as gelatin, alginate, carrageenan or a pectin.
  • a physiologically tolerable gelling agent e.g. a hydrocolloid such as gelatin, alginate, carrageenan or a pectin.
  • Such gelling agents and their gel-forming properties are well known. See for example Phillips GO and Williams PA (Eds.) Handbook of hydrocolloids, Woodhead Publishing, Cambridge (2000). The use of gelatin is especially preferred.
  • the weight ratio of the lipid phase to the aqueous phase in the gelled emulsions is preferably 1 :19 to 3:1 , especially 35:65 to 1 :1 , particularly 2:3 to 1 :1.
  • Emulsion formation may be effected by conventional techniques; however emulsification under a non-oxidising gas, e.g. nitrogen, is preferred.
  • a non-oxidising gas e.g. nitrogen
  • the components of the emulsion are preferably degassed before emulsification and handling and packaging of the set emulsion is preferably performed under such a gas.
  • the gelled emulsions of and used according to the invention may be produced as described in WO 2007/085835 and WO 2007/085840 and PCT/GB2009/002404 and PCT/GB2009/002406 (copies of which are annexed to the description of this application as Annexes A and B) the contents of which are hereby incorporated by reference.
  • the gelled emulsions may if desired be more than biphasic.
  • a water-in-oil emulsion may be emulsified with an aqueous gelling agent phase to produce a water-in-oil-in-water double emulsion, or two oil-in-water emulsions with different oil phases may be combined and intimately mixed before gelling onset.
  • CP 4126 the elaidic acid ester of gemcitabine, may be prepared as described in WO 98/32762 .
  • the oil(s) and CP4126 are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set.
  • the blister tray is thermally sealed with a metal/plastics foil cover sheet.
  • the oil(s) and clindamycin palmitate are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set.
  • the blister tray is thermally sealed with a metal/plastics foil cover sheet.
  • the oil(s) and elacytarabine are emulsified with the aqueous phase and the emulsion is poured in aliquots of .5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set.
  • the blister tray is thermally sealed with a metal/plastics foil cover sheet.

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Abstract

This invention provides pharmaceutical compositions comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety.

