WO2003106168A1 - Particules enrobees, procedes d'utilisation et de fabrication associes - Google Patents

Particules enrobees, procedes d'utilisation et de fabrication associes

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Publication number
WO2003106168A1
WO2003106168A1 PCT/US2002/018654 US0218654W WO03106168A1 WO 2003106168 A1 WO2003106168 A1 WO 2003106168A1 US 0218654 W US0218654 W US 0218654W WO 03106168 A1 WO03106168 A1 WO 03106168A1
Authority
WO
WIPO (PCT)
Prior art keywords
coated particle
phase
nanostructured
nonlamellar
exterior coating
Prior art date
Application number
PCT/US2002/018654
Other languages
English (en)
Inventor
David M. Anderson
Original Assignee
Lyotropic Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/297,997 external-priority patent/US6482517B1/en
Application filed by Lyotropic Therapeutics, Inc. filed Critical Lyotropic Therapeutics, Inc.
Priority to AU2002312476A priority Critical patent/AU2002312476B2/en
Priority to EP02739853A priority patent/EP1534512A4/fr
Priority to PCT/US2002/018654 priority patent/WO2003106168A1/fr
Priority to US10/170,237 priority patent/US6638621B2/en
Priority to CA002488643A priority patent/CA2488643A1/fr
Priority to JP2004513029A priority patent/JP2005529949A/ja
Priority claimed from US10/170,237 external-priority patent/US6638621B2/en
Publication of WO2003106168A1 publication Critical patent/WO2003106168A1/fr
Priority to AU2009201314A priority patent/AU2009201314B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
    • 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
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2984—Microcapsule with fluid core [includes liposome]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2984—Microcapsule with fluid core [includes liposome]
    • Y10T428/2985—Solid-walled microcapsule from synthetic polymer
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2989—Microcapsule with solid core [includes liposome]

Definitions

  • the present invention relates to coated particles and to methods of making and using them. These coated particles have application in the targeting and release of one or more materials into selected environments, the absorption of one or more materials from selected environments and the adsorption of one or more materials from selected environments.
  • Polymer-coated particles have been very important in the development of useful microparticles and of controlled-release vehicles generally.
  • polymers have coating and spreading properties that provide for good encapsulation of various matrices, and they are available in a range of chemistries and molecular weights.
  • Certain polymeric coatings are of such utility and low toxicity that approval has been obtained for their use even in injectable products within the pharmaceutical industry, most notably polylactic-glycolic acid copolymers, and the usefulness of polymeric coatings in oral products is well-established, as in the cases of Eudragits, gelatin, and a number of natural gums. In many settings in fact, microparticle coatings are tacitly assumed to be polymers.
  • polymer-coated particles exhibit several limitations, as the flattened and diffuse response of their polymer coatings to chemical and physical triggers indicates. This is due to two factors. First, the high molecular weight of polymers reduces their diffusion coefficients and their kinetics of solubilization. Second, the neighboring group effect broadens the curves representing the chemical responses to triggers such as, inter alia, pH, salinity, oxidation and reduction, ionization, etc. (The neighboring group effect indicates that chemical changes in one monomeric unit of a polymer significantly alter the parameters governing chemical transitions in each of the neighboring monomeric units.) Further, most polymers are collections of chemical species of broadened molecular weight distribution.
  • the coating processes often entail harsh chemical and/or physical conditions, such as solvents, free radicals, elevated temperatures, dessication or drying, and/or macroscopic shearing forces needed to form the particles; the limited mechanical and thermal stabilities of the polymeric coatings in industrial applications; and adverse environmental impacts in large scale applications of polymer-coated particles, such as in agricultural use.
  • Liposomes also exhibit a number of limitations. Among these are their physical and chemical instabilities. The release of a material disposed within the liposome is usually dependent on the destabilization of the structure of the liposome. In particular, the absence of porosity precludes the pore-controlled release of such materials. The dual requirements of 1) physical stability of the liposome until release is desired on the one hand and 2) release of materials by bilayer destabilization when release is desired on the other, are problematic. (The term liposomes is frequently interchanged with the term vesicles and is usually reserved for vesicles of glycerophospholipids or other natural lipids.
  • Vesicles are self-supported closed bilayer assemblies of several thousand lipid molecules (amphiphiles) that enclose an aqueous interior volume.
  • the lipid bilayer is a two-dimensional fluid composed of lipids with their hydrophilic head groups exposed to the aqueous solution and their hydrophobic tails aggregated to exclude water.
  • the bilayer structure is highly ordered yet dynamic because of the rapid lateral motion of the lipids within the plane of each half of the bilayer.) See O'Brien. D.F. and Rarnaswami, V. (1989) in Mark-Bikales-Overberger-Menges Encyclopedia of Polymer Science and Engineering. Vol. 17, Ed. John Wiley & Inc., p. 108. SUMMARY OF THE INVENTION
  • coated particles that are suitable for solubilizing or containing a wide variety of materials, including materials sensitive to physical, chemical or biological deterioration. It is an object of the invention to provide coated particles that release one or more material disposed within a matrix in their internal cores without requiring the destabilization of that matrix.
  • targeting moieties such as antibodies, lectins, receptors, and complementary nucleic acids
  • coated particles that can be produced by a process that is flexible and can be adapted to a wide range of actives, coatings, and matrices. It is a further object of the invention to provide coated particles that have a polymerized interior matrix which is more permanent chemically, thermodynamically, and structurally than their unpolymerized counterparts.
  • a coated particle that comprises an internal core comprising a matrix and an exterior coating.
  • the matrix consists essentially of at least one nanostructured liquid phase, or at least one nanostructured liquid crystalline phase or a combination of the two and the exterior coating comprises a nonlamellar material that is a nonlamellar crystalline material, a nonlamellar amorphous material, or a nonlamellar semi- crystalline material.
  • the coated particle may be made by 1. providing a volume of the matrix that includes at least one chemical species having a moiety capable of forming a nonlamellar material upon reaction with a second moiety and 2. contacting the volume with a fluid containing at least one chemical species having the second moiety under nonlamellar solid material-forming conditions so as to react the first moiety with the second moiety, and subdividing the volume into particles by the application of energy to the volume, or performing this subdivision into particles before, and/or after, the chemical reaction.
  • the coated particle can be made by one of the following processes: providing a volume of the matrix that includes a material in solution in it that is capable of forming a nonlamellar material that is insoluble in the matrix and causing the aforesaid material to become insoluble in the matrix and subdividing the volume into particles by the application of energy to the volume; dispersing particles of said matrix into a fluid that includes at least one chemical species having a moiety capable of forming a nonlamellar material upon reaction or association with a second moiety and adding to said dispersion at least one chemical species having said second moiety to react said first moiety with said second moiety; dispersing particles of said matrix into a fluid that includes at least one chemical species having a moiety capable of forming a nonlamellar material upon reaction or association with a second moiety, adding to said dispersion at least one chemical species having said second moiety to react said first moiety with said second moiety, and subdividing the resulting material into particles by the application of energy to said material; dispers
  • Fig. 1 is a graphic representation, in vertical section, illustrating a coated particle of the present invention comprising an internal core comprising a 2 by 2 by 2 unit cell matrix and an exterior coating
  • Fig. 2 is a graphic representation, in section, illustrating a coated particle of the present invention
  • Fig. 3 is a scanning electron microscope micrograph of coated particles of the present invention.
  • Fig. 4 is a scanning electron microscope micrograph of other coated particles of the present invention.
  • Fig. 5 is a graph of the measured volume- weighted cumulative particle size distribution for coated particles of the present invention on a volume-weighted particle diameter versus cumulative particle size basis;
  • Fig. 6 is a graph of measured small-angle X-ray scattering intensity versus wave vector q of coated particles of the present invention
  • Fig. 7 is a graph of detector counts versus elution time in minutes for a control using high pressure liquid chromatography.
  • Fig. 8 is a graph of detector counts versus elution time in minutes for coated particles of the present invention using high pressure liquid chromatography.
  • Figure 9 A phase-contrast optical micrograph of PLGA-coated microparticles dispersed in water, showing the core-shell structure.
  • FIG. 10 On the left is a PLGA-coated cubic phase, made according to the instant invention, soaking in linalool, which is a non-solvent for PLGA but a solvent for the cubic phase. On the right, the same cubic phase was soaked in linalool under identical conditions, demonstrating that the cubic phase dissolves in the linalool when not coated.
  • Figure 11 A large (5 mm) particle of coated cubic phase in which the coating consists of amorphous trehalose, obtained by freeze-drying a dispersion of Arlatone G-based cubic phase in a trehalose solution.
  • a coated particle 1 used in the present invention comprises an internal core 10 and a coating 20 exterior to it (hereinafter "exterior coating 20").
  • the internal core 10 comprises a matrix consisting essentially of a nanostructured material selected from the group consisting of a. at least one nanostructured liquid phase, b. at least one nanostructured liquid crystalline phase and c. a combination of i. at least one nanostructured liquid phase and ii. at least one nanostructured liquid crystalline phase.
  • the interior could be a composition that yields one of these phases upon contact with water or other aqueous fluid.
  • the liquid phase material and the liquid crystalline phase material may either contain solvent (lyotropic) or not contain solvent (thermotropic).
  • the exterior coating 20 comprises a nonlamellar material.
  • the term "exterior coating” as used herein is intended to indicate that the coating 20 is exterior to the internal core 10 and is not intended to be limited to meaning that the exterior coating 20 is the most exterior coating of the coated particle 1.
  • a surfactant-rich layer is present at the outer surface of the non-lamellar exterior coating.
  • an antibody or other bioactive material will be adsorbed to, or extending out from, this non-lamellar exterior coating.
  • Nanostructured liquid phase and nanostructured liquid crystalline phase possess unique properties that are not only important in making possible the easy production of particles according to the present invention, but also yield highly desirable solubilization, stability, and presentation properties and other capabilities in the final coated particles of the present invention.
  • non-lamellar structures which exhibit bonding and/or packing rigidity that extends in all three dimensions are strongly preferred in the present invention over lamellar materials, due to the well-known physical and chemical limitations and instabilities of lamellar, and more generally layered, structures, as exemplified by, for example, (a) the instability (even when acquiescent) of emulsions which have droplets coated with lamellar liquid crystalline layers, (b) the chemical instability upon removal of guest molecules in certain Werner complexes, and (c) the dramatically inferior hardness and shear modulus for graphite as compared with diamond.
  • Coated particles 1 used in the present invention may be from 0.1 micron to 30 microns or above in mean caliper diameter, and preferably from about 0.2 micron to about 5 microns in mean caliper diameter. Macroscopic particles can be made as well, i.e., particles with sizes measured in millimeters or even larger, as exemplified in Examples 39 and 40; the ability to make particles of this larger size could open up applications of the present invention in, for example, depot delivery systems for sustained release upon implantation.
  • the coated particle 1 used may also be provided with a stabilizing layer on its exterior, i.e. outside the exterior coating 20 as desired, such as a polyelectrolyte or surfactant monolayer to prevent agglomeration of coated particles 1.
  • the coated particles 1 used in the present invention have application in a variety of modalities of use.
  • the coated particle 1 may, upon release of the exterior coating 20, absorb one or more materials from a selected environment, adsorb one or more materials from a selected environment or release one or more materials, such as active agents disposed in the matrix, into a selected environment, and/or target specific sites for the intended release or ad/absorption.
  • certain exterior coatings possessing porosity such as inclusion compounds and zeolites, do not require release in order to effect the absorption or release of a material of interest into or out of the matrix, and in some such cases very high selectivity can be obtained by the use of properly tuned pore characteristics.
  • a "coating" is composed of a material which behaves as a solid in the common sense, and in the engineering viewpoint, of the term
  • solid namely that it exhibits a rigidity and permanence that contrasts sharply with low- viscosity liquids, and thus represents a significant diffusional barrier to the passage of compounds across that material, in a way that is intuitively different from any protection that a low- viscosity liquid layer could provide.
  • amorphous material such as PMMA (Plexiglass) or ordinary glass-particles of which make up an everyday coating known as ceramic glaze-may technically be a liquid, for the purposes of simplifying nomenclature in the context of this invention these materials will be referred to as solids, as they would in ordinary life outside of the physics laboratory.
  • the matrix is a. thermodynamically stable b. nanostructured and c. a liquid phase or liquid crystalline phase or a combination thereof.
  • Nanostructured The terms "nanostructure” or"nanostructured” as used herein in the context of the structure of a material refer to materials the building blocks of which have a size that is on the order of nanometers (10 "9 meter) or tens of nanometers (10 x 10 "9 meter). Generally speaking, any material that contains domains or particles 1 to 100 nm (nanometers) across, or layers or filaments of that thickness, can be considered a nanostructured material.
  • nanostructured materials are crystalline materials in which the crystallite size is so small that one may not observe peaks in wide-angle x-ray diffraction and which some physicists may refer to as nanostructured materials: the nanostructured liquid and liquid crystalline phases that are defined herein are characterized by nanoscale domains which are clearly distiniguished from neighboring domains by large differences in local chemical composition, and do not include materials in which neighboring domains have essentially the same local chemical composition and differ only in lattice orientation.
  • 'domain' as used herein it is meant a spatial region which is characterized by a particular chemical makeup which is clearly distinguishable from that of neighboring domains: often such a domain is hydrophilic (hydrophobic) which contrasts with the hydrophobicity (hydrophilicity) of neighboring domains: in the context of this invention the characteristic size of these domains is in the nanometer range.
  • hydrophilic hydrophobic
  • hydrophobicity hydrophilicity
  • Nanostructured liquids and liquid crystals which provide the matrix of the internal cores 10 of the coated particles 1 in the present invention, possess unique collections of properties that are not only crucial in making possible the production of particles of the present invention, but also yield highly desirable solubilization, stability, and presentation properties and capabilities in the final coated particles.
  • the material in order that a material provide for ready dispersibility with one of the processes described herein, it is desirable for the material to be of very low solubility in water (otherwise it will tend to dissolve during the dispersing process, limiting dispersibility), yet, at the same time it should contain water - both for the purpose of solubilizing water-soluble reactants used in dispersing and for making possible the solubilization of a large range of active compounds.
  • the interior matrix should contain substantial concentrations of water or other polar solvent.
  • a great many (perhaps a majority) of the compounds listed as useful coatings in the present invention require reactants that are soluble only in polar solvents.
  • organic solvents for solubilization is in most cases inconsistent with the present matrices and/or with active biological compounds such as proteins (used in the present invention as actives or as targeting agents), and in any case is highly disfavored from regulatory, environmental, and health considerations.
  • Nanostructured liquid and liquid crystalline phases are synthetic or semisynthetic materials which adopt these solubilization characteristics, and provide pure, well- characterized, easily produced, and typically inexpensive matrices that also have the following desirable properties: a) versatility in chemical systems forming nanostructured liquid phases and nanostructured liquid crystalline phases, ranging from biological lipids that are ideal for biomolecules, to hardy fluorosurfactants, to glycolipids that bind bacteria, to surfactants with ionic or reactive groups, etc.
  • the desired properties of the nanostructured material of the internal core 10 derive from several related concepts regarding materials that can be described with respect to surfactants by use of the terms “polar,” “apolar,” “amphiphile,” “surfactant” and the “polar- apolar interface, and analogously with respect to block copolymer systems, as described below.
  • Polar polar compounds (such as water) and polar moieties (such as the charged head groups on ionic surfactants or on lipids) are water-loving or hydrophilic: "polar" and "hydrophilic" in the context of the present invention are essentially synonymous. In terms of solvents, water is not the only polar solvent. Others of importance in the context of the present Invention are: glycerol, ethylene glycol, formamide, N-methyl formamide,, dimethylformamide, ethylammonium nitrate, acetamide, N-methylacetamide, dimethylacetamide, N-methyl sydnone, and polyethylene glycol.
  • polyethylene glycol is actually a polymer, thereby illustrating the range of possibilities.
  • polyethvlene glycol is a liquid, and although PEG has not been extensively studied as a polar solvent in combination with surfactants, it has been found that PEG does form nanostructured liquid phases and liquid crystalline phases in combination with, for example, surfactants such as BRIJ-type surfactants, which are nonionic surfactants with PEG head groups ether-linked to alkane chains.
  • polar groups in hydrophilic and amphiphilic molecules including but not limited to polar solvents and surfactants
  • hydrophilic and amphiphilic molecules including but not limited to polar solvents and surfactants
  • polar groups are tabulated below, in the discussion of which polar groups are operative as surfactant head groups and which are not.
  • Apolar An apolar compound is a compound that has no dominant polar group.
  • Apolar (or hydrophobic, or alternatively, "lipophilic") compounds include not only the paraffinic/hydrocarbon / alkane chains of surfactants, but also modifications of them, such as perfluorinated alkanes, as well as other hydrophobic groups such as the fused-ring stracture in cholic acid as found in bile salt surfactants, or phenyl groups as form a portion of the apolar group in Triton-type surfactants, and oligomer and polymer chains that run the gamut from polyethylene (which represents a long alkane chain) to hydrophobic polymers such as hydrophobic polypeptide chains in novel peptide-based surfactants that have been investigated.
  • apolar compound will be lacking in polar groups, a tabulation of which is included herein, and will generally have an octanol-water partition coefficient greater than about 100, and usually greater than about 1,000.
  • Amphiphile an amphiphile can be defined as a compound that contains both a hydrophilic and a lipophilic group. See D. H. Everett. Pure and Applied Chemistry, vol. 31. no. 6, p. 611,1972. It is important to note that not every amphiphile is a surfactant. For example, butanol is an amphiphile, since the butyl group is lipophilic and the hydroxyl group hydrophilic, but it is not a surfactant since it does not satisfy the definition, given below. There exist a great many amphiphilic molecules possessing functional groups which are highly polar and hydrated to a measurable degree, yet which fail to display surfactant behavior. See R.
  • a surfactant is an amphiphile that possesses two additional properties. First, it significantly modifies the interfacial physics of the aqueous phase (at not only the air- water but also the oil-water and solid-water interfaces) at unusually low concentrations compared to nonsurfactants. Second, surfactant molecules associate reversibly with each other (and with numerous other molecules) to a highly exaggerated degree to form thermodynamically stable, macroscopically one-phase, solutions of aggregates or micelles. Micelles are typically composed of many surfactant molecules (10's to 1000's) and possess colloidal dimensions. See R.
  • Lipids and polar lipids in particular often are considered as surfactants for the purposes of discussion herein, although the term 'lipid' is normally used to indicate that they belong to a subclass of surfactants which have slightly different characteristics than compounds which are normally called surfactants in everyday discussion. Two characteristics which frequently, though not always, are possessed by lipids are first, they are often of biological origin, and second, they tend to be more soluble in oils and fats than in water.
  • lipids have extremely low solubilities in water, and thus the presence of a hydrophobic solvent may be necessary in order for the interfacial tension-reducing properties and reversible self- association to be most clearly evidenced, for lipids which are indeed surfactants.
  • a hydrophobic solvent may be necessary in order for the interfacial tension-reducing properties and reversible self- association to be most clearly evidenced, for lipids which are indeed surfactants.
  • such a compound will strongly reduce the interfacial tension between oil and water at low concentrations, even though extremely low solubility in water might make observation of surface tension reduction in the aqueous system difficult.
  • the addition of a hydrophobic solvent to a lipid- water system might make the determination of self-association into nanostructured liquid phases and nanostructured liquid crystalline phases a much simpler matter, whereas difficulties associated with high temperatures might make this difficult in the lipid-water system.
  • any amphiphile which at very low concentrations lowers interfacial tensions between water and hydrophobe, whether the hydrophobe be air or oil, and which exhibits reversible self-association into nanostractured micellar, inverted micellar, or bicontinuous morphologies in water or oil or both, is a surfactant.
  • the class of lipids simply includes a subclass consisting of surfactants which are of biological origin.
  • Polar-apolar interface In a surfactant molecule, one can find a dividing point (or in some cases two points, if there are polar groups at each end, or even more than two, as in Lipid A, which has seven acyl chains and thus seven dividing points per molecule), in the molecule that divide the polar part of the molecule from the apolar part.
  • the surfactant forms monolayer or bilayer films: in such a film, the locus of the dividing points of the molecules describes a surface that divides polar domains from apolar domains: this is called the "polar-apolar interface" or "polar-apolar dividing surface.”
  • polar-apolar interface or "polar-apolar dividing surface.”
  • this surface would be approximated by a sphere lying inside the outer surface of the micelle, with the polar groups of the surfactant molecules outside the surface and apolar chains inside it. Care should be taken not to confuse this microscopic interface with macroscopic interfaces separating two bulk phases that are seen by the naked eye.
  • Bicontinuous In a bicontinuous structure, the geometry is described by two distinct, multiply -connected, intertwined subspaces each of which is continuous in all tliree dimensions; thus, it is possible to traverse the entire span of this space in any direction even if the path is restricted to one or other of the two subspaces.
  • each of the subspaces In a bicontinuous structure, each of the subspaces is rich in one type of material or moiety, and the two subspaces are occupied by two such materials or moieties each of which extends throughout the space in all three dimensions.
  • Sponge, sandstone, apple, and many sinters are examples of relatively permanent though chaotic bicontinuous structures in the material realm.
  • one of the subspaces is occupied by a solid that is more or less deformable and the other subspace, though it may be referred to as void, is occupied by a fluid.
  • Certain lyotropic liquid crystalline states are also examples, one subspace being occupied by amphiphile molecules oriented and aggregated into sheet-like arrays that are ordered geometrically, the other subspace being occupied by solvent molecules.
  • Related liquid crystalline states that contain two incompatible kinds of solvent molecules, e.g. hydrocarbon and water, present a further possibility in which one subspace is rich in the first solvent, the other in the second, and the surface between lies within a multiply connected stratum rich in oriented surfactant molecules.
  • Certain equilibrium microemulsion phases that contain comparable amounts of hydrocarbon and water as well as amphiphilic surfactant may be chaotic bicontinuous structures, maintained in a permanent state of fluctuating disorder by thermal motions, for they give no evidence of geometric order but there is compelling evidence for multiple continuity.
