WO2004082585A2 - Nouveaux conjugues de phenytoine - Google Patents

Nouveaux conjugues de phenytoine Download PDF

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WO2004082585A2
WO2004082585A2 PCT/GB2004/000631 GB2004000631W WO2004082585A2 WO 2004082585 A2 WO2004082585 A2 WO 2004082585A2 GB 2004000631 W GB2004000631 W GB 2004000631W WO 2004082585 A2 WO2004082585 A2 WO 2004082585A2
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phenytoin
drug
pro
polymer
group
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WO2004082585A3 (fr
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Jonathan Clark
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SIRUS PHARMACEUTICALS Ltd
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SIRUS PHARMACEUTICALS Ltd
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Priority claimed from GB0306445A external-priority patent/GB0306445D0/en
Priority claimed from PCT/GB2003/003522 external-priority patent/WO2004014973A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
    • C08G73/10—Polyimides; Polyester-imides; Polyamide-imides; Polyamide acids or similar polyimide precursors
    • C08G73/1092—Polysuccinimides
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to a conjugate of phenytoin having improved solubility and absorption characteristics.
  • the material can be administered as a solid or in solution, either orally or by injection
  • Phenytoin has been used in the treatment of epilepsy or many years and may additionally have uses in the treatment of pain through its sodium channel blocking activity. When administered, patient plasma levels have to be monitored regularly because of variable bioavailability. One factor contributing to this variability is that phenytoin is very insoluble. Phenytoin is usually administered as a sodium salt to improve solubility, however on contact with the acidic environment of the stomach it becomes protonated and is believed to aggregate into lumps. The dissolution of these lumps is then variable contributing to the variable plasma levels.
  • An injectable pro-drug of phenytoin was developed by Parke Davis and is known as phosphenytoin. This compound relies on phosphatase activity to cleave the phosphate group off and to leave a molecule which spontaneously decomposes to release formaldehyde and phenytoin.
  • a first aspect of the invention is a conjugate of a water-soluble polymer and phenytoin or a pro-drug thereof.
  • the conjugate may be used in therapy, e.g. for treating epilepsy or pain.
  • the polymer comprises a carrier system which releases phenytoin through chemical instability and/or enzymatic activity. More particularly, such polymers are water-soluble and largely soluble in the acid environment of the stomach, whereupon they undergo controlled degradation, to release free phenytoin. The undesirable precipitation of phenytoin which occurs when the free drug is administered orally may thereby be substantially mitigated.
  • the water- soluble polymers may also be useful for permitting administration by injection. Description of preferred embodiments
  • alkyl means a straight chain or branched alkyl group of up to 8 carbon atoms. Examples are methyl and ethyl. Alkyl ether i.e. alkoxy may be interpreted accordingly. Examples are methoxy and ethoxy. Alkyl thioether i.e. alkylthio may be interpreted accordingly.
  • Aryl means any aromatic group including heteroaromatic groups, e.g. containing up to three heteroatoms selected from N, O and S, monocyclic or bicyclic, having up to 12, e.g. 5 to 10, ring atoms. Examples are thienyl, phenyl and naphthyl. A preferred aryl. group is phenyl. "Alkyl aryl” may be interpreted similarly. Examples include methylphenyl. "Aryl ether” i.e. aryloxy may be interpreted accordingly.
  • Halogen means F, Cl, Br or I.
  • the phenytoin or pro-drug thereof is linked to the polymer through its N-2 nitrogen atom.
  • phenytoin is connected to the polymer as a pro-drug which releases phenytoin when itself released from the polymer.
  • Preferred pro-drugs of phenyto In are hemiacetals formed at the N-2 atom with formaldehyde and higher aldehydes. Preferably they are connected to the polymer through an acyl group.
  • the preferred pro-drug is given by the following formula:
  • R represents hydrogen, alkyl, aryl or alkylaryl, e.g. of up to 12 or 20 carbon atoms, and is preferably hydrogen.
  • the pro-drug is linked to the polymer by a covalent bond through the hydroxyl moiety.
