Classifications

• • 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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • 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
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • 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
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • 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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • 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
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to micellar compositions for drug formulation and drug delivery.
• micellar formulations are expected to achieve some level of circulation concentration of the drug without precipitation of the drug in the bloodstream.
• the principle behind micelle formation is that amphipathic molecules can form aggregates in an aqueous environment whereby hydrophobic components of the molecules come together to exclude water and make up the inner core of the micelle.
• the hydrophilic components of the molecules are orientated towards the outside of the micelle. This aggregation occurs above the critical micelle concentration (CMC) of the molecules in water.
• CMC critical micelle concentration
• hydrophobic drugs may be solubilized in the inner hydrophobic core of micelles during their formation.
• micellar compositions are typically made by dissolving a hydrophobic drug in a water miscible organic solvent in which the drug is soluble, combining the resulting solution with a micellar composition in an aqueous solution with mixing by vigorous stirring, agitation, or sonication. For example, the mixture might be stirred for up to about 24 hours and any remaining drug not incorporated into micelles then removed.
• micellar solution may then be used directly for administration or freeze-dried into nanoparticles (which may be resuspended in water at a later time) providing the solvent is biocompatible and/or is capable of being removed by freeze- drying or other methods.
• These methods are complicated, expensive, and expose potentially water labile drugs to long periods in aqueous media.
• One process for removal of an organic solvent is by solvent evaporation.
• a hydrophobic drag is typically dissolved in a water-miscible organic solvent and introduced to an aqueous solution of micelles. Subsequently, the organic solvent is evaporated off at elevated temperature.
• the drug and a micelle forming polymer are both dissolved in an organic solvent and the solvent is evaporated at elevated temperature. The resulting mixture is kept at an elevated temperature while warm water or aqueous solution is added with vigorous stirring until polymeric micelles containing the drug are formed.
• a dialysis method can be used, where a suitable water-miscible organic solvent is used to dissolve the hydrophobic drag and the micelle forming polymer. The solution is subsequently dialysed against a buffer solution and then against water. In some cases the duration of dialysis may be as long as 72 hours (Yu B.G. et al. J Controlled Release (1998) 56:285-291).
• US patent 4,745,160 (Churchill J.R. et al.) teaches a process for manufacturing micelle compositions from biodegradable amphipathic copolymers. The patent teaches that in order to incorporate a hydrophobic drug it is necessary to dissolve the drug in a water miscible organic solvent such as dioxan, acetic acid, acetonitrile, methanol or ethanol.
• US patent 5,510,103 (Yokoyama M. et al.) and US patent 5,939,453 (Heller J. et al.) describe micelles made of block copolymers in which hydrophobic drugs are physically trapped. However, the disclosed methods of trapping require heating, ultrasonication, and/or the use of organic solvents and dialysis.
• Zhang X. et al. (Intl. J. Pharmaceutics (1996) 132:195-206) reports the formation of a matrix containing taxol and a diblock copolymer composed of methoxy polyethylene glycol (MePEG) and polylactic acid. Only if the matrix is made with acetonitrile as an organic solvent, will the resulting matrix be capable of forming micelles following evaporation of the solvent. The resulting matrix must be heated to melt the polymer and vigorously agitated in aqueous medium in order to produce drag containing micelles.
• MePEG methoxy polyethylene glycol
• This invention allows for the formulation and non-oral administration by injection of semi-solid mixtures into the body of a patient whereby the semi-solid material spontaneously forms micelles containing the hydrophobic drag which enter the bloodstream.
• the present invention provides for improved hydrophobic drag loading into micelles by using selected amphipathic diblock copolymers including those described by Zhang et al. (1996), without an organic solvent such as acetonitrile being required.
• the micelles are formed from a micelle forming composition comprising a biocompatible, low molecular weight, water soluble polymer (including the PEG "solubilizer” taught in US 6,136,846 and the micelle forming compositions of this aspect of the invention exhibit low critical micelle concentrations (CMC) under about 500 ⁇ M to as low as about 20 ⁇ M as determined by standard techniques).
• Hydrophobic drag loading using this aspect of the invention can achieve drug levels in the micellar composition in excess of 10% (by weight) and as high as about 25% when the CMC is about 50 ⁇ M or less.