  • Bicontinuous morphologies occur also in certain phase-segregated block copolymers. See Anderson. D.M., Davis. H.T., Nitsche. J.C.C. and Scriven. L.E. (1900) Advances in Chemical Physics, 77:337.
  • polar groups which are not operative as surfactant head groups - and thus, for example, an alkane chain linked to one of these polar groups would not be expected to form nanostructured liquid or liquid crystalline phases - are: aldehyde, ketone, carboxylic ester, carboxylic acid, isocyanate, amide, acyl cyanoguanidine, acvl guanyl urea, acyl biuret, N.N-dimethylamide, nitrosoalkane, nitroalkane, nitrate ester, nitrite ester, nitrone, nitrosamine, pyridine N-oxide, nitrile, isonitrile, amine borane, amine haloborane, sulfone, phosphine sulfide, arsine sulfide, sulfonamide, sulfonamide methylimine, alcohol (monofunctional
  • Some polar groups which are operative as surfactant head groups, and thus, for example, an alkane chain linked to one of these polar groups would be expected to form nanostructured liquid and liquid crystalline phases, are: a. Anionics: carboxylate (soap), sulfate, sulfamate, sulfonate, thiosulfate, sulf ⁇ nate, phosphate, phosphonate, phosphinate, nitroamide, tris(alkylsulfonyl)methide, xanthate; b. Cationics: ammonium, pyridinium, phosphonium, sulfonium, sulfoxonium; c.
  • Zwiterionics ammonio acetate, phosphoniopropane sulfonate, pyridinioethyl sulfate; d.
  • Semipolars amine oxide, phosphonyl, phosphine oxide, arsine oxide, sulfoxide, sulfoximine, sulfone diimine, ammonio amidate.
  • Laughlin also demonstrates that as a general rule, if the enthalpy of formation of a 1 : 1 association complex of a given polar group with phenol (a hydrogen bonding donor) is less than 5 kcal, then the polar group will not be operative as a surfactant head group.
  • a surfactant requires an apolar group, and again there are guidelines for an effective apolar group.
  • n is the number of carbons, then n must be at least 6 for surfactant association behavior to occur, although at least 8 or 10 is the usual case.
  • hydrocarbon polymers such as polypropyleneoxide (PPO) which serves as the hydrophobic block in a number of amphiphilic block copolymer surfactants of great importance, such as the Pluronic series of surfactants.
  • PPO polypropyleneoxide
  • hydrophobic groups such as the fused-ring stracture in the cholate soaps (bile salts)
  • cholate soaps bile salts
  • hydrophobic groups also serve as effective apolar groups, although such cases must generally be treated on a case by case basis in terms of determining whether a particular hydrophobic group will yield surfactant behavior.
  • relatively simple mean-field statistical theories are sufficient to predict when nanostructure liquid phase and liquid crystalline phase materials will occur and these are quite general over a wide range of block copolymers.
  • ⁇ is the FloryHuzuins interaction parameter between polymer blocks A and B
  • N is the total index of polymerization defined as the number of statistical units or monomer units in the polymer chain, consistently with the definition of the interaction parameter of the block copolymer
  • nanostructure liquid and liquid crystalline phases are expected when the product ⁇ N is greater than 10.5.
  • ordered nanostructured (liquid crystalline) phases can occur, including ever, bicontinuous cubic phases.
  • the nanostructured liquid phases of utility are of utility.
  • the nanostructured liquid phase material suitable for the nanostructured material of the matrix may be a. a nanostructured LI phase material, b. a nanostructured L2 phase material. c. a nanostructured microemulsion or d. a nanostructured L3 phase material.
  • the nanostructured liquid phases are characterized by domain structures composed of domains of at least a first type and a second type (and in some cases three or even more types) having the following properties: a) the chemical moieties in the first type domains are incompatible with those in the second type domains (and in general, each pair of different domain types are mutually incompatible) such that they do not mix under the given conditions but rather remain as separate domains: for example, the first type domains could be composed substantially of polar moieties such as water and lipid head groups, while the second type domains could be composed substantially of apolar moieties such as hydrocarbon chains: or, first type domains could be polystyrene-rich, while second type domains are polyisoprene-rich and third type domains are polyvinylpyrrolidone-rich; b) the atomic ordering within each domain is liquid-like rather than solid-like, i.e., it lacks lattice-ordering of the atoms; this would be evidenced by an absence of
  • LI phase In an LI phase that occurs in a system based on surfactants, the curvature of the polar-apolar interface is toward the apolar (non-polar) regions, generally resulting in particles — normal micelles — that exist in a water-continuous medium. (Here "water” refers to any polar solvent). When these micelles transform from spherical to cylindrical as conditions or compositions change, they can start to fuse together and bicontinuity can result. In addition to the water continuity, the hydrophobic domains can connect up to form a sample-spanning network: this can still be an LI phase. In addition, there are examples of LI phases that show evidence of having no microstructure whatsoever.
  • thermodynamics does not dictate a phase boundary between a structureless solution and a nanostractured phase. This is, of course, in contrast with the case of a transition between a phase having long-range order (a liquid crystal or a crystal) and a phase lacking long-range order (a liquid), where a phase boundary is required by thermodynamics.
  • the terms 'polar' and apolar may not apply, but in any case there are two (or in some cases more) domain types; we make the convention that the curvature of the A/B interface is toward A domains, so that a typical nanostructure would consist of particles, often sphere-like, of domain type A located in a continuum of B domains.
  • the volume fraction of polystyrene blocks is very low, say 10%, then the usual microstructure will be polystyrene-rich spheres in a continuous polyisoprene matrix. Contrariwise, polyisoprene-rich spheres in a polystyrene-continuous matrix would be the likely stracture for a 10% polyisoprene PS-PI diblock.
  • a compound is expected to be a true surfactant, then the compound is expected to form nanostructured phases in water.
  • nanostractured phases are also expected to form normally, incorporating at least a portion of the hydrophobe present.
  • a non-surfactant amphiphile is added to such a system, and in particular an amphiphilic organic solvent such as a short-chained alcohol, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide, etc.
  • an amphiphilic organic solvent such as a short-chained alcohol, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide, etc.
  • Laughlin also goes on to discuss a number of criteria based on physical observations.
  • One well-known criteria is the critical micelle concentration (CMC) which is observed in surface tension measurements. If the surface tension of an aqueous solution of the compound in question is plotted as a function of the concentration, then at very low concentrations, the surface tension will be seen to drop off sharply if the added compound is indeed a surfactant. Then, at a particular concentration known as the CMC, a sharp break will occur in this plot as the slope of the line decreases drastically, to the right of the CMC, so that the surface tension decreases much less with added surfactant. The reason is that above the CMC, added surfactant goes almost entirely into the creation of micelles rather than to the air- water interface.
  • CMC critical micelle concentration
  • a second criterion tabulated by Laughlin is the liquid crystal criterion: if the compound forms liquid crystals at high concentrations, then it must be a surfactant and will form liquid crystalline phases at concentrations lower than those at which the occur.
  • the LI phase is usually found at concentrations of surfactant just lower than those that form normal hexagonal, or in some cases normal non-bicontinuous cubic phase liquid crystals.
  • the LI phase is optically isotropic in the absence of flow. It does not give a splitting in the 2 H NMR bandshape with deuterated surfactant.
  • Small-angle x-ray scattering does not give sharp Bragg peaks in the nanometer range (nor any range), of course.
  • analysis of the entire curve by several methods from the literature can give the length scale of the nanostructure.
  • the apparent radius of gyration one plots intensity, versus the square of the wave number, and takes the slope to deduce R (the so- called Guinier plot).
  • the radius of gyration is then related to the dimensions of the micellar units by standard well-known formulae. This will fall in the range of nanometers.
  • a bicontinuous domain structure is represented as made up of units which although seemingly 'particles' are in reality only building blocks for construction of a model bicontinuous geometry.
  • the shear modulus of a block copolymer-based micellar phase is determined largely by that of the polymer block forming the continuous domains, polymer B in our convention.
  • a PS-PI diblock which is 10% PS
  • the shear modulus would be close to that of pure polyisoprene with only a slight increase due to the presence of the PS micelles.
  • the elastomeric PI micelles can provide a shock-absorbing component which can improve the fracture characteristics over those of pure, glassy polystyrene.
  • L2 phase This phase is the same as the LI phase except that the roles of the polar region and the apolar region are reversed: the curvature of the polar-apolar interface is toward the polar domains, the interior of the micelles (if they exist) is water and/or other polar moieties, and the apolar domains (typically alkane chains of a lipid) form a continuous matrix ⁇ although it is possible for the polar domains also to connect up to form a bicontinuous L2 phase. As above, this phase can be either nanostractured or structureless.
  • L2 phases are generally more prominent when the HLB is low, for example with ethoxylated alcohol surfactants having a small number of ethylene oxide groups (usually 5 or less, with typical alkyl chain lengths), or with double-chained surfactants. In terms of phase behavior, they generally occur at higher surfactant concentrations than even the reversed liquid crystalline phases: a location that is very common is for the L2 phase to border the reversed hexagonal phase at higher surfactant concentrations.
  • LI phases which are not bicontinuous it is the water self-diffusion which is veiy low, and measurement of the diffusion coefficient (by pulsed-gradient NMR, for example) should give a number on the order of 10 " ⁇ m 2 /sec or less.
  • a Hosemann plot will give the size of the reversed micelles, which will essentially be the water domain size.
  • a microemulsion may be defined as a thermodynamically stable, low viscosity, optically isotropic liquid phase containing oil (apolar liquid), water (polar liquid), and surfactant. See also Danielsson. I. and Lindman. B. (1981) Colloids and Surfaces, 3:391.
  • Thermodynamically stable liquid mixtures of surfactant, water and oil are usually referred to as microemulsions. While being macroscopically homogeneous, they are structured on a microscopic length scale (10-1,000 Angstrom) into aqueous and oleic microdomains separated by a surfactant-rich film. See Skurtveit, R. and Olsson, U. (1991) J. Phys. Chem.
  • a key defining feature of a microemulsion is that it contains an "oil” (apolar solvent or liquid), in addition to water and surfactant; it is always microstructured by definition.
  • an organic solvent capable of co-solubilizing oil and water such as ethanol, THF, dioxane, DMF, acetonitrile, dimethylsulfoxide, and a few others
  • a clear, single-phase liquid containing water and surfactant must be a microemulsion, and one can safely conclude on that basis alone that the phase is nanostractured.
  • a microemulsion can also be an LI or L2 phase especially, if it contains well-defined micelles; however, if it is an LI phase then the micelles are necessarily swollen with oil.
  • the microemulsion is a nanostructured liquid phase. If a liquid with "oil,” water and surfactant has a characteristic domain size larger than the nanometer range, that is, in the micron range, then it is no longer a microemulsion but rather a "miniemulsion” or plain emulsion; both of the latter are non-equilibrium.
  • microemulsion was introduced, despite the fact that LI and L2 phases can contain oil, and can even be bicontinuous, because it is fairly common for three-component oil-water- surfactant/lipid systems to evolve continuously from water-continuous to bicontinuous to oil- continuous with no phase boundaries in between. In this case, it does not make sense to try to set a dividing point between the "LI " and "L2" regions of the phase diagram; so instead, one just refers to the whole region as "microemulsion" ⁇ recognizing that at the high-water- content end of this region the stracture is that of an oil-swollen LI phase, and at the high-oil- content end of this region the structure is that of an L2 phase.
  • microemulsions In terms of Venn diagrams, there are overlaps between microemulsions and LI and L2 phases, though not between LI and L2 phases).
  • the microstructure of microemulsions is quite generally describable in terms of a monolayer film of surfactant that divides oil-rich domains from water-rich domains. This surfactant/lipid-rich dividing film can enclose to form micelles, or connect up into a network stracture to form a bicontinuous microemulsion.
  • an emulsion is not a nanostructured liquid, as the tem is applied herein.
  • the characteristic length scale in an emulsion which essentially is the average size of an emulsion droplet, is generally much larger than the characteristic length scale in a nanostructured liquid, and falls in the range of microns instead of nanometers. While recent efforts to produce emulsions with submicron droplet sizes have given rise to smaller droplet emulsions and to the advent of the term "miniemulsion", there remain crucial differences which exclude emulsions and miniemulsions from the realm of nanostructured liquid phases as applied herein.
  • nanostractured liquid phases described herein exist at thermodynamic equilibrium, in contrast to emulsions which are not equilibrium phases but only metastable materials.
  • a nanostructured liquid which is acquiescent and fully equilibrated is optically transparent, whereas an emulsion is generally opaque —ordinary milk is an emulsion, for example.
  • Friberg for the stracture of an ordinary emulsion to be true, and this is generally recognized in the field, then the distinction at the molecular scale can be seen to be dramatic.
  • emulsion droplets can generally be seen to be stabilized by interfacial films which upon microscopic examination typically prove to be films of nanostructured liquid crystalline phase material; thus, these emulsions have a hierarchical structure in which a nanostructured phase plays the role of a stabilizing layer between the main building blocks, which are the emulsion droplets and the continuous medium.
  • nanostructured instead of “microstructured” is based on the more precise and restricted nature of the term “nanostructured” and its exclusion of other liquid phases which fall into an entirely different realm, such as emulsions.
  • the time-tested way to demonstrate bicontinuity is to use pulsed- gradient NMR and measure the effective self-diffusion coefficients of both oil and water separately; generally it is best to measure also the self-diffusion of the surfactant.
  • Electrical conductivity can also be used to establish water continuity, although this is prone to problems associated with "hopping" processes. Fluoresence quenching has also been used for continuity determination.
  • Small-angle neutron and x-ray scattering analyses have been used to examine bicontinuity.
  • L3 phase L2-phase regions in phase diagrams sometimes exhibit "tongues” sticking out of them: long, thin protrusions unlike the normal appearance of a simple L2 phase region. This sometimes appears also with some LI regions, as described below.
  • L2 phase the surfactant film is generally in the form of a monolayer with oil (apolar solvent) on one side and water (polar solvent) on the other.
  • polar solvent polar solvent
  • the L3 phase is generally considered to be bicontinuous and, in fact, it shares another property with cubic phases: there are two distinct aqueous networks interwoven but separated by the bilayer. So, the L3 phase is really very similar to the cubic phase but lacking the long-range order of the cubic phase.
  • L3 phases stemming from L2 phases and those stemming from LI phases are given different names. "L3 phase” is used for those associated to L2 phases, and "L3 * phase” for those associated to LI phases. Determination of the nanostructured L3 phase. Determination of the L3 phase in distinction to the other liquid phases discussed herein can be a sophisticated problem, requiring the combination of several analyses. The most important of these techniques are now discussed.
  • the L3 phase can have the interesting property that it can exhibit flow birefringence. Often this is associated with fairly high viscosity, viscosity that can be considerably higher than that observed in the LI and L2 phases, and comparable to or higher than that in the lamellar phase. These properties are of course a result of the continuous bilayer film, which places large constraints on the topology and the geometry of the nanostructure.
  • shear can result in the cooperative deformation (and resulting alignment) of large portions of the bilayer film, in contrast with, for example, a micellar LI phase where independent micellar units can simply displace with shear, and in any case a monolayer is generally much more deformable under shear than a bilayer.
  • Support for this interpretation comes from the fact that the viscosity of L3 phases is typically a linear function of the volume fraction of surfactant. Snabre. P. and Porte. G. (1990) Europhys. Len. 13:641.
  • Sophisticated light, neutron, and x-ray scattering methodologies have been developed for determination of nanostructured L3 phases. Safinya, C.R., Roux, D., Smith,.
  • L3 phase is often obtained by addition of a small amount (a few percent) of oil or other compound to a lamellar or bicontinuous cubic phase, or small increase of temperature to these same phases. Since these liquid crystalline phases are easy to demonstrate to be nanostructured (Bragg peaks in X-ray, in particular), one can be confident that the liquid phase is also nanostractured when it is so close in composition to a liquid crystalline phase.
  • the nanostructured liquid crystalline phase material may be a. a nanostructured normal or reversed cubic phase material, b. a nanostractured normal or reversed hexagonal phase material, c. a nanostructured normal or reversed intermediate phase material or d. a nanostructured lamellar phase material.
  • the nanostructured liquid crystalline phases are characterized by domain structures composed of domains of at least a first type and a second type (and in some cases three or even more types of domains) having the following properties: a) the chemical moieties in the first type domains are incompatible with those in the second type domains (and in general, each pair of different domain types are mutually incompatible) such that they do not mix under the given conditions but rather remain as separate domains (for example, the first type domains could be composed substantially of polar moieties such as water and lipid head groups, while the second type domains could be composed substantially of apolar moieties such as hydrocarbon chains: or, first type domains could be polystyrene-rich, while second type domains are polyisoprene-rich, and third type domains are polyvinylpyrrolidone-rich); b) the atomic ordering within each domain is liquid-like rather than solid-like, lacking lattice-ordering of the atoms; (this would be evidenced by an absence of sharp
  • Lamellar phase The lamellar phase is characterized by:
  • the Maltese cross is a supeiposition of two dark bands (interference fringes) roughly perpendicular to each other, over a roughly circular patch of light (birefringence), forming a distinctive pattern reminiscent of the WWI German military symbol.
  • the variations on this texture, as well as its source, is thoroughly described in J. Bellare, Ph.D. Thesis, Univ. of Minnesota, 1987.
  • the "mosaic" texture can be envisioned as the result of tightly packing together a dense array of deformed Maltese crosses, yielding dark and bright patches randomly quilted together.
  • the "oily streaks" pattern is typically seen when the (low viscosity) lamellar phase flows between glass and coverslip; in this pattern, long curved lines are seen, upon close inspection under magnification 400x), to be composed of tiny striations which run roughly perpendicular to the line of the curve, as ties make up a railroad track (to be contrasted with the hexagonal texture discussion below).
  • the lamellar phase will align with its optic axis parallel to the line of sight in the microscope, resulting in a disappearance of the birefringence.
  • Viscosity is low enough so that the material flows (e.g. when a tube containing the phase is tipped upside down),
  • the self-diffusion rates of all components are high comparable to their values in bulk ⁇ e.g., the effective self-diffusion coefficient of water in the lamellar phase is comparable to that in pure water. Since the surfactants that form liquid crystals are usually not liquid at ambient temperatures, the reference point for the self-diffusion coefficient of the surfactant is not clear-cut; and, in fact, the effective (measured) self-diffusion coefficient of the surfactant in the lamellar phase is often taken to be the reference point for interpreting measurements in other phases.
  • the lamellar phase generally occurs at high surfactant concentrations in single-tailed surfactant / water systems, typically above 70% surfactant: in double-tailed surfactants, it often occurs at lower concentrations, often extending well below 50%). It generally extends to considerably higher temperatures than do any other liquid crystalline phases that happen to occur in the phase diagram.
  • Shear modulus is generally lower than other liquid crystalline phases in the same system.
  • the normal hexagonal phase is characterized by:
  • Small-angle x-ray shows peaks indexing as 1:73:2:77:3 . . . . in general, + hk - k 2 ), where h and k are integers ⁇ the Miller indices of the two-dimensional symmetry group,
  • phase generally transparent when fully equilibrated, and thus often considerably clearer than any nearby lamellar phase.
  • Viscosity is moderate, more viscous than the lamellar phase but far less viscous than typical cubic phases (which have viscosities in the millions of centipoise).
  • the self-diffusion coefficient of the surfactant is slow compared to that in the lamellar phase: that of water is comparable to that in bulk water.
  • the H NMR bandshape using deuterated surfactant shows a splitting, which is one-half the splitting observed for the lamellar phase.
  • the normal hexagonal phase generally occurs at moderate surfactant concentrations in single-tailed surfactant water systems, typically on the order of 50% surfactant. Usually the normal hexagonal phase region is adjacent to the micellar (LI) phase region, although non-bicontinuous cubic phases can sometimes occur in between. In double-tailed surfactants, it generally does not occur at all in the binary surfactant-water system.
  • the terms "normal” and “reversed” do not generally apply (although in the case where one block is polar and the other apolar, these qualifiers could be applied in principle).
  • the shear modulus in such a hexagonal phase is generally higher than a lamellar phase and lower a bicontinuous cubic phase, in the same system.
  • the hexagonal phases generally occurs at volume fractions of the two blocks on the order of 35:65.
  • two hexagonal phases will straddle the lamellar phase with, in each case, the minority component being inside the cylinders (this description replacing the 'normal/reversed' nomenclature of surfactant systems).
  • Reversed hexagonal phase In surfactant- water systems, the identification of the reversed hexagonal phase differs from the above identification of the normal hexagonal phase in only two respects:
  • the viscosity of the reversed hexagonal phase is generally quite high, higher than a typical normal hexagonal phase, and approaching that of a reversed cubic phase.
  • the reversed hexagonal phase generally occurs at high surfactant concentrations in double-tailed surfactant / water systems, often extending to, or close to, 100% surfactant.
  • the reversed hexagonal phase region is adjacent to the lamellar phase region which occurs at lower surfactant concentration, although bicontinuous reversed cubic phases often occur in between.
  • the reversed hexagonal phase does appear, somewhat surprisingly, in a number of binary systems with single-tailed surfactants, such as those of many monoglycerides (include glycerol monooleate), and a number of nonionic PEG-based surfactants with low HLB.
  • Normal bicontinuous cubic phase The normal bicontinuous cubic phase is characterized by:
  • Small-angle x-ray shows peaks indexing to a three-dimensional space group with a cubic aspect.
  • the most commonly encountered space groups, along with their indexings are: la3d (#230), with indexing 76:78:714:4... Pn3m (#224), with indexing 72:73:2:76:78: and lm3m (#229), with indexing 72:74:76:78:710...
  • phase is generally transparent when fully equilibrated, and thus often considerably clearer than any nearby lamellar phase.
  • the phase is non-birefringent, and therefore there are no optical textures.
  • Viscosity is high, much more viscous than the lamellar phase and even more viscous than typical normal hexagonal phases. Most cubic phase have viscosities in the millions of centipoise. 2. No splitting is observed in the NMR bandshape, only a single peak, corresponding to isotropic motion.
