CZ197699A3 - Coated particles, process of their preparation and use - Google Patents

Abstract

The coated particle comprises an inner core consisting of a matrix and outer cover. The matrix consists of at least one liquid phase nanostructures, or at least one liquid crystal phase nanostructure, or a combination thereof both phases and the outer coating contains non-lamellar crystalline material. The solution further forms a method of production coated particles and their use.

Description

Technical field

The present invention relates to coated particles, their production and use. The use for these coated particles is to release one or more materials into a selected environment, to absorb one or more materials from a selected environment, and to absorb one or more materials from a selected environment.

BACKGROUND OF THE INVENTION

Two technologies are currently of interest, including polymer coated particles and liposomes. As shown by the flat and dispersed responses of polymer coatings under the effect of chemical and physical agents, the particles coated with polymers exhibit some limitations. This is due to two factors. First, the diffusion coefficients and dissolution kinetics of polymers are limited by their high molecular weight. Secondly, the interaction of adjacent groups extends the curves representing the chemical response to environmental effects such as inter alia, pH, ionic strength, redox potential, ionization, etc. (Interaction of adjacent groups indicates that a chemical change in one monomer unit of the polymer will alter the parameters controlling the chemical shift in all adjacent monomer units). In addition, most polymers consist of a population of molecules with a wide molecular weight distribution. In addition, for a particular application of polymer-coated particles, only a limited amount of polymers is available. This is due to a number of factors: the control inputs; the coating process often requires harsh chemical and / or physical conditions such as diluents, free radicals, elevated temperature, desiccation or drying, and / or macroscopic shear forces required to form particles; the mechanical and thermal stability of polymer coatings for industrial applications is limited, and 9 9 9 9 9 9 9 9 9 9 99 99 9 99 9 moreover, there is a negative environmental impact from large-scale applications of polymer-coated particles, as in agricultural use.

Liposomes also exhibit many limitations. Their physical and chemical instability can be included here. The release of material deposited within the liposome is mostly dependent on the destabilization of the liposome structure. The absence of liposome porosity eliminates the possibility of pore-controlled release of these materials. On the one hand, the need for physical stability of the liposomes prior to the intended release, and on the other hand, the release of the material by destabilizing the bilayer are two requirements that are often difficult to meet. (The term liposomes is often used interchangeably with the term vesicles and is used in connection with phosphatydylglycerollipid vesicles or other natural lipids. Vesicles are self-existent bilayer closed formations composed of several thousand lipid molecules that enclose aqueous content. Lipid bilayer is a two-dimensional solution of lipids with their hydrophobic groups exposed to the aquatic environment while their hydrophobic portions aggregate and expel water.The bilayer is a highly organized but very dynamic structure due to lateral lipid diffusion in both halves of the bilayer.) See O Brian, DF and Ramaswami, V. (1989) in Mark-Bikales-Overberger Menges Encyclopedia of Polymer Science and Engineering, Volume 17, Second Edition, John Wiley & Somns, Inc., p. 108.

SUMMARY OF THE INVENTION

It is an object of the invention to provide coated particles capable of dissolving or transferring a wide variety of materials, including materials susceptible to physical, chemical or biological degradation.

It is an object of the invention to provide coated particles capable of releasing one or more materials carried in a matrix within the inner core without the need to destabilize the matrix.

It is an object of the invention to provide coated particles with a sharply delimited response, comprising releasing or absorbing one or more materials into or from a selected environment, to chemical or physical effects.

It is an object of the present invention to provide coated particles allowing the generation of a variety of coated particle systems that can be adapted to the specific physical, chemical and biological requirements of their intended use, such as mechanical and thermal stability in industrial use of coated particles or absence of adverse effects in large scale use of coated particles. in agriculture.

It is an object of the present invention to provide coated particles coated, if desired, with a porous layer allowing porosity-controlled release of materials deposited within the particles, or porosity-controlled absorption of materials deposited outside the particles.

It is an object of the invention to provide coated particles that can be produced by a simple process, preferably without using drastic physical or chemical conditions.

Said and other uses are provided by coated particles comprised of an inner core formed by a matrix and an outer coating. The matrix consists of at least one nanostructured liquid phase, or at least one nanostructured liquid crystal phase, or a combination thereof, and the outer coating is a non-lamellar crystalline material.

In a preferred embodiment, the coated particle may consist of:

1. by providing a matrix comprising at least one chemical individual having a group capable of forming a non-lamellar crystalline material by reaction with the other group; and

2. combining this space with a solution containing at least one chemical individual having a second group capable of reacting with the first group under conditions of forming a non-lamellar crystalline material and simultaneously dividing the space into particles by applying energy.

Alternatively, the coated particle may be formed

1. providing a volume of a matrix containing therein a solution material capable of forming a non-lamellar crystalline material that is insoluble in the matrix; and

2. by making the aforementioned material insoluble in the matrix and simultaneously dividing the volume into individual particles by applying energy.

Alternatively, a combination of these two methods may be used.

BRIEF DESCRIPTION OF THE DRAWINGS

Giant. 1 shows a graphical representation of a vertical section showing a coated particle according to the invention comprising an inner core composed of 2x2x2 matrix cells and an outer coating;

Giant. 2 is a graphical representation of a section through a coated particle of the present invention;

Giant. 3 is a scanning electron microscope image showing coated particles according to the invention;

Giant. 4 is a scanning electron microscope image showing other coated particles according to the invention;

Giant. 5 is a graph of the measured volume-corrected cumulative particle size distribution of the coated particles in plotting the volume-corrected particle diameter versus the cumulative particle size.

Giant. 6 is a graph of the narrow-angle X-ray scattering intensity versus the wavelength of the coated particles q.

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Giant. 7 shows a graph of pulses from the detector versus elution time in minutes for control using HPLC; and

Giant. 8 shows a graph of pulses from a detector versus elution time in minutes for coated particles of the invention using high pressure liquid chromatography (HPLC).

DETAILED DESCRIPTION OF THE INVENTION

As can be seen from Figures 1 and 2, the coated particle 1 according to the invention consists of an inner core 10 and a coating 20 around the core (hereinafter referred to as "outer coating 20"). The inner core 10 comprises a matrix consisting essentially of a nanostructured material selected from the group consisting of:

at least one nanostructured liquid phase

b. at least one nanostructured liquid crystal phase; and

c. combination

i. at least one liquid phase; and ii. at least one nanostructured liquid crystal phase

The liquid phase and liquid crystal materials may either contain (lyotropic) or not (thermotropic) the solvent. The outer coating 20 comprises a non-lamellar crystalline material. As used herein, the term "outer coating" means that the coating 20 is outside the inner core 10, but this is not meant to be the immediate vicinity of the coated particle 1.

The nanostructured liquid phase and the nanostmctured liquid crystal phase possess unique properties which are not only important for facilitating the simple manufacture of the coated particles of the invention, but also for the highly desirable solubility, stability and other capabilities of the coated particles of the invention.

As for the outer coating 20, the non-lamellar crystalline structure exhibiting binding rigidity and / or compactness in all three dimensions is significantly

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999 99 99 99 99 99 preferred in this invention over lamellar materials because of the well-known physical and chemical instability of lamellar crystalline structures, such as (a) emulsion instability (even if spontaneous), in (b) chemical instability in removing the guest molecule from the lamellar Werner complex, and (c) a dramatic decrease in hardness and modulus of strength as in graphite compared to diamond.

The coated particles I of the invention may be from 0.1 micrometer to 30 micrometers in diameter, and particles from about 0.2 micrometers to 5 micrometers in diameter are preferred. The coated particles can, if desired, also be provided with a stabilizing layer on the surface, i. outside the outer coating 20, such as polyelectrolytes or surface mono layers to prevent agglomeration of the coated particles.

The coated particles of the invention have utility in a variety of applications. The coated particles 1 can absorb one or more materials from the selected environment or release one or more materials, such as matrix deposited active substances, into the selected environment when the outer coating is released. Alternatively, some of the outer porous coatings, such as inclusion compounds and zeolites, do not require release for absorption or release of the desired material into or from the matrix, and in some such cases, high selectivity can be achieved using pores of suitable characteristics. In cases where the particles are used to adsorb the desired substance or substances, neither porosity nor release of the outer coating 20 is required, but porosity can greatly increase adsorption by allowing diffusion of adsorbed material into the matrix and thereby allowing adsorption sites on the outer coating 20 to adsorb. new material. In a preferred embodiment, additional material, such as an active agent, may be deposited in the matrix to be released into the selected environment.

The matrix is a · · · · · · Mat ·

a. thermodynamically stable

b. Nanostructures; and

c. a liquid phase or a liquid crystal phase or a combination thereof. Nanostruktumí: Concept nanostruktumí or nanostructured, in the form in which it is used here in relation to the structure of the material is a material whose structural elements have dimensions in the nanometer range (10 ^-9 M) or tens of nanometers (10 x 10 ⁹ m). Generally, any material containing domains or particles of 1 to 100 nm (nanometers), or if it contains layers or filaments of this thickness, can be considered as nanostructures. (See also Dagani, R., "Nanostmctured materials promise to advance the range of technologies," November 23, 1992, C&E news 18 (1992).) This term was introduced to exclude the so-called "ceramic glasses" that are crystalline materials with such small crystals that sometimes it is not possible to measure the peaks by measuring the wide-angle X-ray diffraction, which is called nanostructured materials by some physicists. The liquid and nanostructured nanostructured phases described herein are characterized by their nanometer dimensional domains that clearly differ from neighboring domains by large differences in chemical composition and do not include materials in which the domains do not differ in chemical composition but only in grid orientation. In this spirit, the term "domain" as used herein is defined as the spatial region of a particular chemical composition that is clearly distinguishable from that of neighboring domains; it is often a hydrophilic (hydrophobic) domain contrasting with the hydrophobicity (s) of adjacent domains; in the context of the invention, the dimensions of these domains are within a nanometer scale. (Often, for micrometer or nanometer domains, the term "microdomain" is used.)

The nanostructured liquid phase and the liquid crystal phase which form the inner core 10 of the coated particles also according to the invention abound in unique

Vlastnost důležité nejen pro vlastnost vlastnost vlastnost vlastnost vlastnost vlastnost φ φ φ φ «« «« «vlastnost vlastnost« «φ« vlastnost vlastnost vlastnost vlastnost «« «« «« «vlastnost vlastnost vlastnost« vlastnost «« «« «« coated particles. As will be discussed in detail in the discussion of the particle manufacturing process in the sense that the material allows dispersion formation in one of the processes described herein, it is desirable that the material be poorly water soluble (otherwise it would dissolve in the dispersion process) but also contain water both to dissolve the water-soluble reactants used to form the dispersion and to allow the dissolution of a wide variety of active ingredients.

Especially when dissolving hydrophilic (especially charged) and amphiphilic substances, the inner matrix should contain a considerable amount of water or other polar solvent to ensure not only good solubility but also to maintain the correct conformation and activity of sensitive compounds of biological origin such as proteins. A large number (if not most) of the compounds listed as useful coatings of the invention require reactants that are solely soluble in polar solvents in order to be as versatile as possible in the choice of coating. Moreover, in most cases the use of an organic solvent is not possible in combination with biologicals such as proteins and is practically never environmentally and health-friendly. Insolubility in water and at the same time the ability to dissolve water-soluble materials are two conditions facing each other and are difficult to meet in one cheap and safe material.

Very effective in fulfilling these two conditions are systems composed of lipids and water in which both water-rich microdomains and hydrophobic microdomains are present which are in very close contact with the aqueous microdomains. The presence of aqueous domains prevents precipitation tendencies occurring in systems where the water structure is interrupted by the presence of large amounts of cosolvents or cosolvents, as is the case with concentrated aqueous polymer solutions. At the same time, the proximity of the hydrophobic domains ensures effective solubility of the amphiphilic compounds (also hydrophobic).

Liquid and nanostructured nanostructured phases are synthetic or semi-synthetic materials having these solvent characteristics, providing pure, well characterized, well-produced and inexpensive matrices, also having the following properties:

(a) Adaptability in chemical systems forming nanostructured liquid and liquid crystal phases, ranging from iological lipids ideal for biomolecules, through hard fluorodetergents, bacterial-binding glycolipids to detergents with ionic or reactive groups, etc .: this ensures their use in a wide range a variety of conditions and uses;

(b) the unsurpassed ability of nanostructured liquid and liquid crystal phases (i) to dissolve a wide range of compounds including many traditionally complex substances such as taxol and biopharmaceuticals, bypassing the need for toxic and increasingly regulated organic solvents; (ii) achieve a high concentration of effects without reducing stability; and (iii) provide a biochemical environment that preserves their structure and function;

(c) true thermodynamic stability ensuring against instabilities known in other carrier species such as active substance precipitation, emulsion failure, vesicle fusion, etc .; and

(d) the presence of a porous space with a selectable pore size in the nanometer scale, implying better control of the release kinetics even when coating release is initiated, in particular for proteins and biomolecules.

The desirable properties of the nanostructured materials of the inner core 10 can be described, with respect to detergents, by using several terms "polar", "4", "4", "4", and "4". "Non-polar", "amphiphilic", "detergent" and "interface between polar and non-polar" and analogous to block copolymer systems as described below.

Polar: polar compounds (such as water) and polar portions of compounds (such as a charged main group of ionic detergents or lipids) are water-like or hydrophilic substances; "Polar" and "hydrophilic" are synonymous in the context of the invention. As for the solvent, water is not the only solvent considered. Other important solvents for the invention are: glycerol, ethylene glycol, formamide, N-methylformamide, dimethylformamide, ethylammonium nitrate and polyethylene glycol. Note that one of these solvents, polyethylene glycol, is inherently a polymer, illustrating the scope of use. At sufficiently small molecular weights, polyethylene glycol (PEG) is a liquid and although PEG has not been studied as a polar solvent in combination with detergents, PEG has been found to form liquid phase and liquid crystal nanostructures in combination with, for example, BRIJ-type detergents which are nonionic detergents. with major PEG moieties linked to the alkali chains via an ether linkage. Regarding polar groups generally in hydrophilic and amphiphilic molecules (which include but are not limited to polar solvents and detergents), a number of polar groups are tabulated below in discussion which polar groups function as active detergent groups and which do not.

Non-polar: Non-polar (or also hydrophobic or lipophilic) compounds include not only paraffinic alkane (hydrocarbon) detergent chains, but also modifications thereof, such as perfluorinated alkanes, as well as other hydrophobic groups such as fusion cyclic structures of cholic acid as found in bile acid detergents, or phenyl groups forming non-polar groups in TRITON or oligomeric detergents, and polymer chains ranging from polyethylene glycol (which represents a long alkane chain) to hydrophobic polymers such as hydrophobic polymers.

Polypeptide chains in novel peptide-based detergents that have recently been investigated. Some non-polar groups and compounds are listed below in the discussion of useful components of the inner part composed of the nanostructured phase.

Amphiphilic: Amphiphilic can be defined as a compound containing both lipophilic and hydrophilic groups. See D. H. Veret, Pure and Aplied CHemistry, Volume 31, Number 6, p. 611, 1972. It is important to note that not every amphiphil is a detergent. For example, butanol is an amphiphil since the butyl group is lipophilic while the hydroxy group is hydrophilic, but is not a detergent because it does not meet the definition below. There are many amphiphilic molecules possessing highly polar functional groups, measurably hydrated, but which are incapable of detergent behavior. See R. Laughlin, Advances in Liquid Crystals, Volume 3, pp. 41.1978.

Detergent: Detergent is an amphiphil having two additional properties. On the one hand, it significantly modifies the interphase physics of the aqueous phases (not only in the water / air, but also oil / water and water / solid phase) at mostly low concentrations as compared to detergent-free substances. Secondly, the detergent molecules reversibly associate with each other (and many other molecules) to form a very high degree of thermodynamically stable solution of aggregates or micelles, macroscopically appearing as a single phase. Micelles are usually made up of many detergent molecules (tens to thousands) and have colloid dimensions. See R. Laughlin, Advances in Liquid Crystals, Volume 3, p. 41, 1978. Lipids, and especially polar lipids, are considered detergents in this work, although they belong to a subset of detergents that have slightly different properties than those commonly used we rank among detergents. Often, but not always, lipids are characterized by their frequent biological origin and, secondly, tend to dissolve better in oils and fats than in water. In addition, many lipid substances are extremely insoluble in water.

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The presence of a hydrophobic solvent is then necessary in the case of lipids, which are additionally detergents, to reduce surface forces and to unequivocally reversible association. For example, low concentrations of substances that severely limit the surface tension between oil and water, despite their extremely low solubility, may make it difficult to observe a decrease in surface tension in aqueous systems; likewise, the addition of hydrophobic solvents to a lipid / water system can greatly simplify the process of determining association and formation of nanostructured liquid and liquid crystal phases, while the difficulties associated with high temperature can significantly complicate this process in lipid / water systems.

Moreover, although lipids and detergents came to the forefront as two fields of study (biological-derived lipids and detergents coming from a more industrialized area), it was precisely the study of nanostructured liquid crystal structures that ultimately linked what was considered to be substantially different, after as nanostructures of lipids were obtained, as is the case with other detergents. In addition, it was of interest that for some synthetic detergents, such as dihexadecydimethylammonium bromide, which were completely non-biological in origin, lipid-like behavior was observed in those hydrophobic solvents commonly used to demonstrate their detergency properties. On the other hand, some lipids such as lysolipids, clearly of biological origin, have phase behavior more or less typical of water-soluble detergents. Finally, it has been clarified that for the purpose of discussion and comparison of mutual association and the ability to reduce surface tension, there is a significant difference between one or two hydrophobic long chains, where the single chain ones usually appeared to be water soluble, while the two chains oil soluble.

Thus, in the context of the foregoing, the detergent is any amphiphile which, at very low concentration, reduces the surface tension between water and the hydrophobic compound, whether considered as a hydrophobic compound of air or oil, and which is capable of reversible mutual association into nanostructured micelles, inverted micelles, or biontinuous morphologies in water or oil, or both. Thus, the lipid class simply comprises a subset containing detergents of biological origin.

Polar-apular interface: There is a dividing point in the detergent molecule (or in some cases two points if it contains a polar group at each end or even more than two as in the case of Lipid A, which has seven acyl chains and thus seven dividing points at one molecule) that separates the polar and non-polar portion of the molecule. In any liquid phase or liquid crystal phase nanostructured, the detergent forms a single layered or bilayer film: in such a film, the dividing points form a plane separating the polar and non-polar domains, which is called the "polar-non-polar interface". For example, in the case of a round micelle, this interface would be approximated by a sphere whose surface would intersect the outer surface of the micelle so that the polar groups of detergents would project outside the sphere while the non-polar chains would be inside. Particular attention should be paid not to confuse these microscopic with macroscopic interfaces separating the two large phases that can be seen with the naked eye.

Bicontinuous: The geometry of the bicontinuous structure is described by two separate, multi-connected intertwined subspaces, each of which is continuous in all three dimensions. Thus, it is possible to pass this system in its entire range in any direction, although the path may be limited to only one subspace. In a bicontinuous structure, each subspace is rich in one type of material or group, and both sub-areas carry two such materials or groups, each of which extends in a given subspace in all three dimensions. Mushroom, sandstone, apple, and many other composite materials are examples of stable, yet chaotic: i4 • 99

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9 9 99 99 99 bontinuous systems in the material world. In these specific examples, one of the subspaces is occupied by a more or less deformable material and the other by a solution, although it can often be referred to as empty. Some lyotropic crystalline states may also serve as examples. One subspace is occupied by amphiphilic molecules oriented and aggregated into papim-like fields that are geometrically arranged, the other subspace being made up of solvent molecules. States of related liquid crystals containing two incompatible solvents such as hydrocarbons and water have another possibility in which one subspace is rich in one solvent and the other in rich other, where the interface between them is formed by layers rich in oriented solvent molecules. Certain microemulsion equilibrium phases containing comparable amounts of hydrocarbons and water as well as an amphiphilic detergent may be examples of a bicontinuous chaotic structure maintained in dynamic equilibrium by the thermal motion of the molecules. Although they do not exhibit geometric alignment, we have convincing evidence of their multiple continuity. Bicontinuous morphology also occurs in certain phase-separated block copolymers. See Anderson D.M., Davis H.T., Nitche J.C.C. and Scriven L.E. (1990) Advances in Chemical Physics. 77: 337.

Chemical Criteria: A number of Robert Laughlin criteria have been discussed and tabulated for detergents to determine whether or not a particular polar group is capable of functioning as a polar detergent group, where the detergent definition includes the formation of nanostmctum phase in water even at low concentrations. crystals 3:41, 1978. The following list includes a group that is unable to function as polar detergent groups and therefore it would not be possible to expect the formation of nanostmctum or liquid crystal phase when interconnected with an alkane chain: aldehyde, ketone, carboxylic acid ester, carboxylic acid , isocyanate, amide, acylcyanoguanidine, acylguanyurea, acylbiuret, N, N-dimethylamide, nitrosoalkane, nitroalkane, nitric and nitrite ester, nitron, nitrosamine, pyridine N-oxide, nitryl, isonitrile, aminoborate, aminohaloboride, sulfone, phosphonate , sulfonamide, sulfonamidmethyimine, alk halo (monobasic), ester (single functional group), secondary amine, mercaptan, thioether, primary secondary and tertiary phosphine.

Here are some polar groups that are able to function as major groups in detergents and therefore it is expected that, for example, an alkane chain attached to one of these groups will be able to form nanostructured liquid and liquid crystal phases:

anions: carboxylic salts (soap), sulfate, sulfamate, sulfonate, thiosulfate, sulfonate, phosphate, phosphonate, phosphinate, nitroamide, tris (alkylsulfonyl) methide, xanthate;

b. Cations: ammonium, pyridinium, phosphonium, sulfonium, sulfoxonium;

c. Bivalent ions: ammonium acetate, phosphoniopropanesulfonate, pyridinioethylsulfate;

d. Partially polar: amine oxide, phosphoryl, phosphine oxide, arsine oxide, sulfoxide, sulfoximine, sulfondiimine, ammonioamidate.

