MXPA02003891A

MXPA02003891A - Magnetic targeted carrier.

Info

Publication number: MXPA02003891A
Application number: MXPA02003891A
Authority: MX
Inventors: Raymond Rudge Scott
Original assignee: Ferx Inc
Priority date: 1999-10-18
Filing date: 2000-10-13
Publication date: 2002-12-09
Also published as: WO2001028587A3; CA2387925A1; JP2003321348A; AU1090501A; JP2005200426A; CZ20021357A3; AU772755B2; NZ518311A; IL149004A0; CN1287859C; CN1420787A; EP1221974A2; WO2001028587A2; HK1045110A1; BR0014877A; ES2182731T1; CZ293919B6; DE1221974T1; JP2003512336A; KR20020064299A

Abstract

The invention relates to magnetically responsive compositions comprising iron-ceramic particles used to carry substances for in vivo medical diagnosis and/or treatment. The particles are formed by joint deformation of iron and ceramic powders. Diagnostic or therapeutic substances may be adsorbed thereon. The particles may be produced by mechanical milling of a mixture of iron and ceramic powders.

Description

OBJECTIVE MAGNETIC CARRIER, COMPOSED OF IRON AND POROUS MATERIALS, FOR THE DELIVERY OF BIOLOGICALLY ACTIVE AGENTS Introduction This invention relates to compositions, methods of • manufacture and methods for delivery of bio-compatible particles to a selected place in a body and, more particularly, refers to particles capable of carrying biologically active compounds and that provide the objectified magnetic transport of the particles and their maintenance in a place predetermined as a 4fck localized therapeutic treatment for diseases, aid for diagnosis, or a bi-functional composition capable of acting both as a diagnostic agent and as a therapeutic agent. The specific site delivery of biologically active agents would allow improvement of the therapeutic activity of the chemotherapy while minimizing systemic or side effects. The magnetic carrier compositions for treating various disorders have been previously suggested and used, and • include compositions that are guided or controlled in a body in response to an externally applied magnetic field. (See Lieberman et al, US Patent 4,849,209, Schroder and 5 co-workers, US Patent 4,501,726, Chang, US Patent 4,652,257, and Mireí1, US Patent 4,690,130).

Such a known composition, which can be delivered by intravascular injection, includes microspheres made of a ferromagnetic component covered with a biocompatible polymer (albumin, gelatin, and polysaccharides) which also contains a medicament (Driscoll, CF et al. , Prog. Am. Assoc. Cancer Res., 1980, p 261). It is possible to produce micro-spheres of albumin up to 3.0 μm in size containing a magnetic material (magnetite Fe304) and the anti-tumor antibiotic doxorubicin (Idder, K. and 0 collaborators, J. Pharm. Sci., 68: 79-82 , 1979). Such microspheres are produced through thermal denaturation and / or albumin chemistry in an emulsion (water in oil), with the dispersed phase A containing a suspension of magnetite in a medicinal solution. A similar technique has been used to produce micro-5 controlled, or guided, capsules magnetically coated with ethylcellulose containing the antibiotic mitomycin-C (Fujimoto, S. et al., Cancer, 56: 2404-2410, 1985). Magnetically controlled liposomes, 200 to 800 nm in size, capable of carrying preparations that can dissolve () atherosclerotic formations are also known. This method is based on the ability of phospholipids to create closed membrane structures in the presence of water (Gregoriadis G., Ryman B.E., Biochem. J., 124: 58, 1971). Such previously known compositions have not always proven practical and / or effective. Commonly, there is a concentration of ineffective medication delivered to the objectified site. Many of the compositions lack adequate transport capacity, exhibit weak magnetic susceptibility, and / or require magnetic fields of extremely high flux density for their control. In some cases, there is no real localization of the particles that allow accurate local therapy. Other deficiencies include non-specific binding and non-target organ toxicity for compositions incorporating antibodies and peptides, and off-site drug diffusion desired for technologies based on intra-tumoral injection. Some compositions are difficult to manufacture or consistently prepare, sterilize, and store without changing their designated properties. Thus, a need remains for an effective biocompatible composition that is capable of being magnetically transported and that is relatively easy to manufacture, store and use.A suggested composition comprises ferrocarbon particles for use as a magnetically controlled material for magnetically controlled compositions. These particles * 3 ^ have a larger dimension (ie, larger diameter) of about 0.2 to about 5.0 μm (and preferably 0.5 to 5.0 μm) and contain about 1.0 to 95.0% (by mass) of carbon, with the carbon strongly connected to the iron.The particles are obtained by means of deforming together (ie, grinding) a mixture of iron and carbon powders.