  • the no ⁇ nal bicontinuous cubic phase generally occurs at fairly high surfactant concentrations in single-tailed surfactant / water systems typically on the order of 70%> surfactant with ionic surfactants.
  • the normal bicontinuous cubic phase region is between lamellar and normal hexagonal phase regions, which along with its high viscosity and non-birefringence make its determination fairly simple.
  • double-tailed surfactants it generally does not occur at all in the binary surfactant- water system.
  • bicontinuous cubic phases in single-component block copolymer systems, the terms "normal” and “reversed” do not generally apply (although in the case where one block is polar and the other apolar, these qualifiers could be applied in principle).
  • the shear modulus in such a bicontinuous cubic phase is generally much higher than a lamellar phase, and significantly than a hexagonal phase in the same system.
  • the bicontinuous cubic phases In terms of phase behavior, the bicontinuous cubic phases generally occur at volume fractions of the two blocks on the order of 26:74.
  • two bicontinuous cubic phases will straddle the lamellar phase with, in each case, the minority component being inside the cylinders (this description replacing the 'normal/reversed' nomenclature of surfactant systems), and hexagonal phases straddling the cubic-lamellar-cubic progression.
  • Reversed bicontinuous cubic phase is characterized by: In surfactant- water systems, the identification of the reversed bicontinuous cubic phase differs from the above identification of the normal bicontinuous cubic phase in only one respect. In terms of phase behavior, the reversed bicontinuous cubic phase is found between the lamellar phase and the reversed hexagonal phase, whereas the normal is found between the lamellar and normal hexagonal phases: one must therefore make reference to the discussion above for distinguishing normal hexagonal from reversed hexagonal. A good rule is that if the cubic phase lies to higher water concentrations than the lamellar phase, then it is normal, whereas if it lies to higher surfactant concentrations than the lamellar then it is reversed.
  • the reversed cubic phase generally occurs at high surfactant concentrations in double-tailed surfactant / water systems, although this is often complicated by the fact that the reversed cubic phase may only be found in the presence of added hydrophobe ("oil") or amphiphile.
  • the reversed bicontinuous cubic phase does appear in a number of binary systems with single-tailed surfactants such as those of many monoglycerides (include glycerol monooleate) and a number of nonionic PEG-based surfactants with low HLB.
  • Small-angle x-ray shows peaks indexing to a three-dimensional space group with a cubic aspect.
  • the most commonly encountered space group in surfactant systems is Pm3n (#223) with indexing 72:74:75: ....
  • the commonly observed space group is Im3m, corresponding to body-centered sphere-packings with indexing 72 :74:76: 78: .... 2.
  • the phase is generally transparent when fully equilibrated, and thus often considerably clearer than any associated lamellar phase.
  • Viscosity is high, much more viscous than the lamellar phase and even more viscous than typical normal hexagonal phases. Most cubic phase have viscosities in the millions of centipoise, whether discrete or bicontinuous.
  • the normal discrete cubic phase generally occurs at fairly low surfactant concentrations in single-tailed surfactant water systems, typically on the order of 40%> surfactant with ionic surfactants.
  • the normal discrete cubic phase region is between normal micellar and normal hexagonal phase regions, which along with its high viscosity and non-birefringence make its determination fairly simple.
  • double-tailed surfactants it generally does not occur at all in the binary surfactant -water system.
  • the terms "normal” and "reversed” do not generally apply (although in the case where one block is polar and the other apolar, these qualifiers could be applied in principle).
  • the shear modulus in such a discrete cubic phase is generally dependent almost entirely on the shear modulus of the polymer that forms the blocks in the continuous phase.
  • the discrete cubic phases generally occur at very low volume fractions of one or other of the two blocks, on the order of 20%> or less.
  • Reversed discrete cubic phase The reversed discrete cubic phase is characterized by:
  • the reversed discrete cubic phase is found between the lamellar phase and the reversed hexagonal phase, whereas the normal is found between the lamellar and normal hexagonal phases: one must therefore make reference to the discussion above for distinguishing normal hexagonal from reversed hexagonal.
  • a good rule is that if the cubic phase lies to higher water concentrations than the lamellar phase, then it is normal, whereas if it lies to higher surfactant concentrations than the lamellar then it is reversed.
  • the reversed cubic phase generally occurs at high surfactant concentrations in double-tailed surfactant / water systems, although this is often complicated by the fact that the reversed cubic phase may only be found in the presence of added hydrophobe ('oil') or amphiphile.
  • the reversed discrete cubic phase does appear in a number of binary systems with single-tailed surfactants, such as those of many monoglycerides (include glycerol monooleate), and a number of nonionic PEG-based surfactants with low HLB. 2.
  • the space group observed is usually Fd3m. #227. 3.
  • the self-diffusion of the water is very low, while that of any hydrophobe present is high; that of the surfactant is generally fairly high, comparable to that in the lamellar phase.
  • the distinction between 'normal' and 'reversed' discrete cubic phases makes sense only in surfactant systems, and generally not in single-component block copolymer discrete cubic phases.
  • Intermediate phases The intermediate phase is characterized by:
  • Normal int(l) phases occur at lower surfactant concentration than the normal bicontinuous cubic phase, adjacent to the hexagonal phase. Viscosity is generally low or moderately low, no higher than that of the normal hexagonal phase.
  • the phase is birefringent, with textures typically similar to those of the hexagonal phase. Self-diffusion of the components is very similar to those in the hexagonal phase. Small-angle x-ray shows a lower-symmetry space group than the cubic phases, typically monoclinic. Fairly sophisticated NMR bandshape and SAXS analyses can be used to distinguish this phase from the normal hexagonal phase. See Henriksson, U., Blackmore, E. S., Tiddy, GJ.T. and Soderman, 0. (1992) J. Phys. Chem.
  • bandshape splittings will be intermediate between those of hexagonal and the zero splitting of the isotropic phase, which provides good evidence of an intermediate phase.
  • Normal int 2 is found at higher concentrations than the normal bicontinuous cubic phase, adjacent to the lamellar phase. These bear close resemblance, both in terms of property and probably also in terms of structure, to the normal bicontinuous cubic phases, except that they are birefringent and show differences in NMR bandshape and SAXS analyses.
  • Optical textures are somewhat unusual, in some cases resembling lamellar textures and in some resembling hexagonal, but these can be considerably coarser than either of the more common phases.
  • the space group is of lower symmetry, typically rhombohedral or tetragonal, requiring two unit cell parameters for characterization and making SAXS analysis difficult.
  • SAXS analysis difficult.
  • the squares of the d-spacing ratios cannot be fit to a simple integral scheme, then an intermediate phase stracture is suspect.
  • Reversed int(2) is found at lower concentrations than the reversed bicontinuous cubic phase, adjacent to the lamellar phase. These are birefringent and show unusual in NMR bandshape and SAXS analyses.
  • the space group is of lower symmetry, typically rhombohedral or tetragonal, requiring two unit cell parameters for characterization and making SAXS analysis difficult.
  • SAXS analysis difficult, though the presence of Bragg peaks in the SAXS spectrum which do not index to a cubic or hexagonal lattice (which have only one lattice parameter) is, together with optical birefringence, indication of an intermediate phase.
  • the nanostructured liquid phase material or the nanostructured liquid crystalline phase material or the combination be one that is in equilibrium with water (polar solvent) or, more precisely, with a dilute aqueous solution.
  • the foregoing nanostructured material need not be one that is in equilibrium with water.
  • the liquid phases that can be in equilibrium with water are:
  • L2 phase (a.k.a. reversed micelles), microemulsion, and
  • L3 phase (but not the L3* phase).
  • the phases that can be in equilibrium with water are preferred from the point of view of making coated particles of the present invention.
  • the interior phase has the additional property that it is in equilibrium with excess aqueous solution during formation of the particles, then concerns of phase transformation are minimized.
  • the concerns of phase changes are likewise minimized, and in some applications this may be advantageous.
  • the nanostractured liquid phase material may be formed from: a. a polar solvent and a surfactant or b. a polar solvent, a surfactant and an amphiphile or hydrophobe or c. a block copolymer or d. a block copolymer and a solvent.
  • the nanostructured liquid crystalline phase material may be formed from: a. a polar solvent and a surfactant. b. a polar solvent, a surfactant and an amphiphile or hydrophobe, or c. a block copolymer or d. a block copolymer and a solvent.
  • Suitable surfactants include those compounds which contain two chemical moieties, one being an operative polar group chosen from those described in that discussion of polar groups, and the other being an operative apolar group chosen from those described in that discussion of apolar groups.
  • Surfactants of utility. Suitable surfactants or block copolymer components (or mixtures thereof) may include: a. cationic surfactant b. anionic surfactant c. semipolar surfactant d. zwitterionic surfactant i . in particular, a phospholipid ii .
  • lipid mixture containing phospholipids designed to match the physico-chemical characteristics of a biomembrane e. monoglyceride f. PEGylated surfactant g. one of the above but with aromatic ring h. block copolymer i. with both blocks hydrophobic, but mutually immiscible ii. with both blocks hydrophilic, but mutually immiscible, iii. with one block hydrophilic and the other hydrophobic, i.e., amphiphilic) i. a mixture of two or more of the above.
  • Suitable lipids include phospholipids (such as phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, or sphingomyelin), or glycolipids (such as MGDG, diacylglucopyranosyl glycerols, and Lipid A).
  • phospholipids such as phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, or sphingomyelin
  • glycolipids such as MGDG, diacylglucopyranosyl glycerols, and Lipid A).
  • Suitable lipids are phospholipids (including phosphatidylcholines, phosphatidylinositols, phosphatidylglycerols, phosphatidic acids, phosphatidylserines, phosphatidylethanolamines, etc.), sphingolipids (including spliingomyelins), glycolipids (such as galactolipids such as MGDG and DGDG, diacylglucopyranosyl glycerols, and Lipid A), salts of cholic acids and related acids such as deoxycholic acid, glycocholic acid, taurocholic acid, etc., gentiobiosyls, isoprenoids, ceramides, plasmologens, cerebrosides (including sulphatides), gangliosides, cyclopentatriol lipids, dimethylaminopropane lipids, and lysolecithins and other lysolipids which
  • surfactants include anionic, cationic, zwittenionic, semipolar, PEGylated, amine oxide and aminolipids.
  • Preferred surfactants are: anionic — sodium oleate, sodium dodecyl sulfate, sodium diethylhexyl sulfosuccinate, sodium dimethylhexyl sulfosuccinate, sodium di-2-ethylacetate, sodium 2- ethylhexyl sulfate, sodium undecane-3 -sulfate, sodium ethylphenylundecanoate, carboxylate soaps of the form IC n , where the chain length n is between 8 and 20 and I is a monovalent counterion such as lithium, sodium, potassium, rubidium, etc., cationic ⁇ dimethylammonium and trimethylammonium surfactants of chain length from 8 to 20 and with chloride, bromide or sulfate counterion, myristyl
  • Preferred surfactants which are FDA-approved as injectables include benzalkonium chloride, sodium deoxycholate, myristyl-gamma-picolinium chloride, Poloxamer 188, polyoxyl castor oil and related PEGylated castor oil derivatives such as Cremophor EL, Arlatone G, sorbitan monopalmitate, Pluronic 123, and sodium 2-ethylhexanoic acid.
  • low-toxicity surfactants and lipids which are of at least relatively low solubility in water, that are preferred for the present invention for products intended for a number of routes of administration, include: acetylated monoglycerides, aluminum monostearate, ascorbyl palmitate free acid and divalent salts, calcium stearoyl lactylate, ceteth-2, choleth, deoxycholic acid and divalent salts, dimethyldioctadecylammonium bentonite, docusate calcium, glyceryl stearate, stearamidoethyl diethylamine, ammoniated glycyrrhizin, lanolin nonionic derivatives, lauric myristic diethanolamide, magnesium stearate, methyl gluceth-120 dioleate, monoglyceride citrate, octoxynol-1, oleth-2, oleth-5, peg vegetable oil, peglicol-5- o
  • Suitable block copolymers are those composed of two or more mutually immiscible blocks from the following classes of polymers: polydienes, polyallenes, polyacrylics and polymethacrylics (including polyacrylic acids, polymethacrylic acids, polyacrylates, polymefhacrylates, polydisubstituted esters, polyacrylamides, polymethacrylamides, etc.), polyvinyl ethers, polyvinyl alcohols, polyacetals, polyvinyl ketones, polyvinylhalides, polyvinyl nitriles, polyvinyl esters, polystyrenes, polyphenylenes, polyoxides, polycarbonates, polyesters, polyanhydrides, polyurethanes, polysulfonates, polysiloxane, polysulfides, polysulfones, polyamides, polyhydrazides, polyureas, polycarbodiimides, polyphosphazenes, polysilanes, polysilaza
  • Preferred polymer blocks are polyethylene oxide, polypropylene oxide, polybutadiene, polyisoprene, polychlorobutadiene, polyacetylene, polyacrylic acid and its salts, polymethacrylic acid and its salts, polyitaconic acid and its salts, polymethylacrylate, polvethylacrylate, polybutylacrylate, polymethylmethacrylate, polypropylmethacrylate, poly-N-vinyl carbazole, polyacrylamide, polyisopropylacrylamide, polymethacrylamide, polyacrylonitrile, polyvinyl acetate, polyvinyl caprylate, polystyrene, poly-alpha-mefhylstyrene, polystyrene sulfonic acid and its salts, polybromostyrene, polybutyleneoxide, polyacrolein, polydimethylsiloxane, polyvinyl pyridine, polyvinyl pyrrolidone, poly
  • block copolymers are polystyrene-b-butadiene, polystyrene-b-isoprene, polystyrene- b-styrenesulfonic acid, polyethyleneoxide-b-propyleneoxide, polystyrene-b-dimethylsiloxane, polyethyleneoxide-b-styrene, polynorborene-b-5-((trimethylsiloxy)methyl)norbomene, polyacetylene-b-5((trimethylsiloxv)methyl)norbomene, polyacetylene-b-norbomene, polyethyleneoxide-b-norbornene, polybutyleneoxide-b-efhyleneoxide, polyethyleneoxide-b- siloxane, and the triblock copolymer polyisoprene-b-styrene-b-2-vinylpyridine.
  • Third component hydrophobe or non-surfact
  • This component can serve multiple functions in a matrix of the present invention, including modulation of phase behavior, tuning of poresize, solubilization of an active, modulation of release properties, etc.
  • Choices appropriate for this invention include: a. alkane or alkene, other long-chain aliphatic compound b. aromatic compound, such as toluene c. long-chain alcohol d. a glyceride (diglyceride or triglyceride) e. an acylated sorbitan, such as a sorbitan triester (e.g., sorbitan trioleate), or sesquioleate, or mixture of sorbitans with different numbers of acyl chains between 2 and 6 f.
  • a glyceride diglyceride or triglyceride
  • an acylated sorbitan such as a sorbitan triester (e.g., sorbitan trioleate), or sesquioleate, or mixture of sorbitans with
  • hydrophobes or non-surfactant amphiphiles include: n- alkane, where n is from 6 to 20, including branched, unsaturated, and substituted variants (alkenes, chloroalkanes, etc.), cholesterol and related compounds, terpenes, diterpenes, triterpenes, fatty alcohols, fatty acids, aromatics, cyclohexanes, bicyclics such as naphthalenes and naphthol, quinolines and benzoquinolines, etc., tricyclics such as carbazole, phenothiazine, etc., pigments, chlorophyll, sterols, triglycerides, sucrose fatty acid esters (such as OlestraTM), natural oil extracts (such as clove oil, anise oil, cinnamon oil, coriander oil, eucalycarbamate, etc.
  • Especially preferred third components are: anise oil, clove oil, coriander oil, cinnamon oil, eucalyptus oil, peppermint oil, beeswax, benzoin, benzyl alcohol, benzyl benzoate, naphthol, capsaicin, cetearyl alcohol, cetyl alcohol, cinnamaldehyde, cocoa butter, coconut oil, cottonseed oil (hydrogenated), cyclohexane, cyclomethicone, dibutyl phthalate, dibutyl sebacate, diocryl phthalate, DIP AC, ethyl phthalate, ethyl vanillin, eugenol, fumaric acid, glyceryl distearate, menthol, methyl acrylate, methyl salicylate, myristyl alcohol, oleic acid, oleyl alcohol, benzyl chloride, paraffin, peanut oil, piperonal, rapeseed oil, rosin
  • the polar solvent (or in the case of a block copolymer, the preferential solvent) can similarly serve multiple functions, including modulation of phase behavior (indeed, making nanostractured phases possible at all, in many surfactant systems), solubilization of the active, providing a polar environment for portions of the active molecule such as for example the polar regions of a protein, etc.
  • the choice of a non- volatile polar solvent like glycerol can be important in processes such as spray-drying.
  • the polar solvent may be: a. water b. glycerol c. formamide, N-methyl formamide, or dimethylformamide d. ethylene glycol or other polyhydric alcohol e. ethylammonium nitrate f. other non-aqueous polar solvents such as N-methyl sydnone, N-methyl acetamide, pyridinium chloride, etc.; g. a mixture of two or more of the above.
  • Desirable polar solvents are water, glycerol, ethylene glycol, formamide, N-methyl formamide, dimethylformamide, ethylammonium nitrate, and polyethylene glycol.
  • a composition that yields a nanostructured liquid or liquid crystalline phase upon contact with water is a nanostructured liquid or liquid crystalline phase.
  • this contact with water or a water-containing mixture could be either during a reconstitution step, or more preferably, during the application of the particle, most preferably after the coating releases, and the de- coated particle contacts an aqueous solution such as blood, extracellular fluid, intracellular fluid, mucous, intestinal fluid, etc.
  • the exterior coating 20 may be formed of a nonlamellar material.
  • nonlamellar as applied to crystal structure herein should be taken in the following context. Lamellar crystalline materials, which are distinct from lamellar liquid crystalline phases, occur in organic compounds (typically polar lipids), inorganic compounds, and organometallics.
  • lamellar liquid crystalline or, commonly, lamellar crystalline coatings stabilize the oil droplets in an oil-and- water emulsion, and the water droplets in a water-in-oil emulsion.
  • the instabilities that are wellknown to the lay person — and in the field referred to as "breaking" of emulsions — are due in large part to the fluidity of these layered coating materials. Even in a quiescent emulsion, these layered coatings undergo continual disruption, streaming and coalescence, and with time any emulsion must ultimately succumb to the destabilizing effect of these disruptions.
  • layered crystalline materials exhibit chemical instabilities of the type that would prevent their application as coatings in embodiments of the current invention.
  • the Werner complexes isomorphous to nickel dithiocyanate tetra(4methylpyridine) that form clathrate compounds with a host lattice containing embedded guest molecules, in most cases yielding permanent pores upon removal of the guest.
  • One such Werner complex was used as the coating in a particle in Example 22, thus illustrating the use of the present invention in creating particles with coatings possessing fixed, controlled-size and highselectivity pores. According to J. Lipkowski, Inclusion Compounds 1, Academic Press, London (1984), p.
  • Nonlamellar amorphous and semi-crystalline materials are materials comprising non- crystalline domains (or lacking crystallinity altogether) in which strong atomic interactions exist in all three dimensions.
  • amorphous trehalose that provides the coating in Example 40, for example, the packing of these sugar molecules and the multiple hydrogen bonds that each individual molecule can participate in make this a compound that exhibits strong interactions in all tliree dimensions (and the amorphous property rales out any lamellar-type structure).
  • amorphous PLGA has strong interactions between the carboxyl groups across neighboring polymer chains which, since the material is optically isotropic, are not limited to two dimensions.
  • the release of a coating in a PLGA-coated particle will be chosen to be based on its hydrolysis rate in the body, as is well-known in the art, and not by mechanical shear or deformation as could occur in a particle coated with a lamellar coating. Since most production protocols used in industrial or pharmaceutical practice involve shear, release upon the application of such shear rates to a lamellar-coated particle system could be detrimental or disastrous in the context of such a process.
  • polymers universally have amo ⁇ hous domains: no polymer is ever 100%> crystalline, and thus even high-crystallinity polymers are semi-crystalline and possess a finite fraction of amorphous domains. Often this is in the range of about 1-50%.
  • the glass transition temperature of these amorphous domains can usually be detected by thermodynamic (e.g., DSC) techniques or rheometric measurements, though in certain very high-crystallinity polymers (greater than about 98%>), this may be a difficult undertaking.
  • an amorphous domain can play important roles: they can mitigate structural problems associated with microcrystallite boundaries, thus conferring greater homogeneity and cohesiveness to microcrystalline polymers; this in turn can have strong effects on rheological properties and behavior as diffusional barriers; according to the fringed micelle model, an amorphous domain can provide a medium that allows for a single chain to extend through several microcrystallites, yielding a physical crosslinking (analogous to the physical crosslinking that occurs in thermoplastic elastomers); and their presence may in fact allow for crystallinity in high-MW polymers where the amorphous domains are the necessary result of chain folding.
  • the exterior coating 20 can protect the internal core 10 and any active agent(s) or component(s) disposed therein, for example, against oxidation, hydrolysis, premature release, precipitation, shear, vacuum, enzymatic attack, degradation from other components of the preparation, and/or conditions external to the coated particles, for example, in their preparation such as pH, ionic strength, or the presence of bioactive impurities such as proteases or nucleases. Examples of each of these are: oxidation: e.g.
  • antioxidants such as vitamin C
  • hydrolysis e.g., for a drug with a labile ester bond: premature release: during storage: precipitation: e.g., for a drug in the protonated (hydrochloride) form that would deprotonate at the body pH and thereby become insoluble
  • shear e.g., in cases where processing after encapsulation endangers shear-sensitive compounds, such as proteins
  • vacuum e.g., in cases where processing involves vacuum-drying
  • enzymatic attack a peptide hormone, such as somatostatin, which is normally quickly digested by enzymes in the body, can be held active in circulation until reaching the site of release and action: degradation from other components: e.g., where even a slight reactivity between an component disposed in the internal core and an exterior one could, over a shelf-life of months or years, pose a problem: external pH: e.