The basic rule demonstrated by Laughlin says that a group will not be able to function as a detergent functional group if the enthalpy of forming an association complex of this polar group with a phenol (hydrogen donor donor) at a ratio of 1: 1 is less than 5 kcal. In addition, the detergent requires, in addition to the polar group, an effective non-polar group for which rules are also given. If n is the number of carbons in the case of the alkane chains, which are, of course, the most common non-polar detergent group, then n must be at least 6 to show the detergent associative behavior, but usually n is at least 8 to 10. An interesting substance is octylamine. it is equal to 6 and the amino group is just polar to be a functional group of the detergent. This substance forms a lamellar phase with water at ambient temperature, but also a nanostructured L2 phase, Wamheim, T., Bergenstahl, B. Henriksson, U., Malmvick, A.-C. and Nielson, P. (1987) J. of Colloid and Interfase Sci. 188: 233. In the case of branched hydrocarbons, in principle the same demands are made on the smallest n value: for example, sodium 2-ethylhexyl sulfate is capable of forming a wide variety of liquid crystal phases, Winsor, P.A. (1986) Chem. Roar. 68: 1. On the other hand, the criteria for the number of carbons n are very different for these two types of branched and linear hydrocarbons in terms of their maximum values. In the case of linear saturated alkane chains, the tendency to crystallize increases so much that n is equal to 18, the Krafft temperature is large and the temperature limit of the liquid phase nanostructures and the liquid crystal phase approaches or exceeds 100 ° C. Therefore, in the context of the invention, for most applications, such detergents will be considered less useful than those whose n lies in the range of 8-18. After the introduction of unsaturated chains or branching, n can dramatically increase. The case of unsaturated chains can be demonstrated using fish oils, for example. The 22 carbon chains have extremely low melting points because they contain up to 6 double bonds, as is the case with docosahexadiene acid, which is contained in monoglycerides, soaps, etc. Moreover, polybutanedien with a very high MW is an elastomeric polymer and block at ambient temperature. copolymers with polybutanedien blocks are known for their ability to form nanostructured liquid crystals. Similarly, by introducing branching, it is possible to form hydrocarbon polymers, such as polypropylene oxide (PPO), which serve as hydrophobic blocks in a number of very important amphiphilic block copolymer detergents, such as the PLURONIC series. Substitution of hydrogen with fluorine, in particular the use of perfluorinated chains, usually reduces the requirement for a minimum value of n. For example, a lithium salt of perfluorooctanoic acid (n = 8) capable of forming a full range of liquid crystal phases, including the intermediate phase I7 relatively rare in detergent systems. As discussed previously, other hydrophobic groups, such as fusion of the cyclic structure occurring in cholate soaps (bile acids) also serve as non-polar groups. However, these cases need to be assessed on a case-by-case basis whether a particular group will act as a detergent.

For single-component block copolymers, it is relatively easy for nanostructured liquid phase and liquid crystal phase materials to appear using simple statistical field theories. These theories are quite generally applicable in a wide variety of block copolymers. If x is a parameter describing the Flori-Higins interaction between blocks A and B of the polymer and N is the absolute degree of polymerization (defined as the number of statistical units or monomer units in the polymer chain corresponding to the definition of the interaction parameter) of the block copolymers, then formation of liquid phase nanostructures can be expected; the liquid crystal phase just when χΝ is greater than 10.5, Leibler, L. (1980) Macromolecules 13: 1602. The ordered nanostructured (liquid crystal) phase, or even the bicontinuous cubic phase, may occur for values greater than 10.5 but Hajduk, DA, Harper, PE, Gruner, SM, Honeker, CC, Kim, G., Thomas, EL, and Fetters, LJ (1994) Macromolecules 27: 4063.

Among the materials composed of the nanostructured phase, suitable to form the nanostructured matrix material, we can include:

a. L1 phase material

b. L2 phase material

c. nanostructured emulsions; or

d. Nanostructured L3 phase * 38 material

Liquid phase nanostructures are characterized by a domain structure consisting of at least the first and second type domains (and in some cases three or more types) having the following characteristics:

(a) chemical groups located in a first type domain are incompatible with groups in a second type domain (in general, the pairs of domains are incompatible with each other) by not mixing under certain conditions and preferably remaining as separate domains (for example, domains) the first type may consist of polar groups such as water or lipid functional groups, while the second type domains may consist essentially of non-polar groups such as hydrocarbon chains, or may be of the first type polystyrene-rich, while the second type domains may be polyisoprene and third to polyvinylpyrrolidone.

b) the atomic structure within the domains resembles a liquid rather than a solid phase, ie there is no grid arrangement of atoms (evidence for this is the absence of sharp Bragg reflection peaks in wide-angle X-ray diffraction analysis).

c) The smallest dimensions (ie, the thickness of the layers in the case of layers, and the diameter of the spherical and cylindrical domains) of virtually all domains are in the nanometer scale (ranging from approximately 1 to 100 nm)

(d) the organization of the domains lacks any arrangement or does not correspond to the periodic grid. This was demonstrated by the absence of sharp Bragg reflections when analyzing narrow-angle X-ray scattering. (In addition, as will be shown below, strong evidence that this is a liquid and not a liquid crystal phase is the absence of high viscosity along with birefringence (BIREFRINGENCE).

First, the individual liquid phases of detergent-based systems were discussed, where the nanostructured solution consists of two types of domains: "polar" and "non-polar". In general, block-based systems have been discussed afterwards. 4 9 9 9 9 9 9 9

99 copolymers. In these systems, the terms "polar" and "non-polar" may not be applicable, but there are types of domains of "A", "B", etc. These domain types of "A" ^and "3"? as defined above (in the definition of nanostructured solutions), they are immiscible with each other.

LI phase: In the LI phase, which occurs in detergent-based systems, the interface between the polar and non-polar regions curves around the non-polar, generally manifested by the formation of particles - normal micelles that may exist in an aqueous medium. polar solvent). In such an environment, bicontinuity may arise after the spherical micelles become cylindrical and due to changing conditions they then begin to fuse. In addition to the continuity of water, the hydrophobic domains can also combine into a sample sharing network; even this phase can still be L1. In addition, there are L1 phases for which there is no evidence of any microstructure. That is, there are no micelles or any well-defined domains, only a detergent mixed in a liquid phase without a structure. This L1 phase is then not a nanostructured material. These unstructured solutions can sometimes be converted into nanostructured phases by simply changing the composition without changing any phase. In other words, thermodynamics is not a factor adjusting the transition between an unstructured solution and a nanostructured phase. This, of course, contradicts the cases where a phase that is extensively spatially arranged (liquid crystalline or crystalline) passes into a phase without this arrangement (liquid), between which the interface is thermodynamic.

In the case of the L1 phase consisting of block copolymers, the terms "polar" and "non-polar" may not be applicable, but in any case this phase comprises two (or more) domain types. We introduce the convention that the curvature of the A / B transition is oriented to A, so that a typical nanostructure will consist of mostly spherical particles of the type A domain located in the domain continuum

B. Polystyrene-polyisoprene diblocks can serve as an example

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copolymers. If the volume percentage of polystyrene blocks is very small, say 10%, then the microstructure will consist of polystyrene-rich beads in a continuous polyisoprene matrix. Conversely, polyisoprene beads in a continuous polystyrene matrix will likely be a structure of 10% polyisoprene PS-PI diblocks.

Identification of L1 phase nanostructures. Since L1 is a liquid phase, techniques have been developed to distinguish the nanostructured L1 phase from the unstructured phase of a liquid solution. In addition to the experimental approaches described below, there is broad knowledge of the criteria by which we can determine whether we can expect a given system to form the nanostructured phase instead of solutions without structure.

Since the formation of liquid phase nanostructures and liquid crystal nanostructures is one of the conditions for a detergent definition, it is extremely useful to have criteria for determining whether a substance is indeed a detergent, criteria providing a number of methods to determine whether a substance is a detergent. A number of criteria were discussed by Robert Laughlin in "Advances in liquid crystals", 3:41, 1987. Laughlin listed chemical criteria to determine a priori whether a substance is a detergent, as discussed in detail above. If a substance is a detergent according to these rules, the substance forms the nanostructured phase in water. Moreover, it is expected that this substance in water and in the presence of a hydrophobic substance is likely to form a nanostructured phase with at least a portion of the hydrophobic substance present.

When an amphiphilic detergent-free amphiphilic substance is added to this system, particularly an amphiphilic organic solvent such as a short chain alcohol, dioxane, tetrahydrofirane, dimethylformamide, acetonitrile, dimethylsulfoxide, etc., an unstructured liquid may be formed because the organic solvent will function in general, the abolition of colloidal aggregates and cosolubilization of all components.

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Laughlin also discusses a number of criteria based on physical knowledge. One such well-known criterion is the critical micelle concentration (CMC) obtainable from the surface tension determination. If we plot the surface tension as a function of concentration, at very low concentrations the surface tension will only drop sharply if the additive is a real detergent. Thereafter, when the concentration reaches a certain value called CMC, a sharp break appears in the graph where, to the right of the CMC, the plot slope drops sharply, so that the surface tension decreases substantially more slowly with the detergent added. This is due to the almost exclusive participation of detergent in micelle formation at the expense of air-water interfaces.

The second Laughlin criterion is the liquid crystal criterion: if the substance forms liquid crystals at high concentrations, then the substance is a detergent and will form liquid crystalline phases at lower concentrations. In particular, the L1 phase usually occurs at detergent concentrations lower than those at which the normal hexagonal, or in some cases cubic, non-bicontinuous form, of the liquid crystal phase is formed.

Another criterion is based on the temperature difference between the maximum Kraft transition and the melting point of the anhydrous chemical. The Kraft transition is a curve in the phase diagram of a binary system containing water and a given substance: below the Kraft curve there are crystals, while crystals melt above it, so that along the Kraft curve there is a dramatic increase in solubility in a very narrow temperature range. In the case of a real detergent, this difference is substantial: for example, sodium palmitate has a melting point of the anhydrous form of 288 ° C, whereas the plateau of the Kraft curve is at 69 ° C, thus the difference is 219 ° C. Laughlin continues with an example of dodecylamine. The temperature difference here is 14 ° C and only a small area of the phase graph corresponds to liquid crystals, which corresponds only to a low degree of tendency to associate colloids. On the other hand, neither

99

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Neither dodecylmethylamine nor dodecanol show a tendency to associate behavior of the detergent type and both have a temperature difference of zero.

As with the liquid crystals discussed herein, there are a number of experimental probes for a given material to determine whether the material, in this case a liquid, is nanostructured. This will be discussed in connection with the L1 phase, however, with appropriate changes it is applicable to all nanostructured solutions. In such assays, it is appropriate to use as many characterizations as possible.

Like all liquid phases, L1 is optically isotropic in the absence of flux. It does not provide ² H NMR cleavage with deuterated detergent.

Also, the L1 phase generally does not show birefringence in moderate flow conditions when tested with cross polarization filters. The birefringence situation is not applicable to block copolymer systems. where it can be complicated by chain birefringence.

Returning to the L1 phase, the viscosity is usually quite low, significantly lower than that of liquid crystals in the same system.

Using pulse gradient NMR to measure the effective self-diffusion coefficients of the various components, the self-diffusion of detergents and any hydrophobic substance is very low, usually on the order of about 10 m / s or less (until the phase becomes bicontinuous; see below). This is because the primary force of diffusion of detergents and hydrophobic substance is the diffusion of the micelles themselves, which is very low. Also the diffusion ratio of detergents to hydrophobic material should be almost identical for the same reason.

Of course, on the nanometer scale, narrow angular scattering (SAXS) does not give sharp Bragg peaks. However, the analysis of the resulting curve by several methods from the literature can provide an indication of the length scale of the nanostructure. By analyzing the decrease in intensity at low wavelengths (but not too low compared to the reciprocal value of the length of the detergent molecule), it is possible to determine • 9 9 9 9 • Í3 • 9 • 99

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9 · the apparent radius of gyration Rg from the slope of the plot of intensity as a function of the square of the wave frequency (the so-called Guinier plot). The gyration radius is then proportional to the dimensions of the micelle units using a standard well known equation. It will move in the order of nanometers. Moreover, when plotting the product of the square of the wave frequency against the wave frequency - the so-called Hosemann plot, one can find a peak which is also proportional to the micelle size. This method has the advantage of being less sensitive to interactions between micelles than that of the gyration radius.

The above is subsequently changed for detergent-based L1 phases. First, the viscosity may increase substantially at the moment the bicontinuity occurs due to the rigidity of the detergent film. Also, the order of detergent self-diffusion can increase dramatically even in the presence of a hydrophobic substance (which can be freely added to the binary system as a marker) so that it can reach or exceed the lamellar phase values of the same system. Although both SAXS, gyration radius, and Hosemann plots result in a nanometer dimension, they must be interpreted as a characteristic length of the bicontinuous domain rather than the dimensions of individual particles. (For some models, such as composite rollers from the author's dissertation, or the Talmon-Prager model, in which the bicontinuous forest is represented by stacked units, which, although they appear to be particles, are in fact only building blocks designed to construct a bicontinuous model geometry).

In the case of the L1 phase of a block copolymer-based system, the same applies to SAXS analyzes. On the other hand, NMR spectra and self-diffusion NMR measurements as well as surface tension measurements are not transferable to this region. However, in the past, instead of NMR measurement of self-diffusion, the vapor transfer measurement method has been successfully applied. Especially when it is possible to find a gas that is soluble in one type of domain without being soluble in the other (s).

• · · · · · · · · ·

Then, it is possible to test the continuity of these domains by measuring the gas transfer of a given domain. If possible, the transport of the continuous domain (type B) in the micelle phase should be only slightly slower than that of pure polymer B, while the transfer of gas dissolved in the type A domains should be very small. The shear modulus of the micellar phase of the block copolymers is largely determined by the polymer that forms the continuous domain, introducing the convention as polymer B. Then, for example, in PS-PI diblocks with 10% PS, so the micelles from PS are formed in a continuous matrix P1, the shear modulus will be close to that of pure polyisoprene, only by a modest increase caused by the presence of PS micelles. Interestingly, otherwise, with 90% PS and thus with P1 micelles and a continuous PS matrix, the elastomeric Pi micelles are able to provide a shock-absorbent component, thus improving fracture characteristics over pure glassy polystyrene.

L2 phase: This phase is the same as the L1 phase except that the roles of the polar and non-polar regions are reversed: the curvature of the interface between the polar and polar regions is oriented against the polar domain, thus the interior of the micelles (if present) is water. other polar substances, while the non-polar domains (mostly alkane chains of lipids) form a continuous matrix - but it is also possible that the polar domains interconnect to form a bicontinuous L2 phase. As already mentioned, this phase may be nanostructured or without structure.

Identification of L2 Phase Nanostructures: The approaches to identify the L2 phase are identical to those listed for the L1 phase, with the following modifications. In this case, only detergent-based L2 phases can be disassembled because in block copolymer systems the two types of micelle phases (A in B, and B in A) are equivalent and the identification of the micelle phase of the block copolymer systems has been discussed above.

First, the L2 phases are generally better when the HLB is low, as in the case of an ethoxylated alcohol detergent having a small number.

Ethylene oxide groups (usually equal to or less than 5 at the usual length of the alkyl chains), or in the case of double-chain detergents. In terms of phase behavior, it is generally found at even higher detergent concentrations than the liquid reverse crystal phase: usually the L2 phase is at the boundary of the reverse hexagonal phase at higher detergent concentrations. In the case of non-biontinuous L2 phases, it is a self-diffusion of water whose values are very low and the measurement of diffusion coefficients (eg pulse gradient NMR) should result in values of the order of 10 ‘m7s or less. Hasemann plots also indicate the size of the reverse micelles, which is essentially the size of the aqueous domain.

Microemulsion: Microemulsion can be defined as a thermodynamically stable, optically isotropic low viscosity microstructure liquid phase containing oil (nonpolar liquid), water (polar liquid) and detergent. See also Danielsson, I., Lindman, B. (1981) Colloids and Surfaces, 3: 391. Thermodynamically stable detergent, water and oil solutions are commonly called microemulsions.

While appearing homogeneous from a macroscopic point of view, on a microscopic scale (10-1000 angstroms) they are structured into water-containing and oil-containing domains separated by a detergent rich film. See also Skurtveit, R. and Olsson, U. (1991) J. Phys. Chem. 95: 5353. A key feature defining microemulsions is that they contain, in addition to water and detergent, an "oil" (a non-polar solvent or liquid); that is to say they are microstructured as already defined. Due to the very strong tendency of water and oil to separate into phases, it can generally be said that in the absence of an organic solvent capable of dissolving oil and water (such as ethanol, THF, dioxane, DMF, acetonitrile, DMSO) and some further), then the clear single-phase solution containing water, oil and detergent must be a microemulsion and it can only be inferred that this phase is 9 9 9 9 * 9

255

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999 ··· nanostmctum. Note that the microemulsion can be both L1 and L2 phases, especially if it contains well defined micelles. However, if the phase is L1, the micelles are necessarily filled with oil. Microemulsion is a nanostructured liquid phase. If the oil, water and detergent solution contains characteristic domains of magnitude larger than nanometers, i.e. in a micrometer range, it is no longer a microemulsion, but rather a "miniemulsion" or an ordinary emulsion. The latter are non-equilibrium. The term microemulsion has also been introduced in spite of the fact that the L1 and L2 phases may contain oil and, moreover, may be biontinuous, since it is common for ternary oil, water and detergent / lipid systems to evolve from a continuous water domain state through a biontinuous, to a state where the continuous domain contains oil, all without creating phase boundaries. In this case, there is no point in trying to establish a separation point between the L1 and L2 regions of the phase diagram. Instead, the whole region is considered to be a "microemulsion" with the high water concentration at its end as the L1 phase with the oil-rich micelles while the high oil concentration at the end as the L2 phase. (There are microemulsion and L1 and L2 phase overlaps in the Venn graph terms, and not just the L1 and L2 phases.) As discussed below, the microstructure of a microemulsion can generally be described such that a single layer of detergent film separates the oil-rich and domain domains rich in water. This detergent / lipid separating film may be sealed to form micelles, or it may be interconnected to form a reticulated structure to form a bi-continuous microemulsion.

It must be emphasized that, as defined herein, the emulsion is not a nanostructured solution. The range within which the characteristic length of the emulsion, which is actually the average droplet size of the emulsion, is generally greater than the characteristic length of the nanostructured solutions and falls in the order of micrometers rather than nanometers. While recent efforts to create an emulsion with a smaller than micrometer droplet size have resulted in emulsions with smaller droplets and

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77 · · · · ·

9 9 • * · ·· ·· the term “mini emulsion”, there remains a key difference to exclude the emulsion and the mini emulsion from the world of nanostructured phases as described here. Liquid phase nanostructures, including microemulsions, are able to exist in thermodynamic equilibrium, unlike emulsions that are not equilibrium but only metastable materials. In addition, a fully equilibrated nanostructured solution is optically transparent, while the emulsion is generally opaque - for example, a common emulsion is milk. Moreover, assuming that the Friberg model corresponds to the structure of a normal emulsion, as is generally believed in this field, there may be dramatic differences at the molecular level. According to this model, it can be assumed that the emulsion droplets are generally stabilized by an interfacial film, which during microscopic analysis proves to be a material from the nanostructured liquid crystal phase. Then, these emulsions have a hierarchical structure arrangement where the nanostructured phase serves as a stabilizing layer between the major building blocks, which are microemulsion droplets in a continuous medium. Our use of the word "nanostructured" instead of "microstructured" stems from a more precise and more limited definition of the term "nanostructured" and from the fact that it does not include other liquid phases belonging to another area, such as emulsions. A simple geometric consideration states that an emulsion wherein the droplet size is of the order of 10 microns and the stabilizing film, which may be a liquid crystal layer, is not sufficient as the interior of the microparticle of the invention, which is usually of the order of 1 micrometer.

Determination of nanostructured microemulsions: The methods and measures mentioned in the previous paragraphs on the determination of the L1 phase are also applicable for the determination of nanostructured microemulsion phases with the following modifications.

For microemulsions that are not clearly fitting in the description of the L1 or L2 phase - which is the last case to be discussed here - it should be noted that most are bicontinuous. And in the case of liquid phases containing water, oil and detergent, bicontinuity is sufficient evidence • ϊ ···; . ·· ........

. . Nanostructures, because emulsions and other common solutions are never bi-continuous. ί nan nan nan ost ost ost ost ost ost ost ost ost ost ost ost This was discussed in: "On the demonstration of bicontinuous structures in microemulsions", Lindman, B., Shinoda, K., Olsson, U. "Anderson, DM, Karlstrom, G., Wennerstrom, H. (1989) Colloids and Surfaces" 38: 205. A proven way to test bicontinuity is to measure effective self-diffusion coefficients of water and alley alone using pulse gradient NMR; it is also generally preferred to measure this coefficient for a detergent. Electrical conductivity measurements can also be used to determine water continuity, but this method is associated with the so-called "skipping" process problems. Fluorescence quenching was also used to determine continuity, Sanchez-Rubio, M., SantosVidals, L.M., Rushforth, D.S., Puig, J.E. (1985) J.Phys. 89: 411. Also, narrow-angle neutron scattering and X-ray scattering analysis were used to test for bicontinuity, Auvray, L., Cotton, R., Ober, R., Taupin, J., (1984) J.Phys. 88: 4586. SAXS curve analysis was used to derive the existence of interphases and hence the existence of nanostructures, Martino, A., Kaler, E.W. (1990) J.Phys. Chem., 94: 1627. Frost-freezing electron microscopy with extremely fast freezing resulting from decades of development of fixation methods of nanostructured solutions was used to study microemulsions; a critical review article discussing the reliability of the results of this method is in: Talmon, Y. in K.L. Mittal and P. Bothorel (eds), Volume 6, Plennum Press, New York, 1986, p. 1581.

If the liquid composed of oil, water and detergent is not a pure L1 or L2 phase and does not show strong evidence of bicontinuity, then no separate technique will be sufficient to demonstrate nanostructure, but a complete analysis will have to be performed. In general, the measurements mentioned in this section, such as SAXS, SANS, NMR measurement of self-diffusion, Cryo CM, etc., would then have to be applied to attempt to explain the data in connection with the nanostructure model.

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L3 phase: the phase phase region L2 sometimes takes the shape of a tongue projecting outwards; a thin protrusion completely unlike the normal shape of the L2 region of the phase diagram. This phenomenon sometimes occurs in some L1 regions as described below. When these regions are studied in detail, especially with the aid of X-ray and neutron scattering, they differ significantly from the L2 phases. In the L2 phases, the detergent film is a simple layer with oil (non-polar solvent) on one side and water (polar solvent) on the other. Conversely, in the "L3 phases" as these are called, the detergent forms a bilayer with water on both sides. The L3 phase is generally considered bi-continuous and thus shares another property with the cubic phase. There are two separate water nets that are intertwined but separated by a two-layer. Thus, the L3 phase is very similar to the cubic phase, but lacks regular spatial arrangement. The L3 phases derived from the L2 phases and those branched from the L1 phases have different names. The "L3 phase" is used for the region associated with the L2 phase region, while "L3 *" is the name of the region associated with the L1 phase.

Determination of L3 phase nanostructures: Determining the L3 phase and distinguishing it from several other liquid phases discussed above may be a sophisticated problem requiring a combination of several analyzes. The most important techniques will now be discussed.

Despite the optical isotropy and the fact that it is a solution, the L3 phase may possess an interesting property, namely it may exhibit flow birefringence. This is often associated with considerable viscosity, which can be significantly higher than that of the L1 or L2 phase and comparable, or higher than the lamellar phase. This, of course, is due to a continuous film consisting of a bilayer, which is widely reflected in the topology and geometry of the nanostructure. The break may then result in cooperative deformation (and the resulting comparison) of large portions of the double layer film, as opposed to, for example, the micellar L1 phase, where the individual micellar units merely displace with the break. In any case, the simple layer is • 9 · · ·

9 «9

generally more plastic to breaks than a double layer. Supporting this interpretation is the recognition that the L3 phase viscosity is a linear function of the bulk detergent fraction, Snabre, P., Porte, G. (1990) Europhys. Lett. 13: 641.

