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WO2005039750A1 - Nouvelles microparticules pour une imagerie de contraste par ultrasons et administration de medicament associee - Google Patents

Nouvelles microparticules pour une imagerie de contraste par ultrasons et administration de medicament associee

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Publication number
WO2005039750A1
WO2005039750A1 PCT/SE2004/001546 SE2004001546W WO2005039750A1 WO 2005039750 A1 WO2005039750 A1 WO 2005039750A1 SE 2004001546 W SE2004001546 W SE 2004001546W WO 2005039750 A1 WO2005039750 A1 WO 2005039750A1
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WIPO (PCT)
Prior art keywords
microparticles
core
shell
microbubbles
liquid
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PCT/SE2004/001546
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English (en)
Inventor
Per Hansson
Björn LINDMAN
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Individual
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Individual
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/10—Complex coacervation, i.e. interaction of oppositely charged particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/225—Microparticles, microcapsules
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • FIELD OF INVENTION Trie invention relates to a new method for producing stable microparticles, microcapsules and microbubbles possessing a core and shell structure, and the product(s) thereof.
  • the microparticles, microcapsules and microbubbles are suitable for use as ultrasound contrast agent(s), drug delivery vehicles, and combined drug vehicles/ultrasound contrast agents for in-situ drug delivery.
  • ultrasound contrast imaging has lacked efficient contrast agents until recently.
  • the most recent ultrasound contrast agents are based on the use of aqueous suspensions of air microbubbles due to the large differences in acoustic impedance between air and the surrounding aqueous medium. Such microbubbles are capable of enhancing ultrasound signals by a factor of up to a few hundreds.
  • Detailed descriptions of the development of ultrasound contrast agents are given in the reviews by C.J. Harvey et al., Eur. Radiol.vol. 11, pp. 675-689 (2001), and J-M. Correas et al., Eur. Radiol. Vol. 11, pp. 1316-1328 (2001).
  • microbubbles A size requirement for these microbubbles exists; they must be injectable intravenously and be small enough to pass through the capillaries of most tissues; i.e., they have to be smaller than about 8 microns.
  • very small microbubbles ca. 1 micron
  • 3-4 microns are considered to be an optimal size (A.L. Klibanov, "Ultrasound Contrast Agents: Development of the field and current status " in Topics in Current Chemistry, Vol. 222, p. 73, Springer- Verlag Berlin, Heidelberg (2002)).
  • a major practical problem with microbubbles is, however, stability.
  • ultrasound contrast agents In ultrasound contrast agents, this refers to stability with respect to time as well as to mechanical strength and resistance to destruction by ultrasonic waves. Air or gas microbubbles in a liquid are difficult to stabilise and present-day solutions lack long-term stability. After injection into the bloodstream, microbubbles are required to survive at least for the duration of examination. For echocardiography, bubble agents persisting for two to 30 seconds, have been used. For other applications such as neurosonography. hysterosalpingography, and diagnostic procedures on solid organs, microbubbles require a lifetime of more than a few circulation times.
  • microbubbles are required to concentrate in organ systems other than the vascular system into which it is injected, implying that some degree of site-specific targeting is also necessary.
  • two principal approaches to increase microbubble stability have been used. The first approach has been to stabilise microbubbles by encapsulation, using sugar matrices, surfactants or lipids, proteins or polymers, or combinations of these materials.
  • the second approach is based on the selection of gases with low diffusion coefficient, to inhibit leakage from the filled microbubbles. Combinations of both approaches have also been attempted.
  • polymeric shells have been considered to possess the best chance for survival after injection, and may be suitable not only for cardiology but also for organ and peripheral vein imaging.
  • a variety of natural and synthetic polymers have been used to encapsulate imaging contrast agents, including air and other gases.
  • US patents 5,487,390 and 5,562,099 describe respectively gas-fille and contrast agent-filled polymeric microcapsules for ultrasound imaging.
  • the polymeric microcapsules in both cases were formed by ionotropically gelling synthetic poly electrolytes by contact with multivalent ions. The synthesis of the polymer, however, may involve strong organic solvents including dimethylsulf oxide .
  • WO 89/06978 describes ultrasonic contrast agents consisting of microparticles containing amyloses or synthetic biodegradable polymers.
  • EP 0441468 describes ultrasound contrast agents consisting of microparticles having a particle diameter of from 0.1 to 40 microns consisting of a biodegradable polymer obtainable from a polymerisable aldehyde and a gas and/or liquid having a boiling point of less than 60 °C.
