WO2004096178A1 - Systemes de relargage de medicaments nanoparticulaires et microparticulaires a base de polyesters contenant des residus dicarboxylate aliphatique et des residus polyols aliphatiques - Google Patents

Systemes de relargage de medicaments nanoparticulaires et microparticulaires a base de polyesters contenant des residus dicarboxylate aliphatique et des residus polyols aliphatiques Download PDF

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WO2004096178A1
WO2004096178A1 PCT/GB2004/001937 GB2004001937W WO2004096178A1 WO 2004096178 A1 WO2004096178 A1 WO 2004096178A1 GB 2004001937 W GB2004001937 W GB 2004001937W WO 2004096178 A1 WO2004096178 A1 WO 2004096178A1
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pharmaceutically
aliphatic
polymer backbone
active agent
nano
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PCT/GB2004/001937
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English (en)
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Martin Charles Garnett
Gillian Hutcheon
Sean Higgins
Paraskevi Kallinteri
Chris St Pourcain
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The University Of Nottingham
Liverpool John Moores University
Aston University
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Publication of WO2004096178A1 publication Critical patent/WO2004096178A1/fr

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • 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
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/12—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from polycarboxylic acids and polyhydroxy compounds
    • C08G63/16—Dicarboxylic acids and dihydroxy compounds
    • C08G63/20—Polyesters having been prepared in the presence of compounds having one reactive group or more than two reactive groups
    • 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
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/12—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from polycarboxylic acids and polyhydroxy compounds
    • C08G63/46—Polyesters chemically modified by esterification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Definitions

  • the present invention relates to nano and microparticle drug delivery systems. More particularly, it relates to such drug delivery systems using, as the carrier for a pharmaceutically-active agent, a derivatised functional polymer. It also relates to a method of making such delivery systems and the use of such systems in therapy.
  • Nanoparticles and nanoparticles are increasingly being researched as drug delivery systems, which can deliver drugs to specific sites in the body.
  • Nanoparticles can potentially be used parenterally to treat diseases where vasculature is leaky, e.g. sites of tumour and inflammation, sites in the reticuloendothelial system (RES), e.g. parasitic diseases such as malaria, and sinusoidal sites in the liver and spleen.
  • RES reticuloendothelial system
  • Nanoparticles also have some potential for lung delivery and for immune stimulation of lymphoid tissue accessed either orally or through mucous membranes.
  • nanoparticles need to evade the reticuloendothelial system, which recognises most particulate materials and effectively removes them from the circulation.
  • a surface layer of poly(ethylene glycol) (PEG) onto the nanoparticles a hydrophilic surface is provided which prevents the adsorption of opsonins and greatly reduces uptake by the RES (1).
  • Nanoparticles fo ⁇ parenteral applications can be made with a core-shell structure, where the core encapsulates the drug and the shell is a hydrophilic layer producing a steric stabilisation to prevent particle aggregation and adsorption of opsonins (2,3).
  • This core-shell arrangement can either be achieved by the adsorption of a surfactant with a hydrophilic segment which is adsorbed onto a core encapsulating the drug or by the use of block copolymers with both hydrophilic and core-forming segments.
  • Systems with adsorbed surfactants have included the use of poloxamers and poloxamines on poly(Iactide-co-glycolide) (PLGA) particles (1), or polysorbates on polycyanoacrylate particles (4).
  • these usually have hydrophobic and hydrophilic segments arranged as either A-B or A-B-A configurations, typified by poly (L-lactic acid)-poly(ethylene glycol) copolymer systems (PLA-PEG copolymer systems).
  • delivery systems may be micelle-like, where the micelles are thermodynamically unstable and so in an equilibrium condition, or alternatively may form particles which are essentially stable (5).
  • hydrophilic segment is PEG with a variety of hydrophobic core blocks including, poly(beta benzyl aspartate), polycaprolactone, poly(gamma-benzyl-L glutamate), polylactide, polylysine, polypropylene oxide and polybutylene oxide.
  • hydrophobic core blocks including, poly(beta benzyl aspartate), polycaprolactone, poly(gamma-benzyl-L glutamate), polylactide, polylysine, polypropylene oxide and polybutylene oxide.
  • microparticles and nanoparticles need to incorporate a high drug loading, need to be stable to aggregation when loaded, and need to be able to release the drug under appropriate conditions.