Sophisticated methodologies of light, neutron and X-ray scattering have been developed to identify nanostructured L3 phases. Safinya, C.R., Roux, D., Smith, G.S., Sinha, S.K., Dimon, P., Clark, N.A., Bellocq, A.M. (1986) Phys. Roar. Lett. 57: 2718; Roux, D., Safinya, C.R. (1988) J. Phys. France 49: 307; Nallet, F., Roux, D., Prost, J. (1989) J. Phys. France 50: 3147. In particular, Roux analysis, published in Roux, D., Cates, M.E., Olsson, U., Bali, R.C., Nallet, F., and Bellocq, A.M. Europys. Lett., Is able to determine that the nanostructure comprises two aqueous networks separated by a bilayer of detergent which give some symmetry due to the equivalence of the two networks.

Fortunately, the determination of nanostructured origin of L3 phases based on phase behavior is more accurate than typical L1 and L2, or even microemulsion phases. This is mainly because the L3 phase is often obtained by adding a small amount of oil (a few percent) or other substance to the lamellar or bicontinuous cubic phase, or by slightly raising the temperature from the same phase. Since it is easy to demonstrate that these liquid crystal phases are nanostructured (especially Bragg peaks in X-ray), we can be sure that the liquid phase is also nanostructured because it has a very close composition, like the liquid crystal phase.

After all, it is highly unlikely that the addition of a few percent oil to the nanostructured liquid crystal phase converts liquid crystals into a liquid without structure. In addition, pulse gradient NMR self-diffusion measurements in the OT-tear system aerosol show that the self-diffusion behavior in the L3 phase is very pure extrapolated to near reverse, biconontinuous, cubic phase behavior. The same L3 phase was investigated by a combination of SANS, self-diffusion and electron microscopy of frost breaks, Strey, R., Jahn, W., Skouri, M., Porte, G., te ····· · · · · · ·

Marignen, J., Olsson, U., in "Stmcture and Dynamics of Supramolecular Aggregates" S.H. Chen, J.S. Huang and P. Tartaglia (editors) of Kluwer Academie Publishers, The Netherlands. In addition, when analyzing the scattering of the SANS and SAXS L3 phase, a broad interference peak was often found in wave vectors that corresponded to the d-distributions, which are of the same magnitude order as those attributed to the bicontinuous cubic phase lying next to the phase graph. The author developed a model of the L3 phase nanostructure, which is an extrapolation of known structures of the bicontinuous cubic phases, Anderson, D.M., Wennerstrom, H., Olsson, U. (1989) J.Phys. 93: 4532.

The nanostructured liquid crystal phase material comprising the components of the coated particles may be:

a) nanostructured material of normal or reverse cubic phase,

b) nanostructured material of normal or reverse hexagonal phase,

(c) nanostructured material of the normal or reverse intermediate phase; or

d) nanostructured lamellar phase material.

Liquid crystal nanostructured phases are characterized by the existence of forest structures composed of at least first and second type domains (in some cases three or more domain types) having the following characteristics:

(a) the chemical residues of the first domain type are incompatible with the residues of the second domain type (in general, each pair of different domains is incompatible with each other) in such a way that they do not mix with each other in the circumstances and remain separate domains; (for example, the first type domains may consist solely of polar groups, such as water, or polar portions of lipid molecules, while the second type domains are composed of non-polar residues such as hydrocarbon chains; or the first type domains may be polystyrene-rich, polyvinylpirolidone);

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b) The arrangement of atoms in each domain corresponds to a liquid rather than a solid, so that it lacks the arrangement of atoms in the lattice; (this can be proven by the absence of sharp Bragg peaks in wide-angle X-ray scattering);

(c) the smallest dimensions (ie thickness in the case of layers, diameter in the case of cylinders and spherical formations) of virtually all domains are on the nanometer scale (from 1 to 100 nm); and

d) domain organization corresponds to a one-, two-, or three-dimensional grid having a grid parameter (or cell size) on a nanometer scale (from 5 to 200 nm). The domain organization then corresponds to one of the 230 tabulated spatial groups in the International Crystallographic Tables and will be proven by the correct shape of the narrow-angle X-ray scattering (presence of sharp Bragg reflections in SAXS measurements with d-distribution of the lowest reflections in 3-200 nm).

Lamellar phase: The lamellar phase is characterized by:

1. narrow-angle X-ray shows peaks with indexes 1: 2: 3: 4: 5: .., in wavebands.

2. to the naked eye, the phase appears clear, or only slightly cloudy, or with little turbidity.

3. In a polarizing optical microscope, the phase exhibits birefringence, and well known patterns are well described by Rosevear and Winsor (ie Chem. Rev. 1968, p. 1). The three most obvious patterns are the "Maltese Cross", "Mosaic" and "Oil Spots". The Maltese Crosses are a superposition of two darker bands (interference fission) roughly perpendicular to each other, above an approximately circular trace of light (birefringence), a feature similar to that of the German Army in World War II. Variations of this texture as well as its source are described in detail by J.Bellare's dissertation, Univ. of Minesota, 1987. The mosaic structure can be seen as the result of a very densified field of Maltese crosses, which is the result of a very dense Maltese cross. Randomly intertwined and intertwined light and dark areas. The texture of the oil spots is most often seen when the lamella phase gets between the slide and cover slip; this pattern is characterized by long warped lines which, when examined in detail at high magnification (ie 400x), are composed of thin strips that lie approximately at right angles to the running line, just as sleepers form a rail (as opposed to the hexagonal pattern described below) ). In some cases, especially when the phase is slightly squeezed between the glasses for some time, the lamellar phase is folded so that its optical axis is parallel to the microscope preview axis, resulting in the disappearance of the birefringence.

For lamellar phase in detergent-water systems:

1. the viscosity is so low that the system is able to flow (i.e., when the container with the lamella phase is tipped upside down).

2. the self-diffusion coefficients of the individual components are comparatively high with the coefficients of the components themselves - ie the effective self-diffusion coefficient of water in the lamellar phase is comparable to that of pure water. Since detergents that form liquid crystals are usually not liquid at room temperature, the values of the self-diffusion coefficients are not determined, therefore, the effective (measured) self-diffusion coefficients in lamellar phases are often taken as starting points to interpret measurements in other phases.

3. if ² H NMR is measured when the detergent is deuterated on its polar group, we find two peaks separated by a double distribution than that of the hexagonal phase.

4. In terms of phase behavior, the lamellar phase occurs mostly in high concentrations of single-chain detergents with water, mostly around 70% of the detergent. In the case of dual-chain detergents, it occurs mostly at lower concentrations, mostly below 50% of the detergent. In general, it is capable of withstanding higher temperatures, any other liquid crystal phases that occur in the phase graph.

For lamellar phase in single component block copolymer systems:

The 1st shear module is generally lower than in other liquid crystal phases of the same system.

2. in terms of phase behavior, the lamellar phase occurs when two blocks are present in the porn approximately 50:50.

Normal hexagonal phase: The normal hexagonal phase is characterized by:

1. In narrow-angle X-ray, peaks occur with indexes 1: ^ 3: 2: ^ 1: 3:, ..; generally ^ (V + hk + k ² ), where h and k are integrals - Miler indexes of groups of two-dimensional symmetry.

2. This phase appears to the naked eye when fully equilibrium. Compared to other close lamellar phases, it is clearer.

3. In a polarizing optical microscope, the phase exhibits birefringence. Well known textures have been described by Rosenvear and Winsor (ie ChemRev. 1968, p. 1). The “fan” texture appears to be most obvious. It is made up of birefringent areas where gentle furrows start in each area, giving the whole the appearance of an Oriental fan. The direction of fan furrowing in adjacent areas is random. The key difference between the lamellar phase and the hexagonal phase is that at high magnification, in the lamella phase, the fine furrowing is made even finer lying on it in a perpendicular direction.

For normal hexagonal phases of detergent-water systems:

1. The viscosity is mild, more viscous than the lamellar phase, but significantly lower than the typical cubic phase (whose viscosity is in millions of centipoise)

2. the self-diffusion coefficient of detergents is almost comparable to the lamella phase; the water coefficient is comparable to pure water.

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3. Using a deuterated detergent, the ² H NMR spectrum yields half cleavage than we get for the lamellar phase.

4. In terms of phase behavior, the normal hexagonal phase generally occurs at low detergent concentrations in single chain detergent / water systems, typically around 50%. The normal hexagonal phase region is mostly adjacent to the phase region (L1), but some cubic phases that do not show bicontinuity may occur between them. In the case of double-chain detergents, it is virtually absent in binary systems.

The terms "normal" and "reverse" generally do not apply to one-component systems of block copolymers (although if one block is polar and the other is non-polar, these terms can in principle be used). The shear modulus in these phases is generally higher than in the lamellar phase and, conversely, lower than in the bicontinuous cubic phase of the same system. Due to the phase behavior, the hexagonal phase of block copolymers occurs at a ratio of two blocks of 35:65. Usually, the lamellar phase is bounded on both sides by the hexagonal phase where the minor component is located inside the rollers (this definition replaces the normal / reverse terminology of detergent-containing systems).

Reverse hexagonal phase: In detergent-water systems, the identification of reverse is different from the normal hexagonal phase in only two ways:

1. The viscosity of the reverse hexagonal phase is usually relatively high, higher than that of a typical normal hexagonal phase, achieving a viscosity of the reverse cubic phase.

2. Due to phase behavior, the reverse hexagonal phase occurs at high detergent concentrations in double-chain detergent / water systems, often reaching values close to 100% detergent. The region of the reverse hexagonal phase usually adjoins the region of the lamella phase with the lower 99 99 99 99 99 9 9 9 9 9 9 9999 9 99 9 9 999

999999 9 9 • 9 9 99 99 9 9 99 detergent concentrations, but the bicontinuous reverse hexagonal phase may also be in between. The reverse hexagonal phase, surprisingly, occurs in many binary single chain detergent systems, such as a variety of monoglycerides (including monooleyl glycerol) and many monoionic detergents based on low HLB PEG.

As mentioned in the description of the normal hexagonal phase, the difference between the normal and reverse hexagonal phases is meaningless when speaking generally of more than a one-component block copolymer hexagonal phase.

Normal Bicontinuous Cubic Phase: This is characterized by:

1. Narrow X-ray shows peaks with indexes falling into a three-dimensional spatial group with cubic characters. The most common groups, together with their indices, are: Ia3d (# 230), with A6.A8: Vl4: 4.Pn3m (# 224), with λ / 2: λ / 3: 2: λ / 6: λ / 8. .a Im3m (229) with indexes ^ 2: ^ 4: ^ 6: 3/8: ^ 10.

2. This phase generally appears clear to the naked eye when it is in equilibrium compared to other close lamellar phases clearer.

3. In a polarizing optical microscope, the phase does not show birefringence and therefore there are no textures.

For the normal bicontinuous cubic phase of detergent / water systems:

1. the viscosity is high, much higher than the lamellar phase, even higher than a typical normal hexagonal phase. Most cubic phases have viscosities in millions of centipos.

2. There is no cleavage in the NMR spectra, only one peak corresponding to the isotropic motion.

3. Due to the phase behavior, the normal bicontinuous cubic phase generally occurs in single-chain detergent / water systems at higher detergent concentrations, typically around 70% of the ionic detergent. Usually, the area of the normal bicontinuous cubic phase is between 9 and 9.

991 9 1 «» 4 »areas of normal cubic and lamellar phase, which together with high viscosity and absence of birefringence greatly facilitates its identification. In binary double-chain detergent systems with water, this phase does not occur at all.

The terms "normal and reverse" generally do not apply to bicontinuous cubic phase systems of one-component block copolymers (however, when one block is polar and the other non-polar, these terms may be applied). The shear modulus in the bicontinuous cubic phase is generally much higher than the lamellar phase and significantly higher than the hexagonal phase of the same system. Due to phase behavior, the bicontinuous cubic phase occurs at a fraction ratio of two blocks of about 26:74. In some cases, the two bicontinuous cubic phases will delimit the lamellar phase, where in both cases the minor component will be represented inside the cylinders (this definition replaces the terms "normal" and "reverse" detergent systems) and the whole cubiclamellamic-cubic series will be bounded by the hexagonal phase.

Reverse Bicontinuous Cubic Phase: This is characterized by:

In detergent / wasp systems, the identification of the reverse bicontinuous cubic phase differs from the above identification of the normal bicontinuous cubic phase at only one point. Due to the phase behavior, the reverse bicontinuous cubic phase is located between the lamellar and the reverse hexagonal phase, while the normal is found between the lamellar and the normal hexagonal phase. In view of the above discussion, it is therefore necessary to distinguish between normal and reverse hexagonal phases. A good rule of thumb is that when the cubic phase is generally found in higher concentrations of water than lamellar, then this is normal, while it is reversed when higher concentrations of detergent are present. Reverse cubic phase generally occurs at higher detergent concentrations in double-chain detergent / water systems, but this is often complicated by the fact that the reverse cubic phase occurs only in the presence of the addition of a hydrophobic ("oil") or amphiphilic substance. Reverse bicontinuous cubic phase occurs:

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9 * 999 • 4 · · 99 99 in a variety of single chain detergent binary systems, such as many monoglycerides (including monooleylglycerol) and a number of non-ionic PEG-based low HLB detergents. It should also be noted that the spatial group # 212 was discovered in the reverse bicontinuous cubic phase, but not in the normal phase. This phase is derived from space group # 230. As noted above, the difference between the normal and reverse bicontinuous cubic phases makes sense only in detergent systems but is generally not applicable to single-component block copolymers of the bicontinuous cubic phases.

Normal split (not bicontinuous) cubic phase: This is characterized by:

1. Narrow X-ray shows peaks with indexes falling into a three-dimensional spatial group with cubic characters. The most common groups, together with their indexes, are: Pm3n (# 223), with indexes ^ 2: ^ 4: ^ 5, .. In single component block copolymers, the group and Im3m corresponding to the centered spherical package with indexes ^ 2 are the most common: λ / 4 : ^ 6: λ / 8: ...

2. Phases generally appear to the naked eye in a steady state and clearer than any associated lamellar phase.

In the normal split cubic phase of detergent / water systems:

1. high viscosity. It is higher than in the lamellar phase and even higher than the typical normal hexagonal phase. Most of the cubic phases have viscosities in millions of centipos, whether split or bicontinuous.

2. there is no cleavage in the NMR spectrum but only one isotropic peak.

3. In terms of phase behavior, the normal split cubic phase generally occurs at relatively low detergent concentrations in single chain detergent and water systems. Usually this concentration is around 40% of ionic detergents. Typically, the area of the normal cubic phase is between the normal micellar and the normal hexagonal phase, making it easy to identify, together with the high viscosity and the absence of birefringence. In binary double-chain detergent systems with water, this phase generally does not occur. In the case of a divided cubic phase of block copolymers, the terms "normal and reverse" are generally not used (however, if one block is polar and the other non-polar, these terms may be used). The shear modulus of such split cubic phases generally depends entirely on the shear modulus of the block-forming polymer in the continuous phase. In terms of phase behavior, the split cubic phase generally occurs at very low volume parts of one or the other block. The order of magnitude is 20% or less.

Reverse split cubic phase: This is characterized by:

In detergent-water systems, the identification of the reverse split cubic phase differs from the above in three points:

1. In terms of phase behavior, the reverse split cubic phase is between the lamellar and the reverse hexagonal phase, while the normal split cubic phase is between the lamellar and the normal hexagonal. It is therefore necessary to distinguish the normal from the reverse hexagonal phase (see discussion above). A suitable rule is that when the cubic phase lies on the side of the higher water concentrations from the lamellar phase, then it is normal, while it is reversed when it is directed towards higher detergent concentrations. Reverse cubic phase generally occurs at high concentrations of double-chain detergent in detergent / water systems, but this is often complicated by the fact that a reverse cubic phase can only exist in the presence of the addition of a hydrophobic substance (oil) or amphiphile. Reverse split cubic phase occurs in a number of binary single chain detergent systems, such as many monoglycerides (including monooleylglycerol) and a variety of PEG based low HLB detergents.

• · · · · · · · · · · · · · · · · · · · · · ·

2. The spatial group Fd3m, # 227 is usually obtained.

3. The self-diffusion coefficient is very low while the coefficient of any hydrophobic component is very high. The detergent coefficient is higher compared to the lamellar phase.

As noted in the description of the normal split cubic phase, the difference between normal and reverse makes sense only in the case of detergent / water systems but generally loses its meaning in one-component block copolymers of cubic phases.

Intermediate phases: These are characterized by:

These phases occur relatively rarely and when found they usually occupy only a very narrow part of the phase graph. Moreover, the structure of many of these phases is currently unknown or still under discussion. The intermediate phase is divided as follows:

The normal int (1) phase occurs at lower detergent concentrations than the normal bicontinuous cubic phase adjacent to the hexagonal phase. The viscosity is generally low or moderately low, but not higher than the normal hexagonal phase. The phase shows birefringence and there are similar textures to the hexagonal phase. The self-diffusion of the individual components is very similar to that of the hexagonal phase. The narrow-angle X-ray usually shows a spatial group with lower symmetry, usually monoclinic. This phase can be distinguished from the normal hexagonal phase by a relatively sophisticated NMR spectrum analysis and SAXS analysis; see Henriksson, U., Blackmore, E. S., Tiddy, G. J. T., Soderman, O. (1992) J. Phys. Chem. 96: 3894. The intensity of the spectral fission will lie between the hexagonal and the zero isotropic phase fission, which is good evidence of the intermediate phase.

Normal int (2) is found at higher concentrations than the normal bicontinuous cubic phase adjacent to the lamella phase. This brings close similarities to both the properties and probably the structures with the normal bicontinuous cubic phase, except that they are binary and have different spectra of NMR and SAXS analyzes. The optical texture is in some sense unusual, in some ways similar to lamellar texture, in some hexagonal, but they are usually significantly coarser than any of the more common phases. This is, like the vint (1) phase, a lower symmetry group, usually rhombohedral or tetragonal, requiring two parameters to characterize the cell, which complicates the SAXS analysis. In general, if the distances D cannot be fitted to a simple integral scheme, it can be assumed to be an intermediate phase structure.

Reverse int (2) is found at lower concentrations than the reverse bicontinuous cubic phase adjacent to the lamella phase. These phases are birefringent and have unusual NMR spectra and SAXS analyzes. As in the vint (1) phase and in the int (2) phase, it is a group with a lower symmetry, usually rhombohedral or tetragonal, requiring two parameters to characterize the cell, which complicates the SAXS analysis. Although SAXS analysis is complex, the presence of Bragg peaks in the SAXS spectrum whose indexes do not match the cubic or hexagonal lattice (which have only one lattice parameter) together with the optical birefringence indicates that this is an intermediate phase. Spatial groups that are likely to be in the biontinuous intermediate phase were discussed in D.M.Anderso, Supplement to J.Physique, Proceedings of the Workshop on Geometry and Interfaces, Aussois, France, Sep. 1990 C7-1-C718.

At the moment when the coated particle 10 is to be formed but the coating 20 is not yet formed, it is highly desirable that the nanostructured material of the liquid or liquid crystal phase or a combination thereof is one that is in equilibrium with water (polar solvent), or more precisely with a dilute aqueous solution. Once the coated particle 10 has an external shell 20, the nanostructured material discussed need not be in equilibrium with water. The liquid phases that are in equilibrium with water are:

L2 phase (eg reverse micelles) of microemulsion and

L3 phase (but not L3 * phase).

These liquid crystal phases may be in equilibrium with water: reverse cubic phase, reverse hexagonal phase, reverse intermediate phase, and lamellar phase.

Phases that may be in equilibrium with water are preferred for the production of the coated particles of the invention. First of all, using the process described herein to disperse a given phase as a matrix, it is desirable that the phase be insoluble in water or in the solvent used to disperse the particles. In addition, if the inner phase has another property that is in equilibrium with excess aqueous solution during particle formation, the risk of phase transformation is minimized. Similarly, the risk of phase changes is minimized when the phase is in equilibrium with an excess of aqueous solution under conditions when the outer shell is released, which may be an advantage in some applications.

While the water insolubility of the matrix (generally, the external solvent) is desirable with respect to particle production, there are applications where water solubility at the time of application is often an advantage. This may be the subject of further invention. For example, consider a matrix of 20% C12E5 (pentaethylene glycol dodecyl ether) in water. At 75 ° C, this composition gives rise to an L3 phase that is in equilibrium with water and will therefore be readily dispersed at 75 ° C. However, if the application temperature is in the range of 0-25 ° C, this composition will be water-soluble and essentially C12E5 will function as a normal water-soluble detergent at room temperature. This will be an advantage when bude Μ · • 4 4 • 4 • 4 4 <4 · «

4

4 · 4 44

A non-greasy, rather purifying, final product after release of the outer particle coating is required.

Nanostructured liquid phase materials may consist of:

a. a polar solvent and a detergent; or

b. a polar solvent, a detergent and a hydrophobic or amphiphilic substance; or

c. a block copolymer; or

d. block copolymer and solvent.

Nanostructured liquid crystal phase materials may consist of:

a. Polar solvent and detergent;

b. a polar solvent, a detergent and a hydrophobic or amphiphilic substance; or

c. a block copolymer; or

d. block copolymer and solvent.

Above, in the paragraph entitled Chemical Criteria, the criteria for selecting a functional polar and a non-polar group were discussed to create a functional detergent. Thus, suitable detergents include those compounds that contain two chemical groups, one functional polar group selected from those described in the polar groups and one functional nonpolar selected from those described in the non-polar groups. Suitable detergents, or block copolymers (or mixtures thereof) include:

1. cationic detergents;

2. anionic detergents,

3. Semi-polar detergents;

4. zwitter detergents

i. especially phospholipids ii. a lipid mixture containing phospholipids composed to meet the physico-chemical properties of biomembranes ···· ·· · 9 ♦ • * «• ·· · ¹ · · ·» · ·· ► 9 * 9 · »· · ·

999 999

9 ·· ··

5. monoglycerides

6. PEGylated detergents

7. one of the above but containing an aromatic ring

8. block copolymers

i. with both hydrophobic but non-miscible blocks; ii. with both hydrophobic but non-miscible blocks iii. with one block hydrophilic and the other hydrophobic (ie amphiphilic)

9. a mixture of one or more of the above

Suitable lipids include phospholipids (such as phosphatydylethanolamine or sphingomyelin), or glycolipids (such as MGDS, diacylglucopyranosylglycerol and Lipid A). Other suitable lipids are phospholipids (including phosphatidylcholines, phosphatidylinositols, phosphatidylglycerols, phosphatidic acids, phosphatidylserines, phosphatidylethanolamines, etc.), sphingolipids (including sphingomyelins), glycolipids (such as galactolipids such as MGDG and DGDG, diacid, and DGDG) related acids such as deoxycholic, glycocholic taurocholic acid, etc., gangliosides, cyclopentatriol-based lipids, dimethylaminopropane lipids and lysolecithins, and other lysolipids which are derived from the above by removal of a single acyl chain.