Description

Lipid-vectored Drug Compositions
This invention relates to orally administrable pharmaceutical compositions comprising a lipid-vectored drug substance contained within the oil phase of a physiologically tolerable oil-in-water emulsion.
Several drug substances are presented as a complex of a targeting moiety and the active moiety to ensure that the active moiety accumulates at the desired body site, e.g. at cancerous tissue where the active moiety is cytotoxic or is an imaging agent. The complex may if desired be biodegradable such that the active agent is preferentially released at the target site in the body in which case the complex would be referred to as a prodrug.
One form of targeting moiety that can be used is a lipid. Thus lipid-targeted drugs can be used in cancer therapy, for example to increase transport into cancerous cells of cytoxic agents.
While drugs can be delivered parenterally, oral administration is generally preferred both for patient comfort and since self administration is facilitated. However with oral administration of drugs there is often a relatively poor uptake of the drug substance from the gut.
We have now found that body uptake of orally administered lipid or lipid group containing drugs is enhanced if the drug substance is in the oil phase of a physiologically tolerable gelled oil-in-water emulsion.
Thus viewed from one aspect the invention provides a pharmaceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety.
By the oil phase containing the drug substance, it is meant that the drug substance is within the oil phase or is anchored to the oil phase by the lipid moiety. If desired, the bond between the lipid moiety and the active drug moiety may be biodegradable, i.e. the drug substance may be in prodrug form. Examples of biodegradable bonds are well known in the pharmaceutical industry, e.g. ester and amide bonds. However ester bonds are preferred, particularly for anti-cancer prodrugs as cancerous cells often have an elevated level of esterases. Thus the lipid moiety is preferably a fatty acid or fatty alcohol, especially one containing 7 to 30 carbons, particularly 12 to 20 carbons, more particularly an unsaturated or polyunsaturated fatty acid or alcohol, in particular a linear acid or alcohol.
Examples of lipid targeted drug substances usable according to the invention include the compounds desired in WO 2007/067071 , WO 2007/098628 and WO 2008/115069. Such compounds, including in particular elacytarabine (the 5'-elaidic acd ester of cytarabine), CP4126 (the 5'-elaidic acid ester of gemcytabine) and CP4200 (a fatty acid ester of azacitidine), are effective for the treatment of cancers and contain a fatty acid linked by an ester bond to an anticancer agent, cytarabine, gemcytarabine or azacitidine. The fatty acid used is typically cis or trans
CH3(CH2)1oCH=CH(CH2)4COOH> CH3(CH2)5(CH=CHCH2)3(CH2)3COOH (e.g. the tri- cis acid), cis or trans
Figure imgf000003_0001
or cis or trans
CH3(CH2)7CH=CH(CH2)7COOH, especially elaidic acid.
Lipid esters can also be used to taste-mask drugs. Thus for example clindamycin palmitate is a water-soluble ester of clindamycin [7 (S)-chloro-7-deoxylincomycin] and palmitic acid. The palmitate ester is rapidly hydrolyzed to the microbiologically active clindamycin base after ingestion. Clindamycin palmitate was introduced in place of clindamycin hydrochloride, because of the objectionable taste of the hydrochloride.
Moreover, a lipid ester prodrug form of cidofovir is available which is orally available for treatment of infection.
The drug substance may typically be included in the compositions of the invention at 10% to 100% of its normal oral daily dose, especially 50% to 100%.
Viewed from a further aspect the invention provides a method of treatment of a mammalian subject (either human or non-human) by oral administration to said subject of an effective amount of a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety, the improvement comprising administering said drug substance in a physiologically tolerable gelled oil-in-water emulsion.
Viewed from a further aspect the invention provides a composition, comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste- masking moiety, bonded to an active drug moiety, for use in medicine.
Viewed from a further aspect the invention provides a composition, comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste- masking moiety, bonded to an active drug moiety, for use in treatment by oral administration of a condition responsive to said active drug moiety.
Viewed from a still further aspect the invention provides the use of a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety for the manufacture of a medicament for use by oral administration in the treatment of a condition responsive to said active drug moiety.
Besides the drug substance, the compositions of the invention may contain further components such as nutrients, e.g. lipids, (especially triglycerides and
phospholipids, typically of plant or marine animal origin), vitamins, minerals, and folic acid, pH modifiers, viscosity modifiers, flavours, aromas, sweeteners, colorants, antioxidants, etc..
The gelled emulsion compositions of the invention will preferably be in dose unit form, with each dose unit having a weight of 50 to 3000 mg, especially 100 to 1500 mg, particularly 400 to 000 mg.
The dose units of the gelled emulsion may be formed for example by moulding, extrusion or cutting or the like. For adult use, the dose units are preferably in tablet or lozenge form; however for child use they may conveniently be presented in child- friendly form, e.g. geometric shapes such as rods, strips and tubes, or animal, doll, or vehicle shapes, for example the shape of a popular cartoon character.