  • nonlamellar coating materials namely, compounds which occur in nonlamellar form over useful temperature ranges, and which are in most cases of low toxicity and environmental impact are: ascorbic acid; ascorbic palmitate; aspartic acid; benzoin; beta-naphthol; bismuth subcarbonate; butylated hydroxytoluene; butylparaben; calcium acetate; calcium ascorbate; calcium carbonate; calcium chloride; calcium citrate; calcium hydroxide; calcium phosphate, dibasic; calcium phosphate, tribasic; calcium pyrophosphate; calcium salicyiate,;calcium silicate; calcium sulfate; carmine; cetearyl alcohol; cetyl alcohol; cinnamaldehyde; citric acid; cysteine hydrochloride; dibutyl sebacate; esculin; ferric oxide; ferric citrate; ferrosoferric oxide; gentisic acid; glutamic acid; glycine; gold
  • Calcium phosphate coatings are of interest in biomedical and pharmaceutical applications, since calcium phosphates are a major component of bone, teeth, and other structural components. For example, in the treatment of osteoporosis, the release of the appropriate pharmaceutical compound could be triggered by physiological conditions that induce dissolution of bone (and thus of the particle coating).
  • Potassium nitrate coatings are of interest in agricultural applications since the coating also act as plant fertilizers.
  • Iodine, aspartic acid, benzoic acid, butylated hydroxytoluene, calcium edetate disodium, gentisic acid, histidine, propyl gallate and zinc oxide can be particularly useful as coatings in potential pharmaceutical applications because they have relatively low water solubility (generally less than 5%) and are on the FDA list of approved inactive ingredients for injectable formulations.
  • coating materials are clathrates. Examples of such materials are as follows:
  • Clathrates and inclusion compounds (some of which retain permanent porosity upon removal of the guest molecules): Werner complexes of the form MX 2 A 4 where M is a divalent cation (Fe, Co, Ni, Cu, Zn, Cd, Mn, Hg, Cr), X is an anionic ligand (NCS-, NCO-, CN-, N0 3 " , C1-, Br-, I-), and A is an electrically neutral ligand-substituted pyridine, alpha-arylalkylamine or isoquinoline, examples of A include 4-methylpyridine, 3,5-dimethylpyridine, 4- phenylpyridine, and 4-vinylpyridine.
  • a wide range of guest molecules can be included in these complexes, examples being benzene, toluene, xylene, dichlorobenzene, nitrotoluene, methanol, chloromefhane, argon, krypton, xenon, oxygen, nitrogen, carbon dioxide, carbon disulfide, etc.; reversible oxygen-carrying chelates such as bis-salicyladehyde-ethylenediiminecobalt and other bis salicyladehyde iminecobalt derivatives, cobalt(II) dihistidine and related cobalt(II) amino acid complexes, iron(II) dimethylglyoxime and nickel(II) dimethylglyoxime; and complexes of the form K 2 Zn 3 [Fe(CN) 6 ] 2 .xH,O, where certain values of the variable x correspond to complexes which yield permanent pores upon removal of the water.
  • Zeolites faujasite-type NaX zeolite; faujasite-type NaY zeolite; and VPI-5 zeolite.
  • the exterior coating of the particles of the present invention comprises nonlamellar materials which are not entirely in crystalline form.
  • Such non-crystalline materials may be amorphous or semicrystalline.
  • amorphous as applied to materials means lacking long-range order; this is in direct contrast to the case of a crystalline material, in which there is long-range order in the positions of atoms, such that their positions conform to a lattice with its associated periodicity.
  • the x-ray diffraction pattern of an amorphous material will be absent of any Bragg reflections, and any short-range correlations can at most give rise to broad maxima in the diffraction pattern, maxima which exhibit neither the sharpness nor the functional form of a true Bragg reflection.
  • sini-crystalline is meant a material which has a mixture of crystalline domains and amorphous domains.
  • amo ⁇ hous materials have a number of properties which make them advantageous for certain embodiments of the current invention. For example, one property of amo ⁇ hous materials is that they are generally faster-dissolving than a corresponding (or comparable) material in crystalline form, and this can be advantageous in cases where fast dissolution of the exterior coating is desirable. Further, amo ⁇ hous materials can be superior to their corresponding crystalline forms in certain material properties. For example, amo ⁇ hous materials tend to exhibit higher ductility, and thus allow the adso ⁇ tion of stress without cracking.
  • small-molecule amo ⁇ hous materials tend to exhibit lessor stability over time than their corresponding crystalline materials.
  • a small-molecule amo ⁇ hous material will often show a tendency to revert to a crystalline fonn over a period of time that is comparable to, or shorter than, timescales that are relevant for the storage and use of a product.
  • the true equilibrium condition may be a crystal
  • kinetics of rearrangement can be so slow that the timescale required for attainment of this equilibrium is for all intents and pmposes infinite, so that the material can be locked into an amo ⁇ hous or semi-crystalline state. For certain applications, this may be highly desirable.
  • elastomers and plastics such as natural rabber (an example of an elastomer) or polymethylmethacrylate (PMMA, also known as Plexiglass, an example of a thermoplastic), are amo ⁇ hous materials.
  • Semi-crystalline materials can in certain ways offer significant advantages, though their occurrence as long-lasting states is largely limited to high-MW polymers.
  • a semi- crystalline polymer with high crystallinity can offer high modulus due to the preponderance of crystalline domains, but a certain amount of ductility due to the presence of amo ⁇ hous domains, which can absorb stress without cracking.
  • a number of the most important polymers, both commodity and engineering plastics, are semi-crystalline.
  • Examples of materials which occur in an amo ⁇ hous or semi-crystalline form that may be utilized in the practice of the present invention include: polydienes, polyallenes, polyacrylics and polymethacrylics (including polyacrylic acids, polymethacrylic acids, polyacrylates, polymethacrylates, polydisubstituted esters, polyacrylamides, polymethacrylamides, etc.), polyvinyl ethers, polyvinyl alcohols, polyacetals, polyvinyl ketones, polyvinylhalides, polyvinyl nitriles, polyvinyl esters, polystyrenes, polyphenylenes, polyoxides, polycarbonates, polyesters, polyanhydrides, polyurethanes, polysulfonates, polysiloxane, polysulfides, polysulfones, polyamides, polyhydrazides, polyureas, polycarbodiimides, polyphosphazenes, polysilanes, polysilazanes
  • lactide-glycolide copolymers provides a particularly pertinent example, because these copolymers are amo ⁇ hous over a range of lactide:glycolide ratios, and crystalline over other ranges. By adjusting this ratio, it is possible to alter the form of the material and thus its properties, thereby “tuning" the rate of hydrolysis of the coating material. This, in rum, "tunes” the rate of release of active agents disposed in either the coating or the particle interior.
  • Proteins and perhaps to a lessor extent polypeptides, can also provide amo ⁇ hous and semi-crystalline coating materials with advantageous properties. Due to the intimacy of interactions that are well-known between proteins and lipid matrices, the crystallization of a protein in an aqueous dispersion of nanostractured liquid or liquid crystalline particles, preferably of the reversed bicontinuous cubic phase, could yield particles of the instant invention wherein the coating was composed of semi-crystalline protein. Alternatively, gelation or precipitation of a protein at the surface of a nanostractured liquid or liquid crystalline particle could yield a particle of the instant invention wherein the coating was composed of amo ⁇ hous protein.
  • the presence of protein in the coating of such particles could serve one or more important roles, including: targeting (that is, the coating itself could serve a dual role as a targeting compound); inhibition of unfavorable protein adso ⁇ tion (e.g., albumin binding); presentation of a biocompatible particle surface that would minimize uptake by the body's defenses (e.g., the RES) and yield long circulation times; and functional proteins that could perform metabolic functions at the site of delivery that might yield enhanced abso ⁇ tion, diminished drug degradation/metabolism, and/or regulation of cellular processes in concert with the drag action.
  • targeting that is, the coating itself could serve a dual role as a targeting compound
  • inhibition of unfavorable protein adso ⁇ tion e.g., albumin binding
  • presentation of a biocompatible particle surface that would minimize uptake by the body's defenses (e.g., the RES) and yield long circulation times
  • functional proteins that could perform metabolic functions at the site of delivery that might yield enhanced abso ⁇ tion, diminished drug degradation/metabolis
  • the coated particles 1 of the present have application in a variety of fields.
  • the coated particles 1 are adapted to absorb one or more materials from a selected environment, adsorb one or more materials from a selected environment or release one or more materials, such as active agents, disposed in the matrix.
  • the coated particles may be used to harvest products or scavenge waste, in biological or chemical reaction processes, to carry catalysts in those processes, to remove toxins, antigens or waste products in medical applications, to identify a few examples.
  • adso ⁇ tion the coated particles may be used as chromatographic media and as adsorbents.
  • the coated particles may be used for the controlled release of pharmaceutical agents such as anticancer agents or photodynamic therapy agents, or cosmetic or cosmeceutical materials.
  • An active agent may be disposed in the matrix for release upon the triggering of release.
  • a pharmaceutical or biologically active material may be disposed in the matrix, that is, it may be either dissolved, or dispersed, or in some cases be partially dissolved and the remainder dispersed.
  • microparticles in drag-delivery or with embedded proteins or polypeptides (in particular receptor proteins), it can be highly advantageous to nave an interior matrix which, although synthetic or semisynthetic, is designed to simulate closely the physiochemical properties of a natural biomembrane from a living cell. This could be important for the proper functioning of a receptor protein or other membrane component, for example, or for promoting assimilation of the interior matrix into the natural biomembrane in drug delivery, or especially in targeting of the microparticles.
  • Physiochemical properties that can be important in such a context include the bilayer rigidity, (a measure of the resistance to bending), bilayer fluidity (a measure of the microviscosity of the bilayer interior), the acyl chain length and bilayer thickness, the order parameter as a function of position on the lipid acyl chains, the surface charge density, the presence or absence of segregated lipid domains of differing composition within the bilayer, bilayer curvature and monolayer curvature (for a discussion of the relationship between these two curvatures see H. Wennerstrom and D.M. Anderson, in Statistical Thermodynamics and Differential Geometry of Microstractured Materials, Eds. H.T. Davis and J.C.C.
  • the bilayer rigidity can be reduced by the addition of amphiphiles, particularly aliphatic alcohols; and bilayer charge can be adjusted by adjusting the ratio between uncharged lipids (such as phosphatidylcholine) and charged lipids (such as phosphatidic acid).
  • uncharged lipids such as phosphatidylcholine
  • charged lipids such as phosphatidic acid
  • the lamellar phase, the reversed bicontinuous cubic phase, the L3 phase, and to a lesser extent the reversed hexagonal phase are in particular well suited for this approach.
  • a particle of the present invention, with the interior matrix being such a phase with tuned physiochemical characteristics for the functioning of inco ⁇ orated proteins or other biomolecules can be very valuable in products for pharmaceutics, clinical assays, biochemical research products, etc.
  • Membrane proteins are generally dependent on a bilayer milieu in order to function properly and even to maintain proper conformation, and for such proteins the present invention - particularly with the bilayer properties tuned as described above - could be an excellent and very useful matrix.
  • membrane proteins include, in addition to receptor proteins, such proteins as proteinase A, amyloglucosidase, enkephalinase, dipeptidyl peptidase IV, gamma-glutamyl transferase, galactosidase, neuraminidase, alpha-mannosidase, cholinesterase, arylamidase, surfactin, ferrochelatase, spiralin, penicillin-binding proteins, microsomal glycotransferases, kinases, bacterial outer membrane proteins, and histocompatibility antigens.
  • antineoplastic agents such as for example, the following: Alkylating Agents
  • Alkyl Sulfonates -Busulfan, Improsuflan, Piposulfan.
  • Etoposide Gallium Nitrate, Hydroxyurea, Interferon-ot, Interferon-P, Interferon-y, Interleukin-2, Lentinan, Lonidamine, Mitoguazone, Mitoxantrone, Mopidamol, Nitracrine,
  • Pentostatin Phenamet, Pirarubicin, Podophyllinic Acid, 2-Ethylhydrazide, Procarbazine,
  • Androgens - Calusterone Dromostanolone Propionate, Epitiostanol, Mepitiostane. Testolactone.
  • Estrogens Fosfestrol, Hexestrol, Polyestradiol Phosphate.
  • Antineoplastic (Radiation Source) Americium, Cobalt, 131 I-Ethiodized Oil, Gold
  • Radioactive Colloidal
  • Radium Radium
  • Radon Sodium Iodide
  • Radioactive Sodium Phosphate
  • Alkylating agent Anabolic steroid, Analgesic, Androgen, Anthelmintic, Antiadrenergic, Antibiotic, Antibiotic, aminoglycoside, Antibiotic, antineoplastic, Antibiotic, polypeptide, Anticholinergic, Anticoagulant, Anticonvulsant, Antifungal, Antihypertensive, Antimetabolite, Antimitotic, Antineoplastic, Antiplatelet, Antipsychotic, Anesthetic, Antirheumatic, Antituberculosal, Antiviral, Antiviral (HIV), Asthma anti-inflammatory, Biological response modifier, Cholinergic muscle stimulant, CNS stimulant, DNA topoisomerase inhibitor, Enzyme inhibitor, Epipodophyllotoxin, Folate antagonist, Gastric antisecretory, Gene therapy agents, Gonadotropin-releasing, Growth hormone, Hematopoietic, Hormone, Immunologic agent,
  • Immunosuppressant Inotropic agent, Local anesthetic, Narcotic agonist/antagonist, Ovulation stimulant, Pituitary hormone, Platinum complex, Sex hormone, Thyroid hormone, TNF inhibitor (arthritis), Urinary cholinergic, Vasodilator, and Vasopressor.
  • functional excipients such as gum benzoin or essential oils that improve abso ⁇ tion of poorly-absorbed drags, in some cases by inhibiting drag efflux proteins.
  • functional excipients such as gum benzoin or essential oils that improve abso ⁇ tion of poorly-absorbed drags, in some cases by inhibiting drag efflux proteins.
  • Paints and inks Including Microencapsulation of pigments; Cationic charging of pigments (where pH-dependence can be important); Fillers and texturizing agents for non-aqueous paints;
  • Paper Including Microcapsular opacifiers (also in paints); Pressure-sensitive ink microcapsules for carbonless copying paper;
  • Non-wovens Including Additives that adhere to fibers throughout processing; 4.
  • Agricultural Including controlled release of pheromones (some of which are otherwise volatile or environmentally unstable if not encapsulated) for insect control; Controlled release of insect chemosterilants and growth regulators (many of which are otherwise environmentally unstable): Controlled release of other pesticides (with temperature independence being important); Controlled release of herbicides; Encapsulation of the plant growth regulators ethylene and acetylene (that are otherwise volatile); Taste modifiers to deter mammalian pests (e.g. capsaicin), Nutrient and fertilizer release;
  • Vaccines Including HIV gag, gag-pol transfection of cells as an example; Adjuvants for the proper presentation of antigens or antibodies;
  • Nuclear medicine Including Separation of two (otherwise mutually-destructive) radionuclides into separate particles for treatment of cancer;
  • Cosmetics Including Antioxidant, Antiaging skin cream: Separation of two components of an antiacne medication; Suntan lotions with encapsulated prostaglandins and vitamins; Encapsulation of fat-soluble vitamins, oxidatively sensitive vitamins, vitamin mixes;
  • Encapsulation of volatile perfumes and other odorants Encapsulated volatile perfumes for scratch and sniff advertisements, Encapsulation of volatile make-up removers or other cosmetics for sheet formation; Encapsulated solvents for nail polish removers (or the polish itself); Aerosol particles containing encapsulated hair dye; Sanitary napkins containing encapsulated deodorant; 9 Veterinary. Including Controlled release of volatile anti-flea compounds; Encapsulated feed additives for ruminants; Encapsulation of anti-microbial and insecticides in animal husbandry;
  • Household Products Including controlled-release air fresheners, perfumes; Controlled- release insect repellants; Laundry detergents (e.g., encapsulated proteases); Other detergency applications; Softeners; Fluorescent brighteners;
  • Polymer additives Including polymer additives for protection of wires,paper cartons etc, from rodents; Impact modifiers; Colorants and opacifiers; Flame retardant and smoke suppressants; Stabilizers; Optical brighteners; Limitations in current polymer-based encapsulation of additives include low melting point (during processing, polymer-polymer incompatibility, particle size limitations, optical clarity, etc. Some polymer additives used for lubrication of the polymer are based on waxes, which suffer from low melting point, except for certain synthetic waxes which are expensive;
  • Food and beverage processing Including Encapsulation of (volatile) flavors, aromas, and oils (e.g., coconut, peppermint); Encapsulation of vegetable fats in cattle feeds; Encapsulated enzymes for fermentation and purification (e.g., diacetyl reductase in beer brewing); Encapsulation as an alternative to blanching, for improved lifetime of frozen foods; Microencapsulated tobacco additives (flavorings); pH-triggered buffering agents; Removal of impurities and decolorization using activated charcoal encapsulated in a porous material; 16. Photographies.
  • Desirable triggers for commencing the release of active agents, or alternatively commencing abso ⁇ tion are:
  • the coated particle may be made by 1. providing a volume of the matrix that includes at least one chemical species having a moiety capable of forming a nonlamellar material upon reaction with a second moiety and 2. contacting the volume with a fluid containing at least one chemical species having the second moiety under nonlamellar solid material-forming conditions so as to react the first moiety with the second moiety and subdividing the volume into particles by the application of energy to the volume, or performing this subdivision into particles before, and/or after, the chemical reaction.
  • the coated particle can be made by one of the following processes: providing a volume of the matrix that includes a material in solution in it that is capable of forming a nonlamellar material that is insoluble in the matrix and causing the aforesaid material to become insoluble in the matrix and subdividing the volume into particles by the application of energy to the volume; dispersing particles of said matrix into a fluid that includes at least one chemical species having a moiety capable of forming a nonlamellar material upon reaction or association with a second moiety and adding to said dispersion at least one chemical species having said second moiety to react said first moiety with said second moiety; dispersing particles of said matrix into a fluid that includes at least one chemical species having a moiety capable of forming a nonlamellar material upon reaction or association with a second moiety, adding to said dispersion at least one chemical species having said second moiety to react said first moiety with said second moiety, and subdividing the resulting material into particles by the application of energy to said material; dispers
  • a volume of the matrix is loaded with a compound A capable of forming a nonlamellar material on reaction with compound B, and a fluid (typically an aqueous solution, often referred to as the "upper solution") containing a compound B is overlaid on this, and the contact between compound A and compound B induces precipitation at the interior/exterior interface, which coupled with the application of energy, such as sonication, causes particles coated with the nonlamellar material to break off into the fluid.
  • a fluid typically an aqueous solution, often referred to as the "upper solution”
  • This method of the present invention is uniquely well-suited for producing aqueous dispersions of coated particles having coatings of materials with low water solubilities, i.e., preferably less than about twenty (20) grams per liter of water and even more preferably less than about ten (10) grams per liter of water. It is highly advantageous in these processes for component A to be dissolved (not merely dispersed or suspended) in the matrix before the contact with B and sonication begins, in order to obtain a homogeneous dispersion of microparticles in the end.
  • a cool temperature or a crystallization promoter, or electric current could be used to produce precipitation.
  • a water-soluble surfactant preferably an amphiphilic block copolymer of several thousand Dalton molecular weight, such as Pluronic F68, is added to the aqueous solution in order to stabilize the coated particles against aggregation as they form. If sonication is used to promote particle formation, this surfactant also serves to enhance the effect of sonication.
  • nonlamellar material-coated particles described in the Examples were made by a process in which two or more reactants react to form a precipitate at the interface between the external solution and the nanostructured liquid or liquid crystalline phase, and the precipitate forms the exterior coating.
  • Another method which bears important similarities, as well as important differences, to this method is a general method in which the material that is to form the coating, call it material A, is dissolved in the liquid phase material or liquid crystalline phase material, with this dissolution being promoted by the change of one or more conditions in the material, such as an increase in temperature (but it could be another chance such as decrease in pressure, addition of a volatile solvent, etc.).
  • the solubility of compound A in the nanostructured liquid phase material or nanostructured liquid crystalline phase material must change with temperature, and the higher the magnitude of the slope of the solubility versus temperature plot, the smaller the temperature increment needed to perform this process.
  • the solubility of potassium nitrate in water is a very strong function of temperature.
  • a fundamental difference between the precipitation reaction process and this type of process is that in this type of process, only one compound (A) is needed in addition to the nanostructured interior matrix.
  • the precipitation reaction method at least two compounds are needed, component A which is in the nanostructured phase, and component B which starts out in the exterior phase ("upper solution") which is overlaid on top of the nanostractured phase.
  • Component B in that case is often simply a suitably chosen acidic or basic component.
  • condition in particular, pH in the acid/base case
  • the compound desired as the particle coating would be added to the matrix in two chemical forms.
  • the first would be the chemical fomi of the final coating, typically the free acid (free base) form of a compound, which would be soluble only at elevated temperature and insoluble in the matrix at the temperature of particular formation.
  • the second would be a precursor form, typically the salt form made by reacting the free acid with a base such as sodium hydroxide (or reacting the free base form with an acid such as hydrochloric acid), where this precursor form would be soluble in the matrix even at the temperature of particle formation.
  • both benzoic acid and sodium benzoate would be added to the matrix, where the matrix is such that is does not dissolve benzoic acid at ambient temperature, but does at a higher temperature.
  • the upper solution would contain the necessary component(s) to convert the precursor form to the final coating form, such as hydrochloric acid in the case of sodium benzoate.
  • coated particles of the present invention could have advantages, in terms of providing two sources of coating material that could result in particle coverage at an earlier stage than with either method separately, thus providing added protection against particle fusion (and possibly leading to a more uniform particle size distribution), and more efficient particle formation with less energy input requirement, etc.
  • Other methods that may be used for making coated particles of the present invention are: A. Electrocrystallization, B. Seeding (with supersaturated solution in matrix, seed in exterior phase), C. Promotion (with supersaturated solution in one phase, crystallization promoter in the other phase), D. Inhibition removal (with supersaturated solution in one phase and seed in the other phase), or E. Time method (precipitate grows slowly from supersaturated solution in interior phase).