  • the synthesis method here is, however, complicated and involves several steps.
  • EP 0576519 describes ultrasound contrast agents comprising gas-filled "microballoons" comprising microbubbles of gas encapsulated by monolayers or one or more bilayers of non-proteinaceous crosslinked or polymerised amphiphilic moieties, excluding however, polyoxyethylene-polyoxypropylene polymer as the crosslinked or polymerised amphiphilic moeities, as well as excluding polyaldehyde microparticles as the contrast agent.
  • the synthesis method here is complicated and involves organic solvents.
  • none of the above methods produced ultrasound contrast agents claiming to have the crucial properties required in such a function; for example, sufficient mechanical stability to resist destruction by ultrasonic waves, long-term stability and storage capacity lasting up to several weeks or even months.
  • the method according to the invention provides a solution to the stability requirement in both ultrasound contrast agents and drug delivery vehicles.
  • the invention provides a method for producing polymer microparticles possessing a core and shell structure, comprising the steps of (a) providing at least one polyelectrolyte microgel, (b) providing at least one colloid in an aqueous solution, (c) allowing mixing of said polyelectrolyte microgel and said colloid in an aqueous solution, (d) obtaining microparticles as a suspension in an aqueous liquid phase.
  • These microparticles are suitable for use, for example, as drug delivery vehicles.
  • the method according to the invention provides a method for obtaining firstly, microparticles possessing rubber-like shells typically accompanied by the presence of a cubic shell microstructure, and having a water swollen gel core, and secondly, microparticles possessing rigid shells typically accompanied by the presence of a hexagonal shell microstructure, and having a liquid- filled core.
  • the invention also provides a method for obtaining essentially liquid- free hollow microcapsules, when said microparticles having rigid shells typically accompanied by the presence of a hexagonal shell microstructure, and having a liquid- filled core, are dried.
  • the invention further provides a method to obtain microbubbles, when said essentially liquid- free hollow microcapsules are reconditioned with any chosen gas.
  • the microbubbles are suitable for use as ultrasound contrast agents as well as drug delivery vehicles.
  • the method according to the invention employs at least one crosslinked polyelectrolyte microgel and at least one colloid having an opposite charge to the polyelectrolyte microgel or network.
  • the invention additionally provides a method for producing microparticles and microbubbles in a range of sizes, making it suitable for various applications.
  • Another object of the invention is to provide a fast method exhibiting good reproducibility, high controllability and economic feasibility.
  • the invention provides a method which avoids the use of extreme heat and toxic stabilisers and organic solvents.
  • the method according to the invention also provides novel microparticles possessing a robust outer or shell layer exhibiting low permeability and high stability, enclosing a water-swollen gel core or alternatively, a liquid-filled core.
  • the invention provides novel microparticles possessing rubber- like shells typically accompanied by the presence of a cubic shell microstructure, and having a water swollen gel core, for use as drug delivery vehicles or carriers for a wide selection of drugs.
  • Such microparticles may be loaded with any selected drug using one or more of the methods known to persons skilled in the area of pharmaceutics. They may also be used for the protective encapsulation and subsequent drug delivery of novel protein drugs which are sensitive to environmental factors such as low pH, heat and digestive enzymes.
  • the method according to the invention further provides novel microparticles possessing rigid shells typically accompanied by the presence of a hexagonal shell microstructure, and having a liquid- filled core.
  • the method according to the invention provides essentially liquid-free hollow microcapsules, when said microparticles having a liquid-filled core, are dried. These microcapsules may also be used as drug delivery vehicles or carriers.
  • the invention provides non-toxic microparticles and microcapsules for use as drag delivery agents, produced using non-toxic stabilisers and which are safe for human consumption, said microparticles being suitable for oral, transdermal, and other commonly employed drug administration methods well known to persons skilled in the field of galenic pharmacy or pharmaceutics.
  • Another object of the invention is to provide microbubbles, when said microcapsules are reconditioned with any chosen gas. Accordingly, the method according to the invention provide microbubbles to be employed as effective ultrasound contrast agents, said microbubbles possessing long-term stability and storage properties, as well as unique mechanical and accoustic properties. In a further aspect, the method according to the invention also provides microbubbles to be used as drug-delivery vehicles under certain conditions.