Other suitable detergent types include anionic, cationic, zwitterionic, semipolar, PEGylated detergents, and ammonium oxide. Preferred detergents are:

anionic - sodium oleate, sodium dodecylsulfate, sodium diethylhexylsulfosuccinate, sodium dimethylhexylsulfosuccinate, sodium 2-ethylbutyrate, sodium 2-ethylhexylsulfate, sodium undecane-3-sulphate, sodium ethylphenylundecanoate, carboxylate handles of form IC _n , where n is between 8 and 20 and such as lithium, sodium, potassium, rubidium, etc .;

• <»• ··· 4

4 4

4

4 4 • 4 4

4

44

4 4

4 4

444 444 • 4 ·· 44 Cationic - dimethylammonium and trimethylammonium detergents with a chain length of between 8 and 20 carbons with a chloride, bromide or sulphate counterion and related alkyl chain of 8 to 18 carbons, benzalkonium benzoate, double-chain detergents containing quaternary ammonium ion with carbon chain between 8 and 18 carbons and a bromide, chloride, or sulfate counterion;

monoionic PEGylated detergents of form C _n Em, wherein the alkane chain length n is between 6 and 20 carbons and the average number of ethylene oxide groups m is from 2 to 80, ethoxylated cholesterol;

zwitterionic and semipolar - Ν, Ν, Ν-trimethylaminodecanimide, amine oxide detergents with an alkane chain length of 8 to 18 carbons; dodecyldimethyl- (1-sulfopropyl) -ammonium ion, dodecyldimethylammonobutyrate, dodecyltrimethylene di (ammonium chloride); decylmethylsulfondiimine; dimethyleicosylaminohexanoate and substances derived from these zwitterions and semipolar substances by an alkyl chain of between 8 and 20 carbons.

Preferred FD A approved detergents are benzalkonium chloride, sodium deoxycholate, myrystylgammapicolinium chloride, Poloxamer 188, castor oil poloxyl 35, sorbitan monopalmitate and sodium 2-ethylhexanoate.

Suitable block copolymers are those consisting of two or more immiscible blocks of the following classes of polymers: polydienes, polyallenes, polyacrylic and polymethylacrylic materials (including polyesters acrylic acid, polymethacrylic acid, polyarylates, polymethylacrylates, polydistributed esters, polyacrylamides, polyacrylamides, polyacrylamides, polyacrylamides, polyacrylamides, polyacrylamides, polyacrylamides) .), polyvinyl ethers, polyvinyl alcohols, polyacetals, polyvinyl ketones, polyvinyl aldehydes, polyvinylnitriles, polyvinyl esters, polystyrenes, polyphenylenes, polyoxides, polycarbonates, polyesters, polyanhydrides, polyurethanes. Polysulfonates, polysiloxanes, polysulfides, polysulfones, polyamides, polyhydrazides, urea polymers, polycarbodiimides, polyphosphazenes, polysilanes, polysilazanes, polybenzoxazoles , polyoxadiazoles, polyoxadiazolidines, polythiazoles, polybenzothiazoles, poly pyromellitimides, polyquinoxalins, polybenzimidazoles, polypiperazines, cellulose derivatives, alginic acid and its salts, chitin, chitosan, glycogen, heparin, pectin, poly- (tri-N-butylfluoride), poly (phosphoryldimethylamide), poly-2,5-selenienylene, poly-4-n-butylpyridinium bromide, poly-2-N-methylpyridinium iodide, polyalylammonium chloride, sodium poly (trimethylene oxyethylene sulfite). Preferred polymeric blocks are polyethylene oxide, polypropylene oxide, polybutadiene, polyisoprene, polychlorobutadiene, polyacetylene, polyacrylic acid and its salts, polymethacrylic acid and its salts, polypolyitaconic acid and its salts, polymethyl acrylate, polyethylacrylate, polybutyl acrylate, polymethylmethacrylate, polymethylmethacrylate, polymethylmethacrylate, polymethylmethacrylate, polymethylmethacrylate, polyacrylamide, polyisopropylakrylamid, polymethacrylamide, polyacrylonitrile, polyvinyl acetate, polyvinylkaprylát, polystyrene, polyalpha-methylstyrene, polystyrensiřičitá acid and its salts, polybromostyren, polybutylene, polyacrolein, polydimethylsiloxane, polyvinyl pyridine, polyvinyl pyrrolidones, polyoxytetramethylen, polydimethylfulven, polymethylphenyl polycyklopentadienenvinilen, polyalkyltiofen, polyalkyl p-phenylene, polyethylene propylene, polynorbomen, poly-5 ((trimethylsiloxy) methyl) norbomen, polythiophenylene, heparin, chitin, pectin, chitosan and alginic acid and salts thereof. Particularly preferred block copolymers are polystyrene-b-butadiene, polystyrene-b-isoprene, polystyrene-bstyrenesulphuric acid, polyethylene oxide-b-propylene oxide, polystyrene-b-dimethylsiloxane, polyethylene oxide-b-styrene, polynorbomen-l-5 ( ) norbomen, acetylen-b-5 ((trimethylsiloxy) methyl) norbomen, polyacetylene-b-norbomen, flflflflflflflflflfl flflflfl flflflflf Polyethylene oxide-b-norbomen, polybutylene oxide-b-ethylene oxide, polyethylene oxide-siloxane, and polyisoprene-b-styrene-b-2-vinylpyridine triblock copolymers.

Third component: a hydrophobic substance or an amphiphile without detergent properties:

a. alkane or alkene, another long-chain aliphatic compound

b. an aromatic compound such as toluene

c. long-chain alcohol

d. glyceride (diglycerides or triglycerides)

e. acylated sorbitan, such as sorbitan triester (trioleylsorbitanester) or sequioleate, or a mixture of sorbitan with different numbers of acyl chains from 2 to 6.

f. other non-detergent hydrophobic or amphiphilic, or a mixture with one or more of the above.

g.

A suitable third component (hydrophobic or non-detergent amphiphil) comprises: n-alkane, wherein n is between 6 and 20 and includes branched, unsaturated and substituted derivatives (alkenes, chloralkanes, etc.), cholesterol and related substances, terpenes, diterpenes , triterpenes, fatty alcohols, fatty acids, flavorings, cycloe hexane, bicyclic compounds such as naphthalenes and naphthols, quinolines, benzoquinolines, etc., tricyclic such as carbazole, phenothiazine, etc., chlorophyll pigments, sterols, triglycerides, natural oil extracts ( clove oil, anise oil, cinnamon oil, coriander oil, eucalyptus oil, peppermint oil), waxes, bilirubin, bromine, iodine, hydrophobic and amphiphilic proteins, and polypeptides (including gramicidin, casein, receptor proteins, lipid anchored proteins, etc.). ), local anesthetics (such as butacaine, ecgonine, procaine, etc.) and low molecular weight hydrophobic polymers (see the overview of polymers above).

Particularly preferred third ingredients are aniseed oil, clove oil, coriander oil, cinnamon oil, peppermint oil, beeswax, benzoin, benzyl alcohol, benzyl benzoate, naphthol, capsaicin, catearyl alcohol, cetyl alcohol,

9999 9 9 9 99 99

99 9 9 9 9 9 9

9 ·· 999 cinnamic acid aldehyde, cocoa butter, coconut oil, flaxseed (hydrogenated) oil, cyclohexane, cyclomethicone, dibutyl phthalate, dibutyl sebacate, dicotyl phthalate, DIPAC, ethyl phthalate, ethylveniline, eugenol, methylglycerate, distearyl, distearyl, distearyl , methyl salicilate, miristylalcohol, oleic acid, oleyl alcohol, benzyl chloride, paraffin, peanut oil, piperonal, rapeseed oil, rosin, sesame oil, sorbitol fatty acid esters, squalene, stearic acid, triacetin, trimiristin, vanillin, and vitamin E.

The polar solvents (or the preferred solvent for block polymers) may be:

a. water

b. glycerol

c. formamide, N-methylformamide, dimethylformamide

d. ethylene glycol, or other polyhydrated alcohols

e. Ethyl ammonium nitrate

f. other non-aqueous solvents such as N-methylsolidone, N-methylacetamide, pyridinium chloride, etc.

g. a mixture of two or more of the above.

Desirable polar solvents are water, glycerol, ethylene glycol, formamide, N-methylformamide, dimethylformamide, ethylammonium nitrate, and polyethylene glycol.

As previously postulated, the outer shell 20 may be a non-lamellar crystalline material. The term non-lamellar, as applied herein, should be understood in the following context. Lamellar crystalline phases, which differ from liquid crystal phases, occur in organic compounds (usually polar lipids), inorganic substances and organometallic compounds. Although these materials may be true crystalline materials and may therefore have three dimensional lattice ** 9 9 • 9 9 9

9 99 • 9 9 9

999

9 the arrangement of atoms (or molecules in the case of organic crystalline materials) in space, strength and interaction between atoms - which include covalent bonds, ionic bonds, hydrogen bonds, steric interactions, hydrophobic interactions, dispersion forces etc. - are much stronger between atoms or molecules that lie in the plane of the slats than in the direction across the membrane. For example, in the graphite layer structure, atoms are covalently bonded to each other into a two-dimensional network, while there are no bonds between the layers, only weaker dispersion forces and steric interactions. The absence of these strong interlamellar interactions gives rise to a variety of physicochemical properties unsuitable for use as the coating material of the invention.

First of all, the physical integrity of lamella crystals is specifically compensated by weak interactions between layers. The glaring evidence is a comparison between graphite (a layered crystalline form of carbon) and a diamond (a crystalline form of carbon having three-dimensional bonds). In addition, the fact that graphite is an important part of certain lubricants, given the ease with which the individual layers move one after another, while diamond is an abrasive substance demonstrates the "liquid" (or liquid crystalline) character of layered crystalline structures due to their shear response. The same inter-lamellar displacement effect is essentially responsible for the much lower viscosity of the lamellar crystalline phase compared to other liquid crystal phases, particularly the very high viscoelasticity of the bicontinuous cubic phase. As another indication of this "liquid" origin, Moh's hardness of graphite is 1.0, while diamond

10. The loss of graphite integrity is visible in everyday life when graphite leads into ordinary pencils. The harmful effect associated with a layered crystalline structure is observable in everyday life even in situations where macroscopic shear is not involved. Due to the widely accepted model of emulsion structure introduced by Stig Friberg - an overview is given in Larsson, K., Friberg, S., editors, 1990, Food Emmissions, Second Edition, Marcel Dekker, Inc. NY 4

4444 ·· Μ • 4 · • * 4 4

44 • 4 4

4 4

444 44 «

The lamellar liquid crystals, or generally lamellar crystalline packages, stabilize the fat droplets in the fat-in-water emulsion, and the water droplets in the water-in-oil emulsions. The instability of widespread emulsions such as milk, mayonnaise, ice cream, etc., known to the general public as "shrinkage" of the emulsion, is largely due to the flowability of these layered packaging materials. Even in the quiescent emulsion, there is a constant disintegration, flow and confluence of these layered packages, and over time each emulsion must finally succumb to the destabilizing effect of these processes.

And on yet another level, layered crystalline materials exhibit! chemical instability, such as to prevent their use as packaging in the packaging according to the invention. Consider the case of the isomorphic Werner complexes of nickel tetra (4-methylpyridine) dithiocyanate, which form host lattice clathrates containing anchored molecules, which usually results in the formation of permanent pores after separation of the guest molecule. One such Werner complex was used as the particle coat in Example 22, which illustrates the use of the invention to form particles with a coat of highly selective, controlled, sized pores. Due to J. Lipovski, Inclusion Compounds I, Academic Press London (1984), p.59: “Ni (NCS) 2 (4MePy) 4 stratified structures are stable only in the presence of guest molecules, while beta-phases retain their porosity and in the absence of guest molecules ”. Three-dimensional, non-layered beta-phase structures are discussed in detail in the same publication, such as: "... beta-phases ... have a three-dimensional system of holes interconnected by molecular size channels".

The outer coating 20 may protect the inner core 10, and any substance (s) or component (s) deposited therein against, for example, oxidation, hydrolysis, premature release, precipitation, friction, vacuum, enzyme attack, degradation by other substances in the formulation and / or external conditions, for example in the extraction process, such as pH, ionic strength, or the presence of «999 ··

9 9 9

9 9 ·

999 999 ·

• 9 · «

99

9 «

9 99

9 9 9 9 • biologically active impurities such as proteases or nucleases. Examples of each are:

oxidation: for example, for antioxidants, such as vitamin C, which are sensitive to oxidation by nature or unsaturated lipids;

hydrolysis: for example, for drugs with labile ester bond; premature release: for example during storage;

precipitation: for example, drugs in protonated (hydrochloride) form that would be deprotonated at body pH and thereby become insoluble;

cleavage: for example, in cases where after-coating processes there is a risk of sensitive substances such as proteins;

vacuum: for example, in cases where processing requires vacuum drying; enzymatic attack: peptide hormones such as somatostatin that are normally very rapidly degraded can be kept active in the circulation until they reach the site of release and effect;

degradation by other substances: for example, in cases where there is even weak reactivity between components deposited in the inner core with the external environment, which, despite the half-life of months or years, could cause problems;

external pH: for example, drugs that are protonated at low pH but without the need for low ambient pH that might otherwise irritate the stomach;

ionic strength of the external environment: in the case of encapsulated proteins that could be salted out and denatured by external impurities such as proteases and nucleases, etc .: when the outer shell is an organic product from which it would be costly to remove proteases.

With respect to the outer coating 20, the non-lamellar crystalline material may be an organic substance, an inorganic substance, a mineral, a metal such as gold, or another crystalline form of elements such as iodine, or an organometallic complex.

The structure of the non-lamellar, crystalline, coating material may be:

«99» 9 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 ·· · 99 ··

a. crystalline, non-porous

b. Crystalline with one-dimensional pore network

c. crystalline with a two-dimensional pore network

d. crystalline with a three-dimensional pore network.

The coating may have the following surface charge characteristics:

1. Surface positive charge

a. under all conditions of normal use

b. under certain conditions occurring in one or more stages of use.

2. Surface negative charge

a. under all conditions of normal use

b. under certain conditions occurring in one or more stages of use.

3. uncharged

a. only at the isoelectric point; or

b. within a pH range that includes normal use; or

c. at the pH that is reached (or induced) during some stage of use (as in collecting particles by flocculation)

Examples of non-lamellar crystalline coating materials, namely compounds occurring in non-lamellar crystalline form within the applicable temperature limits, and which in most cases have low toxicity and environmental impact are:

ascorbic acid; palmitoylaskorbic acid; aspartic acid; benzoin; beta-naphthol; bismuth sub-carbonate; butylated hydroxytoluene; butylparaben; calcium acetate; calcium ascorbate; calcium carbonate; calcium chloride; calcium citrate; calcium hydroxide; calcium phosphate; calcium pyrophosphate; calcium salicylate; calcium silicate; calcium sulfate; carmine; cetearyl alcohol; cetyl alcohol; cinnamon; citric acid; cysteine hydrochloride; dibutylsebekanan; eskulin; iron oxide; ferric citrate; iron (III) oxide; gentisic acid; glutamic acid; glycine; gold;

··· histidine; Hydrochlorothiazide; iodine; iron oxide; lauryl sulfate; leucine; magnesium; magnesium aluminum silicate; magnesium carbonate; magnesium hydroxide; magnesium oxide; magnesium silicate; magnesium sulfate; magnesium silicate; malic acid; maleic acid D- and L-; methyl silicate; methylparaben; sodium glutamate; propylgalonan; propylparaben; silica; silicone; silicone dioxide; sodium aluminosilicate; sodium aminobenzoate; sodium benzoate; sodium carbonate; sodium bisulfate; sodium bisulfite; sodium carbonate; sodium chloride; sodium citrate; sodium metabisulfate; sodium nitrate; disodium hydrogen phosphate; sodium propionate; sodium salicylate; sodium stanan; sodium grape; sodium sulfite; sodium thiosulfate; sodium thiosulfite; grape acid; talc; talc triturate; tartaric acid; tartaric acid DL-; tartrazine; tellurium; titanium dioxide; triacetin; triethylcitronan; trichloromonofluoroethane; tliromethamine and 2-hydroxy-cyclopropylmethylmorphinan hydrochloride; zinc oxide.

Calcium phosphate coatings are at the forefront of biomedical and pharmaceutical applications, since calcium phosphate is a major component of bones, teeth and other structural elements. For example, in the treatment of osteoporosis, the release of a suitable pharmaceutical could be controlled by physiological conditions that induce bone dissolution (and thus particle coating).

Potassium nitrate coatings are at the forefront of agricultural applications as they serve as fertilizers.

Iodine, aspartic acid, benzoic acid, butylated hydroxytoluene, calcium disodium edetate, gentisic acid, histidine, propyl gallate and zinc oxide may be particularly useful as crystalline coatings of potential pharmaceutical applications, because of their relatively low water solubility (generally less than 5%) and are on the FDA list of permitted, inactive ingredients for injectables.

4

5-F

Of particular importance are clathrates as coating materials. Examples of such materials are:

1. Clathrates and inclusion compounds (some of which retain permanent porosity after removal of the guest molecule):

Werner complexes of formula MX2A4, where M is a divalent cation (Fe,

Co, Ni, Cu, Zn, Cd, Mn, Hg, Cr), X is an anion ligand (NCS ', NCO, CN, NO 3', Cl, Br, Γ) and A is an electroneutral ligand substituted pyridine, alpha-arylalkylamine, or isoquinoline; examples A include 4-methylpyridine, 3,5-dimethylpyridine, 4-phenylpyridine and 4-vinylpyridine.

in

A wide variety of guest compounds can be incorporated into these complexes. Examples are molecules such as benzene, toluene, xylene, dichlorobenzene, nitrotoluene, methanol, chloromethane, argon, krypton, xenon, oxygen, nitrogen, carbon dioxide, carbon disulfide, etc.

Chelates reversibly oxygen transfer, such as bis (salycilaldehyd) ethylendiiminokobalt and other bis (salycilaldehyd) iminokobaltnaté derivatives dihistidinkobaltnatý complex and similar complexes of Co with ¹¹ amino acids and dimethylglyoximželeznatý dimethylglyoximnikelnatý complex. Complexes of the formula K ₂ Zn ₃ [Fe (CN) 6] 2 -nH 2 O, where certain values of the variable n correspond to complexes with permanent pores formed by removal of water.

2. Zeolites: faujasite - type NaX zeolite faujasite - type NaY zeolite VPI-5 zeolite

The coated particles according to the invention have applications in various fields. The coated particles 1 are adapted to absorb one or more materials, such as active substances, dissolved in the matrix.

55 '

Due to absorption, there are several cases where coated particles can be used to collect products or dispose of waste from biological and chemical reaction processes, carry catalysts in these processes, remove toxins, antigens, or waste products from medical applications.

Due to the adsorption, the coated particles can be used as chromatography media and gas adsorbents.

Due to the release, the coated particles can be used to control the release of pharmaceuticals, such as antitumor agents, photodynamic therapeutics or cosmetic or cosmeceutical materials. The active ingredient may be deposited in the matrix until release is initiated. For example, a pharmaceutically or biologically active agent may be deposited in a matrix.

In applications where these microparticles are used to transfer drugs, or enveloped proteins or polypeptides (especially receptor proteins), it is very advantageous to have an internal matrix, whether synthetic or semi-synthetic, closely mimicking the physiochemical properties of natural biomembranes of living cells. This may be important, for example, for good function of receptor proteins or membrane components, or to initiate assimilation of the internal matrix into natural biomembranes in drug delivery. Physiochemical properties that may be important in this context are bilayer rigidity (bending resistance measure), bilayer fluidity (microviscosity measure within bilayer), acyl chain length and bilayer thickness, degree of order as a function of position on the lipid acyl chain, surface charge density, the presence or absence of lipid domains within a bilayer differing in composition, folding of the bilayer and folding of the individual layers (the relationship of these two folding is discussed in H. Wennerstrom and DM Anderson in Statistical Thermodermics and Differential Geometry of Microstructured) And · materials, editors HTDavis and JCC Nitsche, Springer-Verlag, 1992, p. 137), cholesterol content, hydrocarbon content, and protein: lipid ratio. By suitably selecting the composition, it is possible to adjust the parameters of the artificial system over a wide range, namely, the nanostructured liquid phase or the liquid crystal phase. For example, the rigidity of the bilayer can be reduced by the addition of an amphiphilic substance, especially aliphatic alcohols. The bilayer charge can be melted by adjusting the porn between charged (such as phosphatidic acid) and uncharged (such as phosphatidilcholine) lipids. Also, the presence of cholesterol is important for the proper functioning of many membrane proteins. Lamellar phases, bicontinuous cubic phases, L3 phases and, to a lesser extent, reverse hexagonal phases are particularly suitable for this technique. Then, the particle of the invention with an internal matrix formed by such a phase with tuned physiochemical characteristics can be valuable in the production of pharmaceuticals, clinical sets, bichemic research products, etc.

Membrane proteins are generally highly dependent on the membrane environment, both for their function and for proper folding. For such proteins, the invention - especially with the tuned bilayer properties as described above - could be an excellent and very useful matrix. In addition to receptor proteins, examples of such proteins are proteins such as proteinase A, amyloglucosidase, enkephalinase, dipeptidyl peptidase IV, gamaglutamyltransferase, galactosidase, neuraminidase, alpha-mannosidase, cholinesterase, arylamidase, surfactin, ferrochelatase, glycine transferase, spiralin, , outer bacterial membrane proteins and histocompatibility antigens.

In view of the demanding requirements for drug delivery in the treatment of cancer, the advantages and flexibility of the present invention are particularly well suited for the delivery of antineoplastic agents, such as the following:

ANTINEOPLASTIKA

Alkylating agents

Alkylsulfonates - Busulfanum, Improsulfanum, Piposulfanum.

Aziridines - Benzodepa, Carboquone, Meturedepa, Uredepa.

Ethylamines and amethylamines - altretamine (hexamethylmelamine), triethylmelamine, triethylphosphoramide, triethylenethiophosoramide, trimethylolmelamine.

Nitrogen mustard - Chlorambucilum, Chlomaphazine, cyclophasphymide, estramustine, ifosfamide, mechlormetamine, mechlormetamine oxide hydrochloride, nmelphalan, novembichin, phenesterin, trophosphamide, have been mustard.

Nitrosoureas - Carmuen, Chlorozotocin, Fotemuen, Lomuen, Nimuen, Ranimuen,

Dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman,

Antibiotics - actacinomycins - actinomycin, anthramycin, azaserin, bleomycin, cactinomycin, carubicin, carubicin, carzinophilin, chromomycin, dactinomycin, daunorubicin, 6-diazo-5-oxo-L-norieucine, mycorubicin, doxorubicin, doxorubicin, , plicamycin, porphiromycin, puromycin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin.

Antimetabolites

Folic acid analogues - denopterin, methotrexate, pteropterin, trimetrexate.

Purine analogues - fludarabine, 6-mercaptopurine, thiamiprine, thioguanine.

Pyrimidine analogues - ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, denocytabine, floxuridine, fluorouracil, tegafur.

Enzymes - L-asparaginase.

Others - aceglatone, amsacrine, bestrabucil, bisantrene, carboplatin, cisplatin, defosfamide, democolcin, diaziquone, eflomithine, elliptinia acetate, etoglucide, etoposide, gallium nitrate, hydroxyurea, interferon-α, interferon-β, interferon-γ, interleukin, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, acidum podophylli, '

4 4 44 4 4 · 4 4 4 4 * 44 · 4444

4 4 4 4 4 4 • 4 ·· ·

2-ethylhydrazide, procarbazine, PSK09, razoxane, sizofiran, spirogermanite, taxol, teniposide, tenuazonic acid, triaziquone, 2,2 ', 2-trichlorotriethylamine, urethane, vinblastine, vincristine, vindesine.