  • polymers to which phenytoin or a pro-drug thereof may be attached include natural polymers such as dextran, dextrin or a synthetic polymer, preferably biodegradable and non-toxic in nature.
  • the drug is connected either directly to the polymer or (more preferably> through a linker which may be a peptide, amino acid, a short carbon cnain such as succinic acid..
  • linker may be formulated to assist in the release of the drug molecule from the rest of the composition or otherwise to modulate the physical and biological properties of he material _
  • phenytoin or pro-drug thereof may be coupled via an ester bond which is cleaved by esterases such as lipases.
  • the linker may be an amino acid. This may endow some enzyme specificity on release of the drug from the complex in addition to release based in chemistry dependent on other bonds that are present.
  • the linker can contain several amino acids in sequence (i.e. be a peptide) to confer greater enzymatic specificity.
  • the linker may also be connected via an ether bond to a glycose sub ⁇ nit.
  • One embodiment of a conjugate of the present invention is as a prodrug or a pro-drug of a pro-drug of phenytoin, typically as an acyl derivative formed at the functional atom.
  • An acyl group may be used that endows the conjugate with desired solubility or other properties , and that can be removed typically by hydrolysis, either by a biological process or by natural chemical decomposition, to release the free functional group and hence the active principle, or to release a pro-drug of phenytoin which then degrades to form the active principle.
  • Suitable acyl groups are those derived from polyethylene glycol (PEG ) acids.
  • PEG polyethylene glycol
  • PEG may be condensed with a diacid e.g. succinic: acid to yield a PEG derivative bearing an acyl group (or two acyl groups) to which the drug may be attached.
  • Examples of PEG conjugates according to this invention are:
  • R a is hydrogen, alkyl, aryl or alkylaryl and m is 0 or an integer of up to 1000, preferably 1 to 10O0, more preferably 5> to 1000, particularly 10 to 500.
  • R a represents Coalkyl, e.g. COMe.
  • R a may also represent COCH CH 2 COO-Drug.
  • Another preferred polymer to which phenytoin or a pro-drug thereof may be conjugated is dextran.
  • a number of dextrans are commercially available e.g . where the number of units per polymer is approximately in the range 50 to 1000. Examples of commercially available dextran include those where this number is 61, 185, 430 or 620. The exact number depends on the supplied batch of dextran. These are all preferred values; by choosing different values, different levels of drug may be delivered.
  • the polymer is dextrin.
  • a number of dextrins are commercially available e.g. where the number of units per polymer is approximately in the range of 50 to 1000.
  • the acyl group is linked to a suitable diamine through which a condensation reaction can be carried out with a diacid such as a PEG containing diacicl.
  • Particularly preferred conjugates according to the invention are co-polymers comprising units of formulae (I) and (II):
  • B is selected from oxygen, sulphur, alkyl, alkyl ether, alkyl thioether, hydro_xyl alkyl and alkyl aryl, e.g. of up to 12 or 20 carbon atoms; s independently represents 0 or an integer of 1 to 100; m is an integer of 1 to 1000; n is 0 or an integer of 1 to 100; A is a functional group; and Z is phenytoin or a pro-drug thereof.
  • a pro-drug of phenytoin is employed which bears an -OH group and Z is connected to A by means of the -OH group on the pro-drug of phenytoin.
  • m represents 4 to 100, especially 4 to 70.
  • Examples of [B] s include O and (CH 2 ) ⁇ -3, e.g. CH 2 , however preferably s represents 0.
  • Functional group A is adapted to provide a point of attachment for the phenytoin or pro- drug thereof.
  • Examples of functional group A include CO, COO, CONR 1 (wherein R 1 is defined below, e.g. H) and preferably include CO.
  • Polymers of this aspect of the present invention may comprise one or more different monomer units (I) and one or more different monomer units (II).
  • the units (I) and (II) may contain different A and B groups.
  • Conjugates according to this aspect of the invention may be prepared by a process generally known, e.g. by polymerisation of a diacid with a diamine.
  • diamine containing substituents may be polymerised with a diamine containing substituents.
  • a diamine is lysine.