The composition of the invention will preferably be uncoated, i.e. not within a capsule or shell-coating. Accordingly, to avoid water loss during storage, the dose units will conveniently be individually packaged, e.g. in foil wrappers or in the blisters of a blister pack.
The oil phase of the oil-in-water emulsion may be any physiologically tolerable lipid, e.g. fatty acid esters such as triglycerides and phospholipids, for example plant or animal oils, especially plant and marine animal oils. Particularly preferably an oil is used which is high in omega-3, omega-6 or omega-9 essential fatty acids, especially omega-3 essential fatty acids, more especially EPA and DHA. In this way the oil phase itself is a highly bioavailable source of nutrient lipids.
In the case that the physiologically tolerable lipid is not an omega-3 acid, the lipid phase preferably also comprises an omega-3 acid. The presence of omega-3 acids in addition to lipophilic prodrugs in the oil phase gives the added advantage of high uptake of the nutritionally valuable omega-3 oils.
Examples of omega-3 acids include a-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA),
tetracosapentaenoic acid and tetracosahexaenoic acid. Examples of omega-6 acids include linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo- gamma-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid, docosapentaenoic acid, and calendic acid. Examples of omega-9 acids include oleic acid, eicosenoic acid, mead acid, erucic acid and nervonic acid.
It is particularly preferred that the compositions according to the invention contain a citrus flavour (e.g. orange or lemon oil) in order to mask any remaining oil taste on chewing. It is also particularly preferred that the compositions according to the invention contain xylitol, e.g. as 0.5 to 50% wt., preferably 1 to 40% wt., e.g. 15 to 40% wt., in order to mask both taste and mouth feel. These may be in the aqueous phase or the oil phase (e.g. as a water-in-oil-in water emulsion), or both; however inclusion in the aqueous phase will generally be sufficient.
Other than the drug substance, the essential fatty acids may form part or the whole of the oil phase in the gelled emulsion, preferably at least 10% wt, more especially at least 50% wt, particularly at least 80% wt. of that phase. They may be used as single compounds or as compound mixtures, e.g. plant or marine oils.
The oil phase of the oil-in-water emulsion may also contain solubilisers in order to increase the solubility of the drug substance in the oil phase. Suitable solubilisers would be known to a person skilled in the art and include Chremophor EL™, castor oil, Tween 80™, Solutol™ HS15, Lutrol™ and Olestra.
The aqueous phase of the gelled emulsion will contain water and a physiologically tolerable gelling agent, e.g. a hydrocolloid such as gelatin, alginate, carrageenan or a pectin. Such gelling agents and their gel-forming properties are well known. See for example Phillips GO and Williams PA (Eds.) Handbook of hydrocolloids, Woodhead Publishing, Cambridge (2000). The use of gelatin is especially preferred. Besides water and the gelling agent, the aqueous phase of the gelled emulsion may contain other water-soluble components, e.g. vitamins, minerals, pH modifiers, viscosity modifiers, antioxidants, colorants, flavours, water-soluble drug substances, etc. as desired.
The weight ratio of the lipid phase to the aqueous phase in the gelled emulsions is preferably 1 :19 to 3:1 , especially 35:65 to 1 :1 , particularly 2:3 to 1 :1.
Emulsion formation may be effected by conventional techniques; however emulsification under a non-oxidising gas, e.g. nitrogen, is preferred. Likewise, the components of the emulsion are preferably degassed before emulsification and handling and packaging of the set emulsion is preferably performed under such a gas.
The gelled emulsions of and used according to the invention may be produced as described in WO 2007/085835 and WO 2007/085840 and PCT/GB2009/002404 and PCT/GB2009/002406 (copies of which are annexed to the description of this application as Annexes A and B) the contents of which are hereby incorporated by reference.
The gelled emulsions may if desired be more than biphasic. Thus a water-in-oil emulsion may be emulsified with an aqueous gelling agent phase to produce a water-in-oil-in-water double emulsion, or two oil-in-water emulsions with different oil phases may be combined and intimately mixed before gelling onset.
The invention will now be illustrated further with reference to the following non- limiting Examples.
Example 1
C4126 Gel
CP 4126, the elaidic acid ester of gemcitabine, may be prepared as described in WO 98/32762 .
Components
Gelatin 84 mg
Gum arabicum 55.5 mg
Sorbitol 155 mg
Xylitol 360 mg
Citric acid 9 mg
Flavour 18 mg
Colour 10.5 mg
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
CP4126* 200 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and CP4126 are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.
[NB dose = 100-2000 mg/day]
Example 2
Clindamycin palmitate Gel
Components
Gelatin 84 mg
Gum arabicum 55.5 mg
Sorbitol 155 mg
Xylitol 360 mg
Citric acid 9 mg
Flavour 18 mg
Colour 10.5 mg
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Clandamycin palmitate* 200 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and clindamycin palmitate are emulsified with the aqueous phase and the emulsion is poured in aliquots of 1.5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.
Example 3
Elacvtarabine gel
Components
Gelatin 84 mg Gum arabicum 55.5 mg
Sorbitol 155 mg
Xylitol 360 mg
Citric acid 9 mg
Flavour 18 mg
Colour 10.5 mg
Plant oil* 0 - 600 mg
Fish oil* 0 - 600 mg
Elycytarabine* 200 mg
Water to 1500 mg
* Total no more than 600 mg
The oil(s) and elacytarabine are emulsified with the aqueous phase and the emulsion is poured in aliquots of .5 g into elongate moulds lined with a metal/plastics laminate blister tray and allowed to set. The blister tray is thermally sealed with a metal/plastics foil cover sheet.