  • Gas-filled microbubbles may be made, according to the method of the invention, having shells made from amphiphilic drugs, protein drugs, or drugs solubilised in the surfactant or lipid aggregates constituting one or more of the components of the shell. Said gas-filled particles are intended for in-situ release of the drug triggered by local stimulus using ultrasound. The large amount of drag that can be stored in the shell is an important advantage compared with other systems designed for the same type of application.
  • a further object of the invention is to produce macroscopic gel particle analogues, typically of 1-cm diameter (see Figure lb), of said microparticles and microbubbles, to be used, for example, as drug-delivery capsules.
  • Figure (la) shows a micrograph of a core/shell microparticle with a fluorescent- labelled shell.
  • Figure (lb) shows a photograph of a macroscopic microparticle (ca. lcm. diam.) having a thick shell enclosing a liquid- filled core.
  • Figure 2 shows a schematic diagram of the steps in the formation of microparticles having liquid-filled cores, when starting from dry microgels.
  • Figure 3 shows the small-angle x-ray scattering (SAX) results of polyacrylic acid-cetyltrimethylammonium bromide (CTAB) microparticles where a cubic and hexagonal shell structure is indicated.
  • SAX small-angle x-ray scattering
  • microparticles refers to the microparticles formed when one or more crosslinked polyelectrolyte network(s) or microgel(s) absorb oppositely charged colloids from aqueous solution, resulting in microparticles possessing a core and shell structure.
  • the microparticles may possess a water swollen gel core ("Type I microparticles") or a liquid- filled core (“Type II microparticles), depending on the conditions of the experiments, for example, the concentration of the aqueous colloid solution, the presence of a salt, the type of colloid used.
  • microcapsules as used in this invention refers to microparticles drained of liquid in the core.
  • microbubbles refers to microparticles having initially a liquid-filled core, with the liquid in the core removed and replaced by air or other chosen gas during the reconditioning stage. Microbubbles may also be defined as air/gas-filled microcapsules.
  • core refers to the central section of the microparticles.
  • shell refers to the outer layer of the microparticles, consisting of closely packed colloids held together through electrostatic interaction by the oppositely charged polymer/polyelectrolyte network chains in-between them.
  • rubber-like shells is herein intended to mean shells displaying rubber elasticity.
  • rigid shells is herein intended to mean shells that are mechanically rigid but not- displaying typical rubber elasticity.
  • structure when referring to core and/or shell structure may be used interchangeably with the word “microstructure” in this application.
  • liquid crystalline microstructure is herein intended to mean states characterised by positional ordering of colloid aggregates, or in colloidal length scales (ca. 1 nm to 500 nm) but no ordering on molecular length scales.
  • solid crystalline microstructure is herein intended to mean states characterised by positional ordering on molecular length scales.
  • gel microstructure is herein intended to mean states characterised by no positional ordering of colloids or colloid aggregates.
  • polyelectrolyte refers to charged polymers possessing either cationic or anionic functional groups in the main chain structure, and their associated counterions.
  • polyelectrolyte network has been used interchangeably with the terms “microgel” or “gel” or “polymer network” in this application and refers to the polyelectrolyte which is crosslinked, and which is swelled in the presence of an aqueous environment.
  • colloids as used in this invention refers to a collective term for surfactants, lipids, amphiphilic drugs or other amphiphilic compounds, proteins, polymers, and solid particles such as silica spheres less than about 500 nm in diameter.
  • polyion refers to charged polymers possessing either cationic or anionic functional groups in the main chain structure, without consideration of counterions.
  • reconditioning refers to the process of filling microparticles with air or any chosen gas to its equilibrium value and rehydrating the shells, to give microbubbles.
  • the term "echocardiography” as used in this invention refers to a method of graphically recording the position and motion of the heart walls or the internal structures of the heart and neighbouring tissues by the echo obtained from ultrasonic waves directed through the chest wall.
  • the invention relates to a new method for producing stable microparticles, microcapsules and microbubbles possessing a core and shell structure, and the product(s) thereof.
  • the microparticles and microbubbles are suitable for use as ultrasound contrast agent(s), drug delivery vehicles, and combined drug vehicles/ultrasound contrast agents for in-situ drug delivery.
  • the invention provides a method for producing polymer microparticles possessing a core and shell structure, comprising the steps of (a) providing at least one polyelectrolyte microgel, (b) providing at least one colloid in an aqueous solution, (c) allowing mixing of said polyelectrolyte microgel and said colloid in an aqueous solution, (d) obtaining microparticles as a suspension in an aqueous liquid phase.