  • the diacid will typically have a range of values for m, the exact range affecting the physical properties of the polymer producted.
  • conjugates according to the invention are prepared by a process which comprises co-polymerising one or more monomers (I'), as just defined, with one or more monomers (I!'):
  • the invention also provides co-polymers obtainable by and obtained by said process.
  • the number of units of each monomer in the polymer is preferably 5 to 30, or up to
  • the preferred cross-linker has the formula:
  • n is preferably 1 to 10, e.g. 3-6, most preferably 4, and p is preferably 1 to 10, e.g. 3-6, most preferably 4.
  • the invention also provides co-polymers obtainable by and obtained by said process.
  • the two carboxylic acid moieties of the diacid monomer (I'j are activated.
  • Suitable activating groups are well known to a skilled person.
  • the acid moieties may suitably be activated by treatment with N-hydroxysuccinimide.
  • diamine monomers include the following:
  • R 1 , R 2 and R 4 are typically selected from hydrogen, alkyl, aryl, alkyl ether, amino acid, peptide, linker and phenytoin (or a pro-drug thereof).
  • monomers (II') include those compounds just mentioned in which R 4 represents phenytoin (or a pro-drug thereof) or R 1 represents phenytoin (or a pro-drug thereof) and R 2 is selected from hydrogen, alkyl, aryl, alkyl ether, amino acid, peptide, linker and phenytoin (or a pro-drug thereof), n is typically 0 or an integer 1 to 10, e.g. 3 to 6, most preferably 4.
  • suitable diamine monomers .(II') include diaminopropionic acid, ornithine and lysine derivatives. They can be used as free carboxylic acids or may be connected to saccharide derivatives such as glucamine or alternatively to polyethylene glycolS; to modulate water solubility.
  • diamine monomers e.g. monomers (II')
  • diamine monomers (II') include the following:
  • X is oxygen, sulphur or nitrogen (e.g. NR 1 wherein R 1 is as defined above, such as NH),
  • R 3 is typically as defined above for R 2 , k is 0 or an integer from 1 to 1000, and preferably represents 1 to 100, and p is 0 or an integer of up to 10, and preferably represents 1 to 10.
  • tri-functional groups such as tri-amines can be added to increase cross- linking. This has significant effect on polymer properties, as will be understood by those skilled in the art of polymer chemistry. Solubility and molecular weight in particular are altered. The degree of cross-linking also has an impact on biodegradability which would also be understood by someone skilled in the art of polymer therapeutics and delivery systems.
  • a typical procedure for the preparation of the polymers of this invention involves prior activation of the di-acid component as an acid chloride, acid bromide, acid fluoride, or as an active ester such as a N-hydroxysuccinimide.
  • the di-acid can be activated in situ using reagents commonly used for the preparation of amide bonds in peptide synthesis.
  • the polymerisation may be carried out by heating the di-acid and diamine components together to dehydrate the material to effect polymerisation.
  • the preferred method is to activate the di-acid prior to use, so that the activated material can be purified and stored for use at a later stage.
  • the preferred activation method is to form the N-hydroxysuccinimide ester from N- hydrqxysuccinimide, di-isopropylcarbodiimide and the di-acid in dichloromethane.
  • the activated di-acid can then be reacted with di-amine in the ratio of one di-acid to one di-amine to provide the polymer of this invention.
  • By controlling the exact ratio of di-acid to di-amine different molecular weights can be achieved. It is probable that, by limiting the di-amine ratio to less than one to one of di-acid, the material will contain cyclic material.
  • the molecular weight can also be controlled by varying the polymerisation conditions, such as temperature, time, concentration and by the addition of components which can stop the polymerisation, such as water, mono-amine, alcohols and alkoxide.
  • branching units such as a tri-amine
  • the molecular weight can be increased dramatically.
  • the ratio of di-acid to di-amine must be adjusted to take into account the addition of the branching agent, which in the case of a tri-amine branching unit would reduce the amount of di-amine required.
  • the aim in this case is to keep the total amine content (di-acid plus diamine) the same as with the di-acid. alone.