ANTINEOPLASTICS (HORMONAL)

Androgens - calusteron, dromostanolone propionate, epitiostanol, mepitiostane, testolactone

Antiadrenalitic preparations - aminoglutethimide, mitotane, trilostane Antiestrogens - tamoxifen, toremifene Estrogens - phosphestrol, hexestrol, polyestradiol phosphate Analoga LH-RH - buserelin, goserelin, leuprolide, triptorelin , I-ethiodised oil, gold (colloidal, radioactive), radium, radon, sodium iodide (radioactive), sodium phosphate (radioactive).

ANTINEOPLASTIC ADDITIVES Folic acid recovery - folinic acid Uroprotective - mesna

Other examples of use of the coated particles of the invention include:

1. colors and inks, including microencapsulation of pigments; cationic charging of pigments (where pH dependence may be important); non-aqueous ink fillings and textures;

2. paper, including microcapsules of opacifiers (including in colors); pressure-sensitive ink microcapsules in carbon-free copy paper.

3. non-wovens, including additives, that adhere to the fibers during processing;

• 9

4. agriculture where controlled release of pheromones (some of which are otherwise toxic or unstable in the environment, unless encapsulated) is included to control insects; Controlled release of insect chemosterilizers and growth regulators (many of which are otherwise unstable in the environment); controlled release of other pesticides (temperature independence is important here); controlled release of herbicides; encapsulation of plant growth regulators of ethylene and acetylene (which are otherwise volatile); taste modifiers for repelling pests from mammals (e.g., capsaicin); release of nutrients and fertilizers;

5. environment and forestry, which include the controlled release of weed-controlling aqueous herbicides; controlled release of other herbicides; controlled release of nutrients in monocultures; soil treatment and nutrient release; encapsulation and release of chelating agents (e.g., heavy metal contamination); controlling the storage of the activity and its environmental impact (by targeted release of the crystalline shell and / or adhesive properties of the cubic phase); encapsulation of hygroscopic substances (e.g. urea and sodium chloride) or other agents as crystallization nuclei for meteorological control;

6. vaccines, including HIV gag, as an example of transfection of gag-pol cells; an adjuvant for good exposure to antigens or antibodies;

7. nuclear medicine; involving separating two radionuclides (otherwise mutually destructive) into different particles in the treatment of cancer;

8. cosmetics, including anti-aging skin creams against aging; separating the two components of the anti-acne preparation; tanning solutions containing encapsulated prostaglandins and vitamins; encapsulation of oil-soluble vitamins, oxidation-sensitive vitamins, vitamin blends; encapsulation of volatile perfumes and other fragrances; encapsulation of volatile perfumes used for "smear and smell" advertising; encapsulation of volatile makeup remover a

9 9 9

9 9 9 ·

9 9 · 9 9 9 other skin straightening cosmetics; encapsulation of volatile nail polish removers (or lacquer alone); aerosol particles comprising encapsulated hair dyes; sanitary wipes containing an encapsulated deodorant;

9. veterinary practice, including the controlled release of volatile substances against insects; encapsulated food supplements for ruminants; encapsulation of antibacterial and insecticidal substances in animal production;

10. Dentistry, which includes the controlled release of toothpaste components, especially hydrolytically unstable anti-tartar substances; delivery of oral anticancer agents (photophyrin);

11. Single-package polymerization catalysts;

12. Household products which include air fresheners and controlled-release fragrances, controlled-release repellents; washing powders (e.g., encapsulated proteases), other detergent ingredients: softeners, fluorescent bleaches;

13. industrial applications which include encapsulation of phosphine, ethylenedibromide and other volatile substances to fume stored products; Catalytic particles; activated carbon microparticles for sorption and purification;

14. Polymer additives, including polymers additives to protect wires, paperboard and other rodents; effect modifiers; dyes and opaque substances, fire-fighting and anti-smoke agents; stabilizers, optical brighteners;

The limitations of the current encapsulation of polymer-based additives include low melting point (during processing), polymer-polymer incompatibility, particle size limitation, optical clarity, etc. Some polymer additives intended for the lubrication of polymers are based on waxes which have the disadvantage of: • H · Very low melting point except for some synthetic waxes, which are expensive. • velmi velmi velmi velmi φ φ φ velmi velmi velmi velmi velmi velmi velmi velmi velmi velmi velmi velmi velmi

15. food and beverage processing, including encapsulation of (volatile) odors, aromas and oils (for example, coconut, peppermint); encapsulation of vegetable oils in cattle diets, encapsulation of enzymes for fermentation and purification (e.g., diacetyl reductase in brewing); encapsulation as an alternative to bleaching to extend the shelf life of frozen foods; microencapsulated tobacco additives (flavoring); pH-activatable buffering agents; Removal of impurities and discoloration with activated charcoal encapsulated in porous material;

16. a photograph that includes films by a fine change with a dispersion of submicrometer photoreactive particles; faster films due to optical purity (and hence faster transfer) and shorter diffusion times of the submicrometer dispersion; microencapsulation of photo processing agents;

17. microencapsulation of explosives and propellants, including both liquid and solid propellants and explosives used in encapsulated form; also water is used in encapsulated form as a temperature moderator in solid fuels;

18. Research into microcapsule packed extraction and separation columns; biochemical tests, in particular in pharmaceutical research and exploration;

19. A diagnostic that includes labels for angiography and radiography and clinical tests containing proteins and glycolipids sensitive to the environment.

The factors required to trigger the release of active substances, or alternatively to trigger absorption, are:

I. release is initiated by dissolution or slackening of the container A. Internal variables

9 ··

99 9 9 99 • 9 «9999 9999

99 «9999

999 99 99 99 99 99

1. pH

2. ionic strength

3. pressure

4. temperature

B. External and other variables

1. Dilution

2. surface reaction

3. Enzyme activity

4. chemical reaction (non-enzymatic)

5. complexation of the target substance

6. Electric current

7. irradiation

8. time (ie slow dissolution)

9. friction (effective critical friction)

II. the need for breakage or dissolution of the packaging is replaced by the fact that the release of absorption takes place through pores in the packaging:

1. with selectivity due to pore size, i.e. relative to the molecular weight of the compound

2. with selectivity due to the pore wall polarity, i.e. to the polarity of the compound

3. with selectivity due to pore wall ionization, i.e. to ionization of the compound

4. with selectivity due to the pore shape, i.e. to the shape of the compound

5. with selectivity, based on the fact that some compounds or ions form a porous coated inclusion compound, while others do not (this is, however, a combination of the above four events).

In a preferred embodiment, the coated particle may be formed such that:

• 4

1. provide a matrix volume that comprises at least one chemical individual having a portion capable of forming a non-lamellar crystalline material upon reaction with the other portion; and

2. associate the contents with a solution containing at least one chemical individual whose second part is capable of reacting with the first part and at the same time dividing the volume into particles by applying energy.

Alternatively, the particle may be formed such that:

1. Containing in its volume a matrix comprising non-lamellar crystalline material in solution; and

2. the non-lamellar crystalline material became insoluble in the matrix and at the same time the energy was divided into particles.

The volume of the matrix is unfilled with substance A capable of forming non-lamellar crystalline material upon reaction with substance B, and the liquid (usually an aqueous solution, often called an "outer solution") outside the matrix contains substance B. Contact between substance A and B induces their crystallization on the inner / outer The interface associated with the application of energy such as sonication causes the particles coated with the non-lamellar crystalline material to break and mix with the solution. Said method according to the invention is clearly suitable for producing an aqueous dispersion of coated particles with a coating material of very low water solubility, i.e. a solubility of less than about twenty (20) grams per liter of water and more preferably less than ten (10) grams is preferred. per liter of water, in order to finally obtain a homogeneous dispersion of microparticles, it is highly desirable that substance A be dissolved in the matrix (i.e. not only dispersed or suspended) before contact with substance B and prior to sonication. As discussed above, this is one of the reasons (apart from the requirements for optimizing the dissolution of active substances, especially biopharmaceuticals in the matrix) why it is important that nanostructured matrices contain aqueous microdomains that allow the solubility of substance A, which in many cases is only soluble in polar solvents. Aqueous media

9 • 99 ·· ··

9 9 9 9 are most suitable and effective for reactions resulting in non-lamellar inorganic crystalline precipitates. The most common reactions which result in non-lamellar organic crystalline precipitates from dissolved precursors are protonation and deprotonation reactions of soluble salt forms of the desired non-lamellar crystalline coating materials, where water (or aqueous microdomains) is a matter of course.

Alternatively, a temperature reduction, crystallization promoter, or electric current may be used to initiate crystallization.

In addition to sonication, other standard emulsification methods such as energy inputs can be used. Included are microfluidization, valve homogenization [Thomberg, E. and Lundh, G. (1978) J. Food Sci. 43: 1553], blade mixing and others. To form the coated particle, a water-soluble detergent, preferably an amphiphilic block copolymer of several thousand Daltons, such as PLURONIC F68, is preferably added to the aqueous solution to stabilize the particles before aggregation. The detergent also serves to enhance the effect of sonication when used to initiate particle formation.

Many of the coated particles formed of the non-lamellar crystalline material described in the Examples herein have been formed by a process in which two or more reactants form a precipitate at the interface of the outer solution and the nanostructured solution or liquid crystal phase and wherein the precipitate forms the outer coating. Another general method is significantly similar to that, but is characterized by important differences. The material to form the coating, called material A, is dissolved in the liquid or liquid crystal phase, where this dissolution was initiated by changing one or more conditions in the material, such as a temperature increase (but it may be another change such as pressure drop , addition of a volatile solvent, etc.). This change must be reversible so that when the conditions are restored - temperature increase, pressure increase, solvent evaporation, etc. - the system returns to the state of a mixture of two phases, nanostructures • 4 4 4 4 4 4 4 4 • 4 4 4 4 4

443 4 4 <4 «4 4 4 4 4 4

The energy input is applied before crystalline material A has time to grow into large crystals, which can be accomplished by ultrasound or other emulsification methodology. This causes the particles coated with non-lamellar crystalline material A to break.

If temperature is used, the solubility of substance A in the liquid phase nanostructured or liquid crystal nanostructured phase must vary with temperature.

in

The higher the order of magnitude of the dissolution solubility in dependence on temperature, the lower the temperature increment required for this process. For example, the water solubility of potassium nitrate is a very strong function of temperature.

The fundamental difference between this method and the precipitation reaction process is that in this process only one substance (A) is required to nanostructure the internal matrix. In the precipitation reaction method, at least two compounds are needed, component A which is in the nanostructured phase and component B that is present in the outer phase (the "outer solution") outside the nanostructured phase. Component B is then often simply a suitably selected acidic or basic component. This will serve to show the similarity between the two processes in the sense that component B in the external environment can alternatively be considered as a "condition" (specifically pH in the case of acid / base) that causes crystallization of A. This means that A can be dissolved alkaline pH, which is a reversible process under acidic pH conditions, which is applied by the presence of an external phase. Probably the biggest difference between the two methods is whether the change caused by crystallization of A occurs only when and where the external phase (the "outer solution") is in contact with the nanostructured phase, as in the A / B precipitation reaction, or whether the reaction proceeds simultaneously throughout the volume of nanostructured phase, as is the case of temperature induced crystallization.

It is also possible to use a process that is a combination of the A / B reaction process and the temperature process described above. Usually, in such a scheme there is a substance, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9, 9

9 9 9 9 9 9

99 9 9 9 9 9 9 9 9 to be used as a coating of particles added to the matrix in two chemical forms. The first form corresponding to the resulting composition of the particle coating is usually a free acid (free base) which is soluble in the matrix only at elevated temperature and insoluble at the temperature at which the particles are formed. The second form is a precursor, usually a salt formed by reacting the free acid with a base such as sodium hydroxide (or by reacting the free base with an acid such as hydrochloric acid), which form is soluble in the matrix even at the particle formation temperature. For example, in the case of a benzoic acid coating, both the benzoic acid and sodium benzoate are added to the matrix, where the matrix is such that the benzoic acid dissolves there only at elevated temperature, while the sodium salt dissolves at normal temperature. The outer solution then carries the components necessary to convert the precursor form to the resulting coating, so that in the case of sodium benzoate, it will contain hydrochloric acid. Upon heating (to dissolve both forms) and subsequent cooling, overlaying with an external solution and sonication, or other energy input to the system, formation of the coated particle includes both cooling-induced precipitation and chemical reaction mediated formation and precipitation of the coating crystals. This method has the advantage of providing two sources of crystalline coating material. This can result in particle coatings at an earlier stage than the individual methods, thus protecting the particles from fusion (probably also leading to a more even particle size distribution), more efficient particle formation with lower energy input requirements, etc.

Other methods that can be used to form the coated particles of the invention are:

A. electrocrystallization,

B. crystallization nuclei (with supersaturated solution in the matrix and crystallization of the nuclei in the outer phase),

9 * ·· 9

9 99 ··· 9999 · 9999 9999

999,999 · 9 9

999 99 99 99 99 99

C. graduation (with supersaturated solution in one phase and crystallization promoter in another),

D. removing the inhibitor (with supersaturated solution in one phase and crystallization centers in the other phase), or

E. time method (crystals grow slowly from supersaturated solution in the internal phase).

In order to be able to form most of the outer coatings, including virtually all inorganic ones, one of the reactants must be soluble only in water or another polar solvent. In particular, most of the salts used in these precipitation reactions are soluble only in very polar solvents. Concerning the matrix material according to the invention, it is at the same time highly desirable, if not necessary, that the inner phase material is not significantly soluble in water, otherwise it would dissolve in the external solution rather than disperse therein. Therefore, in forming the outer coating, the material of the inner matrix needs to meet two conditions:

condition 1: it must contain aqueous domains (or other polar solvent domains) and condition 2: it must have low solubility in water, i.e., sufficiently low (or with sufficiently slow dissolution kinetics) to not show significant phase dissolution during particle formation (usually (from 5 to 100 minutes required to disperse the material into the particles), which would significantly reduce the yield and could suppress the attractiveness of the method.

These conditions are almost contradictory, so very few systems can be found that meet both. Liquid phase nanostructured materials and reverse or lamellar type liquid crystal phases are among these systems.

In some cases, it is preferable to incorporate into the external solution one or more of the components that are in the nanostructured liquid phase or liquid crystal phase, sometimes in considerable amounts. In addition, there are cases where it is advantageous, • 999 • <··· 9999 • 9 99 9 99 9

9 9 9 9 9

99 99 99 to make the outer solution a nanostructured phase rich in detergent. Specifically, this can happen when the matrix is not in equilibrium with water (or a dilute aqueous solution) but is in equilibrium with another liquid or liquid crystal phase such as a micellar phase or even a low viscosity lamellar phase. Therefore, in the above context, it is possible to use this phase, or the phase to which additional components such as reactant B and / or amphiphilic block copolymer stabilizer, have been added as a "solution" in the process. In this case, there may be no complications with introducing such an outer phase into the microparticles, provided that the outer phase is chosen (and generally so selected) to be in equilibrium with the matrix phase (with the possible exception of exchanging the active ingredient between the two materials, which will have certain consequences, but often relatively unimportant). After the formation of the coated particles initially dispersed in this external "solution", this continuous external phase can be converted by filtration or dialysis to another medium such as water, salt, buffer, etc.

The following examples illustrate the invention but should not be construed as limiting the invention.

EXAMPLES

In the following examples 14, 15, 16 and 34, systems with a physically robust coating of mineral materials such as copper (I) cyanide and calcium phosphate are demonstrated. These can ensure the stability of the intact particles even under stronger friction conditions, which can occur when pumping the dispersion of the coated particles, for example during recycling or transportation. These minerals also have low solubility in water, which makes them potentially interesting in applications where release should be controlled by high friction and at the same time the particles should be protected from release due to simple dissolution.

·· ·· 9 · 99 • «999 9999

9999 9999

9 9 9 9 9 • 99 99 99 99

An example of such an application would be a rodent repellent composition, such as capsaicin, or a rodent toxin encapsulated in the coated particles of the invention to impregnate electrical wires and other products requiring protection against rodents and where gnawing would induce release of the active repellent composition or toxin. Low water solubility would prevent premature release of the repellent under the influence of moisture.

Robust organic materials providing coatings with low water solubility are, as shown in Examples 17 and 33, ethylene hydrokuprein. This substance has another property, an extremely bitter taste, which has an additive effect in rodent repellent applications.

Examples 1,2,3,6,7,8,9,10,17,18,19,20,23 and 33 show examples of coatings that are poorly soluble in water at neutral pH but increase in solubility depending on the particular compound, with increasing acidity or alkalinity of the environment. This makes the coated particles interesting, for example in drug delivery, when the coating dissolves preferably within a certain pH range, such as by intestinal release. Alternatively, the coating may allow release at sites of bacterial activity where the pH is typically acidic. Also, by releasing the coating at a certain pH, it would be possible to release the buffer or pH stabilizer. This could be used, for example, in swimming pools to control the pH of water.

In Example 4, silver iodide coated particles are shown which have a very important &quot; shrinking &quot; Because the silver iodide coating is well known for its efficiency and the surface area and its morphology could enhance the effect of the silver iodide. Given the cost of silver compounds, these particles could be of industrial importance, where inexpensive liquid crystals would serve as fillers that would allow the same or better capabilities at a fraction of the cost of simple silver iodide. A similar increase in efficiency due to surface enlargement could prove its worth when using the coated particles as local anesthetic to the mucous membranes. Enhancement of the effect could be achieved by a proper balance between lipids and hydrophobic active anesthetics (such as lidocaine) within the particle.

Example 5 shows the use of sulphides and oxides as coatings of particles, although gaseous reactants must be used to produce them. These materials are well known for their high rigidity, but also for their extreme chemical resistance, which makes such coated particles interesting for use in harsh chemical and physical conditions. Such conditions would be expected when coated particles are used as polymer additives, or in a high friction treatment such as impregnation of color-containing particles of nonwoven materials and the like.

Examples 12 and 13 show the use of water-soluble compounds for the production of coated particles. These can be of importance in applications where rapid release of the packaging is required after simple dilution with water. For example, a spray system spraying two streams containing only a dispersion and a second water. In such a system, the anti-agglomeration coating would dissolve upon spraying when the particles had already been converted to aerosol - in flight. Since the dissolution of the coating would expose the inner, for example, nanostructured cubic phase, the particles could be used to adhere to the surface, eg grain or bronchial surfaces, etc. Because rodents are generally strongly repelled by capsaicin even at very low concentrations, then For example, capsaicin dissolved within the particles of Examples 12 and 13 could be potentially important if, for example, sticky, atomized particles adhere to the grain.

All percentages given in the following examples are by weight unless otherwise indicated. The amounts of the individual components in the following examples may be varied as desired, maintaining the relative amounts as indicated; thus, the number of components may be

9999 «99 99 9 9 9 9 9 9

9 · 99 proportionally increased to the required quantity. Of course, it should be remembered that large quantities will require larger processing equipment.

Unless otherwise indicated in the following examples, the outer coating of each coated particle consists of a non-lamellar crystalline material and each inner core consists of a matrix of at least one nanostructured liquid phase and at least one liquid crystal phase.

EXAMPLE 1

This example demonstrates that a large number of active agents, including those of importance in pharmacy or biotechnology, can be incorporated into the coated particle of non-lamellar crystalline material.

0.266 g of sodium hydroxide was mixed with 20 ml of glycerol and heated with stirring until dissolution was achieved. Next, an equimolar amount of methylparaben, namely 1.01 g, was dissolved again with heating. 0.616 g was removed from this solution and mixed in a test tube with 0.436 g lecithin and 0.173 g oleyl alcohol. At this stage, the active agent (agent) mentioned below was incorporated into the solution, and the solution was vigorously mixed to form a liquid crystal nanostructured material with the active substance dissolved therein. The outer solution obtained by dissolving 0.062 g of PLURONIC F-68 (a block copolymer detergent of polypropylene oxide-polyethylene oxide, commercially available from BASF) and 0.0132 g of acetic acid, was overlaid in a tube of the above solution containing the active substance. The tube containing the mixture of liquid crystals and the external solution was immediately vigorously mixed and sonicated for three hours in a small bench sonicator (model FS6, manufactured by Fisher Scientific). The resulting solution contained large amounts of methylparaben coated particles of the order of one micron size.

444 4444 4444 4444 4444 4444 4444 444 444 444 44 4 44

Example 1A Saicylic acid was incorporated as an active ingredient at a concentration of 2.0% w / w (based on the weight of the inner core of the liquid crystal phase material)

Example 1B Vinblastine sulfate was incorporated as an active ingredient at a concentration of 2.0% w / w (based on the weight of the inner core of the liquid crystal phase material)

Example 1C thymidine was incorporated as active substance at a concentration of 2.4% w / w (based on the weight of the inner core of the liquid crystal phase material)

Example ID As an active substance, a thyropropic hormone was incorporated at a concentration of 1.6% w / w (based on the weight of the inner core of the liquid crystal phase material)

Example 1E An anti-cyclic AMP antibody was incorporated as an active agent at a concentration of 2.9% w / w (based on the weight of the inner core of the liquid crystal phase material)

Example 1F L-Thyroxine was incorporated as an active substance at a concentration of 2.0% w / w (based on the weight of the inner core of the liquid crystal phase material)

Particles such as these with a coating whose solubility increases with increasing pH may be useful in drug delivery where increasing the pH during the gastrointestinal tract from the stomach to the intestines ensures a more uniform dosage of the drug over time.

EXAMPLE 2

The invention demonstrates the long-term stability of the particle dispersion of the invention.

0.132 g of a mixture of amino acids D- and L-leucine was dissolved in 2.514 g of 1M hydrochloric acid to form leucine hydrochloride in solution. The solution was dried on a hot plate under a stream of air but not completely dried. Drying was stopped when the solution reached a weight of 0.1666 g, corresponding to • < 9 ♦ 9 99 99 99

9 9 9 9

9 9 9 9

998 9999 9 9

999 99 99 99 99 99 equimolar amounts of HCl and leucine. 0.130 g of this solution was added to 0.879 g of the reverse, bicontinuous, cubic phase nanostructured material. This material was prepared by mixing the sunflower oil monoglyceride with water, centrifuging it and removing excess water. The external solution was prepared by mixing 1 g of 1M sodium hydroxide with 3 g of water. All the water used was tridistilled. The cubic phase was overlaid with the outer solution, the tube was sealed and sonicated until a milky-colored dispersion of leucine-coated microparticles was formed. A similar dispersion was prepared with the Pluronic F-68 stabilizer. 0.152 g of leucine hydrochloride was added to 0.852 g of reverse bicontinuous cubic phase nanostructured material as described above. This phase was overlaid with an outer solution of 0.08 g F-68, 1 g IM sodium hydroxide and 3 g water and sonicated. Again, a milky colored dispersion of particles was formed, in which case the amphiphilic block copolymer detergent F-68 encapsulated the outer surface of the particles (based on leucine).

In a control experiment to demonstrate the need for leucine to form crystal coated particles, 1.107g of DIMODAN LS (referred to herein as sunflower oil monoglyceride) was mixed with 1,000g of water to form a nanostructured reverse bicontinuous cubic phase material. As in the above procedure using leucine, the nanostructured reverse bicontinuous cubic phase material was overlaid with an outer solution and the sealed tube with this mixture was sonicated. However, no microparticles were produced in this case; The nanostructured reverse bicontinuous cubic phase material remained macroscopic clusters even after several hours of sonication under the same conditions as in the leucine experiment.