  • the invention comprises the production of two types of microparticles, both possessing a core and shell structure, with shells that are robust in nature, exhibiting low permeability and high stability.
  • the shells enclose a water swollen gel core
  • the shells enclose a liquid-filled core.
  • Both types of particles can be made from an almost identical protocol up to the mixing stage (c) just before the microparticles are obtained. From the experimental viewpoint, the difference in the core structures, i.e. a water swollen gel core or liquid- filled core, result most commonly due to a difference in the concentration range used of one of the components, for example, the colloid, or, the presence of added salt, in the reaction mixture.
  • Type II microparticles are suitable for use as drug delivery vehicles or carriers.
  • Type II microparticles are further treated to produce essentially liquid- tree hollow microcapsules (i.e, microparticles drained of liquid), and microbubbles (i.e, microcapsules reconditioned with a suitable chosen gas).
  • Type II microparticles which are also precursors to microcapsules, are suitable for use as drug delivery vehicles or carriers, whereas Type II microparticles resulting in microbubbles may be employed as ultrasound contrast agents as well as drag-delivery vehicles.
  • Type I microparticles are produced by a method comprising the steps of: (a) providing at least one polyelectrolyte microgel, (b) providing at least one colloid in an aqueous solution, (c) allowing mixing of said polyelectrolyte microgel and said colloid in an aqueous solution, (d) obtaining microparticles as a suspension in an aqueous liquid phase.
  • the polyelectrolyte microgel may be allowed to swell from the dry state in an aqueous solution of the colloid, or alternatively, an aqueous solution of the colloid is allowed to mix with an aqueous suspension of the polyelectrolyte microgel.
  • the method to produce Type I microparticles comprises, for example, swelling of at least one dry polyelectrolyte network or microgel in an aqueous surfactant solution, such as dodecyltrimetylammonium bromide (DoTAB), at a defined concentration range, of for example, from about 0.001M to about 0.05M, for example 0.001,0.002,0.003,0.004,0.005,0.006,0.007,0.008,0.009, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045 and 0.050 DoTAB in water, having a final pH of approximately 9, such as from 8.5 to 9.5.
  • DoTAB dodecyltrimetylammonium bromide
  • the appropriate amount of surfactant in an aqueous solution is mixed with an aqueous suspension of the swollen microgel.
  • Both procedures result in core/shell microparticles (Type I microparticles) with a water swollen gel core. (See Figure la). It appears that the presence of a cubic shell structure typically accompanies the formation of Type I microparticles which have a water swollen core.
  • Microparticles possessing a water swollen gel core are suitable for use as drug delivery vehicles or carriers in commonly employed drag administration methods such as oral and parenteral delivery.
  • polyelectrolyte icrogels are known to be able to store large amounts of oppositely charged proteins, it is possible, for example, to load one or more protein drug(s) into the said gel core and to encapsulate said drug(s) by forming a protective shell layer around the core using a polymer, surfactant or other types of colloids.
  • Type I microparticles may be used for the protective encapsulation and subsequent drug delivery of protein and polypeptide drugs, or other drugs sensitive to environmental factors such as pH, heat and digestive enzymes.
  • Type II microparticles are produced by a method described as for Type I microparticles, at least up to the mixing stage (c) just before the microparticles are obtained.
  • the difference in the core structure i.e, the formation of a liquid-filled core instead a water swollen gel core, results most commonly from a difference in the concentration range used of one of the components, for example, the colloid, or, the presence of added salt, in the reaction mixture.
  • the use of a different colloid may also cause this difference in core microstructure. (See example 1).
  • the liquid in the liquid-filled core comprises water or an aqueous solution of an electrolyte or colloid.
  • the concentration of the aqueous solution of the colloid has a range of about 0.00O5 to 0.05M, or preferably, from about 0.001 to 0.01M, or more preferably, from about 0.001 to 0.005M. This concentration is required to give microparticles having a liquid-filled core and not a water swollen core in this case.
  • Figure 2 shows a schematic diagram of the steps in the formation of liquid- filled microparticles when starting from dry microgels.
  • a light grey colour indicates a swollen core
  • a black shaded colour indicates a collapsed surface phase (shell)
  • no colour indicates a liquid-filled core.
  • Step 1 shows a dry polyelectrolyte network (starting material).