• Zhang et al. (1996) found such diblock copolymer formulations required acetonitrile to adequately distribute taxol in a matrix in order for micelles to be produced from the matrix.
• WO9921908 suggests that making a polymeric composition comprising a free water soluble polymer and a hydrophobic drug will result in precipitation of the drag, which is counter-productive to the production of micelles.
• Zhang et al. (1996) suggests that increasing amounts of a water soluble polymer (MePEG) in a matrix results in less efficient micelle production from the matrix and poor distribution of the drag in the matrix.
• This aspect of the invention provides a micelle forming composition
• a micelle forming composition comprising: (a) one or more hydrophobic drugs;
• the micelle forming polymer is a copolymer comprising a hydrophobic and a hydrophilic portion, the hydrophobic portion being selected from the group consisting of: a polyester and a polyanhydride; and, the hydrophilic portion is a polyethylene oxide having a molecular weight of about 750 or more.
• micelles formed from the aforementioned composition are also provided.
• a second aspect of the invention results from the discovery that a micellar composition comprising a biocompatible micelle forming polymer; a biocompatible, low molecular weight water soluble polymer; and, a hydrophobic drag, may be formulated as a semi- solid material (e.g. a wax like substance or a paste) capable of being injected into a patient and which will spontaneously form drug containing micelles at the site of deposition of the material in the patient.
• the water soluble polymer may be one that is liquid or semi-solid at about room temperature (e.g. at about 20-30° C). Once the material has been injected into a patient or is simply placed in an aqueous solution, it will form hydrophobic drug containing micelles without the need for heating or agitation.
• This aspect of the invention has the advantage of providing short to medium term localization of a drug at a specific site of injection in a patient, with the drag being released inside micelles to the physiological environment of the site and ultimately to the bloodstream.
• This aspect of the invention includes compositions comprising a hydrophobic drag, a biocompatible micelle forming polymer and a sufficient amount of a biocompatible low molecular weight water soluble polymer such that the composition is a semi-solid (e.g. a "paste") at temperatures at or about room temperature and is injectable through a syringe.
• This aspect of the invention provides a micelle forming composition
• a micelle forming composition comprising:
• composition (c) one or more biocompatible, low molecular weight, water soluble polymers, wherein the one or more water soluble polymers are present in an amount sufficient that the composition is injectable.
• This invention also provides methods for using the aforementioned compositions to form micelles in vitro and in vivo. In vivo methodologies include injection of the composition to a site in a patient's body where drug containing micelles are formed at the site.
• This invention also provides injection devices such as a syringe containing a micelle forming composition according to this invention.
• Figure 1 is a graph showing size distribution micelles with a peak at a particle size diameter of approximately lOnm. Size distribution was measured on a Zetasizer 3000HS at a temperature of 25 C, at a count rate of 12.0 kCps, with a detector angle of 90.00 and at a wavelength of 633.0.
• Micelle forming polymer refers to an amphipathic polymer that is comprised of both a hydrophilicand a hydrophobic component and which is capable of forming micelles in water. Numerous examples are known and are disclosed in the art. Micelle forming polymers include block (e.g. diblock) copolymers comprising a hydrophobic block and a hydrophilic block such as are disclosed in the prior art documents referred to above and in WO01/87345. The micelle forming polymers known in the art that are employed in this invention are those that are biocompatible and thus pharmaceutically suitable. Such is the case for the specific polymers disclosed herein.
• a “hydrophobic drag” is a water insoluble drug.
• a “drug” is a therapeutically active substance which is delivered to a living subject to produce a desired effect, such as to treat a condition of the subject.
• a drag is also provided to a subject prophylactically to prevent the development of a condition or to decrease the severity of a condition that the subject may develop.
• a “water insoluble drug” has a solubility of less than 0.1 mg/mL in distilled water at 250C.
• a “slightly soluble drag” (solubility: 1-10 mg/mL) and a “very slightly soluble drag” (solubility: 0.1-1 mg/mL) may also be referred to.