  • Drug release may be designed to occur either in response to a stimulus, or in a time dependent manner as a depot formulation.
  • the core should either be capable of retaining a variety of drugs, or be capable of being made with several different properties to accommodate drugs with a variety of different physicochemical properties. Consideration also needs to be given to fine tuning core-drug interactions so that release of the drug can be adequately controlled.
  • biodegradable polymer with chemical functional groups which are readily modified with a variety of chemical structures.
  • a variety of natural biomolecules exist which fit this description, such as polysaccharides (e.g. pullulan, dextran, chitin) and polyamino acids (e.g. poly-L-lysine, poly-L ornithine).
  • polysaccharides e.g. pullulan, dextran, chitin
  • polyamino acids e.g. poly-L-lysine, poly-L ornithine
  • Several of these biomaterials have been modified with substituents to produce nanoparticles in the form of either micelles or vesicles (13-16).
  • these are biological materials they are not necessarily readily degradable in animal tissues, (e.g. dextran) or the functional groups may result in undesirable toxicity (e.g.
  • biodegradable polymers with functional groups have also been prepared and used for preparation of micelles. This has been achieved by acylation of the backbone to provide a hydrophobised interior into which low levels of drug incorporation have been achieved (18,19).
  • chemical synthesis of biodegradable polymers with functional groups can be difficult to achieve because useful functional groups are liable to participate in the polymerisation reaction. Such functional groups may be difficult to protect chemically in a way where deprotection is possible without hydrolysing the biodegradable polymer (20,21).
  • the present invention is based on the discovery that microparticles and nanoparticles of a linear polyester having a polymer backbone containing aliphatic dicarboxylate residues and the residues of an aliphatic polyol have use as carriers for pharmaceutically-active agents in drug delivery systems.
  • the present invention provides a nano or microparticle drug delivery system comprising a pharmaceutically-active agent and nano or microparticles of a linear aliphatic polyester, the polyester having a polymer backbone containing aliphatic dicarboxylate residues and residues of an aliphatic polyol wherein the polymer backbone includes at least one aliphatic polyol residue containing a moiety capable of interacting with the pharmaceutically-active agent.
  • the present invention also provides a method for preparing a nano or microparticle drug delivery system which method comprises providing nano or microparticles of a linear aliphatic polyester having a polymer backbone containing aliphatic dicarboxylate residues and residues of an aliphatic polyol wherein the polymer backbone includes at least one aliphatic polyol residue containing a moiety capable of interacting with a pharmaceutically-active agent, and entrapping a pharmaceutically-active agent within the nano or microparticles of the linear polyester.
  • the present invention further provides a method of delivering a pharmaceutically-active agent to an animal, including a human, which comprises administering a nano or microparticle drug delivery system comprising a pharmaceutically-active agent and nano or microparticles of a linear polyester, the polyester having a polymer backbone containing aliphatic dicarboxylate residues and residues of an aliphatic polyol wherein the polymer backbone includes at least one aliphatic polyol residue containing a moiety capable of interacting with the pharmaceutically-active agent.
  • the polyester used as the carrier in the drug delivery system for a pharmaceutically-active agent is a linear aliphatic polyester which has a polymer backbone comprising aliphatic dicarboxylate residues and the residues of an aliphatic polyol and wherein the backbone includes at least one aliphatic polyol residue containing a moiety capable of interacting with a pharmaceutically-active agent.
  • the aliphatic dicarboxylate residues are those which may be derived from an aliphatic dicarboxylic acid having the formula I
  • R 1 is a straight chain or a branched chain 1 to 12C alkylene group.
  • the group R 1 above is a straight chain alkylene group generally defined as -(CH 2 )- n , where n is 1 to 8.
  • straight chain alkylene groups include methylene, ethylene, propylene, butylene, hexylene and octylene groups.
  • the length of the alkylene chain between the two carboxylate groups in the dicarboxylate residue has an effect on the hydrophobicity of the polyester and, of course, on the separation between one functional group and another functional group on the polymer backbone.
  • the two carboxylate groups in the dicarboxylate residue are separated by an alkylene group selected from methylene, ethylene, propylene . and butylene.
  • an alkylene group selected from methylene, ethylene, propylene . and butylene.
  • a particularly preferred dicarboxylic acid for use in the manufacture of the linear polyester is adipic acid.