  • Step 2 shows a partially swollen gel with surface instabilities due to rapid swelling. There is no (or only a very thin) surface phase layer which exerts no or negligible effect on core swelling.
  • Step 3 shows a partially swollen gel with a dense surface phase (shell). Surface instabilities are suppressed by the shell.
  • Step 4a shows a gel with a swollen core surrounded by a rigid shell.
  • Step 5 a shows a gel with a rigid shell (thicker than in Step 4a) and a partially disassembled core network.
  • Step 6 shows a gel with rigid shell (thicker than in Step 5 a) and a liquid- filled core
  • Step 5b shows a gel in a hypothetical state (never reached) where the elastic shell has contracted and pressed out water from the core.
  • Figure 3 shows the small-angle x-ray scattering (SAX) results of polyacrylic acid-cetyltrimethylammoniumbromide (CTAB) microparticles where a cubic and hexagonal shell structure are indicated. Under conditions where a cubic structure forms, core/shell particles with water swollen gel cores (Type I microparticles) are typically formed.
  • SAX small-angle x-ray scattering
  • core/shell particles with liquid-filled cores are typically formed (Type II microparticles).
  • Type II microparticles The examples illustrate the fact that the method of the invention allows selection of the desired type of microparticles by controlling the shell microstructure.
  • the microparticles having a liquid- filled core in a suspension are dried, essentially liquid- free hollow microcapsules are obtained. The drying may be effected by sedimenting or centrifuging the microparticle suspension and removing the supernatant aqueous phase.
  • These microcapsules may also be employed as drug- delivery vehicles or carriers.
  • microbubbles are obtained. These microbubbles are suitable for use as ultrasound contrast agents as well as for drug delivery vehicles.
  • suitable gases for reconditioning and/or filling the microbubbles are typically gases possessing a low diffusion coefficient, such as sulphurhexafluoride, and fluorocarbons such as hexafluoropropylene, octafluoropropane, hexafluoroethane, octafluoro-2-butene, hexafluoro-2-butyne, hexafluorobuta- 1 ,3 -dien, octafluorocyclobutane, decafluorobutane, dodecafluoropentane, and tetradecafluorohexane.
  • gases possessing a low diffusion coefficient such as sulphurhexafluoride, and fluorocarbons such as hexafluoropropylene, octafluoropropane, hexafluoroethane, octafluoro-2-buten
  • the shells in these gas- filled microbubbles may be made from amphiphilic drugs, protein drags, or drags solubilised in the surfactant or lipid aggregates constituting one or more of the components of the shell.
  • the gas-filled particles are then intended for in-situ release of the drug triggered by local stimulus using ultrasound.
  • the large amount of drag that can be stored in the shell is an important advantage compared with other systems designed for the same type of application.
  • the microbubbles are stored in the form of an aqueous suspension with the aqueous phase saturated with the gas. Even with sparingly soluble gases conventional microbubble suspensions have short storage lifetime.
  • the main reason for this is the fusion of bubbles in the suspension or when in contact after "creaming"(due to the tendency of low density bubbles to accumulate near the top of the container).
  • the robust shells of the particles formed by the present method effectively prevent fusion, thus ensuring long shelf life-time of the microbubbles.
  • the method according to the invention employs at least one crosslinked polyelectrolyte microgel or network and at least one colloid having an opposite charge to the polyelectrolyte microgel.
  • the method is generally applicable to all
  • the method according to the invention may employ as starting material any suitable available pre-synthesized crosslinked polyelectrolyte microgel.
  • the invention does not include methods for synthesis of polyelectrolyte microgels or crosslinking of polyelectrolytes to form microgels.
  • the one or more polyelectrolyte microgel(s) or network(s) used in the method according to the invention may be cationic or anionic, and may be of synthetic or natural origin.
  • polyacrylate salts such as crosslinked sodium polyacrylate, carboxymethylcellulose, dextrane sulfate, alginate, glycosaminoglycans (keratan sulfate, hyaluronate, chondroitin sulfate, heparin, heparan sulfate, dermatan sulfate), proteoglycans, polyglutamate, co-polymers of maleic acid, polyvinylsulfate, polyimines, chitosan, cationic cellulose and starch derivatives.