Claims

Claims:
1. A pharmaceutical composition comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety.
2. A method of treatment of a mammalian subject (either human or non- human) by oral administration to said subject of an effective amount of a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety, the improvement comprising administering said drug substance in a physiologically tolerable gelled oil-in-water emulsion.
3. A composition, comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety, for use in medicine.
4. A composition, comprising a physiologically tolerable gelled oil-in-water emulsion containing in the oil phase thereof a drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety, for use in treatment by oral administration of a condition responsive to said active drug moiety.
5. The use of drug substance which comprises a lipid moiety, e.g. a targeting or taste-masking moiety, bonded to an active drug moiety for the manufacture of a medicament for use by oral administration in the treatment of a condition
responsive to said active drug moiety.
6. A composition, method or use as claimed in any of the preceding claims wherein said lipid targeting moiety is the residue of a fatty acid or alcohol.
7. A composition, method or use as claimed in any one of the preceding claims wherein said active drug moiety is the residue of a cytotoxic agent.
8. A composition, method or use as claimed in any one of the preceding claims wherein said drug substance is the 5'-elaidic acid ester of cytarabine or
gemcytabine.
PCT/GB2011/000559 2010-04-14 2011-04-11 Lipid-vectored drug compositions WO2011128629A2 (en)

Applications Claiming Priority (2)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998032762A1 (en) 1997-01-24 1998-07-30 Norsk Hydro Asa Gemcitabine derivatives
WO2007067071A1 (en) 2005-12-08 2007-06-14 Clavis Pharma As Dioxolane derivates for the treatment of cancer
WO2007085835A1 (en) 2006-01-25 2007-08-02 Probio Nutraceuticals As Chewable capsules
WO2007098628A1 (en) 2006-03-01 2007-09-07 Neopreg Ag Apparatus for the production of sprueless molded parts in a transfer molding process and an injection-compression molding process
WO2008115069A2 (en) 2007-03-20 2008-09-25 Clavis Pharma Asa Fatty acid esters of glucocorticoids as anti-inflammatory and anti-cancer agents

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090130211A1 (en) * 2007-11-16 2009-05-21 Aly Gamay Gelled colloidal emulsion for appetite suppression
WO2010039039A1 (en) * 2008-10-03 2010-04-08 Clavis Pharma Asa Oral formulations of gemcitabine derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998032762A1 (en) 1997-01-24 1998-07-30 Norsk Hydro Asa Gemcitabine derivatives
WO2007067071A1 (en) 2005-12-08 2007-06-14 Clavis Pharma As Dioxolane derivates for the treatment of cancer
WO2007085835A1 (en) 2006-01-25 2007-08-02 Probio Nutraceuticals As Chewable capsules
WO2007085840A1 (en) 2006-01-25 2007-08-02 Probio Nutraceuticals As Emulsion
WO2007098628A1 (en) 2006-03-01 2007-09-07 Neopreg Ag Apparatus for the production of sprueless molded parts in a transfer molding process and an injection-compression molding process
WO2008115069A2 (en) 2007-03-20 2008-09-25 Clavis Pharma Asa Fatty acid esters of glucocorticoids as anti-inflammatory and anti-cancer agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Handbook of hydrocolloids", 2000, WOODHEAD PUBLISHING

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