  • the polymer backbone of the linear aliphatic polyester molecule comprises residues derived from at least one aliphatic polyol, i.e. polyhydric alcohol, containing at least three hydroxyl groups.
  • the use of such polyols results in a polymer backbone provided with pendant hydroxyl groups which may be derivatised or substituted to provide pendant moieties capable of interacting with a pharmaceutically-active agent.
  • the aliphatic polyols from which the residues in the polyester backbone are derived will have the general formula II R —(OH) m (ii)
  • R 2 is a straight or branched chain hydrocarbyl group having from 3 to 8 carbon atoms and m is 3 to 8.
  • the aliphatic polyol from which the residues in the polyester backbone are derived will have the general formula III
  • Such polyols according to the general formula III include glycerol, mesoerythritol and linear pentitols and hexitols.
  • the aliphatic polyol according to general formula III above will be one selected from glycerol, mesoerythritol, xylitol, mannitol and sorbitol. Glycerol is especially preferred as the aliphatic polyol.
  • the polymer backbone of the linear aliphatic polyester contains at least one residue of an aliphatic polyol which residue contains at least one moiety capable of interacting with a pharmaceutically-active agent.
  • the polymer backbone of the linear aliphatic polyester will contain at least one aliphatic polyol residue wherein at least one pendant hydroxyl group is preferably derivatised or substituted to produce a moiety which is capable of. interacting with a pharmaceutically- active agent.
  • a pendant hydroxyl group which is not derivatised or substituted may, itself, be capable of interacting with a pharmaceutically-active agent.
  • the polymer backbone includes at least one residue of an aliphatic polyol which contains a moiety that is capable of promoting at least one molecular interaction with the pharmaceutically-active agent.
  • a moiety capable of interacting with a pharmaceutically-active agent may, as described above, be an unmodified or unsubstituted hydroxyl group but preferably is provided on the polymer backbone of the polyester by derivatising or substituting a pendant hydroxyl group of one of the aliphatic polyol residues using an appropriate chemical reagent to react with the hydroxyl group.
  • An example of a chemical reagent that will react with a pendant hydroxyl group is an activated acyl-containing compound. The reaction between such an activated acyl-containing compound and a pendant hydroxyl group of an aliphatic polyol residue in the polyester backbone results in a pendant group attached to an aliphatic polyol residue via an oxyacyl linkage.
  • One example, which relates to a preferred embodiment of the present invention, is the provision of at least one pendant group attached to the polyester polymer backbone by an oxycarbonyl linkage.
  • a pendant group may be produced by acylating a pendant hydroxyl group attached to the polymer backbone using an appropriate activated carboxylic acid or derivative thereof.
  • the moiety capable of interacting with a pharmaceutically- active agent is an optionally-substituted alkyl, alkenyl or alkynyl group formed by acylating a pendant hydroxyl group with an optionally-substituted alkyl, alkenyl or alkynyl carboxylic acid chloride.
  • the moiety capable of interacting with a pharmaceutically-active agent is a pendant group, attached to an aliphatic polyol residue in the polymer backbone, having the general formula IV
  • R 3 is an optionally-substituted 1 to 20C straight or branched chain alkyl group or is an optionally-substituted 2 to 20C straight or branched chain alkenyl or alkynyl group. More preferably, R 3 is an optionally-substituted 1 to 18C straight or branched chain alkyl group or an optionally-substituted 2 to 18C alkenyl or alkynyl group. Particularly preferred is when R 3 is an optionally-substituted straight chain 2 to 18C alkyl group.
  • Such optionally-substituted alkyl, alkenyl or alkynyl groups, for R 3 may be substituted by one or more groups which may additionally promote a molecular interaction with a pharmaceutically-active agent.
  • Typical substituent groups include the groups -OR 4 , -NR 5 R 6 , -COOR 7 and SO 2 OR 7 where each of R 4 , R 5 and R 6 is, independently, selected from H and 1 to 6C alkyl which alkyl may optionally be substituted by -OR 7 , -NR 8 R 9 , -COOH and -SO 3 H; and wherein each of R 7 , R 8 and R 9 is independently selected from H and 1 to 6C alkyl groups.
  • the moiety capable of interacting with a pharmaceutically-active agent may comprise a heterocyclic or aromatic ring structure.