  • polyacrylate salts such as crosslinked sodium polyacrylate, carboxymethylcellulose, dextrane sulfate, alginate, glycosaminoglycans (keratan sulfate, hyaluronate, chondroitin sulfate, heparin, heparan sulfate, dermatan sulfate), proteoglycans, polyglutamate,
  • the one or more colloid(s) used in the method according to the invention shall possess an opposite charge to the polyelectrolyte microgel(s) or network(s), and may be anionic or cationic in nature, and of many different types, including for example, association colloids such as surfactants, lipids, or other types of amphiphilic molecules including amphiphilic drugs, synthetic or natural polymers, proteins, polypeptides and solid particles such as silica spheres less than about 500 nm in diameter.
  • association colloids such as surfactants, lipids, or other types of amphiphilic molecules including amphiphilic drugs, synthetic or natural polymers, proteins, polypeptides and solid particles such as silica spheres less than about 500 nm in diameter.
  • surfactants these may include all common or typical anionic and cationic surfactants, biodegradable surfactants, synthetic and naturally-derived surfactants, such as those based on aminoacids, that can form cylinder shaped micelles in complexes with oppositely charged polyions involving or not involving to some extent simple counterions.
  • the method according to the invention is also characterised by good reproducibility, high controllability and the possibility to produce microparticles, microcapsules and microbubbles in a range of sizes.
  • the particle size (diameter) range obtained by this method for the core/shell microparticles, microcapsules and microbubbles may be in a range from about 0.1 microns to 10 cm, such as from about 0.1 microns to about to about 100 microns, such as from about 0.5 microns to about 100 microns, such as from about 1 to 5 microns.
  • the size of the microparticles and microcapsules is set by the size, polydispersity and other properties of the starting microgels, such as degree of crosslinking and charge density.
  • the final size depends, in a controllable and reproducible way, on interaction with the oppositely charged colloid(s) selected.
  • Many of the applications disclosed in this specification require a small size range of microparticles, microcapsules and microbubbles.
  • macroscopic (centimetre size) core/shell microparticles may also be obtained by the method according to the invention.
  • microbubbles to be used as contrast agents in ultrasonography, or microparticles for intravenous administration of drugs may be made in the size range 1-5 microns.
  • This size range possible allows the ultrasound contrast agents made by the method to be used for other applications besides echocardiography, applications including neurosonography, hysterosalpingography, and diagnostic procedures on solid organs, where the contrast agents need to possess a lifetime of more than a few circulation times.
  • Stability and the shell layer As discussed earlier, mechanical stability and resilience, as well as long-term stability in use and in storage, are properties that are lacking in present-day microparticles for drag delivery and microbubbles for use as ultrasound contrast agents.
  • the method and products provided by the invention give a solution to this stability requirement.
  • the presence of a robust shell or outer layer in the microparticles is a key factor in the products provided by the invention.
  • the shells have unique mechanical and physico-chemical properties that can be fine tuned by controlling their composition and structure on the molecular level, simply through varying conditions during the formation of the microparticles.
  • the thickness and diameter of the shell may also be controlled through varying experimental conditions.
  • a problem with existing microbubbles is poor mechanical stability and the inability to resist destruction by ultrasonic waves.
  • the presence of the robust shell layer provides mechanical stability as well as limits outward diffusion of air or gas from the microbubbles.
  • the lifetime of single microbubbles depends on the rate of escape of the enclosed gas and the ability of the shell layer to resist the destructive and dispersing action of the ultrasound.
  • the choice of a suitable gas also supports the performance of the shell layer. By using a gas with low solubility and low diffusion constant in water, the escape rate can be reduced considerably. Suitable gases for this function may include various fluorinated compounds.
  • suitable gases are: sulfurhexafluoride and fluorocarbons such as hexafluoropropylene, octafluoro- propane, hexafluoroethane, octafluoro-2-butene, hexafluoro-2-butyne, hexafluoro- buta-l,3-dien, octafluorocyclobutane, decafluorobutane, dodecafluoropentane, and tetradecafluorohexane.
  • the microbubbles and ultrasound contrast agents produced by the method according to the invention are expected to be stable over several months or years in ready-to-use form.
  • the storage time will be limited by the rate of leakage of gas from the container and by the degradation rate of the polyelectrolyte network, not by the fusion of microbubbles.
  • ultrasound contrast agents that can be stored for substantial periods of time (for example, at least twelve months, or even up to two or three years) in "ready-to-use” form.
  • Echovist® and Levovist® which involve microparticulate systems, have to be preformulated prior to adminstration, which gives problems in practice.