  • condition 1 it must contain aqueous (or other polar solvent) domains: and condition 2: it must be of low solubility in water, i.e., sufficiently low (or with sufficiently slow dissolution kinetics) that substantial dissolution of the phase does not occur during the process of particle production from the phase (typically 5 to 100 minutes to disperse the entire material into particles), since this would substantially reduce the yield efficiency and could thus diminish the overall attractiveness of the method.
  • condition 2 it must be of low solubility in water, i.e., sufficiently low (or with sufficiently slow dissolution kinetics) that substantial dissolution of the phase does not occur during the process of particle production from the phase (typically 5 to 100 minutes to disperse the entire material into particles), since this would substantially reduce the yield efficiency and could thus diminish the overall attractiveness of the method.
  • condition 2 it must be of low solubility in water, i.e., sufficiently low (or with sufficiently slow dissolution kinetics) that substantial dissolution of the phase does not occur during the process of particle production from the phase (typical
  • the matrix phase is not in equilibrium with water (or a dilute aqueous solution) but is in equilibrium with another liquid or liquid crystalline phase, such as a micellar phase or even a low- viscosity lamellar phase.
  • advantages can be obtained by using a precursor to the coating material that localizes preferentially the surface of particles of the nanostructured liquid or liquid crystalline matrix, and dispersing the nanostructured liquid or liquid crystalline phase-often with the aid of this surface-localized precursor-prior to converting this precursor to the actual coating material.
  • This is especially preferred in the case where a surface-active precursor can be found, or when the precursor can otherwise be substantially localized near the surface of the dispersed particles, by a favorable interaction with another component (ionic pairing, hydrogen bonding, etc.), or by a non-specific effect such as the hydrophobic effect, or by selecting a precursor or precursor-containing solution with the proper surface energy.
  • Example 41 the localization of the precursor at the particle surface can be maintained throughout its conversion to the coating resulting in good intimacy between the particle and coating and efficient use of the coating material.
  • the sodium salt of N-acetyltryptophan which is a surface-active compound (due to the hydrophobicity of N-acetyltryptophan, augmented by the polarity of the ionized carboxylate group at one end), is used to disperse a cubic phase into microparticles with a particle surface that is rich in this precursor to the final coating material, which in this case is the zinc salt of N-acetyltryptophan.
  • Other approaches for localizing the precursor at the particle surface include: ion-pairing the precursor to an oppositely-charged molecule that partitions strongly into the cubic phase; using a melted or solubilized form of the precursor such that the surface energy of the melted precursor or precursor solution favors its localization in between the nanostructured phase and the exterior phase in which the nanostractured phase is dispersed; choosing a precursor that has favorable interactions such as extensive hydrogen bonding with the nanostructured phase surface, particularly in the case where the precursor (and coating) is a polymer, so that it is by virtue of its high MW excluded from the interior of the nanostractured phase particle; invoking specific interactions such as antibody-antigen or receptor-ligand interactions; and using a precursor, preferably a polymer or biomacromolecule (protein, nucleic acid, polysaccharide, etc.) that is substantially insoluble in the nanostructured phase but contains hydrophobic anchor groups that partition into the nanostractured phase, where such hydrophobic anchors are known in the art
  • Example 42 a related approach is one in which the matrix is dispersed in the precursor itself. That is, the precursor forms the continuous (exterior) phase of a dispersion of microparticles of the matrix. Then, this precursor is converted to the coating material, entrapping the microparticles (if and when they remain as nanostructured liquid or liquid crystalline bodies) within the coating material.
  • the step of dispersing the matrix material with in many cases the precursor playing a central role as a dispersant or matrix, followed by the step of converting the precursor to the coating material, be it by chemical reaction (often as simple as an acid-base reaction or formation of a complex by the introduction of multivalent ions, as in Example 41), cooling, evaporating a volatile solvent, or other method.
  • This series of actions can result either in a dispersion of coated microparticles, or conglomerates of such particles which one may want to separate by a second dispersing step (or it can yield a combination of conglomerates and dispersed microparticles).
  • the interior matrix will be a dehydrated variant of the desired phase, that will form the desired nanostructured liquid or liquid crystalline phase upon contact with a water-containing fluid.
  • a matrix or, in this case dehydrated matrix is dispersed in a non-aqueous solution or melt that is, or contains, a precursor of the coating material; upon cooling or otherwise converting this precursor to the coating, the dehydrated matrix would then be the encapsulated entity.
  • a second general method is to apply a drying process, such as freeze- drying, electrospinning, or preferably spray-drying, to a water-containing dispersion of the particles in which the coating material (or a precursor thereof) has been dissolved or very finely dispersed.
  • a third general method is to dissolve or disperse all the components of the coating and of the matrix, either including or excluding the water, in a volatile solvent and applying a drying process, again preferably spray-drying.
  • amo ⁇ hous and semi-crystalline materials as exterior coatings in the instant invention makes it all the more practical to inco ⁇ orate, in a number of different ways, chemicals or chemical groups that can be invoked to target particles temporally and spatially, for example, to target particles to specific sites in the body.
  • bioactive compounds inco ⁇ orated on or in the coating could serve important functions, such as: abso ⁇ tion enhancers such as menthol could be present so as to increase permeability of abso ⁇ tion barriers (lipid bilayers, gap junctions) prior to or concomitant with the release of drug; proteins or other adso ⁇ tion-modulating materials could be inco ⁇ orated that would inhibit unfavorable binding of endogenous proteins such as albumin; adjuvants could be inco ⁇ orated that would enhance the effect of vaccine components or other immune modulating materials.
  • abso ⁇ tion enhancers such as menthol could be present so as to increase permeability of abso ⁇ tion barriers (lipid bilayers, gap junctions) prior to or concomitant with the release of drug
  • proteins or other adso ⁇ tion-modulating materials could be inco ⁇ orated that would inhibit unfavorable binding of endogenous proteins such as albumin
  • adjuvants could be inco ⁇ orated that would enhance the effect of vaccine components or other immune modul
  • an amo ⁇ hous or semi-crystalline material can, for example, inco ⁇ orate molecules or even submicron solids as embedded materials, more readily and efficiently than with crystalline materials which tend to exclude other materials during their crystallization—particularly when the crystallization is performed in accordance with the tight regulations that govern the pharmaceutical industry.
  • covalent or ionic attachment of organic groups to polymers at their surfaces is a well-developed art.
  • U.S. patents 6,344,050 and 5,484,584 are examples of methods known in the art for attaching molecular targets to polymers and microparticle coatings in particular.
  • Antibodies, steroids, hormones, oligo- or polysaccharides, nucleic acids, vitamins, immunogens, and even nanoprobes are all examples of a wide range of materials that could be attached to particles of the instant invention with an exterior phase of amo ⁇ hous, semi-crystalline, or less likely crystalline, material.
  • targeting moieties could be substantially localized at one or more of the following sites in reference to the coated microparticle: 1) in the interior of the particle, i.e., dissolved or dispersed in the nanostructured liquid or liquid crystalline phase interior; this locality can offer the distinct advantage of providing a
  • biomimetic milieu for the targeting moiety a milieu which can comprise a lipid bilayer as well as hydrophilic domains each of which can be tuned to optimize the environment;
  • a flexible spacer e.g., a polymer that is attached (e.g. by covalently bonding) at one end to a component of the particle (interior or exterior) and at the other end to the targeting moiety.
  • Patent 6,214,966 (the contents of which are hereby inco ⁇ orated by reference in entirety) provides examples wherein PEGylation of polypeptides can enhance their performance in the body, including reduced immunogenicity and slower clearance. Furthermore, this effect can be even more dramatic when the peptide is associated with a hydrophobic chain (or cholesterol-like group) in conjunction with the PEG chain.
  • U.S. Patent 6,309,633 (the contents of which are hereby inco ⁇ orated by reference in entirety) provides examples of peptides that show greatly increased stability, resistance to enzymes, and oral abso ⁇ tion when coupled to PEGylated hydrophobic chains or ring systems.
  • Many of the surfactants and lipids referred to in this specification are PEGylated, or contain other oligomeric or polymeric chains that can substantially modify the fate of drugs in the body — or of targeting moieties, as is suggested here.
  • a number of compounds could potentially be used as targeting moieties in a pharmaceutical application of particles of the instant invention.
  • certain lipids such as Lipid A
  • block copolymers in which one of the blocks could have targeting potential such as glycogen and heparin
  • Small molecules that could be present either in the interior or exterior to achieve a degree of targeting include sterols, fatty acids, gramicidin, fragments or simulants of appropriate protein epitopes, and amino acids including aspartic acid, cysteine, tryptophan, leucine and others.
  • Leucine is an example of a compound that is recognized and bound by a specific protein in the body (the branched-chain amino acid transporter).
  • receptor proteins such proteins as proteinase A, amyloglucosidase, enkephalinase, dipeptidyl peptidase IV, gamma-glutamyl transferase, galactosidase, neuramimdase, alpha-mannosidase, cholinesterase, arylamidase, surfactin, ferrochelatase, spiralin, penicillin-binding proteins, microsomal glycotransferases, kinases, bacterial outer membrane proteins, and histocompatibility antigens), many of which could serve a targeting role if inco ⁇ orated in particles of the instant invention.
  • membrane proteins such proteins as proteinase A, amyloglucosidase, enkephalinase, dipeptidyl peptidase IV, gamma-glutamyl transferase, galactosidase, neuramimdase, alpha-mannosidase, cholinesterase,
  • polymeric components adsorbed to the exterior coating that could serve as attachment points for targeting moieties, include, for example, stabilizing layers on the exterior, i.e., outside the exterior coating 20 such as polyelectrolytes or surfactant monolayers (as discussed above).
  • stabilizing layers on the exterior i.e., outside the exterior coating 20
  • the Pluronic F-68 that is used in a number of the Examples is one such polymeric surfactant.
  • "externally-directed targeting" of the coated particles may be achieved. This may be accomplished by directing particles coated with certain magnetically responsive materials discussed above (e.g. ferric oxide) through the application of magnetic fields.
  • Antibodies are broadly useful for targeting to specific sites or molecules in the body or other environments, and can be inco ⁇ orated at various sites in a particle as discussed above. In particular, intact antibodies with their more hydrophobic Fc fragment are prone to partitioning into matrices of the type used in this invention, and furthermore it is well known that antibodies can be adsorbed or attached (including covalently) to solid surfaces with retention of binding and binding specificity.
  • Commercial sources supply antibodies to, for example, each of the following:
  • AAV adeno virus
  • ACHE acetylcholinesterase
  • ACHER acetylcholine and NMDA receptor
  • acid phosphatase ACTH
  • Actin cardiac, smooth muscle, and skeletal
  • Actinin Adeno-associated virus
  • adenosine deaminase Adipophilin (adipocy differentiation related peptide)
  • Adrenomedulin 1 -6 Advanced glycation end- products (AGE), alanine transaminase, albumin, alcohol dehydrogenase, aldehyde dehydrogenase, aldolase, Alfentanil AB, Alkaline Phosphatase, alpha Actinin, Alpha- 1-anti- chymotrypsin, alpha- 1-antitrypsin, alpha-2-macroglobulin, alpha-catenin, beta-catenin and gamma cateinin, Alpha-Fetoprotein
  • Cytochrome oxidase Cytochrome P450, Cytokeratin Types I and II, Cytomegalovirus, DAP Kinase, Dendritic cells, Desmin, Desmocollin 1, 2 and 3, Desmoglein 1, 2 and 3, Desmoplakin 1 and 2, Dextranase, DHT (Dihydrotestosterone), Dihydrofolate Reductase (DHFR), Dioxin, Diptheria toxin, Distemper, DJ-1, DNA single-stranded, DNA double stranded, DNA Topoisomerase II and Phospho-topoisomerase Ila + II alpha/beta, Dopamine, Dopamine Beta-Hydroxylase, Dopamine Receptor, Dopamine Transporter, Drebrin,
  • Dysferlin Dystrobrevin, E.Coli expression plasmid, Elastase, Elastin, Endocrine Granu, Constituent (EGC), Endo ⁇ hin, Endothelial cell, Endothelin, Endothelin Receptor, Enkephalin, enterotoxin Staphylococcus aureus, Eosinophil Peroxidase, Eosinophil derived neurotox, (EDN), Eotaxin, Eotaxin-2, Epidermal Growth Factor, Epidermal Growth Factor 2, epidermal growth factor receptor, testostosterone, Epithelial Proliferating antigen, Epithelium Specific Antigen, c-MYC, HA.l, VSV-G Tag, Glu-Glu, EEEYMPME, Thioredoxine (trx), Epstein Barr virus and Epstein Barr Virus capsid antigen gpl20, ERK (ERK1, ERK2, ERK3, pan ERK also called MAP
  • GIP gastric inl ibitory peptide
  • GIP gastric inl ibitory peptide
  • GO-protein bovine
  • GDNF GDNF-Receptor
  • Giardia intestinalis Glial fibrillary acidic Protein
  • Glial filament protein Glial filament protein
  • Glucagon/Glycentin Glucose oxidase
  • Glucose 6 Phosphate Dehydrogenase, Gluco, Tranporter GLUT 1-4, GLUT 1-5, Glutamate Dehydrogenase, Glutamic Acid decarboxyla (GAD), Glutathione, Glyceraldehyde-3- phosphate dehydrogenase GAPDH, Glycerol-3 -phosphate dehydrogenase, Glycerol kinase, glycine transporter (GLYT1, GLYT2), Glycogen Phosphor
  • Releasing factor GRP78, Hantaviras, HCG, HDL (high density lipoprotein), Heat Shock Protein HSP-27, HeK 293 Host Cell Proteins, Helodermin, helospectin, Hemeoxygenase, Hemoglobin, Heparin, Hepatitis A, Hepatitis B Core Antigen, Hepatitis B virus surface antigen, Hepatitis C virus, Hepatistis E virus, Hepatitis G Virus, Hepatocyte Growth Factor, Heregulin (Neu differentiation factor/Neuregulin), He ⁇ es Simplex Virus, Hexokinase, Histamine, His Tag, 6-His vector tags, HIV-1 p24, p55/17, gp41, gpl20, tat, nef, rev, HIV reverse transcriptase, HLA Class I, HLA Class II, HLA-DM, HLA DQwl, HLA DRw 52, Peroxidase, HPV 16 Late
  • Interleukin 3/interleukin 5/GM-CSF Receptor common chain Interleukin 4, Interleukin 5, Interleukin 6, Interleukin 6 receptor alpha chain, Interleukin 7, Interleukin 7 receptor alpha, Interleukin 8, Interleukin 8 receptor, Interleukin 9, invertase, Involucrin, IP- 10, Keratins, KGF, Ki67, KOR-SA3544, Kt3 epitope tag, lactate dehydrogenase, Lactoferrin, lactoperoxidase, Lamins, Laminin, La (SS-B), LCMV (Lymphocytic Choriomeningitis
  • Virus Legionella pneumophilia serotype, Legionella pneumophila LPS, Leptin and Leptin Receptor, Lewis A Antigen, LH (leutenizing Hormone), LHRH (leutenizing Hormone Releasing), L, (leukemia Inhibitory Factor), 5-Lipoxygenase, LPS Francesella tularensis, luciferase, Cancer Marker (MOC-1, MOC-21, MOC-32, Moc-52), Lymphocytes, lymphotactin, Lysozyme, Ml 3, Fl Filamentous Phages, Macrophages/monocytes,
  • Macrophage Scaveng Receptor, Matrix metalloproteases, M-CSF, Major Basic Protein, malate dehyrogenase, Maltose Binding Protein, Mannose Receptor (macrophage), Mannose- 6-phos ⁇ hate receptor, MAP kinase antibodies (ERK, ERK, ERK2, ERK3), MASH1 (Mammalian achaete schute homolog 1 and 2), MCL-1, Mcm3, M, (MCAF), MCP-2, MCP- 3, Melanocortin Receptors (1 through 5), Met (c-met), Mineralcortocoid Receptor (MR/MCR), Melanoma Associated Antigen, MGMT (methylguanine-DNA- methyltransferase), MHC Antibodies (inch HLA DATA PACK), Milk F, Globule Membrane, Milk Mucin Core Antigen, MIP-1 alpha, MIP-1 beta, Mitochondrial
  • Podocyte Protein (Synaptopodin), PAH (Polyaromatic Hydrocarbons), PACAP (pituitary adenylate cyclase activating peptide), Pancreas Polpeptide (PP), Pancreastatin, Pancreatic Islet Cell, papain, Papillomavirus (HPV), Parainfluenza type 2 viruses, Parathion, Parkin, PARP (Poly- A, Riobose Polymerase) PARP-1 and PARP-2, Patched- 1, Patched-2, Paxillin, polychlorinated biphenyls, Pemphigus vulgaris (desmoglein 3), Penicillin, penicillinase, pep- carboxylase, pepsin, Peptide YY, Perform and polyclonals, Perilipin, Peripherin, Perlecan, Petrole, Hydrocarbons (total), PPAR (peroxisome proliferation activated receptors), P- Glycoprotein (multi-drug resistance), PGP9.5, Phen
  • RANTES, RDX, RecA Receptor for advanced glycation end products (RAGE), Red Blood cells, Regulatory subunit, RELM alpha and Beta (resistin like molecules), Renin, Rennin, Replication Protein A (RPA p32 and p70), Resistin, Respiratory syncytial virus (RSV), Retinoblastoma (Rb), phospho-specific RB (ser780), Ribonuclease A, RNA Polymera, Arna3, RNP (70KdaUl), A Protein, B Protein, RO (RO52, Ro60), Rotavirus group specific antigen, Rubella virus structural glycoprotein El, Ryanodine Receptor, S-100 Protein, saccharomyces cerevisiae, Salmonella O-antigens, Salmonel, typhimurium, Sarcosine Oxidase, SDF-1 Alpha and SDF-1 Beta, secretin, Selenoprotein P, Serotonin, Serotonin Receptor,
  • Staphylococcus aureus Staphylococcus aureus enterotoxin, STAT1, Stat2, Stat, Stat4, Stat5 Stat6, Stem Cell Factor (SCF) and SCFR/C-kit
  • Streptavidin Streptococcus B
  • Stromal Cell Derived Factor- 1 SDF-1 alpha and beta
  • Substance P Sufentanil AB, Superoxide Dismutase, Surfactant Associated Proteins (A,B,C,D), Symplekin, Synapsin I, Synapsin Ila, Synaptophysin, Synaptopodin (Podocyte Protein), Syndecan 1, Synphilin-1, Synuclein
  • TGF-alpha SV40 Large T antigen and small T antigen
  • Talin TARC, TAU, Taurine transporter, Tenascin, Testosterone
  • TGF-alpha TGF-beta
  • TGF beta receptor Endoglin
  • THC Thomsen Friedenreich Antigen
  • TF THY-1 25kd Brain
  • Thymocytes Thombin and Thrombin Receptor
  • Thyroglobulin 24TG/5E6 and 24Tg/5F9
  • Thyroid Binding Globulin Thyroid Hormone Receptors, Thyroid Peroxidase, Thyroid Stimulating Hormone (TSH), Tyrosine Hydroxylase, Thyrotropin Releasing Hormone (TRH), Thyroxine (T4), TIe-1 and TIe-2, TIMP-1, TIMP-2, TIMP-3 (Tissue Inhibitors, metalloproteinase), Titin, TNF receptor associated factors 1 and 2, TNF Receptor, T
  • Triiodothyronine T3
  • Trinitrotoluene TNT
  • TRK A TRK B, TRK C
  • Tropon (cardiac)
  • Troponin I Troponin T
  • trypsin trypsin inhibitor
  • trypsinogen TSH
  • TUB Gene Tubulin alpha and beta, Tubulin beta specific
  • Tumor Marker related Antibodies Tumor Necrosis Factor Alpha, Tyrosinase, Tweak, (caspase-4), Ubiquitin, Ubiquitin-Ll, Uncoupling Proteins (UCP 1 , UCP2, UCP3 , UCP 4 and UCP5), Urease, Uricase, Urocortin, Uroplakin,
  • Vasopressin Vasopressin Receptor, VEGF, Vesicular acetycholine transport, (VACht ), Vesicular monoamine transporter (VMAT2), Villin, Vimentin, Vinculin, VIP (Vasoactive Intestinal Peptide), Vitamin B12, Vitamin B12, Vitamin D metabolites, Vitamin D3 Receptor, Von Willebrand Factor, VSV-G Epitope Tag, Wilm's tumor Protein X, Oxida, Yeast, hexokinase, SOD, cytochrome oxidase, carboxypeptidase, and Yersinia eterocolotica.
  • many of the substances noted above may in and of themselves be useful as targeting substances and may be inco ⁇ orated into the particles of the present invention.
  • other chemical compounds such as PEG may also be used for targeting and may be inco ⁇ orated. It is important to point out that in addition to targeting compounds per se, active compounds, functional excipients such as abso ⁇ tion enhancers, and other bioactive materials as gleaned from the lists of materials given herein can be inco ⁇ orated in any of these localization sites.
  • particles inco ⁇ orating certain radiopaque or optically dense materials could themselves be used for imaging, and when coupled to targeting compounds as described herein could target specific sites in the body and allow their visualization.
  • somatostatin receptors are known to be localized at certain tumor sites, so that the attachment of a target to coated particles as per the instant invention that would bind selectively to somatostatin receptors could target a tumor and allow visualization via, e.g., x- ray, MR imaging, or radioimaging.
  • a similarly targeted particle could then carry a radioactive material that would emit radiation intended to induce necrosis of the tumor.
  • the possibility of polymerizing the cubic phase in the interior of a particle of the instant invention opens up a number of possibilities, particularly as relate to increasing the stability of the interior phase and modulating its interaction with the body, and cell membranes in particular.
  • polymerization of the same interior matrix might create a particle interior that would retain its integrity throughout its interaction with the same biomembrane, and this could have dramatic consequences as to the fate of the particle and to a drug inside the particle.
  • bilayer-bound drug hydrophobic small molecule, membrane protein, etc.
  • polymerization yielding a slow- release particle.
  • a more permanent, precisely-defined pore structure, with precisely tunable poresize might make possible improved controlled release of a drug, and/or sequestration of the drug from degradative or other enzymes by size-exclusion from the pores of the polymerized matrix.