  • the moiety capable of interacting with a pharmaceutically-active agent is selected to be hydrophobic. If it is desired to use, in the present invention, a linear aliphatic polyester having pendant hydrophobic moieties, it is preferred that the moieties have the general formula IV above wherein R 3 is a long chain, typically, 8 to 18C alkyl group which is unsubstituted. If the alkyl is substituted, the substituents should not, in this particular case, substantially increase the hydrophilicity of the group.
  • R 3 is a long chain, typically, 8 to 18C alkyl group which is unsubstituted. If the alkyl is substituted, the substituents should not, in this particular case, substantially increase the hydrophilicity of the group.
  • the choice of moiety used will, of course, depend on the type of, and chemical character of, the pharmaceutically-active agent to be used in the nano or microparticle drug delivery system of the invention.
  • moieties on the polyester backbone which themselves contain charged groups or ionisable groups.
  • moieties containing groups which are, or can be made, positively charged, for instance tertiary amine groups are advantageous in the case where the pharmaceutically-active agent is, or comprises, an oligonucleotide or DNA polyelectrolyte complex.
  • the moieties may have other characteristics which will facilitate interactions between the core of the nano or microparticle and the pharmaceutically-active agent, e.g. amino acids which are acetylated on the alpha amino group, or desamino analogs of amino acids.
  • the polymer backbone of the linear aliphatic polyester includes at least one aliphatic polyol residue containing a molecule of a pharmaceutically-active agent which can further interact with other molecules of pharmaceutically-active agents.
  • a pharmaceutically-active agent such as a poly(amino acid)
  • An attachment in this way creates a hydrophobic segment in the polymer which enables the formation of particles which tend to be micelle-type particles.
  • the pharmaceutically-active agent thus conjugated to the polymer backbone is capable of interacting with non- covalently attached pharmaceutically-active agent.
  • the proportion of pendant hydroxyl groups on the polyester polymer backbone that are derivatised or substituted, as described above, to produce moieties capable of interaction with a pharmaceutically-active agent is in the range of from 0.1 to 1.0. In some cases, however, the presence of pendant hydroxyl groups (non-derivatised or non-substituted hydroxyl groups) on the polymer backbone may directly interact with a pharmaceutically-active agent or may enhance the amount of water that is included into the core of the nanoparticles into which the pharmaceutically-active agent can dissolve.
  • the polymer backbone of the linear aliphatic polyester may also contain the residues of one or more alkylene diols, for example polymethylene glycols such as ethylene glycol, propan-1,3-diol and butan-1,4-diol.
  • the polymer backbone of the linear aliphatic polyester is provided with at least one pendant group containing the residue of hydrophilic polymer to produce a copolymer having a hydrophilic segment which can form a sterically stabilising layer on the nano or microparticles.
  • a surface layer of PEG have a prolonged circulation in the bloodstream, i.e. a reduced uptake by the RES, because the hydrophilic surface of PEG prevents the adsorption of opsonins and, thus, prevents the recognition of the nanoparticles, by the RES, as foreign particles.
  • the polymer backbone of the polyester contains at least one residue of an aliphatic polyol to which is attached a PEG group. Attachment of a PEG group may conveniently be achieved by linking it to a pendant hydroxyl group of the polymer backbone, for instance by means of a dicarboxylate link. In general, from 1 to 90% of pendant hydroxyl groups on the polymer backbone may be attached to PEG groups to provide nanoparticles having a PEG surface layer. PEG which may be attached to the polyester backbone in carrying out the present invention will typically have a molecular weight in the range of from 500 to 20,000.
  • Linear polyesters with pendant hydroxyl groups for use in the present invention may be prepared, as described above (22,23), by reacting an activated diester of an aliphatic dicarboxylic acid, such as the divinyl ester, with an aliphatic polyol containing at least three hydroxyl groups in the presence of a catalytic amount of a lipase, immobilised on a support, at a temperature typically higher than 30°C.
  • An amount of an aliphatic glycol may be used in addition to the aliphatic polyol containing at least three hydroxyl groups to make up the polyol component of the reaction mixture.
  • the ratio of glycol to polyol containing at least three hydroxyl groups will, of course, have an effect not only on the hydrophilicity of the polymer backbone of the resulting polyester but also on the total number of pendant hydroxyl groups on the resulting polymer backbone and, therefore, on the total possible number of pendant groups that are capable of interacting with a pharmaceutically-active agent, as described above.