• hydrophobic drags include the following agents including their water soluble derivatives and analogs:
• Amphotericin used for the treatment or prevention of infection of an open wound by topical administration or for the treatment or prevention of an infection in an exposed wound after surgery by local application. Amphotericin is an antifungal and is insoluble in water at pH 6 to 7 (The Merck Index.).
• Anthralin used for the treatment of "wet" psoriasis by topical application. Anthralin is an agent for psoriasis therapy and is practically insoluble in water (The Merck Index).
• Beclomethasone used for the reduction of local inflammation by peri-ophthalmic and inside the eyelid or intranasal (e.g., for the treatment of rhinitis) application. Beclomethasone is a corticosteroid and is very slightly soluble in water. See, for example, Gennaro, (ed.), Remington's Pharmaceutical Sciences. I 7th Edition, (Mack Publishing Company 1985).
• Betamethasone used for the reduction of local inflammation by oral (e.g., canker sore), intravaginal, and intrarectal application. Betamethasone is a corticosteroid and has a solubility of 190 ⁇ g/mL water. See, for example, Gennaro, (ed.), Remington 's Pharmaceutical Sciences, 17th Edition, (Mack Publishing Company 1985).
• Camptothecin used for the treatment of diseases involving cellular proliferation such as cancer, arthritis, psoriasis, restenosis, surgical adhesions. Camptothecin has a water solubility of 1-2 ⁇ g/mL.
• Curcumin a potent antioxidant and potential antiarthritic drag. Curcumin is practically insoluble in water.
• Dexamethasone used for the reduction of local inflammation by oral application (e.g., post wisdom tooth removal). Dexamethasone is a corticosteroid and has a solubility of 10 ⁇ g/mL in water (The Merck Index).
• Genistein a tyrosine kinase inhibitor and potentially used for the treatment of diseases involving cellular proliferation. Genistein is practically insoluble in water.
• Indomethacin used for the treatment of symptoms of gout by intraarticular or intramuscular injection or for the reduction of local inflammation by peri-ophthalmic and inside the eyelid, oral, intranasal, intravaginal and intrarectal application. Indomethacin is a non-steroidal anti-inflammatory (NSAID) and is practically insoluble in water (The Merck Index).
• NSAID non-steroidal anti-inflammatory
• Lidocaine provides local anesthesia by intramuscular injection, or administration by application to mucus membranes, including periophthalmic and inside the eyelid, oral, intranasal, intravaginal and intrarectal. Lidocaine is a local anesthetic and is practically insoluble in water. See, for example, Gennaro, (ed.), Remington's Pharmaceutical Sciences, 17th Edition, (Mack Publishing Company 1985).
• Taxol e.g. Paclitaxel: used for the treatment of angiogenic related diseases such as arthritis, cancer, restenosis, psoriasis, or surgical adhesions.
• Paclitaxel has a water solubility of 1-2 , ⁇ g/mL.
• Tetracycline used for the treatment of eye infections by periophthalmic and inside the eyelid application. Tetracycline is an antibacterial and has a solubility of 400 pg/mL water. See, e.g., Gennaro, (ed.), Remington 's Pharmaceutical Sciences, 17th Edition, (Mack Publishing Company 1985).
• Tretinoin a retinoic acid that is potentially an anticancer agent. Tretinoin is practically insoluble in water.
• Therapeutic proteins proteins that are practically insoluble in water, such as insulin, are contemplated for use in this presently described polymeric drug delivery system.
• organic solvent as used herein with reference to this invention means a non- polymeric solvent, such as an aromatic hydrocarbon, ester, ether, ketone, amine, alcohol, nitrated hydrocarbon and chlorinated hydrocarbon, which non-polymeric solvents include: acetone, ethanol, tetrahydrofuran, acetonitrile and pyrrolidones.
• This invention makes use of a biocompatible, low molecular weight, water soluble polymer in place of an organic solvent as defined above. This obviates the need to remove an organic solvent and permits the formation of hydrophobic drag containing micelles without heating, agitation, vigorous stirring or sonication. It also makes possible the preparation of a semi-solid capable of forming micelles in vivo, for administration by injection to a patient.
• injectable refers to compositions having a viscosity that permits injection of the material into the body of a patient using a syringe and a needle cannula with the amount of pressure required to inject the material being that which may be comfortably exerted through hand pressure.