  • Examples 14, 15, 16, and 34 demonstrate systems with coatings made of physically robust mineral materials, such as cupric ferrocyanide and calcium phosphate, that can provide for stability of the intact particles under stronger shear conditions, such as during pumping of a dispersion of the coated particles, for example, for recycling or transport.
  • These minerals are also of low aqueous solubility, making them of potential interest in applications requiring release of the particle coating by strong shear, while at the same time protecting against release due to simple dilution with water.
  • a rodent deterrent such as capsaicin, or rodent toxin
  • a rodent deterrent such as capsaicin, or rodent toxin
  • the particles impregnated into electrical wires, corrugated boxes, and other products requiring protection against pawing by rodents, and the pawing action of a rodent would induce release of the active deterrent or toxin.
  • the low water solubility would prevent the deterrent from premature release due to damp conditions.
  • a robust organic material that provides a coating that is also of low aqueous solubility is ethylhydrocupreine, as in examples 17 and 33, and this compound has the additional characteristic that it has an extremely bitter taste that could provide an additional deterrent effect in a rodent-deterent application.
  • Examples 1, 2, 3, 6, 7, 8, 9, 10, 17, 18, 19, 20, 23 and 33 provide examples of coatings that are of low water solubility at neutral pH, but that increase substantially in solubility as the pH becomes either acidic or basic, depending on the compound.
  • This can make the coated particles of importance in, for example, drug delivery, where a coating that releases preferentially in a particular pH range is desired, such as for intestinal release. Or such a coating could release, allowing the release of an antibacterial compound, at sites of bacterial activity, where pH is typically acidic. Or the release of the coating at a particular pH could allow the release of a pH stabilizing compound or a buffer system, for example in microparticles designed to control the pH of water in swimming pools.
  • Example 4 gives an example of particles with a coating, silver iodide, that could provide very useful properties as a cloud-seeding agent, since the silver iodide coating is well-known for cloud-seeding effectiveness, and the surface area and surface mo ⁇ hology afforded by the particle shape and size could amplify the effect of the silver iodide. This could be of commercial importance due to the expense of silver compounds, in which case the inexpensive liquid crystal interior could serve the role as a filler that would provide the same or greater seeding potential at a fraction of the cost of simple silver iodide.
  • a similar increase in effectiveness due to amplification of surface area might prove of interest in the use of the particles as local anesthetics for mucous membranes, and the proper balance of lipids and active anesthetic hydrophobes (such as lidocaine) in the particle interior could be used to enhance the effect.
  • active anesthetic hydrophobes such as lidocaine
  • Example 5 demonstrates that compounds such as sulfides and oxides can be used as coatings in the coated particles of the present invention, even when they require gaseous reactants for formation.
  • Such compounds are well-known for being not only high-stiffness materials, but also chemically extremely resistant, which could make such coated particles of interest in applications where the particles encounter harsh chemical and physical conditions, such as would be expected in use of the particles as polymer additives, or in processing involving high shear, such as impregnation of dye-containing particles in nonwoven materials, etc.
  • Examples 12 and 13 demonstrate the use of high water-solubility compounds as coatings, that can be of importance in applications requiring quick and convenient release of the coating by simple dilution with water.
  • a spray system that would merge two streams, one containing the dispersion and the other water, could provide an aerosol in which the particle coating, useful for preventing agglomeration prior to spraying, would be dissolved after spraying when the particles were already aerosolized ⁇ in flight, so to speak. Since this dissolution could expose, for example, a nanostructured cubic phase interior that was very tacky, the particles could be used to adhere to, e.g., crops, or the bronchial lining, etc.
  • the capsaicin loaded into the interior in Examples 12 and 13 would make this product of potential importance in providing rodent resistance after deposition of the tackv aerosolized particles onto crops, for example, since rodents are generally strongly repelled by the taste of capsaicin even at very low concentrations.
  • Examples 39 and 40 demonstrate the use of amo ⁇ hous materials as exterior coatings for the particles of the present invention.
  • Example 39 utilizes the amo ⁇ hous polymer
  • Example 40 utilizes a small molecule (the sugar trehalose).
  • Examples 41 and 42 demonstrate variations in the processes used to create particles, and in particular they involve processes in which milling or particle size reduction are applied after formation of the coating material, in some cases in addition to sonication or microfluidization that is applied prior to coating material precipitation.
  • Examples 1 (part E), 27, 28 and 43 demonstrate the inco ⁇ oration of active targets, including receptors, lectins, and antibodies, in particles according to the instant invention, and the retention of their binding capabilities.
  • each coated particle comprises a nonlamellar material
  • each interior core comprises a matrix consisting- essentially of at least one nanostructured liquid phase, at least one nanostructured liquid crystalline phase or a combination of at least one nanostructured liquid phase and at least one nanostructured liquid crystalline phase.
  • Example 1 A 2.0 wt% of salicylic acid (based on the weight of the internal core of liquid crystalline phase material) was inco ⁇ orated as an active agent.
  • Example IB 2.0 wt% Vinblastine sulfate (based on the weight of the internal core of liquid crystalline phase material) was inco ⁇ orated as an active agent.
  • Example 1 C 2.4 wt% Thymidine (based on the weight of the internal core of liquid crystalline phase material) was inco ⁇ orated as an active agent.
  • Example 1 D 1.6 wt% Thyrotropic hormone (based on the weight of the internal core of liquid crystalline phase material) was inco ⁇ orated as an active agent.
  • Example 1 E 2.9 wt %> Anti 3', 5'cyclic AMP antibody (based on the weight of the internal core of liquid crystalline phase material) was inco ⁇ orated as an active agent.
  • Example 1 F 2.0 wt% L-Thyroxine (based on the weight of the internal core of liquid crystalline phase material) was inco ⁇ orated as an active.
  • Particles such as these with a coating which increases substantially in solubility as the pH increases could be useful in drug delivery, where the increase in pH moving along the gastrointestinal tract from the stomach to the intestines could result in effective delivery to the lower gastrointestinal tract, giving rise to a more uniform delivery rate over time.
  • This example demonstrates the long-term stability of a dispersion of particles of the present invention.
  • the amino acid D,L-leucine in the amount of 0.132 grams, was dissolved in 2.514 grams of 1 M hydrochloric acid, resulting in the formation of leucine hydrochloride in solution.
  • the solution was dried on a hot plate under flow of air, but was not allowed to dry to complete dryness: drying was stopped when the weight reached 0.1666 gram, which corresponds to one molar equivalent addition of HCl to the leucine.
  • An amount of 0.130 grams of this compound were added to 0.879 grams of a nanostractured reverse bicontinuous cubic phase material prepared by mixing sunflower oil monoglycerides and water, centrifuging, and removing the excess water.
  • An upper solution was prepared by mixing 1.0 grams of 1 M sodium hvdroxide with 3 grams of water. All water used was triply-distilled. The upper solution was overlaid on the cubic phase, the test tube sealed and sonicated, resulting in the formation of a milky- white dispersion of microparticles coated with leucine.
  • a similar dispersion was prepared with the use of Pluronic F-68 as stabilizer.
  • An amount of 0.152 grams of leucine hydrochloride was added to 0.852 grams of nanostructured reverse bicontinuous cubic phase material as above, and an upper phase consisting of 0.08 grams of F-68, 1.0 gram of 1 M sodium hydroxide, and 3.0 grams of water was overlaid on the nanostrucrured reverse bicontinuous cubic phase material and sonicated.
  • a milky- white dispersion of leucine-coated microparticles was formed, where this time the F-68 amphiphilic block copolymer surfactant coated the outer (leucine-based) surface of the particles.
  • the nanostructured reverse bicontinuous cubic phase material remained as large, macroscopic chunks even after several hours of sonication under the same conditions as the leucine experiment.
  • This dispersion of the coated particles of the present invention was examined regularly for a period of twelve months and did not show signs of irreversible flocculation. With even slight agitation, it showed no signs of irreversible flocculation over time scales of weeks. In the absence of agitation, it did show signs of flocculation, but upon mild shaking for 5 seconds or more, any flocculation reversed.
  • a droplet of the dispersion was examined in an Edge Scientific R400 3-D) microscope at 1,000 magnification (lOOx objective, oil immersion, transmitted light) and shown to have a very high loading of submicron particles.
  • Particles such as these, with relatively weak organic coatings can be used, for example, in acne creams, where an active material such as triclosan could be inco ⁇ orated and the shear associated with applying the material to the skin would release the coating.
  • paclitaxel was inco ⁇ orated at the level of 0.5% of the internal core.
  • the particle coating was leucine, which in other examples herein has been shown to provide longterm stability.
  • a paclitaxel-containing nanostructured reverse bicontinuous cubic phase material was produced by mixing 4 mg of paclitaxel, dissolved in 2 ml t-butanol, in a nanostructured reverse bicontinuous cubic phase material containing 0.280 gm lecithin, 0.091 gm of oleyl alcohol, and 0.390 am glycerol: after evaporation of the butanol under argon, a nanostructured reverse bicontinuous cubic phase material formed that was viscous and optically isotropic. The sample was centrifuged for one hour, during which time no precipitate appeared. Optical isotropy was verified in a polarizing optical microscope.
  • a leucine hydrochloride solution in glycerol was produced by mixing 0.241 grams of leucine, 2.573 grams of 1 M HCl, and 0.970 grams of glycerol, after which the water and excess HCl were evaporated under air flow on a 50°C hot plate, drying for three hours. Next, 0.882 grams of this leucine-HCl in glycerol solution were added to the nanostractured reverse bicontinuous cubic phase material. The upper solution was then prepared by adding 0.102 grams of Pluronic F-68 to 4.42 grams of an aqueous buffer at pH 5.0. After overlaying the upper solution onto the nanostractured reverse bicontinuous cubic phase material, the nanostructured reverse bicontinuous cubic phase material was dispersed into microparticles by sonicating for 2 hours.
  • Particles such as these could be used for the controlled release of the antineoplastic agent paclitaxel.
  • the coating was silver iodide, which has the potential to make the particles useful in photographic processes.
  • Silver iodide is somewhat unusual in that, even though it is a simple salt (with monovalent ions only), it has a very low solubility in water.
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.509 grams of Dimodan LS (commercially available as from Grinstedt AB and referred to herein as "sunflower monoglycerides”), 0.563 grams of triply-distilled water, and 0.060 grams of sodium iodide.
  • An upper solution was prepared by adding 0.220 grams of silver nitrate, 0.094 grams of Pluronic F-68, and 0.008 grams of cetylpyridinium chloride to 3.01 grams of water. A dispersion of microparticles was then produced by overlaying the upper solution onto the nanostructured reverse bicontinuous cubic phase material and sonicating for one hour. The particle coating was silver iodide, which has a low solubility in water.
  • cadmium sulfide was used as the coating. It is a nonlamellar crystalline compound that exhibits large changes in physical properties when doped with small amounts of other ions.
  • a gas such as hydrogen sulfide gas, can be used in the present invention to induce crystallization and particle formation.
  • a nanostructured reverse bicontinuous cubic phase material was prepared by thoroughly mixing 0.641 grams of Dimodan LS with 0.412 grams of water, and to this was added 0.058 grams of cadmium sulfate hydrate. After this, 0.039 grams of calcium sulfide was overlaid on the mixture, and the test tube was purged with argon gas and capped.
  • An upper solution was prepared by adding 0.088 grams of Pluronic F-68 and 1.53 grams of glycerol to 1.51 grams of IM HCl and then sparging the solution with argon. The upper solution was taken up in a syringe, and added to the first test tube.
  • a solution of leucine hydrochloride in water was made by mixing 0.122 grams of leucine with 1.179 grams of IM HCl and evaporating x til approximately 1 gram of solution remained. To this was added 0.922 grams of sunflower monoglycerides, and 10 drops of a strongly colored aqueous solution of methylene blue. An upper solution was produced by adding 0.497 grams of IM NaOH and 0.037 grams of Pluronic F-68 to 3.00 grams of pH 5 buffer. The upper solution was overlaid, the system sonicated, and a dispersion of microparticles formed. An aliquot of the dispersion was filtered to remove any undispersed liquid crystal, and 0.1 grams of 100 mesh zinc dust added.
  • EXAMPLE 7 In this example a leucine coating protects the methylene blue dye in the particle interior from contact with ferrous chloride, as easily seen by the absence of the expected color change when ferrous chloride is added to the dispersion. This indicated that the coating was substantially impermeable even to ions.
  • a solution of leucine hydrochloride in glycerol was made by mixing 0.242 grams of leucine, 2.60 grams of IM HCl, and 1.04 grams of glycerol, and then drying on a 50°C hot
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing this leucine-HCl solution, 0.291 agams of lecithin (Epikuron 200, from Lucas-Meyer), 0.116 grams of oleyl alcohol, and 0.873 grams of glvcerol; this was colored by the addition of a pinch of methylene blue.
  • An upper solution was prepared by adding 0.042 grams of Pluronic F-68 surfactant to 4.36 grams of pH 5 buffer, overlaid on the nanostructured reverse bicontinuous cubic phase material, and the system sonicated to produce a dispersion of microparticles.
  • Example 6 shows that encapsulated compounds such as methylene blue which are sensitive to, in this case, reducing agents, can be protected against reducing conditions outside the particle until release of the coating. This could be useful in, for example, electrochemical applications where the effect of application of electrical current would be gated by the chemical release of the coating.
  • Example II when considered along with Example IA and Example 10, demonstrates that particles of the present invention coated with methyl paraben can be produced in two entirely different ways: either by a thermal process, such as a heating-cooling method, or by a chemical reaction, such as an acid-base method.
  • a thermal process such as a heating-cooling method
  • a chemical reaction such as an acid-base method
  • a nanostructured reverse bicontinuous cubic phase material produced by mixing 0.426 grams of sunflower monoglycerides (Dimodan LS) with 0.206 grams of acidic water at pH 3, were added 0.051 grams of methyl paraben and a trace of methylene blue dye. The mixture was heated to 110 °C, shaken and put on a vibro-mixer, and plunged into 23 °C water for 5 minutes. Two milliliters of a 2%> Pluronic F-68 solution, acidified to pH 3 with HCl were overlaid, the test tube scaled with a twist cap, and the tube shaken and then sonicated for 30 minutes. This produced a dispersion of microparticles coated with methylparaben.
  • Example 10 Since this experiment alone with Example 10 demonstrate that particles coated with the same compound,n this case methyl paraben, can be produced either by a thermal method or by a chemical precipitation method, this provides an extra degree of versatility which can be important in optimizing production efficiency and minimizing costs, for example in large- scale pharmaceutical production of microencapsulated drags.
  • the nanostractured reverse bicontinuous cubic phase material in this example is based on nonionic surfactants, which are generally approved for drug formulation, and which yield liquid crystalline phase materials with properties tunable by small temperature changes.
  • nonionic surfactants which are generally approved for drug formulation, and which yield liquid crystalline phase materials with properties tunable by small temperature changes.
  • this could be used to achieve detergent (cleansing) properties at the temperature of application, but insolubility at the temperature of formulation.
  • this since it is based on a tuned mixture of two surfactants, and since the phase and properties thereof depend sensitively on the ratio of the two surfactants, this provides a convenient and powerful means to control the properties of the internal core.
  • this example resulted in a transparent dispersion. This is noteworthy because even a small fraction of particles with a size larger than about 0.5 microns gives rise to an opaque dispersion.
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.276 grams of "OE2" (an ethoxylated alcohol surfactant commercially available as “Ameroxol OE-2", supplied by Amerchol, a division of CPC International, Inc.) with 0.238 grams of "OE5" (an ethoxylated alcohol surfactant commercially available as “Ameroxol OE- 2", supplied by Amerchol, a division of CPC International, Inc.), and adding 0.250 grams of water (includes excess water). To this was added 0.054 grams of methyl paraben and a trace of methylene blue dye. The mixture was heated to 110° C, shaken and put on a vibro-mixer, and plunged into 23 C water for 5 minutes.
  • OE2 an ethoxylated alcohol surfactant commercially available as "Ameroxol OE-2", supplied by Amerchol, a division of CPC International, Inc.
  • OE5 an ethoxylated alcohol surfactant
  • This example shows that methyl paraben-coated particles can be created by a heating- cooling process, in addition to the acid-base method of the previous example. This example also demonstrates that a mixture of two phases can be dispersed.
  • Lecithin (Epikuron 200, 0.418 grams) was mixed with 0.234 grams of oleyl alcohol and 0.461 grams of acidic water at pH 3, resulting in a mixture of nanostructured reverse bicontinuous cubic phase material and nanostructured reversed hexagonal phase material. Out of this was taken 0.50 grams, to which were added 0.049 grams of methyl paraben, and mixed well. This was heated to 120°C, stirred while hot, then reheated to 120°C. The test tube was removed from the oven, and the test tube plunged into cold water for 5 minutes.
  • This example demonstrates that a mixture of two co-existing nanostructured phases can provide the interior of the microparticles.
  • This example shows that water-free particle interiors can be produced, such as for protection of water-sensitive compounds.
  • Example 10 The same procedure used in the preparation of Example 10 was used, but the water was replaced by glycerol (which was present in excess) in the preparation of the nanostractured bicontinuous reversed cubic phase liquid crystalline material.
  • the amounts were: lecithin 0.418 grams, oleyl alcohol 0.152 grams, glycerol 0.458 grams, and methyl paraben 0.052 grams.
  • the result was a milky- white dispersion of microparticles coated with methyl paraben.
  • the protection of water-sensitive active compounds is important in, for example, oral health care products inco ⁇ orating actives that are hydrolytically unstable.
  • capsaicin was inco ⁇ orated in particles coated with potassium nitrate, and where the nanostructured reverse bicontinuous cubic phase material is based on extremely inexpensive surfactants.
  • the coating is easily removed by simply adding water ⁇ such as in a crop-spraying gun which merges a stream of the dispersion with a stream of water, as it aerosolizes the liquid into droplets.
  • the potassium nitrate would serve a dual pu ⁇ ose as a fertilizer.
  • the nonionic surfactants "OE2" 0.597 grams
  • OE5" 0.402 grams
  • the active compound capsaicin in pure crystalline form, obtained from Snyder Seed Co ⁇ oration
  • 0.552 grams of this mixture were removed, 0.135 grams of potassium nitrate were added, and the complete mixture heated to 80°C for 5 minutes.
  • An upper solution was prepared by taking a 2%> aqueous solution of Pluronic F-68 and saturating it with potassium nitrate. The melted mixture was shaken to mix it, then put back in the 80°C oven for 2 minutes.
  • test tube was the plunged in 20°C water for 5 minutes, at which point the upper solution was overlaid, and the entire mix stirred with a spatula, capped, shaken, and sonicated.
  • the result was a dispersion of microparticles coated with potassium nitrate, and containing the active ingredient capsaicin in the interior.
  • the coating was dissolved (in accordance with the high solubility of potassium nitrate in water at room temperature), and this was manifested as a rapid coagulation and fusion of the particles into large clumps.
  • the interior of each particle was a tacky liquid crystal, so that in the absence of a coating, flocculation and fusion occur.
  • capsaicin is a non-toxic compound (found in red peppers and paprika) that causes a burning sensation in the mouth at concentrations in the range of a few parts per million.
  • capsaicin has a record of commercial use as a deterrent to rodents and other animals.
  • the concentration of capsaicin achieved in the cubic phase particles was two orders of magnitude higher than in pharmaceutical preparations used in the treatment of arthritis.
  • potassium nitrate is a well-known fertilizer.
  • This example used capsaicin / potassium nitrate as in the previous example, but here the nanostructured reverse bicontinuous cubic phase material is based on lecithin, which is an essential compound in plant and animal life, and can be obtained cheaply.
  • This nanostructured reverse bicontinuous cubic phase material is also stable over a wide temperature range, at least to 40°C as might be encountered under normal weather conditions.
  • Soy lecithin (Epikuron 200), in the amount of 1.150 grams, was mixed with 0.300 grams of oleyl alcohol, 1.236 grams of glycerol, and 0.407 grams of potassium nitrate. The active capsaicin was added to this in the amount of 0.150 grams, and the mixture thoroughly mixed.
  • the applications are similar to those of Example 12, except that the use of lecithin in the interior could provide for better integration of the particle interior with the plant cell membranes, possibly yielding better delivery.
  • cupric ferrocyanide-coated particles were shown to be resistant to shear.
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.296 grams of sunflower monoglycerides (Dimodan LS) with 0.263 grams of a 10%> aqueous solution of potassium ferrocyanide.
  • An upper solution was prepared by adding 0.021 grams of cupric sulfate and 0.063 grams of Pluronic F-68 to 4.44 grams of water.
  • the upper solution was overlaid onto the nanostructured reverse bicontinuous cubic phase material, the test tube sealed with a twist cap, and the system sonicated for 45 minutes.
  • the result was a high concentration of microparticles, coated with cupric ferrocyanide, and with diameters on the order of 3 microns. This process produces microparticles without requiring temperature excursions, except those associated with sonicating, and these can be circumvented by using another form of emulsification. Furthermore, no excursions in pH were required.
  • cupric ferrocyanide-coated particles were fairly resistant to shear; when the cover slip was massaged over the dispersion, light pressure with the fingers did not induce any noticeable loss of shape or fusion of the particles. This was in contrast with, for example, particles coated with magnesium carbonate hydroxide, where light pressure induced a high degree of shape loss and fusing of particles.
  • Particles with coatings resistant to shear could be important in applications requiring pumping of the particles, where traditional polymer-coated particles are known to suffer lifetime limitations due to degradation of the coating with shear.
  • capsaicin was inco ⁇ orated at a fairly high loading, namely 9 wt %>, into the interiors of crystal-coated particles of the present invention.
  • a nanostractured reversed bicontinuous cubic phase was produced by mixing 0.329 grams of lecithin, 0.109 grams oleyl alcohol, 0.611 grams glycerol, and 0.105 grams of capsaicin (obtained in crystalline form as a gift from Snyder Seed Co ⁇ ., Buffalo, NY). To this cubic phase were added 0.046 grams of cupric sulfate.