  • the total amount of polyol or polyol-glycol component in the reaction mixture will typically be such as to provide an equimolar amount with respect to the activated diester used.
  • the reaction is, as mentioned above, carried out in the presence of a catalytic amount of a lipase.
  • lipases that can be used in the enzyme-catalysed condensation reaction include lipase isolated from Candida antarctica (available under the trade name Novozym 435), Candida rugosa, Pseudomonas fluorescens and Mucor miehei (available under the trade name Lipozyme IM).
  • the reaction is preferably carried out in the presence of an organic solvent, such as tetrahydrofuran or acetonitrile, to facilitate mixing of the monomers and to keep the forming oligomers in solution, thus allowing the polymerisation reaction to continue.
  • an organic solvent such as tetrahydrofuran or acetonitrile
  • the resulting polymer may be separated from the immobilised enzyme by filtration and then washed with solvent prior to removal of the solvent, typically by evaporation.
  • the pendant hydroxyl groups on the polymer backbone of the linear polyester may then, if desired, be treated with appropriate reactants to produce pendant moieties that are capable of interacting with a pharmaceutically-active agent.
  • the linear polymer containing the pendant hydroxyl groups may be treated with the appropriate aliphatic carboxylic acid chloride, typically in the presence of pyridine as a catalyst and acid scavenger.
  • the appropriate aliphatic carboxylic acid chloride may conveniently be prepared by the reaction of the parent carboxylic acid with thionyl chloride.
  • the hydrophilic polymer group may be attached to the linear polyester backbone by a reaction carried out prior to or subsequent to the acylation reaction using the carboxylic acid chloride described above.
  • PEG groups may be attached to the polymer backbone by first reacting the PEG, for instance as monomethyl ether, with succinic anhydride to form the half ester (24), converting the terminal acid group of the half ester to the acid chloride by reaction with thionyl chloride, after azeotropic drying (25), and then acylating one or more pendant hydroxyl groups on the linear polyester backbone using this acid chloride.
  • Nano or microparticles of the linear polyester may be formed according to the prior art procedures (26,27). Typically, a solution of the polymer in an organic solvent, such as acetone, is added into an excess of water with stirring. After the organic solvent has been allowed to evaporate, the produced particles can be filtered. The particles may then be cleaned by gel filtration through a sepharose column using water as eluant.
  • an organic solvent such as acetone
  • nanoparticles means particles having an average particle size up to, but not including, 1000 nm.
  • microparticles as used herein, means particles having an average particle size equal to or greater than 1000 nm, typically up to about 50 ⁇ m.
  • the nano or microparticle drug delivery system is prepared by entrapping a pharmaceutically-active agent within the nano or microparticles of the linear polyester. This may be achieved, for instance, by dispersing the particles of the polymer carrier in an aqueous solution of the pharmaceutically-active agent.
  • a pharmaceutically-active agent which may be entrapped in the nano or microparticles of the linear polyester described above is any substance, natural or synthetic, which has a physiological action on a living body, for example a natural or synthetic drug, a protein or a nucleic acid which has a therapeutic effect on the living body.
  • the surfactant may be incorporated into the aqueous phase containing the pharmaceutically-active agent into which the particles of the linear polyester are dispersed.
  • the present invention also provides a method of delivering a pharmaceutically-active agent to an animal, including a human, which comprises administering the nano or microparticle drug delivery system described above to the animal body.
  • the drug delivery system may be formulated according to methods known in the art. Typically, the system will be formulated for administration to a patient parenterally in water or saline solution, although formulations for administration to a patient by other means is possible.
  • the synthesis was carried out in three steps - backbone formation, acylation, and PEGylation - each of these shall be discussed separately below.
  • the figures in brackets relate to the molecular weight of the original mPEG (550, 2000, or 5000), before activation, the chain length of the linear aliphatic acid chloride used (C8, C14, C16, or C18), or the approximate molecular weight of the parent backbone polyester as determined by reference to polystyrene standards.
  • the order of the steps is important as the percentage values were calculated depending on the average unit molecular weight.
  • the enzyme Novozyme 435 (a lipase derived from Candida antarctica and immobilised on an acrylic macroporous resin), was stored over P 2 O 5 at 5°C prior to use.