• Material having viscosities between about 5 and about 200 poise which may be measured using known techniques (for example with a parallel plate rheometer).
• Material that is injectable according to this invention is injectable in a typical temperature range for injection.
• the material is injectable from about room temperature to about body temperature.
• the material is injectable in a temperature range from about 20° C to about 40° C.
• composition comprises none, or essentially none of the ingredient.
• ingredient may be present in such small amounts in the composition that do not affect the properties or pharmaceutical utility of the composition.
• Micelle forming compositions according to this invention may be prepared using standard techniques whereby the required polymeric ingredients and a hydrophobic drug are thoroughly mixed or intermingled. Mechanical mixing procedures may be employed, such as are taught in the Examples below. The goal is to achieve a thorough blending of the ingredients of the composition.
• Injection devices such as syringes may be prepared so as to contain micelle forming compositions of this invention by using any technique whereby the composition is placed within the injection device in a manner that the composition becomes injectable by the device.
• a composition of this invention may be placed within the barrel of a syringe by mechanical means or extrusion.
• compositions of this invention may be stored for substantial lengths of time. When a hydrophobic drag is present in a composition of this invention, it is preferred that the composition be stored at a temperature below that of room temperature in accordance with the stability parameters of the selected drug.
• Compositions of this invention may be placed in sterile containers for subsequent pharmaceutical formulation. Such a container may be a sealed vial which preferably will contain sufficient space for the subsequent addition of an aqueous, physiologically acceptable carrier.
• the compositions of this invention may be employed for production of drag containing micelles within the aforementioned container after introduction of the aqueous carrier. Dissolution of the composition in the carrier with concomitant formation of drag containing micelles may be accelerated by agitation (e.g. shaking) although the compositions of this invention will dissolve over time, without agitation. Long term or vigorous agitation or sonication is not necessary.
• compositions according to this invention and drug containing micellar suspensions made from such compositions may be done according to methods known in the art. Methodologies for injection of such compositions or solutions at a selected site within the body of a patient may be selected and performed by a medical professional.
• the composition will comprise one or more biocompatible micelle forming polymers.
• micelle forming polymers may be any such polymer known in the art, including the references referred to above and in WO 01/87345.
• one or more micelle forming polymers in compositions of this invention will be a diblock copolymer suitable for formation of micelles as taught in the art or as specifically described herein.
• Hydrophobic portions of such diblock copolymers may comprise one or more hydrophobic polymers, such as polyesters, polyanhydrides, polyglycolic acids, polybutrylactones, polyhydroxybutyrates, polylactic acids and polylacaprolactones.
• the hydrophobic portion of the copolymer may comprise one or more different hydrophobic polymers in random or block orientation.
• the hydrophobic portion of a copolymer will have a molecular weight from about 200 to about 5000.
• the preferred micelle forming polymers described above are capable of forming micelles at very low critical micelle concentrations (CMC), which allows for loading of high concentrations of hydrophobic drags.
• Preferred hydrophilic portions of micelle forming copolymers that may be used in this invention have a molecular weight of about 750 or greater up to about 8000.
• the molecular weight will be in the range of about 1000 or 2000 - 3000 or 5000.
• Most preferred is a molecular weight of polymer as the hydrophilic portion of the micelle forming polymer being about 2000.
• Biocompatible water soluble polymers for use in this invention include any suitable water soluble polymer capable bf fluidizing a micelle forming polymer as used in this invention.
• Such water soluble polymers include pluronics that is a liquid or solid at room temperature, or low molecular weight polyesters such as glycolitic or lactic acid polymers of sufficiently low molecular weight that the polymer is a liquid or semi- solid at room temperature (e.g. about 20 to 30° C).
• Preferred water soluble polymers for use in this invention are polyethylene oxides of a molecular weight of about 1000 or less, including PEG and MePEG.
• Weight ratios of hydrophobic and hydrophilic components of micelle forming polymers used in this invention may be adjusted to provide for a desired CMC.
• the amount of water soluble polymer employed in compositions of this invention may be adjusted to achieve a desired consistency of the resulting mixture of matrix. For injection, it is preferred that the amount of water soluble polymer be such that the resulting mixture or matrix is injectable, as defined herein.