  • the termini of the polymer chains will have activated acid groups at the ends.
  • additional activated di-acid can be added at the end bf the bulk polymerisation to achieve a similar result, but generally of a polymer with higher molecular weight.
  • the termini can then be reacted with further components, such as cell- targeting agents, proteins, peptides, saccharides; polysaccharides or cross-linking reagents such as tri-amines.
  • the co-polymer contains amine equivalents to acid equivalents in a ratio of 1:1 or (1 : 1)+1 or (1:1)- 1 to take account of the fact that the termini of the polymer may be formed from diacid monomer or the diamine monomer, or one may be diacid monomer and the other may be diamine monomer.
  • this ratio will be the ratio of monomers (I') to (I I').
  • cross linking components are used (whether acid or amine), then a correction will need to be applied accordingly.
  • the polymers are preferably straight-chain. In other cases they are preferably cross-linked.
  • the polymer may also be cyclic (in which case the ratio would be 1:1). In order to make it more likely that one of the monomers forms the termini then an excess of that monomer can be used.
  • the termini of the polymer may be derivatised Ccapped), e.g. an acid terminus with an alcohol (to form an ester) or an amine (to form an amide) and/or an amine terminus with an acid (to form an amide) .
  • the polymer may be capped with a substance K capable of usefully modifying the properties of the polymer.
  • polymer property-modifying agents include targeting agents.
  • a targeting agent K will be an agent capable of directing or aiding direction of the polymer to the target for the therapeutic agent.
  • targeting agents include cell adhesion moieties. Such substances can assist with intracellular delivery.
  • targeting agents which can direct the polymer to neuronal cells, for example a neuronal cell adhesion moiety, e.g. a sensory nerve adhesion moiety.
  • nerve adhesion moieties include antibodies and in particular those which have affinity for nerve cell mem branes, lectins such as lectins derived from vertebrates, mammals or humans or other lectins such as plant lectins, and in particular wheat germ agglutinin, hormone receptor ligands, cytokines, growth factors, such as nerve growth factor, epidermal growth factor and insulin-related gro-wth factors, neuropeptides such as endorphins, vasoactive intestinal polypeptide, calcitonin, cholceystokinin, substance P, somatostatin, neuropeptide Y, fragments of neurotrop hie viruses such as viral coat proteins of herpes simplex virus, polio virus, rabies virus or fragments thereof, bacterial toxins and in particular non-toxic fragments thereof such as cholera toxin B chain and tetanus toxin fragment C, or fragments thereof.
  • lectins such as lectins derived from vertebrates, mammals or
  • K may be an agent capable of enhancing the solubility of the polymer, e.g. a polyethylene glycol or a derivative thereof.
  • K. may be a saccharide (e.g. a polysaccharide). If the group K is a precursor of a polymer property-modifying agent, then it may be converted to the polymer behaviour-modifying agent in one or more further synthetic steps.
  • K may be a reactive group (or such a grou . in protected form) which may be reacted with a targeting agent, or other polymer property-modifying agent, after the polymer has been formed.
  • the one or more such termini may be reacted with a substance bearing amine groups, e.g. a protein with surface lysine 5 residues.
  • a substance bearing amine groups e.g. a protein with surface lysine 5 residues.
  • examples include lectins such as wheat germ agglutinin. It may be necessary to activate the acid termini to facilitate reaction, e.g. by reaction with N-hydroxysuccinimide.
  • the co-polymer contains up to 10,000, and more preferably up to 1000 units of each monomer.
  • the polymer contains at least 5, more preferably at least 10 units of each monomer.
  • the nu ber of units is 5 to 30, e.g. 10 to 30, especially 15 to 10 20.
  • monomer (I') is preferably a compound of formula:
  • n is as defined for formula (I).
  • m represents an integer 4-100, especially 4-
  • Such monomers can be prepared by treating a polyethylene glycol (PEG) with succinic anhydride under standard conditions.
  • the reagents may be mixed in the presence of dimethylaminopyridine 20 (DMAP) in an inert solvent such as dichloromethane (DCM).