  • Divinyl adipate was purchased from Flurochem UK, and used as received.
  • Glycerol, polyethylene glycol methyl ether (mPEG) (M n 550, 750, 2000 and 5000), alditols (meso-erythritol, xylitol, D-mannitol and D-sorbitol), succinic anhydride, and anhydrous benzene were obtained from Aldrich and used as received.
  • Acid chlorides (capryloyl, myristoyl, palmitoyl, and stearoyl) were purchased from Aldrich, or synthesised, by standard procedures, from the parent acid using thionyl chloride, and distilled prior to use. Chloroform, dichloromethane (DCM), diethyl ether, pyridine and tetrahydrofuran (THF) were obtained from Merck. THF was freshly distilled from sodium/benzophenone ketyl prior to use. Reactions requiring anhydrous conditions were conducted in oven-dried (130°C) glassware. Mechanical stirring was accomplished using a standard mechanical mixer at 200rpm, using a Teflon paddle. The activated mPEG was prepared in two steps.
  • Synthesis was carried out using a large water bath to maintain constant temperature (50°C), and a mechanical stirrer (200 rpm), using a paddle type stirrer blade.
  • a mechanical stirrer 200 rpm
  • an oven dried 500ml three-necked RB flask, equipped with centre stirrer guide, and an open top condenser - to act as an outlet for the acetaldehyde produced was charged with divinyl adipate (108.82g, 0.549moles), and glycerol (50.53g, 0.549moles), 4A molecular sieves (2g), and 200ml anhydrous THF. This mixture was stirred for 30 mins to allow reactants to warm to the water bath temperature (50°C).
  • Nanoparticles were produced by the interfacial polymer deposition method (27,28). Polymer (4mg/ml, 20mg) was dissolved in acetone, and the dissolved polymer was added dropwise into an excess of water (15ml) under stirring. After addition of the polymer, the particle solution continued to be stirred overnight to allow evaporation of the solvent. Particles were filtered to remove aggregated material and then cleaned by gel filtration through a sepharose 4B column (2.5 x 30cm) using water as the eluent. Incorporation of drug or surfactant
  • Hydrophilic drug dexamethasone phosphate
  • Hydrophilic drug was loaded into the nanoparticles by dissolution into the water (0-12.0mg) to which the polymer was added.
  • this was also included in the aqueous phase (0.1-0.4% v/v) prior to polymer addition.
  • Particle preparation was carried out with a range of polymers with different characteristics. Polymers were acylated with either C8 or C18 groups following the procedure described above at 20, 40, 60 and 80% acylation of hydroxyl groups. These polymer specifications were available either with or without PEG 2000 attached at 2% hydroxyl group substitution. Stable particles were formed by this method by polymers both with and without PEG in the absence of either drug or surfactant. This showed that the acyl groups provided sufficient interaction to cause particle formation, and also that the remaining pendant hydroxyl groups and terminal groups (either hydroxyl or carboxyl) were sufficient to stabilise the particles. Particle sizes were in the range 150-240nm diameter as measured by photon correlation spectroscopy.
  • Drug loading was assessed using a hydrophiiic drug dexamethasone phosphate. Drug loading varied in a non-linear way with changes in the degree of substitution by acyl groups. The presence of drug resulted in a decrease in particle size suggesting that the presence of drug increased the interactions in the core of the nanoparticle.
  • a graph showing the change in drug loading with increased amount of drug is shown in Fig. 1 and the change in drug concentration with acyl substitution is shown in Table 3.
  • Amounts of drug incorporated reached a maximum of 31% of input drug loaded and drug entrapment of 11.45% w/w drug in particles entrapped.
  • the entrapment of such a high proportion of hydrophilic drug compares very favourably with that reported for PLA-PEG particles, and suggests that both the hydrophobic moieties and the hydrophilic drug groups may play a part in enhancing drug incorporation.
  • the variation in properties with polymer specification also confirms the expectation that flexibility in polymer specification will lead to more effective drug delivery systems.
  • the drug loading in a delivery system according to the present invention was studied using, as drug models, a range of bases and nucleotides. These can be viewed as models of the closely-related cytotoxic drugs 5-fluorouracil, 5-fluorouridine and cytosine arabinoside.
  • the study also provides an insight into the effect of drug structure on incorporation into the nanoparticles.