The dispersion of the coated particles of the invention was periodically examined for twelve months without showing signs of irreversible flocculation. Using gentle stirring, the dispersion did not show signs of flocculation for a period of the order of weeks. Without mixing, signs of flocculation were registered, but after 4 44

4 4

4 4

444 444

4

44 44 44 44 44 44 44 was stirred for 5 seconds or more and was dispersed completely restored. The dispersion drop was studied using an Egde Scientific R400 3-D microscope at 1000X magnification (100x objective, immersion oil, transmitted light). It has been shown that there is a high density of submicrometer particles in the droplet.

Such particles with a relatively weak organic coating may be used, for example, in anti-acne creams. The active material, such as triclosan, may be contained in the particle and by friction associated with spreading the face cream, the coating may be released.

EXAMPLE 3

In this example, taxol was incorporated into the inner core at a concentration of 0.5%. The particle coating was formed from leucine, which, as is evident from other examples, is stable over the long term.

The nanostructured reverse bicontinuous cubic phase material containing taxol was formed by mixing 4 mg of taxol dissolved in 2 ml of t-butanol in a nanostructured reverse bicontinuous cubic phase material composed of 0.280 g lecithin, 0.091 g oleyl alcohol and 0.390 g glycerol. After butanol was evaporated in an argon atmosphere, a viscous and optically isotropic nanostructured reverse bicontinuous cubic phase material was formed. No precipitate appeared during a subsequent centrifugation of 1 hour. Optical isotropy was verified by optical polarization microscope. A glycerol solution of leucine hydrochloride was formed by mixing 0.241 grams of leucine, 2.573 grams of 1M HCl and 0.970 grams of glycerol. Excess water and HCl were evaporated on a plate at 50 ° C, under a stream of air for three hours. In the next step, 0.882 grams of a glycerol solution of leucine hydrochloride was added to the nanostructured reverse bicontinuous cubic phase material. The outer solution was then prepared by adding 0.102 grams of PLURONIC-F68 detergent to 4.42 grams of an aqueous buffer at pH 5.5. After overlaying with the outer solution, the nanostructure was 4 &apos; 4 &apos; 4 &apos; 4 &apos; &quot; A &quot; &quot; A &quot; Material of reverse bicontinuous cubic sonication.

These particles can be used antineoplastics of taxol.

EXAMPLE 4

The use of silver iodide as a coating in this example makes the particles potentially useful in photographic processes. Silver iodide is an extraordinary compound because, although it is a simple salt (only monovalent metal), it is very poorly soluble in water.

The nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.509 grams of DIMODAN LS (commercially available from Grinstedt AB and found in this work as sunflower oil monoglyceride), 0.563 grams of tristilled water and 0.060 grams of sodium iodide. The outer 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. The microparticle dispersion was then prepared by superimposing the reverse bicontinuous cubic phase nanostructured material with an external solution and one hour sonication. The coating of these particles consisted of silver iodide, poorly soluble in water.

EXAMPLE 5

In this example, cadmium sulfide was used as the outer coating. It is a non-lamellar crystalline material that strongly changes the physical and chemical properties when enriched with small amounts of other ions. This example also demonstrates the possibility of using a gas such as hydrogen sulfide to initiate crystallization and particle formation.

Nanostructured bicontinuous cubic phase material was prepared by thoroughly mixing 0.641 g of DIMODAN LS with 0.412 g of water. To this mixture was added 0.058 g cadmium sulfate hydrate. This mixture was phase dispersed for 2 hours for controlled release.

Coated with 0.039 g of calcium sulfide, the tube was flushed with argon and sealed. The outer solution was added via syringe to this tube. During the addition of the solution, the smell of hydrogen sulfide and the formation of a yellowish precipitate can be detected in the tube, indicating the formation of cadmium sulfide (CdS) from hydrogen sulfide and cadmium sulfate. The system was sonicated to produce a dispersion of cadmium sulfide coated microparticles.

EXAMPLE 6

This example shows the protection of the inner core of the particle from contact with external conditions by the crystalline coating, which is here leucine. Any contact of methylene blue with zinc dust turns this color into a colorless solution in less than one second. In this example, adding zinc did not cause discolouration for some 24 hours. Although color loss has been reported, it is considered to be a simple effect of zinc on the leucine coating. The leucine hydrochloride solution was prepared by mixing 0.122 g of leucine with 1.179 g of 1M HCl and evaporating until 1 g of solution remained. To this solution was added 0.922 g of sunflower oil monoglycerides and ten drops of a strongly colored methylene blue solution. The outer solution was prepared by adding 0.497 g of 1M NaOH and 0.037 g of PLURONIC F68 to 3.00 grams of buffer, pH 5. The microparticle dispersion was formed by superimposing the system with the outer solution and sonication. An aliquot of the dispersion was filtered from any non-dispersed liquid crystal and 100 grains of zinc dust were added. (When zinc is added to a methylene blue solution, it is a matter of seconds before the zinc reducing effect removes the blue color). However, in the case of the microencapsulated methylene blue produced by the process, 24 hours were required to decolorize to a white dispersion. Despite the interaction of zinc with the leucine-damaging coating, the coating provided such protection that the zinc reduction time was prolonged by 4-5 orders. This example demonstrates the possibility of using leucine coated particles to prevent contact between the encapsulated compound and the particle surrounding. Thus, such particles can be used in such articles in which the mixing of two substances (such as the antibacterial triclosan, sensitive to oxidation and a strong oxidizing and cleaning agent, benzoyl peroxide) must be avoided.

EXAMPLE 7

This example demonstrates that the leucine coating will protect the methylene blue inside the particles from contact with ferrous chloride. This can simply be observed in the absence of the expected color change upon the addition of ferric chloride to the dispersion. This shows that the coating is not permeable to ions.

The leucine hydrochloride solution was prepared by mixing 0.242 g of leucine,

2.60 g of 1M HCl and 1.04 g of glycerol, followed by drying the mixture on a plate at 50 ° C under a stream of air for 1.5 hours. The nanostructured reverse bicontinuous cubic phase material was prepared by mixing a solution of leucine hydrochloride with 0.291 g of lecithin / EPIKURON 2000 from Lucas-Mayer), 0.116 g of oleyl alcohol and 0.873 g of glycerol. the mixture was stained with a pinch of methylene blue. The outer solution was prepared by adding 0.042 g of PLURONIC F-68 detergent to 4.36 g of buffer, pH 5. The microparticle dispersion was formed by superimposing the reverse bicontinuous cubic phase nanostructured material with the outer solution followed by sonication. 0.19 g of reducing agent was added to the dispersion aliquot. The absence of color change showed that the methylene blue was protected from contact with the ferrous compound by encapsulating the glucose coating, while the addition of ferrous chloride to the methylene blue solution normally turned color to blue-green (turquoise). Similar to Example 6, these experiments show that encapsulated compounds, such as methylene blue, sensitive to, in this case, reducing conditions, can be protected from reducing conditions of the environment until the coating is released. This could be useful, for example, in electrochemistry, where the effect of applying electric current would be combined with the chemical release of the coating.

• · · · · · · · · · · · · · · · · · φ · φ · φ · φ · φ ·

ΦΦΦΦΦΦ · φ φ φφφ φφ φ · φφ φφ φ φ

EXAMPLE 8

This example, together with Example 1A and Example 10, show that methylparaben-coated particles of the invention can be prepared in two ways. Firstly, the thermal process using the heating and cooling method, and the chemical reaction using the acid-base method.

Nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.426 g of sunflower oil monoglyceride (DIMODAN LS) with 0.206 g of acidic water at pH 3. 0.051 g of methylparaben and a trace of methylene blue were added to this mixture. The mixture was heated to 110 ° C, stirred and placed in a vibration mixer thermostated with water at 23 ° C for 5 minutes. The mixture was overlaid with two milliliters of a 2% solution of PLURONIC F-68 acidified to pH 3 with HCl. The test tube was sealed with a screw cap, mixed and sonicated for 30 minutes. Thus, a dispersion of methylparaben-coated microparticles was prepared.

This example together with example 10 show particles coated with the same substance, methylparaben. The particles can be formed by both a thermal method and a chemical precipitation method, giving high flexibility that can be useful in optimizing production and reducing costs, for example, in large pharmaceutical products of microencapsulated drugs.

EXAMPLE 9

The nanostructured reverse bicontinuous cubic phase material in this example is based on a non-ionic detergent generally approved for drug production. The result is a liquid crystal material whose properties are controllable by small temperature changes. By way of example, an anti-acne cream could provide detergent (cleaning) properties at the application temperature while at the manufacturing temperature it would be insoluble. In addition, since the system is based on a mixture of two detergents, and the properties of the phase depend on sensitivity to the ratio of the two detergents, the system provides a convenient and powerful way to control. φ φ φ · · · · vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností vlastností Moreover, this example resulted in a transparent dispersion, which is noteworthy because a small fraction of particles larger than about 0.5 microns would render the dispersion opaque.

The nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.276 g of "OE2" (commercially available detergent under the name "Amerexol OE2", based on ethoxylated alcohol supplied by Amerchol, CPC Inemational, Inc) with 0.238 g of OE55 (commercially available detergent under the name 'Amerexol OE5', based on ethoxylated alcohol, supplied by Amerchol, CPC Inemational, Inc.) And with 0.250 g of water (includes excess water). To this mixture was added 0.054 g methylparaben and a trace of methylene blue. The mixture was heated to 110 ° C, stirred, placed on a vibration mixer and tempered to 23 ° C for 5 minutes. The mixture was overlaid with two milliliters of a 2% solution of PLURONIC F-68 acidified to pH 3. The tube was sealed with a screw cap and sonicated for 30 minutes after mixing. The product was a dispersion of methylparaben-coated microparticles. Interestingly, the submicrometer particle size resulted in a transparent dispersion.

EXAMPLE 10

This example shows that methylparaben coated particles can be prepared in addition to the acid-base method of the previous example, as well as by heating and cooling. This example also shows that the mixture of the two phases can be dispersed.

Lecithin (EPIKURON 200 - 0.418 grams) was mixed with 0.234 g of oleyl alcohol and 0.461 g of acidic water at pH 3. This mixture gave rise to a reverse bicontinuous cubic phase nanostructured material and a reverse hexagonal phase nanostructured material. 0.5 g of this mixture was mixed with 0.049 g methylparaben and mixed well. The mixture was heated to 120 ° C with stirring to cool and reheated to 120 ° C. Test tube 4 4 4 4 4 4 4 4 4 4

9 9 9 · 4 • 4 44 9 9 99 was removed from the oven and cooled in a cold water bath for 55 minutes. The cap was then removed and the mixture was overlaid with a 2% solution of PLURONIC F-68 acidified to pH 3 with HCl. The tube was capped, stirred and finally sonicated. The result was a milky white dispersion of methylparaben coated particles. Analysis by optical microscope showed microparticles between 2 and 10 microns in size. An excess of crystalline methylparaben material was also observed.

This example shows that the interior of a particle can be a mixture of two coexisting nanostructured phases. This could be used, for example, in controlled drug release where a mixture of two drug-containing phases would be used to achieve the desired pharmacokinetics. For example, the different kinetics in the two phases will follow the release in the mixture of the reverse hexagonal phase and the cubic phase. This is due to the different pore space geometry and the resulting kinetics will be a combination of the two profiles.

EXAMPLE 11

This example demonstrates the production of anhydrous particles useful for protecting water-sensitive compounds.

The same method of producing the nanostructured bicontinuous liquid cubic reverse phase liquid crystal was used as in case 10, except that the water was replaced with glycerol (which was present in excess). The following amounts were used: lecithin 0.418 g; oleyl alcohol 0.152 g; glycerol 0.4558 g and methylparaben 0.052 g. This resulted in a milky-colored dispersion of methylparaben-coated microparticles.

Protection of compounds from water is important, for example, when using active substances susceptible to hydrolysis in oral health care.

EXAMPLE 12

In this example, capsaicin was incorporated into the potassium nitrate coated particles. At the same time, the nanostructured material is a reverse bicontinuous • · • 9 • 9999 999 9

9999 9999 • 9 * 9999 9 9 • ·· · * 99 9 9 99 99 The cubic phase is based on extremely cheap detergents. The coating is easily removable by the mere addition of water, as is the case, for example, in grain sprayers where the flowing dispersion and water aerosol are mixed. Note that potassium nitrate will serve another purpose as a fertilizer.

The non-ionic detergent "OE2" (0.597 g) and "OE5" (0.402 g) were mixed with 0.642 g of water saturated with potassium nitrate. To this mixture was added 0.045 g of the active ingredient capsaicin (in pure crystalline form from Snyder Seed Corporation). Next, 0.552 g of the mixture was taken and 0.135 g of potassium nitrate was added. The resulting mixture was heated to 80 ° C for 5 minutes. The outer solution was prepared by saturating a 2% PLURONIC F-68 solution with potassium nitrate. The dissolved mixture was shaken and returned to the oven at 80 ° C for 2 minutes. The tube was cooled in a water bath at 20 ° C for 5 minutes. The outer solution was used to overlay, the mixture was mixed with a spatula, capped and sonicated. The result was a dispersion of potassium nitrate coated microparticles containing the active ingredient capsaicin inside.

The coating dissolved (due to the high solubility of potassium nitrate in water at room temperature) when the dispersion was diluted with an equivalent amount of water, resulting in rapid coagulation and particle fusion to form large clumps. The interiors of all particles are sticky liquid crystals, so that in the absence of the coating they immediately agglomerate and aggregate.

This example discussed herein is the case of a spray applicable to ornamental plants and / or cereal, repelling leaf-eating animals. We have succeeded in encapsulating capsaicin, a non-toxic compound (found in pepper and paprika) that causes burning in the oral cavity in concentrations of several ppm. Capsaicin is commercially used to repel rodents and other animals.

Pure capsaicin was encapsulated into the inner core from the cubic phase of potassium nitrate coated particles - salty pepper. The solution outside the particles was a saturated potassium nitrate solution that prevented the coating from dissolving. Dilution

9 9 9 9 9 9 9 9 9 99 99 99 9 99 99 99 dispersion with water approximately 1: 1 resulted in dissolution of the coating of particles. (This dissolution was recorded on the videotape, and analysis of the videotape showed dissolution of the coating and subsequent fusion of the internal particle content).

After dilution and subsequent dissolution of the coating, the interior of the particles, the cubic phase, was exposed with the following properties:

A) was insoluble in water;

(B) is extremely tacky and adhesive; and

C) had a high viscosity.

The exposed cubic phase with these properties should adhere to the plant leaves and, thanks to property A, should not dissolve even in the rain.

The same properties were also critical in the success of the cubic phase tests used as a control paste in the dosing of photodynamic therapy (PTD) pharmaceuticals in the treatment of oral cancer.

The concentration of capsaicin achieved in the cubic phase particles was two orders of magnitude higher than that of the pharmaceutical preparations used in the treatment of arthritis. Higher doses of up to 20% are also possible.

From a commercial point of view, all components of the dispersion are extremely cheap and approved for use in food, topical application and the like. In addition, potassium nitrate is well known as fertilizer.

EXAMPLE 13

As in the previous example, capsaicin / potassium nitrate is also used here. Here, however, the nanostructured reverse bicontinuous cubic phase material is based on lecithin, which, as an essential component of plant and animal life, is cheaply accessible. This nanostructured material from the reverse bicontinuous cubic phase is also stable over a wide temperature range, at least up to 40 ° C, that is, temperatures that can occur under normal atmospheric conditions.

1.150 g soya lecithin (EPIKURON 200) was mixed with 0.300 g oleyl alcohol, 1.236 g glycerol and 0.407 g potassium nitrate. To this · · fl fl f f f f f f f f f f f f f f f f f f f f množství množství množství množství f množství množství množství množství množství množství množství množství množství 0,1 0,1 množství g of active capsaicin and the mixture was thoroughly mixed. An additional 0.50 g of potassium nitrate was added to the mixture, and the whole complex mixture was heated to 120 ° C for 5 minutes. The external solution was prepared from a 2% aqueous solution of PLURONIC F-68 by saturation with potassium nitrate. The dissolved mixture was stirred and returned to 120 ° C for 3 minutes. The tubes were cooled in cold water for 5 minutes. Thereafter, the mixture was overlaid with an outer solution, mixed with a spatula and, after sealing, alternately sonicated and shaken for 30 such cycles.

The result was a dispersion of the microparticles containing, as an active ingredient, about 5% capsaicin coated with potassium nitrate inside. Also, excess potassium nitrate crystals were present.

The application of these particles is similar to Example 12, except that the use of lecithin could improve the integration of the particles into plant cell membranes, which could lead to better dosing.

EXAMPLE 14

In this example, it was shown that the particles coated with copper ferrocyanide were friction resistant. The nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.296 g of sunflower oil monoglycerides (DIMODAN LS) with 0.263 g of a 10% aqueous solution of potassium ferrocyanide. The outer solution was prepared by adding 0.021 g of copper sulfate and 0.063 g of PLURONIC F-68 to 4.44 g of water. The nanostructured material from the reverse bicontinuous cubic phase was overlaid with the outer solution, the tube was sealed and sonicated for 45 minutes. The result was a high concentration of copper ferrocyanide coated microparticles of the order of 3 microns. This process does not require raising the temperature to form microparticles, except for sonication heating, which can be bypassed using another emulsification method. Moreover, the method requires no pH changes.

• 99 99 999 99 99 9 9 9 9 99 99 99 99

When a drop of dispersion was placed between a slide and a cover slip during microscopic analysis, it was found that the particles coated with copper (I) ferrocyanide were fairly resistant to friction. Light pressure of the fingers on the coverslip did not cause any changes in particle shape or fusion. These findings are consistent with the high stiffness of copper ferrocyanide.

Particles with a friction-resistant coating may be important where particle pumping is required, where a traditional polymer coating reduces the life of the particles due to friction damage.

EXAMPLE 15

In this example, a particle according to the invention having a crystalline coating of high concentration capsaicin, namely to 9% by weight, was incorporated inside. Nanostructured reverse bicontinuous cubic phase was prepared by mixing 0.329 g of lecithin, 0.109 g of oleyl alcohol, 0.611 g of glycerol and 0.105 g of capsaicin (obtained in crystalline form as a gift from Sny der Seed Corp., Buffalo, NY). To this cubic phase was added 0.046 g of copper sulfate. The outer solution was prepared by mixing 0.563 g of a 10% aqueous solution of ferrocyanide with 2.54 g of water. A mixture of cubic phase and copper sulfate was overlaid with an outer solution, which was sonicated for 2 hours. The reaction of the formation of copper ferrocyanide was readily observable by the formation of a deep red-brown coloration of the compound. The cubic phase was dispersed into copper plated ferrocyanide coated particles by this procedure. The coating consisted of a hard copper copper ferrocyanate material, partially permeable to sulfate ions. Since the coating material is a robust crystal, as seen from Example 14, and capsaicin has a very unpleasant taste, these particles can be used as effective rodent repellents to prevent damage to cardboard boxes or agricultural plants, etc., especially where the particles must be partially resistant against slight friction (such as in the manufacture of boxes containing particles, or in the application of particles to grain), until rodents

9 «• 4 4 · 4 9 4 ·· ··· 4 9 ·

9 44

4 4 4

their teeth will not damage the particles and their taste cells will not be exposed to capsaicin.

In this example, the same method of making copper plated ferrocyanide coated particles as in Example 14 was used except that the antibody was used as the active agent. Specifically, it was an antibody to 3 ', 5' -cyclic adenosine monophosphate (cAMP), which was incorporated as an active substance at a concentration of 1% (by weight) into the nucleus. The cubic phase was prepared by mixing 0.501 g of sunflower oil monoglycerides with 0.532 g of water. Potassium ferrocyanate was added in an amount of 0.048 g to the cubic phase along with 0.010 g of antibody. Excess solution was removed after centrifugation. The outer solution was prepared by mixing 0.032 g of copper nitrate and 0.06 g of PLURONIC F-68 with 3.0 g of water. After coating with the outer solution and sonication, a milky-colored dispersion of the particles coated with copper ferrocyanide was achieved. Such particles can be used in biotechnology, such as a bioreactor, in which a solid cupric copper ferrocyanate coating can be used to limit release during mild friction (e.g., in a pressure plug) before the desired release of the coating and thereby the bioactive antibody.

EXAMPLE 17

In this example, an extremely hard ethylhydrocuprein coating is formed. In this case the acid-base method was used. The nanostructured reverse bicontinuous cubic phase material was formed by mixing 0.648 g of sunflower oil monoglycerides (DIMODAN LS) with 0.704 g of water. 0.084 g of ethylene hydrocupreine hydrochloride and a trace of methylene blue were added here. The external solution was prepared by adding 1.01 g 0.1 M sodium hydroxide and 0.052 g PLURONIC F-68 to 3 g water. After the liquid crystals were superimposed with this solution, the system was sonicated. The result was a dispersion of ethylhydrocuprein (free base) coated microparticles. Microscopic analysis revealed that most of the particles were smaller in size than one micrometer.

• • 9 • 9 * 9

Particles that retain integrity even when dried can be used, for example, in slow release of active ingredients in agriculture (herbicides, pheromones, pesticides, etc.) where dry weather could cause premature release of active ingredients in less resistant particles.

EXAMPLE 18

In this example, the coated particles were prepared using a heating and cooling protocol. Nanostructured reverse bicontinuous cubic phase material was prepared by mixing 1.51 g of sunflower oil monoglycerides (DIMODAN LS) with 0.723 g of water. To 0.52 g of this mixture was added 0.048 g of DL-leucine. The mixture was well mixed and heated to 80 ° C. It was then cooled to room temperature in water. The mixture was immediately overlaid with a 2% aqueous solution of PLURONIC F-68, mixed well and then sonicated. The result was a milk dispersion of leucine-coated microparticles.

The possibility of preparing some coatings (in this case leucine) by both thermal and acid-base methods provides significant manufacturing flexibility, since some active substances (eg proteins) are very easily denatable by temperature, but may be quite pH resistant, while other substances may be resistant to temperature, but can be hydrolyzed at acidic or basic pH.

EXAMPLE 19

This example shows that the interior of the particle can be protected against oxygen even if oxygen has been bubbled through the external medium (in this case, water).

Nanostructured reverse bicontinuous cubic phase material (with excess water) was prepared by mixing 2.542 g of sunflower oil monoglycerides with 2.667 g of water. 0.60 g of this nanostructured material was collected. Next, 0.037 g of DL-leucine and 0.497 g of 1M HCl were mixed and dried. After drying, 0.102 g of water was added to form the hydrochloride solution.