  • DMAP dimethylaminopyridine 20
  • DCM dichloromethane
  • the functional group A preferably comprises a carbonyl moiety, i.e. it is derived from a carboxy group, and optional linker J such that a preferred monomer (II * ) is a compound of the 25 formula:
  • J is an optional linker and Z is a pro-drug of phenytoin and J-CO is connected to Z by means of a -OH group on the pro-drug of phenytoin.
  • n represents an integer of 1 to 10, especially 3 to 6, most preferably 4.
  • J therefore represents a linker or a bond, but preferably J represents a linker.
  • J represents a linker it preferably represents the group J 1 -J 2 -J 3 .
  • Suitable linkers include amino acids, peptides or a chain such as 6-aminohexanoic acid, 5-aminopentanoic acid, 4-aminobutanoic acid and 3-aminopropanoic acid.
  • 5-Aminopentanoic acid is a particularly preferred linker.
  • a process for preparing a polymer comprises co-polymerising one or more first monomers (I'):
  • J 1 -J -J 3 represents a linker moiety and Z is connected to J 3 by means of an OH group on the pro-drug of phenytoin.
  • the invention also provides polymers obtainable and obtained by such a process.
  • Phenytoin or pro-drug moiety Z contains a free hydroxy group which allows it to be connected to the diamine via linker J 1 -J 2 -J 3 if present. Z may then be released from the polymer by hydrolysis of the ester connection.
  • J 1 preferably represents a sulphur, oxygen or an amino group (e.g. NH or N e, preferably NH), preferably oxygen or an amino group, especially an amino group.
  • J 2 preferably represents a spacer group.
  • J 3 preferably represents a carbonyl group. This permits Z to be released from the polymer by hydrolysis of the ester connection between J 3 and Z.
  • Spacer group J 2 may represent an alkylene group e.g. a C- M oalkylene group e.g. -(CH 2 )3-e.
  • the preferred linker J 1 -J 2 -J 3 is - NH(CH 2 ) 4 CO-.
  • a preferred monomer (II') is:
  • w 0 to 100, preferably 1-10, more preferably 3-6, especially 4; and Rt is selected from hydrogen, alkyl, aryl and alkylaryl, e.g. of up to 12 or 20 carbon atoms and is preferably hydrogen.
  • n represents 1 to 10, e.g. 3 to 6, most preferably 4.
  • a preferred conjugate of the invention has units of the formulae:
  • n 4
  • w 4
  • m has an average value of 4 to 70 and the number of diacid and diamine units shown is each 5 to 30 or up to 10,000 in some preparations with a trifunctional cross-linker added.
  • the preferred cross-linker has the formula
  • polymers according to the invention may be prepared in which more than one monomer (I') (which different monomers may, for example, differ in chain length m) with more than one monomer (II') (which different monomers may, for example, differ in values for n and nature of (I)).
  • monomer (I') comprises a dispersion of chain length m based on the dispersion of the polyethylene glycol from which it will have been derived.
  • components such as therapeutically active agents, targeting agents and the like may be incorporated into the polymer by incorporating such components into monomer (II').
  • components such as therapeutically active agents, targeting agents and the like may be incorporated into the polymer by incorporating such components into monomer (II').
  • precursors include derivatives such as protected derivatives and other chemical intermediates.
  • it may be desired or necessary to incorporate the compound of formula (I) into monomer (II') in protected form and to deprotect it after polymerisation has taken place.
  • novel pharmaceutical compositions comprise a polymer incorporating phenytoin as herein described together with a pharmaceutically acceptable diluent or carrier.
  • Polymers incorporating therapeutic substances according to the present invention may be administered in therapy by whatever route of administration and in whatever presentation may be deemed most suitable.
  • formulations for parenteral injection may comprise a polymer according to the present invention dissolved in an aqueous carrier.
  • the aqueous carrier may include conventional excipients such as buffers, preservatives and the like.
  • formulations for oral administration include capsules and tablets. These may comprise a polymer according to the present invention together with conventional excipients such as diluents, dispersing aids and the like.