  • An upper solution was prepared by mixing 0.563 grams of 10%) potassium ferrocyanide aqueous solution with 2.54 grams of water.
  • the upper solution was overlaid onto the cubic phase-cupric sulfate mixture, and the tube sonicated for two hours.
  • the reaction that forms cupric ferrocyanide was easily evidenced by the deep reddish-brown color of the compound.
  • the cubic phase was dispersed into cupric ferrocyanide-coated particles.
  • the coating was made of cupric ferrocyanide, which is a strong material and has some selective permeability to sulfate ions.
  • this coating material is a robust crystal, as seen from Example 14, and capsaicin is extremely unpleasant to the taste of rodents, these particles could be useful as rodent deterrents in preventing damage to corrugated boxes, agricultural plants, etc., particularly where the particles must be resistant to mild shear (as during production of the particle-laced boxes, or deposition of the particles onto plants), prior to the gnawing action of rodents which would open the microparticles and expose the capsaicin to the animal's tastebuds.
  • microparticles with a cupric ferrocyanide coating were produced using the same procedure as in Example 14, but in this case an antibody was inco ⁇ orated as the active agent.
  • anti 3', 5' cyclic adenosine monophosphate (AMP) antibody was inco ⁇ orated as an active agent at a loading of 1 wt% of the interior.
  • a cubic phase was prepared by mixing 0.501 grams of sunflower monoglycerides with 0.523 grams of water. Potassium ferrocyanide, in the amount of 0.048 grams, was added to the cubic phase, together with approximately 0.010 grams of the antibody. Excess aqueous solution was removed after centrifuging.
  • An upper solution was prepared by adding 0.032 grains of cupric nitrate and 0.06 grams of Pluronic F-68 to 3.0 grams of water. After overlaying the upper solution and sonicating, a milky- white dispersion of microparticles, coated with cupric ferrocyanide, was obtained. Such particles could be useful in a biotechnology setting such as a bioreactor, in which the stiff cupric ferrocyanide coating would be useful in limiting release during mild shear conditions encountered (for example, in a pressurized inlet), prior to the desired release of coating and availability of the bioreactive antibody.
  • EXAMPLE 17 In this example ethylhydrocupreine forms an extremely hard shell. In this example an acid-base process was used.
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.648 grams of sunflower monoglycerides (Dimodan LS) with 0.704 grams of water. To this were added 0.084 grams of ethylhydrocupreine hydrochloride, and a trace of methylene blue.
  • An upper solution was prepared by adding 1.01 grams of 0. IM sodium hydroxide and 0.052 grams of Pluronic F-68 to 3.0 grams of water. After overlaying the upper solution onto the liquid crystal, the system was sonicated, resulting in a dispersion of microparticles coated with ethylhydrocupreine (free base). Most of the particles were less than a micron in size, when examined with optical microscopy. Particles which maintain integrity with dessication could be useful in, for example, slow-release of agricultural actives (herbicides, pheromones, pesticides, etc.), where dry weather conditions could cause premature release of less resistant particles.
  • agricultural actives herebicides,
  • leucine-coated particles were created by a heating-cooling protocol.
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 1.51 grams of sunflower monoglycerides (Dimodan LS) with 0.723 grams of water. To 0.52 grams of the nanostractured reverse bicontinuous cubic phase material taken from this mixture were added 0.048 grams of DL-leucine. The mixture was stirred well and heated to 80° C, then cooled to room temperature by plunging in water. Immediately a 2% solution of Pluronic F-68 in water was overlaid, the mixture shaken, and then sonicated. This resulted in a milky dispersion of microparticles coated with leucine.
  • the ability to make the same coating (in this case leucine) by either a thermal method or an acid-base method provides important flexibility in production, since, for example, certain actives (proteins, for example) are very easily denatured with temperature but can be quite resistant to pH, whereas other compounds can be resistant to temperature but can hydrolyze at acidic or basic pH.
  • This example shows that interior components can be protected from contact with oxygen, even when oxygen was bubbled into the exterior medium (here water).
  • a nanostractured reverse bicontinuous cubic phase material (with excess water) was prepared by mixing 2.542 grams of sxmflower monoglycerides with 2.667 grams of water. From this, 0.60 grams of nanostructured reverse bicontinuous cubic phase material were removed. Next, 0.037 grams of DL-leucine and 0.497 grams of IM HCl were mixed and dried, after which 0.102 grams of water were added, to yield a solution of leucine hydrochloride, which was added to the 0.60 grams of nanostructured reverse bicontinuous cubic phase material, along with a trace of methyl red dye.
  • the nanostractured reverse bicontinuous cubic phase material was a strong yellow color, but when spread out as a film it turned crimson-red in about 3 minutes, due to oxidation.
  • An upper solution was prepared by mixing 0.511 grams of IM sodium hydroxide, 0.013 grams of Pluronic F-68, and 2.435 of water.
  • a dispersion of leucine-coated, methyl red-containing microparticles was prepared by overlaying the upper solution onto the liquid crystal and sonicating. It was first checked that a solution of methyl red in water, with or without F-68 added, quickly changes from yellow to crimson-red when air was bubbled through.
  • Particles such as these which are able to protect the active compound from contact with oxygen could be useful in protecting oxygen-sensitive compounds, such as iron dietary supplements for example, during long storage.
  • the water substitute glycerol was used both in the interior nanostructured reverse bicontinuous cubic phase material, and as the exterior (continuous) coating, thus substantially excluding water from the dispersion.
  • a dispersion of microparticles was prepared using glycerol instead of water, by mixing soy lecithin and oleyl alcohol in the ratio 2.4:1, then adding excess glycerol and mixing and centrifuging.
  • An amount of 0.70 grams of this nanostructured reverse bicontinuous cubic phase material was mixed with 0.081 grams of methyl paraben.
  • An upper solution was prepared by adding cetylpyridinium bromide to glycerol at the level of 2%.
  • the nanostractured reverse bicontinuous cubic phase material-methyl paraben mixture was sealed and heated to 120°C, mixed well, reheated to 120°C, and then plunged into cold water, at which point the upper solution was overlaid and the test tube re-sealed (with a twist-cap) and sonicated. This resulted in microparticles, coated with methyl paraben, in a glycerol continuous phase. Such a glycerol-based dispersion is of interest in the microencapsulation of water-sensitive actives.
  • microparticle dispersions such as these, hydrolytically unstable actives, which are encountered in a wide range of applications, can be protected against contact with water even after release of the coating.
  • EXAMPLE 21 Similar to Example 6 above, where zinc is used to challenge encapsulated methylene blue, but here the coating is potassium nitrate. In addition, the same dispersion is also subjected to challenge by potassium dichromate.
  • a nanostractured reverse bicontinuous cubic phase material was prepared by mixing 0.667 grams of soy lecithin, 0.343 grams of oleyl alcohol, 0.738 grams of glycerol, and a trace of methylene blue. To 0.469 grams of the equilibrated phase was added 0.225 grams of potassium nitrate. An upper solution was prepared by adding 2% Pluronic F-68 to a saturated aqueous solution of potassium nitrate. This was overlaid onto the liquid crystal, and the system sonicated until the liquid crystal was dispersed into microparticles, coated with potassium nitrate. The color of the dispersion was light blue.
  • potassium dichromate was added to another aliquot of the original light-blue dispersion. This changed the color to a greenish color, with no hint of the pxi ⁇ lish-brown that results if methylene blue in solution were contacted with potassium dichromate.
  • Coated particles of this Example feature an extremely cost-effective coating material, potassium nitrate, and yet protect active compounds against chemical degradation from outside conditions, making them of potential importance in, for example, agricultural slow- release.
  • microparticles with a permselective coating of a inclusion compound This particular inclusion compound, a so-called Werner complex, has the property that the porosity remains when the guest molecule is removed.
  • Clathrate and inclusion compound coatings are of interest as coatings of selective porosity, where selectivity for release or abso ⁇ tion can be based on molecular size, shape, and/or polarity.
  • a nanostructured reverse bicontinuous cubic phase material was first prepared by mixing 0.525 grams of sunflower monoglycerides and 0.400 grams of water. To this were added 0.039 grams of manganese chloride (MnCl 2 ) and 0.032 grams of sodium thiocyanate. An upper solution was prepared by adding 0.147 grams of 4-picoline (4-methylpyridine) to 3.0 ml of a 2% aqueous solution of Pluronic F-68. The upper solution was overlaid on the liquid crystal mixture, and the test tube sealed and sonicated.
  • MnCl 2 manganese chloride
  • Pluronic F-68 Pluronic F-68
  • the nanostractured reverse bicontinuous cubic phase material was thus dispersed into microparticles coated with the manganese form of the Werner complex, namely Mn(NCS) 2 (4-MePy) 4 .
  • the coating in this example may find use in the removal of heavy metals from industrial streams.
  • the coating can be a porous crystal — known as a clathrate ⁇ which permits atomic ions to pass across the coating and into the cubic phase interior, which is an extremely high-capacity absorbent for ions due to the high surface charge density (using an anionic surfactant, or more selective chelating groups such as bipyridinium groups, etc.). Most likely permanent pores would be the best.
  • the selectivity afforded by the clathrate coating circumvents the reduction in sorbent power that is inevitable with traditional sorbents (such as activated carbon and macroreticular polymers), due to larger compounds that compete with the target heavy metal ions for the available adso ⁇ tion sites. Regeneration of the sorbent could be by ion-exchange, while keeping the particles and coatings intact (this latter step would, incidently, be an example of release).
  • traditional sorbents such as activated carbon and macroreticular polymers
  • coated particles with an outer coating comprising methyl paraben and having a special dye disposed in the nanostractured reverse bicontinuous cubic phase material were challenged with a cyanide compound, which would cause a color change in the event of contact with the dye. Since the cyanide ion is extremely small, the success of this test shows that the coating is impervious even to very small ions.
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.424 grams of sunflower monoglycerides and 0.272 grams of water. To this were added 0.061 grams of methyl paraben and a trace of the dye l,2-pyridylazo-2 -naphthol. An upper solution of 1% cetylpyridinium bromide was prepared. The liquid crystal was heated in a
  • cuprous cyanide was added to an aliquot of the dispersion of dye-containing particles, there was no color change, showing that the dye was protected from contact with the cuprous cyanide by the methyl paraben coating.
  • the protection of active compounds from contact with ions from the outside environment could be useful in, for example, drug delivery, in particular in delivery of a polyelectrolyte which could be complexed and inactivated by contact with multivalent ions.
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.434 grams of sunflower monoglycerides and 0.215 grams of water. To this were added
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.913 grams of soy lecithin (Epikuron 200), 0.430 grams of oleyl alcohol, and 0.90 grams of glycerol (excess glycerol). After mixing thoroughly and centrifuging, 0.50 grams of the nanostructured reverse bicontinuous cubic phase material were removed and 0.050 grams of dibasic sodium phosphate added.
  • An upper solution was prepared by adding 0.10 grams of calcium chloride to 3 ml of an aqueous solution containing 2% Pluronic F-68 and 1%> cetylpyridinium bromide. After overlaying the upper solution on the liquid crystal - sodium phosphate mixture, the test tube was sealed and sonicated. The result was a dispersion of microparticles coated with a calcium phosphate. Calcium phosphate coatings were of inherent interest in biological contexts since calcium phosphates were a major component of bone, teeth, and other structural components.
  • Example 26A A nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.110 grams of the "tung-sorbitol product", 0.315 grams of soy lecithin, and 0.248 grams of water, mixing thoroughly, and centrifuging. To this was added 0.085 grams of potassium carbonate. An upper solution was then prepared by adding 0.118 grams of Pluronic F-68 and 0.147 grams of magnesium sulfate to 5.34 grams of water. The upper solution was overlaid onto the liquid crystal, and the test tube sealed, shaken, sonicated for 2 hours, and finally shaken well again. The result was a milky- white dispersion of microparticles coated with magnesium carbonate hydroxide.
  • Example 26B The dispersion produced in Example 26A was heated to 40° C. According to phase behavior determinations, at this temperature the interior phase was a nanostractured liquid L2 phase material. The dispersion remained milky-white, and under the microscope showed the retention of microparticles as well. Since this L2 phase contains oil, water, and surfactant (namely the lecithin), it was also a nanostructured microemulsion.
  • EXAMPLE 27 receptor proteins are disposed within the matrix of a nanostractured reverse bicontinuous cubic phase material in the internal core of magnesium carbonate-coated particles, then the coated particles were in turn embedded in a hydrogel.
  • the coating on the particles can be used to protect the receptor protein during shipping and storage, and then easily removed by washing just before use.
  • This example and Example 28 presage the use of coated particles of the present invention for, e.g., affinity chromatography, using hydrogel beads with coated particles of the present invention embedded in them.
  • the hydrogel was furthermore fragmented into bits with size approximately 30 microns. This was accomplished by pressing the hydrogel through a wire mesh with a 40 micron mesh size.
  • receptor proteins were disposed in the internal core of coated particles of the present invention where the coating was potassium nitrate, and the coated particles in turn immobilized in hydrogel beads.
  • the receptor-laden beads were successfully tested for binding activity in radioassays performed at UC Davis.
  • An amount of 0.470 grams of soy lecithin (Epikuron 200) was mixed with 0.185 grams of the "tung-sorbitol product" (described above), and 0.368 grams of water. To this was added 0.198 grams of potassium nitrate, and the contents thoroughly mixed.
  • a preparation of to ⁇ edo nicotinic acetylcholine receptor was prepared as described in the previous Example.
  • the upper solution was overlaid onto the test tube containing the receptor-loaded nanostractured reverse bicontinuous cubic phase material, and the test tube sealed, shaken, and sonicated for 2 hours. This resulted in a dispersion of potassium nitrate-coated, receptor-containing microparticles, a substantial fraction of which were in the size range of 0.3 to 1 micron.
  • microparticles were then immobilized in a polyacrylamide hydrogel.
  • Acrylamide (0.365 grams), methylene-bis-acrylamide (0.049 grams, as crosslinker), ammonium persulfate (0.072 grams of a 2%> solution, as initiator), and tetramethylethylene diamine (TMED, 0.011 grams, as co-initiator) were added to the dispersion, resulting in polymerization of the acrylamide into a crosslinked hydrogel in a matter of hours.
  • TMED tetramethylethylene diamine
  • the hydrogel was furthermore fragmented into bits with size approximately 30 microns. This was accomplished by pressing the hydrogel through a wire mesh with a 40 micron mesh size. At a 40 micron bit size, one can estimate that the diffusion time for a small molecule into the center of a bit is on the order of a second or less, which does not have a significant impact on the receptor tests reported next.
  • EXAMPLE 29 As in Example 22 above, clathrate-coated particles were produced in this example.
  • the nanostructured reverse bicontinuous cubic phase material interior can be polymerized, by the effect of oxygen which can pass through the coating (the coating nevertheless prevents passage of water).
  • Lecithin extracted from Krill shrimp was obtained as Krill shrimp phosphatidylcholine from Avanti Polar Lipids of Birmingham, Alabama. An amount of 0.220 grams of this lecithin was mixed with 0.110 grams of "tung-sorbitol product", 0.220 grams of water, 0.005 grams of a cobalt dryer (from the art materials supply company Grumbacher) containing cobalt naphthenate, and 0.30 grams of potassium thiocyanate. This formed a green-colored nanostractured reverse bicontinuous cubic phase material.
  • An upper solution was prepared by adding 0.309 grams of manganese chloride, 0.105 grams of 4- picoline (4-methyl pyridine), 0.113 grains of Pluronic F-68, and 0.021 grams of cetylpyridinium bromide to 5.10 grams of water.
  • the upper solution was overlaid on the nanostructured reverse bicontinuous cubic phase material, the test tube sealed, shaken, and sonicated, with ice water filling the sonication bath water.
  • the reaction caused a color change to brown.
  • substantially all of the nanostructured reverse bicontinuous cubic phase material had been dispersed into particles, which were mostly submicron in size.
  • the coating was a Werner compound, which according to the literature has channels that allow the abso ⁇ tion of (or passage of) molecular oxygen.
  • a nanostractured reversed hexagonal phase material was prepared by mixing 0.369 grams of soy lecithin (Epikuron 200), 0.110 grams of sorbitan trioleate, and 0.370 grams of glycerol. To this nanostructured reversed hexagonal phase material was added 0.054 grams of magnesium sulfate. An upper solution was prepared by adding 0.10 grams of potassium carbonate, 0.10 grams of Pluronic F-68, and 0.02 grams of cetylpyridinium bromide to 5 grams of water.
  • the upper solution was overlaid on the nanostructured reversed hexagonal phase material, and the test tube sealed, shaken and sonicated for one hour, resulting in a dispersion of most of the nanostructured reversed hexagonal phase material into microparticles coated with magnesium carbonate hydroxide.
  • the dimensionality of the pores (cylindrical) in the reversed hexagonal phase provides a unique release kinetics profile which could be useful in, for example, controlled drug delivery.
  • Soy lecithin (0.412 grams), linseed oil (0.159 grams), and glycerol (0.458 grams) were thoroughly mixed, producing a nanostractured reversed hexagonal phase material at room temperature.
  • To this nanostractured reversed hexagonal phase material was added 0.059 grams of magnesium sulfate.
  • An upper solution was prepared by adding 0.10 grams of potassium carbonate, 0.10 grams of Pluronic F-68, and 0.02 grams of cetylpyridinium bromide to 5 grams of water.
  • the upper solution was overlaid on the nanostructured reversed hexagonal phase material, and the test tube sealed, shaken and sonicated for 30 minutes, resulting in a dispersion of most of the nanostractured reversed hexagonal phase material into microparticles coated with magnesium carbonate hydroxide.
  • the nanostractured lamellar phase material was dispersed using a chemical reaction process.
  • a nanostractured lamellar phase material was prepared by mixing 0.832 grams of soy lecithin (Epikuron 200) and 0.666 grams of water. To approximately 0.80 grams of this nanostructured lamellar phase material was added 0.057 grams of magnesium sulfate.
  • An upper solution was prepared by adding 0.10 grams of potassium carbonate, 0.10 grams of Pluronic F-68, and 0.02 grams of cetylpyridinium bromide to 5 grams of water.
  • the upper solution was overlaid on the nanostractured reversed hexagonal phase material, and the test tube sealed, shaken and sonicated for five minutes, resulting in a dispersion of most of the nanostructured lamellar phase material into microparticles coated with magnesium carbonate hydroxide.
  • the particles in this Example bear a structural relationship with polymer-encapsulated liposomes, but do not suffer from the harsh chemical conditions used to produce polymer- encapsulated liposomes; the ability to produce, in a single step, lamellar phase-interior particles coated with a wide range of crystalline coatings, and under mild conditions, could make the present invention of importance in controlled release drag delivery.
  • the sealed (twist-cap) test tube was put in a 140° C oven for at least 20 minutes, and the ethylhydrocupreine (or neutral red free base) was checked to have melted.
  • the test tube was then plunged into water, which was below room temperature (about 10° C) in some cases and room temperature water in others; no difference was found in the dispersions in the two cases.
  • the viscosity was checked to be very high, indicating a nanostructured reverse bicontinuous cubic phase; in some cases the sample was observed through crossed polars for optical isotropy (the crystalline coating domains are much smaller than the wavelength of light, too small to affect the optical properties).
  • the Pluronic upper solution was poured into the test tube until about half full. The tube was then shaken, by hand and with the use of a mechanical mixer. The solution became increasingly opaque as the bulk nanostructured reverse bicontinuous cubic phase material disappeared and went into dispersion. SEM characterization. Scanning electron microscope (SEM) preparation did not involve any fixation technique whatsoever.
  • a drop of dispersion was simply placed on a glass slide, the water evaporated, and a thin (2 nm) coating of carbon sputtered on to avoid charging effects.
  • the sample was deliberately held for about 5 minutes at a vacuum of 5 x 10 "4 Torr. This was done to test the robustness of the particle coating.
  • the SEM used was a Hitachi S-800 field-emission SEM, and was operated at 25 kV.
  • Figure 3 shows an SEM micrograph of an ethylhydrocupreine dispersion, and particles in the range of about 0.5-2 micron diameter are seen (the bottom half is a lOx magnification of the area boxed in the top half, so that the magnification is 500 on top and 5,000 on the bottom). Many of the particles, remarkably, distinctly show a polyhedral shape.
  • the measured particle size distribution for this sample (see the next section) showed that particles on the order of 0.5 - 2 microns diameter dominate in this dispersion, and this agrees well with the particles seen in the micrograph.
  • the thickness of the ethylhydrocupreine coating in a 0.5 micron particle was about 10 nm, and this was clearly thick enough that it was able to protect the liquid components in the interior of the particles from evaporation in the 0.5 mTorr vacuum.
  • the nanostructured reverse bicontinuous cubic phase material was loaded with lithium sulphate as a marker before dispersing, and indeed the EDX spectra of particles in this dispersion showed a sulfur peak. Lithium cannot be detected by the EDX used, and other peaks in the spectrum were attributed to the glass substrate.
  • Figure 4 shows an SEM micrograph of a neutral red dispersion. Substantially all of the particles have sizes in the range of 0.3 - 1 micron.
  • Particle size distribution A Malvern 3600E laser diffraction particle sizer was used to measure the distribution. For each dispersion checked, a few drops were added to the carrier fluid (water), resulting in a large dilution of the concentration so as to avoid multiple scattering. The particle size was computed as the diameter of a sphere of the same volume, which is a good measure considering the polyhedral shape of the particles. (See below.) The instrument is capable of measuring particles down to at least 0.5 micron, and data on the distribution include contributions at least down to 0.5 microns.
  • the particle size distribution of a dispersion prepared with a 13:1 ratio of GMO:ethylhydrocupreine is shown in Figure 5.
  • a small particle size was measured for a dispersion prepared with a lower GMO: ethylhydrocupreine ratio, with a distribution averaging 0.8 microns, and a span of 1.2.
  • particle size can be controlled by the ratio of nanostractured reverse bicontinuous cubic phase material to crystalline coating agent, with the particle size decreasing with decreasing ratio.