9 9 • 9 9 9 · * 9 9 99 · 9 9 9 · * 9 9 9 9 9 ♦ · 9999 leucine. This solution was added along with a trace of methyl red to 0.60 g of reverse bicontinuous cubic phase nanostructured material. The nanostructured reverse bicontinuous cubic phase material had a deep yellow color, but when it was smeared as a film, the color changed to carmine red due to oxidation within about 3 minutes. The outer solution was prepared by mixing 0.511 g of 1M sodium hydroxide, 0.013 g of PLURONIC F-68 and 2.435 g of water. Dispersion of leucine-coated particles containing methyl red was prepared by superimposing the liquid crystals with an external solution and sonication. First, it was verified that a solution of methyl red in water with or without the addition of F-68 rapidly changed color from yellow to carmine red as the solution was bubbled with oxygen. However, the color change did not occur when a dispersion of methyl red containing microparticles was bubbled with oxygen. Thus, the protection of methyl red from oxidation by its encapsulation into microparticles has been demonstrated.

Such particles capable of protecting oxidation-sensitive substances from contact with oxygen could be useful in protecting substances such as trace elements in food during long-term storage.

EXAMPLE 20

In this example, glycerol was used as a replacement for water, both in the inner nanostructured reverse bicontinuous cubic phase material and the outer (continuous) coating. This essentially eliminated water from the dispersion. A microparticle dispersion was prepared using glycerol instead of water, mixing soy lecithin and oleyl alcohol in a ratio of 2.4: 1. Excess glycerol was then added, the mixture was stirred and centrifuged. 0.70 g of the reverse bicontinuous cubic phase nanostructured material was mixed with 0.081 g of methyl paraben. The outer solution was prepared by adding cetylpyridinium bromide to glycerol to a final concentration of 2%. The mixture of the reverse bicontinuous cubic phase and methylparaben nanostructured material was sealed and 4 4 4 4 4 ••• 44 · 4 · 44 44 ·· «· heated to 120 ° C, mixed thoroughly and reheated to 120 ° C. The mixture was then immersed in cold water. At the same time, the mixture was overlaid with an external solution, sealed (screw cap) and sonicated. The result was methylparaben coated microparticles in a continuous glycerol phase. Such a glycerol-based dispersion is important in the microencapsulation of water-sensitive active ingredients.

Water-sensitive active substances that occur in a variety of applications can use a microparticle dispersion such as this to protect from contact with water even after the coating has been released.

EXAMPLE 21

Similar to Example 6, zinc encapsulated blue attack is used here, but in this example a potassium nitrate coating is used. In addition, the same dispersion is subjected to a potassium dichromate attack.

The nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.667 g of soya lecithin, 0.343 g of oleyl alcohol, 0.738 g of glycerol and traces of methylene blue. To 0.467 g of the equilibrium phase was added 0.255 g of potassium nitrate. The outer solution was prepared by adding 2% PLURONIC F-68 to a saturated aqueous potassium nitrate solution. The liquid crystal phase was overlaid with this solution and the system was sonicated to produce a dispersion of potassium nitrate coated microparticles. The dispersion was light blue. Two tests were used to test whether methylene blue was protected by encapsulation. To about 1 ml of the dispersion was added about 0.1 g fine zinc dust. Contact of zinc dust with methylene blue results in loss of color. After mixing, the mixture was centrifuged very briefly. The total centrifugation time, including loading into the centrifuge, was about 10 seconds. This was done to avoid zinc dust interference when determining color loss. If found, only very little discoloration due to zinc treatment shows that the microparticle coating was able to prevent contact of methylene blue with zinc. To another aliquot of the light blue dispersion was added potassium dichromate. This caused a color change to a greenish color, but without hinting of a purple-brown color, which is normally the product of contacting methylene blue in solution with potassium dichromate.

The coated particles in this example show a very cost effective coating material, potassium nitrate, but which still protects the material from degradation by environmental conditions. This makes these particles potentially important for example in slow release agriculture.

EXAMPLE 22

An example of microparticles with a selectively permeable coating of an inclusion particle is provided herein. Specifically, it is an inclusion compound called the Werner complex, which has the property that pores are retained even after removal of the guest molecule. Coatings of clathrates and inclusion compounds are of interest as coatings with selective porosity, where the selectivity of release or absorption is based on the size, shape and / or polarity of the molecules.

The nanostructured reverse bicontinuous cubic phase material was first prepared by mixing 0.525 g of sunflower oil monoglycerides and 0.400 g of water. To this mixture was added 0.039 g manganese chloride (MnCL) and 0.032 g sodium thiocyanate. The external solution was prepared by adding 0.147 g of 4-picoline (4-methylpyridine) to 3.0 ml of a 2% aqueous solution of PLURONIC F-68. After the liquid phase was overlaid with an external solution, the tube was sealed and sonicated. Thus, the nanostructured material from the reverse bicontinuous cubic phase was dispersed into manganese coated microparticles of the Werner Mn (NCS) 2 (4-MePy) ⁴ complex.

The coating in this example could find application in the removal of heavy metals from industrial waters. In this case, the coating may be a porous crystal - known as clathrate - that will allow atomic ions to enter through the coating into the inner cubic phase. It is an absorbent with extreme capacity, due to the high surface charge density (using anionic detergents, or more selective chelating groups such as bipyridinium groups, etc.). Most likely these will be permanent pores. The selectivity afforded by clathrate coatings bypasses the reduction in sorption capabilities inevitable in conventional sorbents (such as activated carbon and macroreticular polymers), due to the competition of target heavy metal ions with larger compounds for accessible absorption sites. The regeneration of the sorbents can take place by ion exchange, while the particles and their coatings remain intact (this last step is also an example of release).

EXAMPLE 23

In this example, methylparaben-coated particles containing a special dye deposited in the reverse bicontinuous cubic phase nanostructured material were subjected to a cyano compound which would cause discoloration upon contact with the dye. Due to the extremely small size of the cyanide ion, the success of this test is evidence of the impermeability of the coating even to very small ions. The nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.424 g of sunflower oil monoglycerides and 0.272 g of water. In addition, 0.061 g methylparaben and a trace of 1,2pyridylazo-2-naphthol were added. An external solution of 1% cetylpyridinium bromide was prepared. The liquid crystals were heated to 120 ° C in an oven for five minutes, mixed thoroughly and reheated and cooled in cold water. At this point, they were overlaid with an outer solution, the tube was sealed and sonicated. As a result, microparticles with an average size of 1 micron were coated with methylparaben. Copper cyanide was used to demonstrate the protection of the dye from contact with the external phase. When copper (I) cyanide was added to a solution of 1,2-pyridyllazo-2-naphthol (either in the presence or absence of F68), the color changed from orange to strongly purple. However, when copper (I) cyanide has been added to the dispersion, 44 44 44 44 44 44 44 microparticles containing the coloring agent. , there was no color change, indicating that the dye is protected from methylparaben coating. It can be calculated that the time required to diffuse the copper ion into the center of a 1 micron diameter particle is within a few seconds, which would not prevent discolouration if the particles were not sealed. Protecting the active substances from contact with ions from the outside could be useful, for example, in drug dosing, especially in the dosing of polyelectrolytes, which can be complexed and inactivated in contact with multivalent ions.

EXAMPLE 24

In this example, the test of the previous example is repeated with cyanide ions, this time with nitrate coated particles.

The nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.434 g of sunflower oil monoglycerides and 0.215 g of water. 0.158 g of potassium nitrate and a trace of 1,2-pyridylazo-2-naphthol dye were added here. 1% cetylpyridinium bromide in a saturated aqueous solution of potassium nitrate was prepared as the external solution. The liquid crystals were heated in an oven at 120 ° C for five minutes, then thoroughly mixed and reheated. After cooling in cold water, they were overlaid with an outer solution, the tubes were sealed and sonicated. The result was a dispersion of potassium nitrate coated microparticles. After the addition of cuprous cyanide to the dispersion aliquot, there was only a slight discoloration, suggesting a significant protection of the colorate mediated by the nitrate coating from contact with cuprous cyanide.

The use of these particles is similar to that described in Example 23, except that a less expensive potassium nitrate coating was used.

EXAMPLE 25

Nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.913 g of soya lecithin (EPIKURON 200), 0.430 g of oleyl alcohol and 0.90 g of glycerol (excess glycerol). After thorough mixing and centrifugation, 0.50 g of reverse bicontinuous cubic phase nanostructured material was collected and 0.050 g of sodium monohydrogen phosphate was added. The outer solution was prepared by adding 0.10 g of calcium chloride to 3 ml of an aqueous solution containing 2% PLURONIC F-68 and 1% cetylion bromide. After superimposing the liquid crystals with the outer solution, the tube was sealed and sonicated. The calcium phosphate coating was very interesting from a biological point of view, since it is a major component of bones, teeth and other structural parts.

EXAMPLE 26

This example shows that the magnesium carbonate coated particles are able to retain their integrity even on drying, i.e. when the external water has been completely dried. Thus, it is possible to produce a dry powder which, however, contains a water-rich liquid crystal phase in its interior.

Preparation of the 'tung oil and sorbitol nut oil compound' This compound was prepared as follows:

110 g of tung oil (obtained as Chinese tung oil from Alnor Oil) was mixed in a reaction vessel with 11.50 g of sorbitol. The bottle was flushed with argon, sealed, and heated to 170 ° C with magnetic stirring. After addition of sodium carbonate (3.6 g), the mixture was stirred at 170 ° C for 1 hour. Subsequently, 3.4 g of 3-chloro-1,2-propanediol was added and the mixture was cooled at room temperature. After mixing 75 ml of this oil phase from this reaction with 300 ml of acetone and centrifuging, a white precipitate was removed. Next, 18 g of water and 100 ml of acetone were added. After centrifuging the mixture, the bottom oil was removed. 44 g of water were added and the lower phase was removed again. Finally, 20 g of water were added. This time, however, an oily residue from the bottom was removed and dried under a stream of argon. The result was approximately 50 ml of a sorbitol tung fatty acid ester, which is referred to herein as a "tung sorbitol compound".

Example 26A. The nanostructured material from the reverse biotinic cubic phase was prepared by mixing 0.110 g of the "tung-sorbitol compound", 0.315 g of soya lecithin and 0.248 g of water, vigorously mixing and centrifuging. To this mixture was added 0.085 g of potassium carbonate. The outer solution was prepared by adding 0.118 g of PLURONIC F-68 and 0.147 g of magnesium sulfate to 5.34 g of water. The outer solution was overlaid with a liquid crystal. The tube was sealed, stirred and sonicated for 2 hours. The tube was then stirred again. The result was a milky dispersion of magnesium carbonate coated microparticles. This was diluted by adding two parts water to one part dispersion to dissolve the excess inorganic material. A small drop of dispersion was dried on a microscope slide. After 10 minutes of drying, the water outside the particles was almost completely dried. However, microscopic analysis showed that the particles retained their shape and did not become amorphous lumps as was the case with uncoated particles dried in a similar manner (when the dried liquid crystals were converted to liquid).

Example 26B. The dispersion produced in Example 26A was heated to 40 ° C. According to the determination of the phase behavior, the inner phase at this temperature was a nanostructured material of the liquid L2 phase. The dispersion remained milky white and the microscope showed that the particles retained their shape. Since the L2 phase contains oil, water and detergent (namely lecithin), it was simultaneously a nanostructured microemulsion. EXAMPLE 27

In this example, receptor proteins are deposited in a matrix of magnesium carbonate coated particles of nanostructured reverse bicontinuous cubic phase inner core material. Subsequently, the coated particles were coated with a hydrogel. The coating of these particles can be used to protect the receptor proteins during transport and storage and can then simply be removed by washing.

9 9 9 9 9 before use. This Example and Example 28 illustrate the use of coated particles of the invention, for example, by waffle chromatography with hydrogel matrices and with coated particles inside.

0.470 g of soya lecithin (EPIKURON 200) was mixed with 0.183 g of 'tungsorbitol compound' and 0.359 g of water. 0.112 g of potassium carbonate was added to the mixture. After centrifuging the mixture for several hours, excess aqueous phase was removed. The preparation of nicotinic acetylcholine receptors from stingrays was carried out according to the protocol described by L.Pradier and M.G. McNamee in Structure and Fimction of Membranes (ed. P. Yeagle, 1992, pp. 1047-1106). This method yielded 50 micrograms of the receptor protein contained in 50 microliters of lipids, most of which were dioleylphosphatidylcholine (DOPC). (The rest were other membrane components such as other phospholipids, cholesterol, etc.). This amount was added to the mixture of reverse bicontinuous cubic phase nanostructured cubic phase with potassium carbonate and the whole mixture was stirred gently but for a long time. Sufficient agitation was confirmed by the absence of birefringence. The external solution was prepared by adding 0.328 g of magnesium sulfate, 0.324 g of PLURONIC F-68 and 0.0722 g of cetylion bromide to 20.02 g of water. Five grams of the outer solution was overlaid with nanostructured reverse bicontinuous cubic phase receptor-containing material. The tube was sealed and sonicated for two hours. As a result, potassium-carbonate-coated receptor-containing particles were dispersed. A significant fraction contained particles ranging in size from 0.5 to 1 micron.

The microparticles were subsequently immobilized in a polyacrylamide hydrogel. Acrylamide (0.296 g), methylene-bis-acrylamide (0.024 g, for cross-linking), ammonium persulfate (0.005 g as initiator) and tetramethylene diamine (TEMED; 0.019 g as catalyst) were added to the dispersion. The polymerization resulted in the formation of a crosslinked hydrogel in less than 30 minutes. During the study of the hydrogel slice by microscope, the same high concentration of particles was found as in the original dispersion.

The hydrogel was finally divided into pieces of approximately 30 microns by passing through a 40 micron mesh screen.

TRANSLATION

In this example, receptor proteins are deposited in a matrix of potassium nitrate-coated particles of nanostructured reverse bicontinuous cubic phase inner core material. Subsequently, the coated particles were coated with a hydrogel. The receptor-bearing matrix was successfully used to bind activity in radioactivity experiments to UC Davis.

0.470 g of soya lecithin (epicuron 200) was mixed with 0.185 g of the "thymorbitol compound" and 0.368 g of water. After adding 0.198 g of potassium nitrate, the mixture was thoroughly mixed. Nicotinic acetylcholine receptors from stingrays were prepared as in the previous example. This preparation contained 50 micrograms of protein for every 50 microliters of lipids, most of which were dioleylphosphatydilcholine (DOPC). 55 mg of the preparation was added to a mixture of reverse bicontinuous cubic phase nanostructured material and potassium carbonate. The mixture was gently but long mixed to ensure good mixing. The outer solution was prepared by adding 0.128 g of PLURONIC F-68 and 0.015 g of cetylion bromide to 6.05 g of saturated aqueous potassium nitrate solution. A mixture of the reverse bicontinuous cubic phase nanostructured material and potassium nitrate was heated to 40 ° C to dissolve the potassium nitrate. The tube was then cooled in 4 ° C cold water for 10 minutes. The nanostructured receptor-containing material was overlaid in the tube with an outer solution, and after sealing the tube, the mixture was mixed and sonicated for 2 hours. The result was a dispersion of receptor-containing microparticles coated with potassium nitrate, most of which were between 0.3 and 1 micron in size.

· · · · ·

The microparticles were subsequently immobilized in a polyacrylamide hydrogel. Acrylamide (0.365 g), methylene-bis-acrylamide (0.049 g, for cross-linking), ammonium persulfate (0.072 g 2% as initiator) and tetramethylene diamine (TEMED; 0.011 g as catalyst) were added to the mixture. The polymerization, achieved in the order of hours, resulted in the formation of a cross-linked hydrogel. When studying a slice of hydrogel by microscope, the concentration of particles (except for the bottom of the hydrogel) was as high as in the original dispersion.

The hydrogel was finally divided into pieces of approximately 30 microns by passing through a 40 micron mesh screen.

It can be estimated that diffusion of a small molecule into the center of a 40 micron piece is no longer than one second, which has no significant effect on the receptor assay below.

Using iodine I-labeled bungarotoxin as ligand, receptor binding immobilized in the reverse bicontinuous cubic phase nanostructured material system described above was measured. (Standard measurement of receptor binding was described in the Dr. Mark McNameese group publication.) The result showed that the receptor immobilized in the reverse bicontinuous cubic phase nanostructured material system had about 70% ligand binding capability over the standard receptor preparation. This showed that the activity of the receptors was maintained not only during the immobilization procedure, but also over time, from the preparation of the receptors to the preparation itself.

The following examples 26-28 show the application of particles in biochemical assays and show a great increase in stability compared to commonly used liposomes whose unpleasant property is their instability. These tests are important in clinical diagnostics as well as in pharmaceutical drug research.

EXAMPLE 29

As in Example 22, particles coated with clathrates are produced here. In this example, the nanostructured reverse bicontinuous cubic phase material can be polymerized with oxygen capable of passing through the coating (yet the coating prevents water penetration).

Lecithin extracted from Krill's gamma was purchased from Avanti Polar Lipids of Birmingham, Alabama, as Krill shrimp phosphatydilcholine. 0.220 g of this lecithin was mixed with 0.110 g of a tung sorbitol compound, 0.220 g of water, 0.005 g of a cobalt desiccant (available from Grumbacher supplying artistic material) containing cobalt naphthenate and 0.3 g of potassium thiocyanate. This mixture produced a green colored nanostructured reverse bicontinuous cubic phase material. The external solution was prepared by adding 0.309 g of manganese chloride, 0.105 g of 4-picoline (4-methylpyridine), 0.113 g of PLURONIC F-68 and 0.021 g of cetylpyridinium bromide to 5.10 g of water. After overlaying the nanostructured material from the reverse bicontinuous cubic phase with an external solution, the tube was sealed, mixed and sonicated in an ice water bath. When the green-colored nanostructured material was dispersed from the reverse bicontinuous cubic phase into the microparticles, the color changed to brown due to the chemical reaction. After two hours, virtually all of the material was dispersed into microparticles, most of which had submicrometer dimensions. The coating was a Werner compound, which according to the literature contains channels allowing oxygen absorption (or passage). The high proportion of unsaturated bonds of Krill lecithin and the "tung-sorbitol compound" allowed, together with the catalytic activity of the cobalt desiccant, the polymerization of this microencapsulated nanostructured material from the reverse bicontinuous cubic phase in the presence of air oxygen.

The clathrates described in this example have already been described above (Example 22).

• ·

EXAMPLE 30

In this example, the nanostructured material was dispersed from the reverse hexagonal phase.

Nanostructured reverse hexagonal phase material was prepared by mixing 0.369 g of soya lecithin (EPIKURON 200), 0.110 g of trioleylsorbitol and 0.370 g of glycerol. To this nanostructured material from the reverse hexagonal phase was added 0.054 g of magnesium sulfate. The outer solution was prepared by adding 0.10 g of potassium carbonate, 0.10 g of PLURONIC F-68 and 0.02 g of cetylpyridinium bromide to g of water. After overlaying the reverse hexagonal phase nanostructured material with an external solution, the tube was sealed and sonicated for one hour after mixing. Most of the reverse hexagonal nanostructured material was thus dispersed into the magnesium hydroxide carbonate coated microparticles. The size and shape of the pore (cylindrical) in the reverse hexagonal phase provides a unique release kinetics useful, for example, in controlled drug delivery.

EXAMPLE 31

Unlike most of the above examples, in this example, the nanostructured material is dispersed from a reverse hexagonal phase that is not in equilibrium with an excess of water but is insoluble in water.

Soya lecithin (0.412 g), flaxseed oil (0.1559 g) and glycerol (0.4558 g) were thoroughly mixed. Thus, at room temperature nanostructured material came from the reverse hexagonal phase. To this nanostructured hexagonal phase material was added 0.059 g magnesium sulfate. The outer solution was prepared by adding 0.10 g of calcium carbonate, 0.10 g of PLURONIC F-68 and 0.02 g of cetylpyridinium bromide to 5 g of water. After overlaying the nanostructured material from the reverse hexagonal phase, the tube was sealed and sonicated for 30 minutes. Most of the reverse hexagonal nanostructured material was thus dispersed into the magnesium hydroxide carbonate coated microparticles.

The ability to disperse nanostructured material that is not in equilibrium with excess water extends the range of chemical applications in which the present invention can be used. This plasticity is particularly important in desirable applications such as drug dosing, in which a number of product requirements must be met simultaneously.

EXAMPLE 32

In this example, a chemical reaction process was used to disperse the nanostructured material from the lamellar phase. The nanostructured lamellar phase material was prepared by mixing 0.832 g of soya lecithin (EPIKURON 200) and 0.666 g of water. To about 0.80 g of this lamellar phase nanostructured material was added 0.057 g of magnesium sulfate. The outer solution was prepared by adding 0.10 g of PLURONIC F-68 and 0.02 g of cetylpyridinium bromide to 5 g of water. After overlaying the nanostructured lamellar phase material with an external solution, the tube with this mixture was sealed, mixed and sonicated for five minutes. The result was a dispersion of microparticles consisting mostly of nanostructured lamellar phase material and coated with magnesium hydroxide.

in

The particles formed in this example bear structural similarity to liposomes encapsulated in polymers. However, these particles do not suffer under such harsh chemical conditions as are used to produce liposomes encapsulated in polymers. The ability of a one-step production of particles whose interior is formed by a lamellar phase coated with a wide variety of crystalline coatings and all under mild conditions could bring the invention to the forefront of controlled drug release.

EXAMPLE 33

Preparation of the free bases: both ethylhydrokuprein and neutral red were ordered in protonated, hydrochloride form. In both cases the salt was •

100 ALIGN!

9999 9999 * 9999 9999

99 99 9 99 99 dissolved in water to which dissolved sodium hydroxide was added in a molar ratio of 1: 1. The product of the mixture of the two aqueous solutions was a white precipitate which was rinsed with water (to remove NaCl and unreacted NaOH). After centrifugation, the precipitate was dried at a temperature higher than the melting point of the free base.

Preparation of nanostructure dispersion of reverse bicontinuous cubic phase:

The dispersion preparation is based on the following mixture:

0.417 g monooleylglycerol (GMO)

0.191 g glycerol

0.044 g of ethylhydrokuprein (or neutral red - both in free base form).

In this example, instead of the conventional monoblyceride-water reverse nanostructured material, a monoglyceride-water mixture was used, the monoblyceride-glycerol reverse nontostructured material.

The outer solution was prepared by dissolving PLURONIC F-68 in water to a final concentration of 2%.

After weighing the components into a test tube and mixing with a spatula, it was sealed with a screw cap and heated in an oven at 140 ° C for at least 20 minutes. After verifying that the ethyl hydrokuprein (or neutral neutral base) melted, the tube was immersed in water. There was no difference between dispersions where the water temperature reached room temperature and the water temperature was lower (about 10 ° C).

After five minutes in the cooling bath, a very high viscosity was noted, indicating the presence of reverse bicontinuous cubic phase nanostructures. In some cases the optical isotropy of the sample was investigated by cross polarization filters (the dimensions of the crystalline coating domains are considerably smaller than the wavelength of light, therefore they were not able to influence the optical

101

Properties). The outer PLURONIC solution was poured into about half of the tube. The tubes were then mixed by hand and using a mechanical mixer. The solution became opalescent when the reverse bicontinuous cubic phase nanostructured material turned into a dispersion.

SEM characterization: Scanning Electron Microscopy (SEM) preparation did not involve any fixation technique. The dispersion droplet was simply placed on the glass film and, after drying, was dusted with a thin (2 nm) carbon coating to avoid the charging effect. In the dusting apparatus, the sample was held under a vacuum of 5 x ¹⁰ -4 Torr for about 5 minutes. This test was performed to test the robustness of the particle coating. The apparatus used, Hitachi S-800 Field-Emission SEM, was operated at 25 kV.