  • the investigation used acylated polyesters, prepared as described above, with 80% acylation by C ⁇ 8 groups (80% C 18 (4kDa) ) or with 40% acylation by C ⁇ 8 groups (40% C 18 (10kDa) ). Using 20mg polymer and 4mg drug/base, the particle size, zeta potential and actual drug loadings were determined and these are set out in the following Table 4. TABLE 4
  • the steroid nucleus would be expected to interact well with the alkyl chains, and it is thought to be the water solubility of the phosphate group which allows a good incorporation using the interfacial deposition technique.
  • the heterocycles of the nucleoside drugs are not particularly hydrophobic and, thus, are not expected to be predisposed to interact with the alkyl chains. The interactions are more likely to be hydrogen bonding with the free hydroxyl groups.
  • I. Uchegbu Polyamino acid vesicles, WO 99/61512. 16. M.D. Brown, A. Schatzlein, A. Brownlie, V. Jack, W. Wang, L. Tetley, A.I. Gray, I.F. Uchegbu, Preliminary characterisation of novel amino acid based polymeric vesicles as gene and drug delivery agents. Bioconjugate Chem. 11 , 880-891 , 2000.

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  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un système de relargage de médicaments nanoparticulaires ou microparticulaires qui contiennent un agent pharmaceutiquement actif ainsi que des nanoparticules ou des microparticules d'un polyester aliphatique linéaire. Ce polyester possède un squelette polymère qui contient des résidus dicarboxylate aliphatique ainsi que des résidus polyol aliphatique. Le squelette polymère comprend au moins un résidu polyol aliphatique pourvu d'une fraction qui peut interagir avec l'agent pharmaceutiquement actif. Ce système de relargage de médicaments nanoparticulaires ou microparticulaires peut être utilisé pour administrer un agent pharmaceutiquement actif à un animal, voire à l'homme.
PCT/GB2004/001937 2003-05-02 2004-05-04 Systemes de relargage de medicaments nanoparticulaires et microparticulaires a base de polyesters contenant des residus dicarboxylate aliphatique et des residus polyols aliphatiques WO2004096178A1 (fr)

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GB0310178.9 2003-05-02
GB0310178 2003-05-02

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WO2004096178A1 true WO2004096178A1 (fr) 2004-11-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161841A2 (fr) 2014-04-23 2015-10-29 Martin-Luther-Universität Halle-Wittenberg Systèmes supports injectables et implantables, à base de polyesters modifiés d'acides dicarboxyliques avec des di- ou polyols, servant à la libération contrôlée de principes actifs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1978000011A1 (fr) * 1977-06-07 1978-12-21 Garching Instrumente Forme d'implant medicamenteux et procede de preparation
DE4136930A1 (de) * 1990-11-14 1992-08-20 Debio Rech Pharma Sa Verfahren zur herstellung einer pharmazeutischen zusammensetzung, die pharmazeutische zusammensetzung sowie deren verwendung
EP1270024A1 (fr) * 2001-06-29 2003-01-02 Ethicon, Inc. Compositions et dispositifs médicaux à base de cires polymères bioabsorbables de type alkyd

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1978000011A1 (fr) * 1977-06-07 1978-12-21 Garching Instrumente Forme d'implant medicamenteux et procede de preparation
DE4136930A1 (de) * 1990-11-14 1992-08-20 Debio Rech Pharma Sa Verfahren zur herstellung einer pharmazeutischen zusammensetzung, die pharmazeutische zusammensetzung sowie deren verwendung
EP1270024A1 (fr) * 2001-06-29 2003-01-02 Ethicon, Inc. Compositions et dispositifs médicaux à base de cires polymères bioabsorbables de type alkyd

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161841A2 (fr) 2014-04-23 2015-10-29 Martin-Luther-Universität Halle-Wittenberg Systèmes supports injectables et implantables, à base de polyesters modifiés d'acides dicarboxyliques avec des di- ou polyols, servant à la libération contrôlée de principes actifs
DE102014005782A1 (de) * 2014-04-23 2015-10-29 Martin-Luther-Universität Halle-Wittenberg lnjizierbare und implantierbare Trägersysteme auf Basis von modifizierten Poly(dikarbonsäure-multiol estern) zur kontrollierten Wirkstofffreisetzung

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