• the amount of hydrophobic drug included in the composition will be such as to provide a desired amount of drag loaded micelles, preferably not exceeding an amount that can be sufficiently distributed within the micelle forming composition.
• Methoxypolyethylene glycol (MePEG) oligomers of molecular weight 750 and 2000 and stannous octoate were obtained from Sigma-Aldrich (St. Louis, MO), while ⁇ - Caprolactone was obtained from Aldrich (Milwaukee, WI). Chloroform and dichloromethane (DCM) were HPLC grade (Fisher Scientific, Fair Lawn, NJ).
• Copolymers of methoxypolyethylene glycol (MePEG) and poly( ⁇ -caprolactone) were prepared as follows. MePEG oligomers with molecular weights of 750 and 2000 were combined with ⁇ -caprolactone in varying weight ratios to control the final molecular weight of the copolymer. The total weight of the two reagents was 50 g. The reagents were placed in a round bottom flask sealed with a ground glass stopper and immersed in a heavy mineral oil bath heated to 140°C. The temperature was controlled using a Dyna- Sense MK-1 controller (Scientific Instruments Inc., Skokie, IL).
• the reagents were stirred using a teflon coated 2.5 cm magnetic stir bar. After the reagents were mixed for 30 minutes to produce a homogeneous liquid, 0.15 ml of stannous octoate was added to the flask. The polymerization reaction was allowed to proceed for 6 hours. Cooling the polymer to room temperature terminated the reaction.
• paclitaxel Hauser chemicals
• MePEG methoxypolyethylene glycol
• Angiotech Pharmaceuticals Angiotech Pharmaceuticals, Vancouver Canada
• a 20 ml glass vial was stirred at 50°C using a spatula.
• the mixture formed a miscible composition in which all the drag was dissolved.
• the mixture was sucked up into a 1 ml syringe through an 18 gauge needle and allowed to cool to room temperature.
• the waxy material could be injected easily through a 21 -gauge needle without compromise of the integrity of the composition.
• 100 ⁇ l of the mixture was injected into 5 ml of water the mixture slowly dissolved. There was no precipitation of any of the components.
• the formulation self assembled into micelles with a particle size of approximately lOnm diameter, as shown in Figure 1. This solution had a paclitaxel concentration of 1 mg/ml, almost 1000 fold greater than the free solubility of the drug in water.
• MePEG molecular weight 350
• PCL1 caprolactone
• PCL5 caprolactone
• the waxy material could be injected easily through a 21 gauge needle without compromising the integrity of the composition.
• 100 ⁇ l of the mixture was injected -into 5 ml of water and * water acidified to pH 1, the mixture slowly dissolved and there was no precipitation of any of the components.
• the formulation self assembled into micelles.
• micellar formulation of paclitaxel along the perivascular margins of the carotid artery of a rat for the treatment of restenosis
• Wistar rats weighing 400g to 500g were anesthetized with halothane.
• a vertical incision was made over the trachea and the left external carotid artery was exposed.
• Connective tissue around the left common carotid artery was left untouched.
• Two ligatures were placed around the external carotid artery and an arteriotomy was made between them.
• a 2 French Fogarty balloon was introduced into the external carotid artery and pushed into the left common carotid artery and the balloon was inflated with saline. The balloon was passed up and down the entire length of the carotid artery three times to stretch the vessel and denude the endothelium. The balloon was removed and the ligatures tied off on the external carotid artery.
• a 3% paclitaxel loaded self-assembling micellar composition based on poly-L-lactic acid ⁇ MePEG blended with MePEG 350 in a 60/40 weight ratio was injected through a 24 G angiocatheter between a distal segment of the common carotid artery and the surrounding connective tissue.
• 0.1 to 0.2 ml of paste was applied around the artery in 4 injections in order to cover the whole circumference of the vessel on a length of approximately 1cm. The wound was then closed and the animals recovered.
• the waxy material could be injected easily through a 21 gauge needle without compromise of the integrity of the composition.
• 100 ⁇ l of the mixture was injected into 5 ml of water the mixture slowly dissolved. There was no precipitation of any of the components.
• the formulation self assembled into micelles.

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