  • the microbubbles and ultrasound contrast agents produced by the method allows storage over long periods of time, and comprise "ready-to-use" systems that are available at need.
  • Shell/core formation mechanism The exact mechanism behind the formation of, for example, liquid-filled microparticles, is not known. However, it is believed that the first step in the process is critical. In the case of using a surfactant as the colloid component, the process is thought to involve simultaneous swelling and absorption of surfactant from solution, where the latter process is instantly followed by complex formation between surfactant and polyion in the particle. The process is thought to involve aggregation of surfactant to micelles, electrostatic attraction of polyion to the micelles to form complexes, and a cooperative association of complexes to form a separate surface phase in the microparticles, the latter referred to here as "the shell".
  • the polyelectrolyte component not taking part in the complexation constitutes the core of the microparticle.
  • the core network is consumed and progressively converted to shell.
  • an essential requirement in the process is the formation of cylinder shaped micelles assembled in to an ordered hexagonal structure in the shell.
  • An important point is that the shape of the micelles is determined by the ionic composition of the aqueous phase, which is easy to control.
  • CTAB interacting with sodium polyacrylate gels it has been shown by small angle x-ray scattering measurements (see figure 3) that above a critical concentration of bromide ions in the solution, the shells have a hexagonal microstructure. Below a certain concentration, the microstructure is observed to be of a cubic type.
  • the transition is due to the incorporation of bromide ions into the polyion/micelle complexes, affecting the intricate balance of electrostatic and hydrophobic interactions in the interfacial region of the micelles.
  • the microstructure strongly influences the fate of the gels during swelling and shrinking in water.
  • microparticles having a liquid-filled core are typically formed when the shell microstructure is hexagonal.
  • a cubic microstructure appears to lead to the formation of core/shell microparticles possessing a water swollen gel core.
  • Investigations of the corresponding processes in centimetre-size gels show that shells with cubic micro- structure have rubber-like elasticity, responding to deformations by spontaneously relaxing to an isotropic undeformed state.
  • Example 2 Objective: Preparation of an aqueous suspension of air filled microbubbles.
  • microparticles were prepared as disclosed in Example 1 using CTAB as the surfactant.
  • the solution above the microparticles in the beaker was removed with a pipette, and the liquid filled microcapsules were than vacuum dried for about 24 hours at 40 °C.
  • the dried essentially liquid- free microcapsules were then placed in a closed container containing air saturated with water vapour for 24 hours.
  • the shells absorb water, thereby regaining their mechanical properties, shape, and size they possessed in the wet state. At the same time, this forces air to fill the voids inside the microcapsules. Water is then poured onto the re-conditioned microcapsules, which were then dispersed in the water by stirring, to form a suspension of microbubbles.
  • Core/shell microparticles of a size suitable for ultrasongraphy (ca. 2 microns).
  • Core/shell particles 1 g gel suspension was mixed with 50 g of a 5 mM CTAB/5 mM NaBr solution. Core/shell particles had formed after 10 min. The suspension was slowly stirred during that time period.
  • Cationic microgel particles were obtained by polymerising (3-acrylamidopropyl)- trimethylammonium chloride (AAPTAC) (Aldrich) in the presence of methylene- bis-acrylamide (1 mole% of total monomer) according to the method used to prepare the networks in Example 1. Particles with in the range 10-100 microns, were collected by sieving and stored in 10 mM sodium chloride (aq). i) Particles with gel core. 0. 1 mL of the microgel suspension were added to a beaker containing 0.3 L 0.005 M sodium dodecylsulfate (SDS) (Sigma) and 10 mM sodium chloride (room temperature). Core/shell particles, ca.
  • AAPTAC (3-acrylamidopropyl)- trimethylammonium chloride
  • SDS sodium dodecylsulfate
  • Cationic gel particle/fatty acid i) Particles with gel core As in example 4i) but gels were added to 0.001 M lauric acid (sodium salt, Acros Organics)/0.01 M potassium chloride aqueous solution, ii) Particles with liquid core. As in example 4ii) but gels were added to 0.005 M palmitic acid()/0.01 M potassium chloride aqueous solution.
  • Cationic gel particle/bile salt A core/shell particle with gel core was obtained as in example 4i) but gels were added to 0.1 L of a solution of sodium deoxycholate. The solution was prepared by dissolving 0.15 g Deoxycholic acid (sodium salt, Fluka) in 0.1 L water.