  • SAXS Small-angle X-ray scattering
  • the MCA has the capacity for 8,192 channels, but only 2,048 resolution was used to increase the counts per channel. Counting times on the order of an hour were used because the volume fraction of nanostructured reverse bicontinuous cubic phase material in the dispersion (which was about 85% of the particle volume) was on the order of 10%.
  • the software package "PCA" was used for analysis of the data.
  • Figure 6 shows the measured SAXS intensity versus wave vector q plot.
  • the wave vector q is related to the diffraction angle ⁇ and the wavelength ⁇ of x-rays by the formula: q - 4 ⁇ (sin ⁇ )/ ⁇ .
  • the Miller indices (hkl) for the allowed peak positions, and the value of h 2 +k 2 +l 2 are: (110), 2; (111), 3; (200), 4; (211), 6; (220), 8; (221), 9; (222), 12; and higher. Looking at the data and the expected peak positions, it is clear that the peaks at the (110) and (222) positions are strongly supported by the data.
  • the (111) peak appears as a shoulder to the (110) peak on the right side of the scan, and as a small but discernible peak on the left side.
  • the (200) peak is supported at least on the right side of the scan; this peak is always measured to be much less intense than the (110) and (111) peaks in monoglyceride Pn3m phases, and in Pn3m phases in general, and this has been found to be in accord with theoretical amplitude calculations [Strom, P. and Anderson, D.M. (1992) Langmuir, 8:691].
  • the (211) peak is supported by data on the left side of the scan, and the (221) by data on the right side.
  • High-performance liquid chromatography was used to characterize the integrity under shear and pressure of two dispersions, one chosen to have a rigid coating ⁇ cupric ferrocyanide ⁇ and the other a soft, easily disrupted coating, the latter, to act essentially as a control, to quantify any release under pressure of the more rigid coating.
  • concentration of marker in the two dispersions were approximately the same, and the release of marker in the rigid system were a small fraction, say. x% (where x is substantially less than 100), of the release of marker in the soft system, then one could conclude that only x%> of the particles in the rigid system broke up under the pressure, and the remaining (100 - x)%> remained intact during the HPLC.
  • this percentage 100 - x is a lower limit; the actual percentage of intact rigid particles would be calculated to be higher if it were found that some fraction of the soft particles in the control had actually remained intact, though this possibility is remote. In any case, the calculations were assumed to be on a worst case scenario, by assuming that all the control particles broke up.
  • Example 34A A nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.499 grams of soy lecithin, 0.163 grams of oleyl alcohol, 0.900 grams of glycerol, and 0.1.24 grams of capsaicin. To 0.842 grams of the nanostructured reverse bicontinuous cubic phase material from this system was added 0.043 grams of sodium cholate. An upper solution was prepared by adding 1 drop of IM HCl to 3.00 grams of pH 5 phosphate buffer. The upper solution was overlaid onto the liquid crystalline material, and the test tube sealed and sonicated, resulting in a milky- white dispersion of microparticles.
  • Example 34B A nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.499 grams of soy lecithin, 0.163 grams of oleyl alcohol, 0.900 grams of glycerol, and 0.1.24 grams of capsaicin. To 0.842 grams of the nanostructured reverse bicontinuous cubic phase material from this system was added 0.0
  • a nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.329 grams of soy lecithin, 0.108 grams of oleyl alcohol, 0.611 grams of glycerol, and 0.105 grams of capsaicin. To this were added 0.046 grams of cupric sulfate.
  • An upper solution was prepared by adding 0.563 grams of 10% potassium ferrocyanide solution to 2.54 grams of water. The upper solution was overlaid onto the liquid crystal and the test tube sealed and sonicated, resulting in a milky- white dispersion of microparticles coated with cupric ferrocyanide. The concentration of marker, namely capsaicin, was comparable in the two samples.
  • Table 1 gives the integrated intensity of this peak as 3,939,401.
  • Table 2 gives the intensity as 304.29.
  • the ratio of the normalized peak intensity for the cupric ferrocyanide case to the Example 34B case is 0.101 ⁇ that is, at most 10.1% of the cupric ferrocyanide particles released the capsaicin marker under the HPLC conditions.
  • These particles have a coating which is a mineral of low aqueous solubility, making them of potential utility in applications requiring release of the particle coating by strong shear, while at the same time protecting against release due to simple dilution with water.
  • a rodent deterrent such as capsaicin, or rodent toxin
  • the particles impregnated into electrical wires, corrugated boxes, and other products requiring protection against gnawing by rodents, and the gnawing action of a rodent would induce release of the active deterrent or toxin.
  • the low water solubility would prevent the deterrent from premature release due to damp conditions.
  • Peak #13 is the main capsaicin peak. Peak Area 1 2914 8096
  • Peak intensities corresponding to Figure 8 for HPLC analysis of cupric ferrocyanide-coated particles containing capsaicin Peak #10 is the main capsaicin peak. Peak Asea 1 1681172
  • a nanostructured cubic phase liquid crystal was prepared by mixing 0.77 grams of soy lecithin (Epikuron 200, from Lucas-Meyer), 0.285 grams of oleyl alcohol, and 0.84 grams of glycerol, to which was added 0.11 grams of auric chloride. No heating was used in the equilibration of this mixture, only mechanical stirring with a spatula. An amount 0.595 grams of this mixture was removed and smeared along the bottom half of the inner surface of a test tube. An upper solution was prepared by dissolving 0.14 grams of ferrous chloride and 0.04 grams of Pluronic F-68 in 1.74 grams of distilled water.
  • test tube containing the cubic phase was sonicated, resulting in a dispersion of microparticles coated with a gold coating.
  • a control sample in which the upper solution contained the F-68 but no ferrous chloride, was sonicated side by side with the first sample and did not result in a dispersion of microparticles.
  • the reaction between ferrous chloride and auric chloride results in the precipitation of elemental, nonlamellar crystalline gold, which in the case of the first sample resulted in the creation of microparticles covered with gold, with cubic phase interior.
  • a glycerol- water mixture with a density approximately 1.2 gram/cc was then prepared by mixing 0.62g of glycerol with 0.205 grams of water, and approximately 0.1 grams of the dispersion was added to this, and the new dispersion centrifuged.
  • gold-coated particles could be useful in safe, environmentally-friendly products demanding chemically and physically stable coatings. Furthermore, such particles could be effective in the treatment of arthritis, by providing greatly increased surface area of gold over other colloidal forms.
  • a nanostractured liquid phase containing the antineoplastic drug Paclitaxel was prepared by solubilizing 0.045 grams of Paclitaxel, 0.57 grams of eugenol,15 grams of soy lecithin (Epikuron 200), 0.33 grams of glycerol, and 0.06 grams of cupric nitrate with 0.61 grams of methanol, and then evaporating off the methanol in an evaporating dish, with stirring during evaporation.
  • An glycerol-rich upper solution was prepared by dissolving 0.09 grams of potassium iodide, 0.05 grams of Pluronic F-68, 0.44 grams of water and 1.96 grams of glycerol.
  • the system was sonicated, resulting in the dispersing of Paclitaxel-containing, nanostructured liquid phase into microparticles coated with crystalline iodine. Since these ingredients were chosen for their general acceptance as safe, inactive (except for the Paclitaxel itself) excipients in pharmaceutical preparations, this formulation or a variation thereof could be of importance in the delivery of Paclitaxel for the treatment of cancer.
  • the loading of Paclitaxel in the particle interior was quite high, namely on the order of 3 wt%, which in this case was so high that precipitation of some of the Paclitaxel within the interior of each particle may occur since the solubilization of Paclitaxel in this cubic phase at this high loading was metastable.
  • a Paclitaxel-containing cubic phase liquid crystal was prepared by mixing 0.345 grams of soy lecithin (Epikuron 200), 0.357 grams of anisole, 0.26 grams of water and 0.02 grams of Paclitaxel (from LKT Laboratories): equilibration was speeded by plunging a test tube of the mixture, after vigorous stirring, into boiling water for one minute then cooling to room temperature. To provide a coating material, 0.07 grams of propyl gallate was stirred in and the test tube again heated in boiling water. It had previously been checked that propyl gallate does not dissolve appreciably in this cubic phase at room temperature, but that the solubility increases substantially at 100°C. An upper solution consisted of 2.25 grams of a 2% Pluronic F-68 solution.
  • the cubic phase-propyl gallate mixture was heated to 100°C, cooled to about 80 °C, stirred with a spatula at the elevated temperature, and reheated to 100°C. After cooling the mixture for about 30 seconds, the upper solution was then overlaid on this mixture and the test tube placed in a sonication bath for one hour. A dispersion of microparticles with Paclitaxelcontaining interior and coated with propyl gallate was obtained. The dispersion had a high concentration of extremely fine microparticles (estimated particle diameter less than 0.4 micron), which were observable in the optical microscope at lOOOx by virtue of their Brownian motion. The overall particle size distribution was fairly broad, with some particles as large as 1-2 microns.
  • the liquid phase was overlaid on the liquid crystalline phase containing the iodide, and the mixture sonicated for 1.5 hours.
  • the result was a dispersion of sliver iodide-coated particles in an external medium of the nanostractured liquid phase.
  • This Example illustrates the use of nanostractured liquid crystalline phases based on block copolymers as interior matrices for particles of the present invention.
  • water was used as a preferential solvent for the polyethyleneoxide blocks of the block copolymer, and eugenol as preferential solvent for the polypropyleneoxide blocks of the block copolymer (which are insoluble in water).
  • This Example also illustrates the use of a general approach discussed above, namely the use of a nanostructured phase as the mixture that serves as the "upper solution", providing moiety B which reacts with moiety A in the interior phase to cause precipitation of a crystalline coating material.
  • B is the silver nitrate, which induces precipitation of silver iodide on contact with the interior matrix A (the cubic phase) which contains sodium iodide.
  • this upper solution it is generally desirable to choose this upper solution so that it is in equilibrium with the interior matrix, or, as in this case, very nearly so (the only deviation from trae equilibrium being due to the addition of a single drop, about 0.01 grams or less than 0.5%) of eugenol to the upper solution).
  • the interior matrix so that it is a viscous material, much more so than the upper solution which should be of relatively low viscosity.
  • PLGA-coated particles of two types were microparticles of cubic phase coated with PLGA. A significant fraction of these microparticles were large enough to see structural detail in a phase-contrast optical microscope. An optical micrograph is shown in Figure 9. The shell is visible in the larger particles. The irregular thickness of this shell layer is evidence that this layer is not an optical artifact. This is also evident when adjusting the focus on the microscope: if this were an artifact, its thickness would change as the focus changed, and this does not occur.
  • the second type of particle that came out of the process was a large, millimeter-sized particle that clearly behaved as a solid-coated particle.
  • a reddish-orange dye methyl red
  • methyl red which is of low solubility in both water and ethyl acetate
  • the millimeter-sized particles were strongly red-orange, demonstrating that the cubic phase is encapsulated inside the PLGA. Millimeter-sized particles of this type could be suspended on the tip of a needle, for example, without flowing, in contrast with uncoated cubic phase which could not be suspended in this fashion.
  • FIG. 10 shows a side-by-side comparison of the PLGA-coated (on the left) and xmcoated (on the right) cubic phases soaking in linalool, demonstrating clearly the insolubility of the coated cubic phase — the original color photograph shows that there is essentially no color to the linalool for the PLGA-coated sample, whereas the linalool containing the uncoated cubic phase is strongly red-orange. This experiment proves that the cubic phase is truly encapsulated by the PLGA.
  • a cubic phase containing solubilized methyl red was first prepared by mixing 2.118 grams of Arlatone G, 0.904 grams of water, 1.064 grams of oil of ginger, and 0.012 grams of methyl red, and stirring thoroughly.
  • a trehalose solution was prepared by dissolving 2.00 grams of trehalose in 10.005 grams of water. Then 1.002 grams of the cubic phase were dispersed in the trehalose solution by a combination of shaking and mild sonication. This dispersion was then freeze-dried in a lyophilizer.
  • Trehalose solutions are known to yield amo ⁇ hous solid on freeze-drying. The resulting material flowed freely, and gave no hint of the greasy, sticky feel and behavior that characterizes the uncoated cubic phase.
  • This Example demonstrates a method of production of coated microparticles in which a precursor to the coating material, which is surface-active when dissolved in water, is used to disperse a cubic phase into particles; then after reacting to convert this precursor to a solid coating, energy input is again applied to reduce the particle size to submicron.
  • a precursor to the coating material which is surface-active when dissolved in water
  • energy input is again applied to reduce the particle size to submicron.
  • one advantage of this method is that it localizes the coating precursor at the particle surface, so that the cubic phase readily becomes encapsulated upon conversion of this precursor to the coating.
  • the active compound in this Example was triclosan.
  • a cubic phase was prepared by mixing 0.886 grams of linalool, 0.960 grams of Pluronic P123 (BASF), 0.104 grams of triclosan, 0.189 grams of 2-ethylhexanoic acid, and 0.879 grams of distilled water, and then stirring thoroughly. This cubic phase was then smeared onto the sides of a test tube, 3.33 grams of a sodium N-acetyltryptophan (Na-NAT) solution (6 wt% based on the NAT) overlain, and the mixture shaken and sonicated briefly to disperse the cubic phase; the Na-NAT thus acts as a dispersant or surfactant in this step.
  • Na-NAT sodium N-acetyltryptophan
  • a 30%) zinc acetate solution in the amount 0.37 grams, was then added and mixed with the dispersion, followed by 0.52 grams of 2N NaOH. Five minutes were allowed for the reaction to begin, after which the material was further sonicated.
  • a surfactant solution (0.10 grams) containing Cremophor EL (9%) and Pluronic F-68 (12.5%) was then added, and the mixture sonicated for 15 minutes.
  • the solid-coated nature of the resulting microparticles was evident in phase contrast optical microscopy, where shearing the dispersion between glass and coverslip clearly showed that the microparticles behaved as solid-coated particles rather than as the readily-deformable cubic phase particles that result without application of the coating.
  • This Example reports a process in which coating material is melted, and a cubic phase dispersed therein, following which the temperature is lowered to solidify the coating, after which energy input is applied to create particles.
  • Such a process can be applied to crystalline materials as well as to amo ⁇ hous or semi-crystalline coating materials, where in the case of an amo ⁇ hous material the cooling may result in an amo ⁇ hous material (and is thus not a true "freezing", but rather a vitrification).
  • the nutriceutical compound Coenzyme Q10 was inco ⁇ orated into a cubic phase based on the ethoxylated, hydrogenated castor oil surfactant Arlatone G (from Uniquema).
  • Coenzyme Q10 (10 mg) was solubilized in a mixture of 0.302 grams of essential oil of ginger, 0.201 grams of water, and 0.606 grams of Arlatone G. This cubic phase was placed in a test tube and 2.994 grams of hydrogenated cottonseed oil added, and the entire contents were heated to 90°C to melt the oil. The sample was immediately sonicated in a hot water bath with vigorous shaking every 30 seconds, for 3 minutes. The test tube was then placed in an ice bath to solidify the oil with particles dispersed throughout the trigylceride. The resulting solid was then milled by the application of mechanical energy to an average particle size of several hundred microns; further reduction in size can readily be accomplished by milling methods well known in the art.
  • Example 41 shows that a lectin inco ⁇ orated into a cubic phase microparticle-the microparticle that would result after the dissolution of the zinc N-acetyltryptophan coating of a particle of the type produced in Example 41-retains its ability to bind oligosaccharides.
  • a cubic phase was first prepared by mixing 0.752 grams of Pluronic PI 23 (an insoluble surfactant), 0.705 grams of linalool, and 0.703 grams of water.
  • Anti Concanavalin A Vector AS-2004, Lot 0321, 1 mg/ml stock solution prepared; working solution prepared by diluting 1 : 10 to 0.1 mg/ml: 51 microliters added.
  • Concanavalin A Sigma C-5275, Lot 60K8934 prepared as 1 mg/ml stock solution; working solution prepared by diluting 1:10 to 0.1 mg/ml: 16 microliters added.
  • Biotinylated mannotriose , V-labs, NGB1336, prepare a 1 mg/ml stock solution, working solution prepared by diluting 1:100 to 0.01 mg/ml: 20 microliters added.
  • the total volume in the cuvette was 3.0 ml.
  • absorbance readings at 620 nm were monitored continuously. After the readings stabilized at 0.40 absorbance units, 500 microliters of Displacement Solution were added. This solution was composed of saturated alpha methylmannoside in 50 mM sodium acetate pH 4.5 containing 4 mM MnCl 2 and 4 mM CaCl 2 . Upon addition of this alpha methylmannoside — the analyte — the absorbance dropped from 0.40 to 0.26 absorbance units.

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Abstract

L'invention concerne une particule enrobée d'un matériau non lamellaire, tel qu'un matériau cristallin non lamellaire, un matériau amorphe non lamellaire ou un matériau semi-cristallin non lamellaire; laquelle particule comprend un noyau matriciel interne présentant au moins une phase liquide nanostructurée, ou au moins une phase cristalline nanostructurée, ou encore, une combinaison de ces deux phases. Cette particule enrobée est utilisée pour administrer des principes actifs, tels que des produits pharmaceutiques, des nutriments, des pesticides, etc. La particule enrobée décrite dans cette invention peut être fabriquée selon plusieurs techniques différentes; l'enveloppe extérieure consistant en un matériau non lamellaire, tel qu'un matériau cristallin non lamellaire, un matériau amorphe non lamellaire, ou un matériau semi-cristallin non lamellaire.
PCT/US2002/018654 1997-09-09 2002-06-13 Particules enrobees, procedes d'utilisation et de fabrication associes WO2003106168A1 (fr)

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PCT/US2002/018654 WO2003106168A1 (fr) 2000-08-16 2002-06-13 Particules enrobees, procedes d'utilisation et de fabrication associes
US10/170,237 US6638621B2 (en) 2000-08-16 2002-06-13 Coated particles, methods of making and using
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JP2004513029A JP2005529949A (ja) 2002-06-13 2002-06-13 被覆粒子、製造方法および使用
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EP1878425A1 (fr) * 2005-04-28 2008-01-16 Japan Science and Technology Agency Accelerateur d absorption transdermique
WO2011138701A1 (fr) * 2010-05-06 2011-11-10 Basf Se Dispersion à effet pesticide comprenant une phase dispersée nanostructurée
EP2488018A1 (fr) * 2009-10-16 2012-08-22 Copperhead Chemical Company Procédés et compositions pour de nouveaux systèmes de distribution de cristaux liquides
US8853269B2 (en) 2010-02-04 2014-10-07 Copperhead Chemical Company Inc. Composition and method for treating infections and promoting intestinal health
US8875813B2 (en) 2006-09-21 2014-11-04 Smith International, Inc. Atomic layer deposition nanocoatings on cutting tool powder materials
CN111731671A (zh) * 2020-06-28 2020-10-02 四川汇利实业有限公司 一种液体药品包装袋用复合材料
CN113620759A (zh) * 2021-07-16 2021-11-09 西北工业大学 一种基于多尺度改性硝胺氧化剂的复合固体推进剂及制备方法
CN114560463A (zh) * 2022-03-23 2022-05-31 福州大学 一种核壳结构的氮掺杂碳壳包裹碳化钼核微米球材料的制备方法
CN114618573A (zh) * 2022-04-01 2022-06-14 中触媒新材料股份有限公司 一种嵌入式Ni基催化剂、制备方法及应用
CN115160624A (zh) * 2022-07-15 2022-10-11 华南理工大学 一种具备细菌检测能力的食品抑菌保鲜膜及其制备方法

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Cited By (17)

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EP1878425A1 (fr) * 2005-04-28 2008-01-16 Japan Science and Technology Agency Accelerateur d absorption transdermique
EP1878425A4 (fr) * 2005-04-28 2009-08-26 Japan Science & Tech Agency Accelerateur d absorption transdermique
US9095560B2 (en) 2005-04-28 2015-08-04 Japan Science And Technology Agency Method of enhancing transdermal absorption using a composition comprising POE octyl dodecyl ether and squalane
US8875813B2 (en) 2006-09-21 2014-11-04 Smith International, Inc. Atomic layer deposition nanocoatings on cutting tool powder materials
EP2488018A1 (fr) * 2009-10-16 2012-08-22 Copperhead Chemical Company Procédés et compositions pour de nouveaux systèmes de distribution de cristaux liquides
EP2488018A4 (fr) * 2009-10-16 2013-07-03 Copperhead Chemical Company Procédés et compositions pour de nouveaux systèmes de distribution de cristaux liquides
US8853269B2 (en) 2010-02-04 2014-10-07 Copperhead Chemical Company Inc. Composition and method for treating infections and promoting intestinal health
WO2011138701A1 (fr) * 2010-05-06 2011-11-10 Basf Se Dispersion à effet pesticide comprenant une phase dispersée nanostructurée
CN111731671A (zh) * 2020-06-28 2020-10-02 四川汇利实业有限公司 一种液体药品包装袋用复合材料
CN113620759A (zh) * 2021-07-16 2021-11-09 西北工业大学 一种基于多尺度改性硝胺氧化剂的复合固体推进剂及制备方法
CN113620759B (zh) * 2021-07-16 2022-06-07 西北工业大学 一种基于多尺度改性硝胺氧化剂的复合固体推进剂及制备方法
CN114560463A (zh) * 2022-03-23 2022-05-31 福州大学 一种核壳结构的氮掺杂碳壳包裹碳化钼核微米球材料的制备方法
CN114560463B (zh) * 2022-03-23 2023-10-20 福州大学 一种核壳结构的氮掺杂碳壳包裹碳化钼核微米球材料的制备方法
CN114618573A (zh) * 2022-04-01 2022-06-14 中触媒新材料股份有限公司 一种嵌入式Ni基催化剂、制备方法及应用
CN114618573B (zh) * 2022-04-01 2023-11-07 中触媒新材料股份有限公司 一种嵌入式Ni基催化剂、制备方法及应用
CN115160624A (zh) * 2022-07-15 2022-10-11 华南理工大学 一种具备细菌检测能力的食品抑菌保鲜膜及其制备方法
CN115160624B (zh) * 2022-07-15 2023-06-16 华南理工大学 一种具备细菌检测能力的食品抑菌保鲜膜及其制备方法

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