  • the compositions are administered in a manner compatible with the dosage required and in such amount as will be therapeutically or prophylactically effective.
  • the quantity to be administered which is generally in the range 5pg to 10g, preferably 250 ⁇ g to 10mg per dose depends on a number of factors. These include the subject to be treated, and the degree of therapeutic or prophylactic activity desired and, if applicable, the size of the area to be treated. Precise amounts of active ingredient required to be administered may depen d on the judgment of the practitioner and may be peculiar to each subject.
  • compositions of the present invention may also potentially be administered by the ocular, intraocular., intrathecal and intraarticular routes.
  • Further aspects of the invention include the use of polymers incorporating phenytoin according to the invention in the manufacture of a medicament for the treatment of epilepsy or pain and a method of treatment of epilepsy or pain which comprises administering to a patient a polymer incorporating phenytoin according to the invention.
  • the conjugates of the invention have the advantage that they may result in more consistent pharmacokirietics of phenytoin, may be more bioavailable, may be more water or plasma-soluble, may be more orally active, may have longer duration of action, may effect more complete drug release, may more rapidly release drug, may be more biodegradable, may be more benign or otherwise less toxic, are susceptible to more ready or economic synthesis or have other advantages over prior art formulations and derivatives of phenytoin. Further details concerning biodegradable polymers for use in the invention may be found in International Patent Application No. PCT/GB 03/03522 which is herein incorporated by reference in its entirely. Abbreviations:
  • Figure 1 shows the NMR spectrum for a phenytoin-polymer conjugate (Example 1).
  • Figure 2 shows a linear plot of the plasma concentration of phenytoin with time following administration of phenytoin sodium or phenytoin polymer conjugate
  • Figure 3 shows a log/linear plot of the plasma concentration of phenytoin with time following administration of phenytoin sodium or phenytoin polymer conjugate
  • Figure 4 shows photographs of solutions of free phenytoin (labelled -) and phenytoin polymer conjugate (labelled +) as described in Example 4.
  • Boc-Lys-(Boc)-5-aminovaleric acid (5.48g, 12.30 mmol), 1.0 eq), DIC (1.93 mL, 12.&0 mmol, 1.0 eq) and DMAP (150 mg, 1.23 mmol, 0.1 eq) were dissolved in dry dioxane (50 rrt L) and stirred for 15-20 min at room temperature. N-2-(hydroxymethyl)-phenytoin was added to t e now cloudy solution as a solution in dry dioxane. The reaction was then allowed to stir at room temperature overnight. The reaction mixture was evaporated to dryness and the residue partitioned between ethyl acetate and water.
  • BocLys(Boc)-(5-aminovalerate)-N-2-(hydroxymethyl)-phenytoin 0.5g was dissolved in TFA (10 mL) and stirred at room temperature for 30 min. The. solvents were evaporated, the residue taken up in water (15 mL) and freeze dried to give the deprotected material.
  • Lys-linker-N-2-(hydroxymethyl)-phenytoin (0.15 mmol) and bis (succinic acid N- hydroxysuccinimide ester) poly(ethylene glycol) ester (0.15 mmol) were dissolved in DMF (400 ⁇ L) and treated with NMM (64 ⁇ L, 0.58 mmol) . The oil was left to stand overnight, then precipitated from ether. The resulting polymer was dried on high vac line for 30 min.
  • N-Boc-1 ,4-diaminobutane monohydrochloride (430 mg, 2.25 mmol, 1.0 eq) was dissolved in water (15 mL) and MeCN (10mL). Sodium carbonate (120 mg, 1.12 mrnol, 0.5 eq) was added as a solution in water (5 mL), followed by Boc-Lys(Boc)OSu (1.0 g, 2.25 mmol, 1.0 eq) as a solution in MeCN (20 mL). The reaction was then left to stir overnight. The reaction mixture was concentrated and water added before being extracted with DCM (3 x 50 L).
  • a pharmacokinetic study was designed to compare plasma concentration v rsus time data for phenytoin following single oral dose of phenytoin as a polymer conjugate of the present invention with that of phenytoin sodium free drug given b»y the oral route.