  • Anionic gel particle/degradable surfactant i)Preparation of sodium polyacrylate core/shell particles with a liquid core A solution was prepared by dissolving 0.15 g of dodecyltrimethylglycine hydrochloride () and 0.1 g NaBr in 100 g water. 20 g of the solution was added to a beaker containing 1 mg of dry sodium polyacrylate microgel powder, prepared as in example 1. The pH was adjusted to 7 by adding small aliquots of a 0.1 M NaOH solution. The suspension was carefully stirred using a magnetic stirrer. Core/shell particles possessing a liquid core were formed within 20 min. ii)Degradation: The particles were observed in the microscope at different times after preparation.
  • a single AAPTAC microgel (diameter ca. 30 microns) from the preparation in example 4 was equilibrated during 5 min in 0.01M NaCl aqueous solution.
  • the particle was held in position inside a glass tube of diameter 1mm in a flow of the liquid phase using a micropipette connected to suction pump.
  • the particle was observed in the microscope as the salt solution was replace by a 40 mg/L aqueous solution of insulin containing 0.01 M NaCl.
  • the gel diameter had reduced to ca. 10 microns, and transformed into a core/shell particle; a thin but very dense shell could be observed in the exterior parts of the gel particle. No further shrinking was observed after that point.
  • the insuline solution was prepared by dissolving Porcine Insulin (Aldrich) in a small volume of 0.1 M hydrochloric acid, and the diluting it with 0.01 M NaCl, and adjusting the pH to 8.
  • Core/shell particles loaded with a cationic amphiphilic drag i) Core/shell particles with gel core.

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Abstract

L'invention concerne une nouvelle méthode de production de microparticules, de microcapsules et de microbulles stables présentant une structure de noyau et de coquille, ainsi que le ou les produits associés. Ces produits sont appropriés à une utilisation en tant qu'agent(s) de contraste ultrasons, que véhicules d'administration de médicaments, que véhicules de médicaments/agents de contraste ultrasons combinés pour une administration de médicaments in situ.
PCT/SE2004/001546 2003-10-24 2004-10-25 Nouvelles microparticules pour une imagerie de contraste par ultrasons et administration de medicament associee Ceased WO2005039750A1 (fr)

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Cited By (7)

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WO2008091228A3 (fr) * 2007-01-24 2009-04-02 Univ Singapore Encapsulation couche-par-couche en phase inverse de matières hautement solubles dans l'eau
US8332020B2 (en) 2010-02-01 2012-12-11 Proteus Digital Health, Inc. Two-wrist data gathering system
US8419638B2 (en) 2007-11-19 2013-04-16 Proteus Digital Health, Inc. Body-associated fluid transport structure evaluation devices
US9014779B2 (en) 2010-02-01 2015-04-21 Proteus Digital Health, Inc. Data gathering system
US9084566B2 (en) 2006-07-07 2015-07-21 Proteus Digital Health, Inc. Smart parenteral administration system
US9125979B2 (en) 2007-10-25 2015-09-08 Proteus Digital Health, Inc. Fluid transfer port information system
CN115317630A (zh) * 2022-10-14 2022-11-11 山东百多安医疗器械股份有限公司 一种用于超声的胃肠助显胶囊及其制备方法

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9084566B2 (en) 2006-07-07 2015-07-21 Proteus Digital Health, Inc. Smart parenteral administration system
WO2008091228A3 (fr) * 2007-01-24 2009-04-02 Univ Singapore Encapsulation couche-par-couche en phase inverse de matières hautement solubles dans l'eau
US9125979B2 (en) 2007-10-25 2015-09-08 Proteus Digital Health, Inc. Fluid transfer port information system
US8419638B2 (en) 2007-11-19 2013-04-16 Proteus Digital Health, Inc. Body-associated fluid transport structure evaluation devices
US8332020B2 (en) 2010-02-01 2012-12-11 Proteus Digital Health, Inc. Two-wrist data gathering system
US9008761B2 (en) 2010-02-01 2015-04-14 Proteus Digital Health, Inc. Two-wrist data gathering system
US9014779B2 (en) 2010-02-01 2015-04-21 Proteus Digital Health, Inc. Data gathering system
US10376218B2 (en) 2010-02-01 2019-08-13 Proteus Digital Health, Inc. Data gathering system
CN115317630A (zh) * 2022-10-14 2022-11-11 山东百多安医疗器械股份有限公司 一种用于超声的胃肠助显胶囊及其制备方法

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