Giant. 3 shows the SEM micrograph of an ethyhydrokuprein dispersion where particles are predominantly in the range of about 0.5-2 microns (a 10x magnified square from the upper half is seen in the lower half so that the magnification is 500 in the upper half and 5000 in the lower half). Polyhedral shapes can be found on many particles. The measured particle size distribution for this sample (see the next section) showed that particles in the range of 0.5 - 2 nm predominate in the dispersion, which agrees with the micrograph knowledge. It can be estimated that the thickness of the 0.5 µm ethylhydrocapine coating is about 10 nm. This thickness was clearly sufficient to prevent evaporation of the aqueous constituents of the particle under a vacuum of 0.5 mTorr.

Lithium sulfate was added to the nanostructured reverse bicontinuous cubic phase material prior to dispersion formation as a label. Indeed, on the EDX spectrum of this dispersion it was possible to find a peak belonging to the sulfur. Lithium could not be detected by the EDX used and other peaks were assigned to the glass substrate.

Giant. 4 shows SEM neutral red dispersion micrography. The size of practically all particles ranged from 0.3 to 1 micrometer.

• · · ·

102 • · · · · · ···

Particle size distribution: The Malvem 3600E particle size measuring instrument based on laser diffraction was used to measure the distribution. For all dispersions measured, a few drops were added to the carrier solution (water). Multiple scattering was prevented by such a high dilution. The particle size was calculated as the diameter of the spheres of the same volume, which corresponds to the polyhedral shape of the particles. (See below). The instrument is capable of measuring particles of at least 0.5 microns in size and distribution data includes contributions of particles of this size.

The particle size distribution of the dispersion made from GMO-ethylhydrokuprein in a ratio of 13: 1 is shown in Figure 5. Generally, with increasing ratio of nanostructured material from the reverse bicontinuous cubic phase to the crystalline coating substance, the particle size increases. Based on the size average, the data for this dispersion showed that the 10% particle size is less than 0.6 micrometer, representing D (v; 0.1) = 0.6 micrometer. Narrow distribution is presented in two ways. Both D (v; 0.9) and D (v; 0.1) are spaced by a factor of 2 from the diameter (weighted average volume) D (v; 0.5) = 1.2 microns. Second, the overlap indicating the breadth of distribution, given as the overlap = [D (v; 0.9) D (v; 0.1)] / D (v; 0.5), is 1.4. These results indicate a low degree of agglomeration.

A narrower distribution was shown for the dispersion with a ratio of GMO: neutral red = 10: 1. There is an overlap of 1.1 and the (differential) size distribution was easily detectable by a sharp drop above 2 micrometers.

The small particle size was measured for dispersions with a lower ratio of GMO: ethylhydrokuprein, where the average distribution was 0.8 microns and an overlap of 1.2. The particle size can therefore be controlled by the ratio of the nanostructured reverse bicontinuous cubic phase material to the crystalline coating agent. particle size decreases with decreasing ratio.

• ···

103 • · · · · · · · · · · · · · · · · · · · ·

Narrow X-ray scattering (SAXS). This methodology was used to verify that the interior of the particles in the ethylene hydrokuprein dispersion is a nanostructured reverse bicontinuous cubic phase material. The dispersion - and not the particulate concentrate - was transported to a Dr.Stephena Hui laboratory at the Roswell Park Cancer Center Biophysics Department in a 1.5 mm X-ray capillary. The SAXS camera was equipped with a rotating anode. Measurements were performed at 100 kV and 40 mV (40kW). Data was captured using a position-sensitive, linear detector electronically connected to a Nucleus Multichannel Analyzer (MCA). MCA capacity is 8192 channels. But a resolution of only 2048 was used to increase pulses per channel. The bulk fraction of the nanostructured material from the reverse bicontinuous cubic phase (which accounted for about 85% of the particle volume) in the dispersion was of the order of about 10%, therefore, citation times of the order of hours were used. The “PCA” software package was used for data analysis.

Figure 6 shows a graph with the measured SAXS intensity plotted against the wave vector q. The wave vector q can be obtained from the diffraction angle 0 and the wavelength λ of the X-rays according to the formula:

q = 47r (sin θ) / λ d-The distribution can then be calculated from the value of q of the Bragg peaks: d = 2π / ς

In Fig. 6, the exact positions of the Bragg peaks calculated from the lattice of the spatial group Pn3m with a lattice parameter of 7.47 nm are indicated by vertical lines. This spatial group is generally recognized in the case of reverse cubic phase nanostructures of monoolein-water systems, particularly those in equilibrium with excess water. (Indeed, in the case of reverse cubic nanostructures that are in equilibrium with an excess of water, the Pn3m spatial group is practically exclusively present). Grid parameters of nanostructured reverse cubic phases of the system

104 • The monoolein-water of the Pn3m spatial group is also close to 8 nm. • φ φ φ φ φ φ φ φ φ mon mon mon mon mon mon mon mon mon mon mon mon mon A closer comparison was made impossible by the replacement of water with glycerol in the case under investigation. In any case, the data measured with SAXS is in exact agreement with the data reported in the reverse cubic phase monoglyceride nanostructured literature.

The Miller indices (hkl) of allowed vertex positions and the value of h ² + k ² + l ² in the spatial group Pn3m are: (110), 2; (111), 3; (200), 4; (211), 6; (220) 8; (221) 9; (222), 12 and higher. From the data point of view, it is clear that the peaks at the expected positions (110) and (222) are consistent with the measured data. The vertex (111) appears at the foot of the vertex (110) on the right side of the record and as a small but distinguishable vertex on the left side. This peak always has, in the case of monoglyceridic Pn3m phases and Pn3m phases in general, much less intense than (110) and (111), which corresponds to theoretical amplitude calculations [Strom, P. and Anderson, DM (1992) Langmuir, 8: 691 ], Peak (221) is based on data on the left side of the record, while Peak (222) on the right. The absence of a low intensity region between peaks (221) and (222) is due to the low concentration (10%) of the reverse biontinuous phase nanostructure in the dispersion, since the intensity of the reflected X-rays varies with the square of the volume concentration. Despite all this, the steadfast positions of the peaks (110) and (222) and the perfect match of the derived lattice and lattice parameter with similar systems in the literature strongly support the conclusion that SAXS data showed an arrangement of nanostructures of reverse bicontinuous cubic phase within particles.

These particles may be useful, for example, in controlled dosing of antiseptics in mouthwashes, where the solubility of the coating at a slightly lower pH (around pH 5) causes release at sites of bacterial activity.

9

105

9999 999 9

98 99 · 9 9 9

999999 9 9

999 99 99 99 99

EXAMPLE 34

High pressure liquid chromatography (HPLC) has been characterized by the effect of friction on two dispersions, one having a rigid copper ferrocyanide coating and the other with a soft coating, slightly damaged, which served essentially as a control to quantify any pressure release. In other words, if the concentration of the label in the two dispersions was approximately the same and, in a rigid coating system, a small portion of the label, say x% (where x must be less than 100), was released compared to the soft coating system, it can be deduced that ux% of the particles in the rigid system were damaged while (100-x)% of the particles remained intact during HPLC. (In addition, the number (100-x) is the lower limit of the number of intact particles: the actual percentage of intact particles will be higher because some of the soft particles remain intact. In any case calculations were performed for worst case assuming all soft particles were destroyed.)

Preparation of dispersion.

Example 34A. The nanostructured material from the reverse bicontinuous cubic phase was prepared by mixing 0.499 g of soya lecithin, 0.163 g of oleyl alcohol, 0.900 g of glycerol and 0.124 g of capsaicin. 0.043 g of sodium cholate was added to 0.842 g of reverse bicontinuous cubic phase nanostructured material. The outer solution was prepared by adding 1 drop of 1M HCl to 3.00 g of pH 55 phosphate buffer. Overlaying the liquid crystal material with the outer solution, mixing and sonication of the sealed tube resulted in a milky white dispersion of microparticles.

Example 34B. The nanostructured reverse bicontinuous cubic phase material was prepared by mixing 0.329 g of soya lecithin, 0.108 g of oleyl alcohol, 0.611 g of glycerol and 0.105 g of capsaicin. Here, 0.046 g of copper sulfate was added. The external solution was prepared by adding 0.563 g of a 10% potassium ferrocyanate solution to 2.54 g of water. The liquid crystals were superimposed on the outer

106 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Solution, test tube sealed, mixed and sonicated. The result was a milky-white dispersion of the copper ferrocyanide coated particles.

The concentration of the label, namely capsaicin, was comparable in both samples. The final concentration of the cupric ferrocyanide dispersion was 2.44% compared to the 3.196% achieved in Example 34B - this 30% difference will be used for the calculations below.

Pure capsaicin was injected on HPLC. An elution time of 22 minutes was measured for this material (data not presented). Both dispersions were analyzed under the same conditions. The data pertaining to the particles of Example 34B are shown in Fig. 7 and the data pertaining to the particles with the copper ferrocyanide coating in Fig. 8. In Tables 1 and 2, the HPLC computer output values after integration of the peaks of Figs. 7 and 8 are measured during sampling. 5 Hz.

In Figure 7, a peak with an elution time of 22 minutes, designated by the computer as number 13, is shown in Fig. 7, the intensity of which is 3939401 in Table 1. The much smaller peak at 22 minutes (computer 10) was measured in Figure 8. from Table 2 is 304929.

The integrated peak values were normalized to the capsaicin concentration in the two samples analyzed, namely for Example 34B 3939401 / 0.0319 and for the copper ferrocyanide coating 304929 / 0.0244. The ratio of these two normalized values is 0.101 - i.e., a maximum of 10.01% of the copper plated ferrocyanide coated particles released capsaicin under HPLC conditions.

These particles have a mineral coating, poorly soluble in water, which could find application where release under severe friction is required, while protecting against release by simple dilution with water. An example of such an application is the encapsulation of a toxin, or rodent repellent, such as capsaicin, and the subsequent impregnation of electrical cables, cartons and other products requiring rodent protection in this encapsulated form. Feeding would then result in the release of the active repellent or toxin.

107 • · «♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦

• Β ΒΒ ΒΒ ΒΒΒ • • • •

Β · · ·

Low water solubility would then prevent premature release due to wet conditions.

TABLE 1: Intensities of the integrated peaks of the HPLC analysis of Fig. 7, for the capsaicin-containing particles in Example 34B. Peak 13 represents the elution of capsaicin.

Peak Area

2914

8096

2848

29466

11304

2254

12871

4955

124833

113828

19334

7302

3939401

39153

255278

755868

52623

19395

4899

105519

5102

1481

108 • 4 4 4 4 ·· 4 4 44 44 • 4 4 4 4 4 444 4

4 44 44 4444

4 · 44 44 444 444

4444443 · 4

44444 44 44 4 · · ·

344230

9971

194442

89831

80603

105163

186224

194020

368055

2115

23296

4327

5166

90236

62606

44523

110347

4391

1275597

1353000

238187

TABLE 2: Intensities of the integrated peaks of the HPLC analysis of Figure 8, for the capsaicin-containing particles coated with cupric ferrocyanide in Example 34A. Peak 10 represents the elution of capsaicin

Peak Area

1681172

3011241 • «··

109

44 44 44

4444 444 • 44 44 4 4 4 4

444444 4 4 • 44 44 4 · 4 · ··

106006

2760

59059

38727

163539

44134

6757

304929

10466

141800

332742

14442

6996

15008

11940

91446

250214

251902

203000

44658

110901

24296

19633

25527

15593

75442

40245

421437 ·· ··

100 9 «100 9

9 99 · 9 9 · • 999

• 999999 9 9

99999 99 99 99 99

EXAMPLE 35

The nanostructured liquid crystal phase material was prepared by mixing 0.77 g of soya lecithin (EPIKURON 200, from Lucas-Mayer), 0.2855 g of oleyl alcohol and 0.84 g of glycerol. To this mixture was added 0.11 g of gold chloride. Heating was not used to equilibrate the mixture, but only with spatula mixing. 0.595 g of this mixture was spread over the lower half of the test tube surface. An outer solution was prepared by dissolving 0.14 g of ferrous chloride and 0.04 g of PLURONIC F-68 in 1.74 g of distilled water. After superimposing the cubic phase with the outer solution, the tube was sonicated. The result was a dispersion of gold coated microparticles. The control sample contained F-68 but did not contain ferrous chloride. There was no formation of microparticle dispersion when sonicated with the first sample. The reaction between the gold chloride and the iron chloride resulted in the precipitation of elemental, non-lamellar, crystalline gold, which in the first sample resulted in the formation of gold-coated gold particles with a cubic phase interior. By mixing 0.62 g of glycerol, 0.205 g of water and about 0.1 g of dispersion, a glycerol-water mixture having an approximate density of 1.2 g / cm ³ was prepared. The new dispersion was centrifuged. A substantial fraction of the particles was at the bottom of the tube after three hours of centrifugation, indicating that the particle density was slightly higher than 1.2. Since the cubic phase density is less than 1.2, this effect was due to the presence of a gold coating. In addition, the portion of the cubic phase that was not dispersed during sonication appears as a lower density band during centrifugation, indicating that the liquid had an even lower density than the original dispersion.

Because of its well-known chemical inertness of gold and its mechanical properties when in the form of a thin film and at the same time because the FDA permits many modes of administration, gold coated particles could be useful in safe, environmentally friendly products requiring chemically and physically stable coatings. In addition, such • 9 99 ·· 99 ,,. ·· · · 9 9 9 9 9

111 · · ···· 9 * 99

9999999 9 9

99999 99 99 99 99 particles to be effective in the treatment of arthritis by increasing the surface of gold over other colloidal forms.

EXAMPLE 36

The nanostructured liquid phase containing the antineoplastic drug taxol was prepared by dissolving 0.045 g of taxol, 0.57 g of eugenol, 0.615 g of soya lecithin (EPIKURON 200), 0.33 g of glycerol, 0.06 g of copper nitrate in 0.61 g of methanol. Thereafter, the methanol was evaporated in a evaporation dish while stirring. The glycerol-rich outer solution was prepared by dissolving 0.09 g of potassium iodide, 0.05 g of PLURONIC F-68 and 1.96 g of glycerol in 0.44 g of water. After coating the system with an external solution and sonication, a dispersion of taxol-containing microparticles in the nanostructured liquid phase coated with crystalline iodine was formed. Since the ingredients have been chosen in this case in terms of their harmlessness, absence of activity (except taxol alone) and use in pharmaceutical preparations, this form could become important in dosing taxol in the treatment of cancer. The concentration of taxol inside the particle was relatively high, reaching 3% by weight. In this case, the concentration was so high that taxol could precipitate within the particles, as the solubility of taxol on such a large scale in the cubic phase was metastable. However, studies have shown that precipitation is very slow, taking hours to days at such a dosage so that virtually all taxol will remain in solution during particle production. The encapsulation of taxol into the interior of the microparticles thus prevents the formation of large crystals (larger than the micrometer). If the concentration of taxol in the interior of the particles was reduced to 0.7% or less, then taxol became truly soluble (thermodynamic equilibrium). Thus, precipitation was completely prevented and the microparticles of the invention coated with non-lamellar crystalline iodine can be produced as described in this example. Thus, this system provides several variants useful for dosing taxol in the treatment of cancer.

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112

9 9 9 9 9

9 9 9 9 9 9 9 9 9 ^# 9 9 9 9 9 9 9 9 9

EXAMPLE 37

The cubic liquid crystal phase containing taxol was prepared by mixing 0.345 g of soya lecithin (EPIKURON 200), 0.357 g of anisole, 0.26 g of water and 0.02 g of taxol (Paclitaxel from LKT Laboratories). Equilibration was accelerated by placing the tube after thorough mixing in boiling water for 1 minute and then cooling to room temperature. The coating material was prepared by mixing 0.07 g of propyl gallate and reheating in boiling water. It has been previously verified that propyl gallate does not sufficiently dissolve in the cubic phase at room temperature, but solubility has substantially increased at 100 ° C. The outer solution consisted of 2.25 g of a 2% PLURONIC F-68 solution. The cubic phase propyl gallate mixture was heated to 100 ° C, cooled to 80 ° C, mixed with a spatula at elevated temperature and reheated to 100 ° C. After cooling the mixture for about 30 seconds, it was overlaid with an external solution and sonicated for one hour. The result was a dispersion of taxol-containing microparticles inside coated with propyl gallate. The dispersion contained a high concentration of extremely fine microparticles (estimated particle diameter was less than 0.4 microns) that were discoverable in an optical microscope at 100x magnification with their Braun motion. The overall particle size distribution was relatively broad. Some particles thus reached the size of 1 - 2 micrometers. Only a very small amount of taxol precipitate was discovered in the form of needles, so almost all had to be inside the microparticles. The concentration of taxol in this case was high enough that the solute was metastable. The consequences of this were discussed in the previous example. Since the concentration of antineoplastic taxol within the particles was about 2% and the microparticle components are included in the list of permitted inactive FD A substances suitable for oral dosing (and almost all for injectable use), this dispersion could be very important in the treatment of cancer.

9999

113 ·················· 9 9 9 9 9 9 9 9 9 9 9

9

99 99 99

EXAMPLE 38

1.655 g of amphiphilic polyethylene oxide-polypropylene oxide block copolymers PLURONIC F-68 (also called POLOXAMER 188) were mixed with 0.705 g of eugenol and 2.06 g of water. After centrifugation, two phases were separated - the lower one, composed of liquid phase nanostructures and the upper one, of cubic nanostructures. To 0.68 g of the collected liquid-crystalline phase was added 0.05 g of sodium iodide. A drop of eugenol was added to 2.48 g of the bottom phase to ensure low viscosity. This nanostructured liquid crystal phase, after addition of 0.14 g of silver nitrate, served as an external solution in the dispersion of the liquid crystalline phase. Thus, an iodide-containing liquid crystalline phase was overlaid with the liquid phase. The mixture was sonicated for 1.5 hours. The result was a dispersion of silver iodide coated particles in the nanostructured liquid crystal outer medium. This example outlined the use of liquid crystal nanostructured phases based on block copolymers as the inner cores of the particles of the invention. In this case, water was used as the preferred solvent of the polyethylene oxide blocks of the block copolymer, while eugenol was used as the preferred solvent of the polypropylene oxide blocks (which are insoluble in water).

This example also demonstrates the use of general, previously discussed principles. Specifically, the use of the nanostructured phase as a mixture serving as an "external solution" providing component B that reacts with component A from the internal phase, resulting in precipitation of the crystalline coating material. In this case, component B is silver nitrate, which upon contact with the inner core A (cubic phase) containing sodium iodide gives rise to a silver iodide precipitate. As mentioned above, it is highly desirable to select this outer solution to be in equilibrium with the inner core, or as in this case to be very close to this equilibrium (the only deviation from the actual equilibrium is the addition of a single drop, about g or less than 0.5%, eugenol to external ····

114 ·· flfl flfl flfl * • * · · · · · · and · • fl • · ·· flflflfl flfl flflflfl · • flflflfl flfl flfl flfl flfl solution). As in this procedure, it is useful to choose the inner core from a much more viscous material than the outer solution, which should have a relatively low viscosity.

It will be understood that many variations and modifications of the invention may be introduced without departing from the spirit and scope of the invention. Of course, the invention is not limited to the particular constructions and arrangements described herein, but includes modified forms based on the appended rights. The specific encapsulations described are exemplary only and the invention is limited only by the appended claims.

Claims (36)

PATENT CLAIMS A coated particle comprising a. an inner core consisting of a matrix that is formed i. the least one liquid phase nanostructured ii. at least one nanostructured liquid crystal phase; or iii. a combination of (1) at least one liquid phase nanostructure (2) of at least one liquid crystal nanostructure, and b. an outer coating composed of a non-lamellar crystalline material. The coated particle according to claim 1, consisting of a nanostructured liquid phase composed of a. L1 phase nanostructured material b. L2 phase nanostructured material c. a nanostructured microemulsion; or d. L3 phase nanostructured material. The coated particle according to claim 1, comprising the nanostructured liquid crystal phase material consisting of: a. Normal or reverse cubic nanostructured material b. Normal or reverse hexagonal nanostructured material c. Nanostructured material from normal or reverse intermediate phase d. lamellar phase nanostructured material. 116 «9 <9 <> t t 3 3 3 3 3 3 3 3 3 3 3 1 1 1 »» 9 · · · · · · · «« 9 ·· 9 9 99 · t The coated particle according to claim 1, comprising the nanostructured liquid phase material comprising: a. a polar solvent; and b. Detergents or lipids. The coated particle of claim 1, which comprises a nanostructured liquid phase material comprising: a. a polar solvent; b. Detergents or lipids; and c. Amphiphilic or hydrophobic substances The coated particle of claim 1, which is a liquid phase nanostructured material consisting of: a. block copolymers. The coated particle of claim 1, comprising a nanostructured liquid phase material comprising: a. A block copolymer; and b. Solvents. The coated particle of claim 1, which comprises a nanostructured liquid crystal phase material comprising: a. a polar solvent; and b. Detergents. The coated particle of claim 1, comprising the nanostructured liquid crystal phase material consisting of: a. a polar solvent; b. Detergents; and • 9 • 9 c. Amphiphilic or hydrophobic substances. The coated particle according to claim 1, comprising the nanostructured liquid crystal phase material consisting of: and a block copolymer. The coated particle of claim 1, which comprises a nanostructured liquid crystal phase material comprising: a. a block copolymer; and b. Solvents The coated particle of claim 1, comprising said inner core in a matrix of which the active agent is deposited. The coated particle according to claim 10, comprising the active ingredient taxol. The coated particle according to claim 10, comprising the active ingredient capsaicin The coated particle according to claim 10, comprising as an active substance a photodynamic drug. The coated particle according to claim 10, comprising as an active substance a receptor protein. The coated particle of claim 10 having an inner core composed of a reverse cubic phase material. 11? • · · · · The coated particle according to claim 17, having the active agent deposited in the matrix of the inner core. The coated particle of claim 18, comprising the active ingredient taxol. The coated particle according to claim 18, comprising the active ingredient capsaicin. The coated particle of claim 18, comprising as an active agent a photodynamic drug. The coated particle of claim 18, comprising a nucleic acid as the active agent. The coated particle according to claim 18, comprising glycolipids as active substance. The coated particle of claim 18, comprising an amino acid as the active agent. The coated particle of claim 18 comprising a polypeptide as an active agent. The coated particle of claim 18, comprising a protein as an active agent. The coated particle of claim 18, comprising as an active agent an antineoplastic drug. 119 · The coated particle according to claim 18, comprising as an active ingredient antihypertension vum. The coated particle of claim 18, comprising a rodent repellent active agent. The coated particle according to claim 18, comprising pheromone as active substance. The coated particle of claim 18, comprising as an active agent a receptor protein. The coated particle of claim 1, wherein the matrix is composed of a material with physicochemical properties of the biomembranes. The coated particle of claim 32, wherein said biomembrane comprises biologically active polypeptides. 34. The coated particle of claim 32, wherein the matrix comprises a polypeptide or protein immobilized in said biomembrane. The coated particle of claim 1, wherein the outer coating consists of a non-lamellar crystalline material with a solubility of less than about 10 g per liter of water. The coated particle of claim 1, wherein the outer coating is clathrates.