  • Group 1 received a single oral dose of phenytoin polymer conjugate according to the present invention (as per Example 1), whilst animals of Group 2 received a single oral dose of phenytoin sodium. The animals were fasted for 14 hours prior to dosing. Doses were administered using a rubber catheter and disposable syringe (oral gavage). The dose volume was lOrnl/'kg, adjusted according to bodyweight recorded on day of dosing.
  • phenytoin polymer conjugate and phenytoin sodium were dissolved in distilled water and appeared as clear solutions. Each animal received an equivalent phenytoin dose of 20 mg/kg, which equated to 181.8 mg/kg and 21.8 mg/kg of phenytoin polymer conjugate and free phenytoin sodium, respectively. Blood samples were obtained at the following time points relative to dosing: 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after dosing
  • the analyte was ionized using the TubolonSprayTM interface operating in positive mode. Methetoin was used as internal standard. The characteristic ion dissociation transitions m/z 253 -> 182 (phenytoin) and m/z 219 -» 159 (methetoin) were monitoredyia tandem MS.
  • the plasma concentration with time is shown in linear plot and log/linear plot in Figures 2 and 3 respectively.

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Abstract

L'invention concerne des conjugués de phénytoïne et de polymères solubles dans l'eau, qui présentent des caractéristiques améliorées de solubilité et d'absorption.
PCT/GB2004/000631 2003-03-20 2004-02-17 Nouveaux conjugues de phenytoine Ceased WO2004082585A2 (fr)

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GB0306445A GB0306445D0 (en) 2003-03-20 2003-03-20 Conjugate
GB0306445.8 2003-03-20
PCT/GB2003/003522 WO2004014973A2 (fr) 2002-08-13 2003-08-13 Polymere biodegradable

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005094897A3 (fr) * 2004-04-01 2006-06-22 Cardiome Pharma Corp Derives de composes de modulation des canaux ioniques, compositions pharmaceutiques et utilisations
WO2005113011A3 (fr) * 2004-04-01 2006-08-03 Cardiome Pharma Corp Promedicaments de composes modulant les canaux ioniques et leurs utilisations
WO2012082995A1 (fr) * 2010-12-15 2012-06-21 Nektar Therapeutics Composés d'hydantoïne contenant un oligomère
CN113773256A (zh) * 2021-09-16 2021-12-10 精华制药集团南通有限公司 一种琥布宗的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4280995A (en) * 1979-12-31 1981-07-28 Pharmaceutical Associates, Inc. Oral suspension of phenytoin
US4719182A (en) * 1985-03-18 1988-01-12 Eastman Kodak Company Fluorescent labels and labeled species and their use in analytical elements and determinations
WO2004014973A2 (fr) * 2002-08-13 2004-02-19 Sirus Pharmaceuticals Ltd Polymere biodegradable

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005094897A3 (fr) * 2004-04-01 2006-06-22 Cardiome Pharma Corp Derives de composes de modulation des canaux ioniques, compositions pharmaceutiques et utilisations
WO2005113011A3 (fr) * 2004-04-01 2006-08-03 Cardiome Pharma Corp Promedicaments de composes modulant les canaux ioniques et leurs utilisations
US7786119B2 (en) 2004-04-01 2010-08-31 Cardiome Pharma Corp. Drug conjugates of ion channel modulating compounds
US7977373B2 (en) 2004-04-01 2011-07-12 Cardiome Pharma Corp. Prodrugs of ion channel modulating compounds and uses thereof
WO2012082995A1 (fr) * 2010-12-15 2012-06-21 Nektar Therapeutics Composés d'hydantoïne contenant un oligomère
US9540330B2 (en) 2010-12-15 2017-01-10 Nektar Therapeutics Oligomer-containing hydantoin compounds
CN113773256A (zh) * 2021-09-16 2021-12-10 精华制药集团南通有限公司 一种琥布宗的合成方法
CN113773256B (zh) * 2021-09-16 2022-11-18 精华制药集团南通有限公司 一种琥布宗的合成方法

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