US Patent 5,549,915; 5,651,989; 5,705,195 and patent application US 09 / 003,286, and 09 / 226,818, which are incorporated herein by reference. Previous requests for this technology emerged from a desire to make alloys that were not achieved through foundry processes. Not all conceivable alloys can be made by casting, since the solubility of a metal Melt in another limits the concentrations that mixtures can achieve. The ground ferrocarbon particles were derived 0 as an adaptation of a technique for making alloys. The grinding technique is finely adjusted to produce a durable connection between the two materials without intimately mixing them as an alloy, which would result in reduction or elimination of both the magnetic moment and / or the ability to carry medications. The idea of combining iron and carbon by grinding arose from its natural mixing capacity, as in the processes of casting to form alloys. Compendium of the Invention It has now been found that iron-ceramic particles can be produced by the milling method. This is ^^ surprising because alloys using these materials had not been previously demonstrated. Thus, it had not been thought that a durable interface between the iron and the ceramic material could be formed. The composite particles of iron-ceramic show great versatility to bind to various drugs that are adsorbed on the particle surface for easy incorporation of the active agent. Additionally, iron-ceramic particles use metallic iron with a higher magnetic susceptibility than iron oxides, thereby facilitating and expediting mobility to the treatment site. Moreover, the biocompatibility properties of ceramics are well known. Biocompatible and biodegradable ceramic materials based on hydroxyapatite and other materials derived from calcium phosphate have been used as bone replacement material in dental and skeletal procedures. However, the concept of magnetically objectifying a ceramic material used as a carrier is completely novel. This invention provides a magnetically responsive composition that carries biologically active substances. Generally, the iron-ceramic composite particles can be used to objectify the delivery of a number of biologically active, diagnostic, or bifunctional agent compositions. Their production and use methods are also provided. The object of this invention is to improve some parameters of magnetically controlled compositions used for the objectified transport of a biologically active substance, including: allowing the use of natural bone constituents in the carrier particle, expanding the categories of therapies and diagnostics for which this technology can be used, increase the capacity of relative absorption and magnetic susceptibility by, for example, providing a large number of ionic groups that allow the binding of compounds by ionic interactions, improve biocompatibility and biodegradability, intensify the diagnostic and therapeutic effect, simplify the manufacturing technology of the • magnetically controlled composition, and ensure its long-term storage capacities guaranteed without changing the desired characteristics. This is achieved by using suitable composite, iron-ceramic particles as a magnetically 4fe susceptible material for a magnetically controlled composition. The particles are disk-shaped and spherical, approximately 5 0.1 to 10 μm in diameter, and contain 1.0 to 95% ceramic (or a ceramic derivative) and 5.0 to 99% iron, by mass. They are obtained by deforming together (i.e., milling) a mixture of iron and ceramic powders. The adsorption occurs on the surface, or modified surface, of the particle such that the drug is readily available and capable of incorporation into the treatment site. The powders are combined in a planetary, or attrition, ball mill with a solvent (ie, ethanol). The resulting composite powder is then screened or separated magnetically to obtain the desired fraction of the product, and so corresponding, the desired magnetic susceptibility. The biologically active agent or diagnostic assistant is adsorbed to or deposited in the compound and administered to the patient in a suspension of the compound in a sterile diluent. Methods of use include methods for diagnosis or localized in vivo treatment of diseases by providing a magnetically responsive iron-ceramic carrier that has • adsorbed to a biologically active substance for its effectiveness in diagnosing or treating the disease, and injecting the carrier into the body of a patient. For example, the carrier is injected by inserting delivery means into an artery within a short distance of a site of the body to be treated and a branch or branches (preferably the most intermediate) to a network of arteries carrying blood to the site. 5 The carrier is injected through the delivery means into the blood vessel. Just prior to injection, a magnetic field is established on the outside of the body and adjacent to the site with sufficient field strength to guide a substantial amount of the injected carrier to, and retain the substantial amount of the carrier at, the site. Preferably, the field ^^ magnetic is of sufficient strength to carry the carrier within the soft tissue to the site adjacent to the network of vessels, thus preventing substantial embolization of any of the larger vessels by the carrier particles. See, for example, provisional application US 60 / 160,293, which is incorporated in the present by reference. It is therefore an object of this invention to provide a composition that magnetically responds strongly to optionally carry biologically active substances and their methods of production and use. It is another object of this invention to provide a magnetically responsive carrier for biologically active substances that has high magnetic response, but which is durable during storage and use. It is another object of this invention to provide a magnetically responsive composition comprising particles of approximately 0.1 to 10.0 μm in diameter, each iron-ceramic particle containing 1.0 to 95.0% ceramic (or a ceramic derivative) and 5.0 to 99.0% of iron, by mass. It is yet another object of this invention to provide a composition used for localized in vivo diagnosis or treatment of diseases including a carrier with iron-ceramic particles composed of approximately 0.1 to 10 μm in diameter, each iron-ceramic particle containing 1.0 to 95.0 % ceramic (or a ceramic derivative) and 5.0 to 99.0% iron, by mass, and having adsorbed on them one or more biologically optional active substances selected for efficacy in diagnosing and / or treating a particular disease. With those and other objects in view, which will become apparent to a technician in the matter from the next Description, this invention resides in the construction, combination, arrangement of parts and methods novel substantially as described below, and more particularly defined by the appended claims, it being understood that changes in the precise embodiment of the invention disclosed in the present are intended to be included as they come within the scope of the claims. ^ Brief Description of the Drawings Figure 1 is a magnified photograph (X1000) of 0 composite iron-silica particles. Figure 2 is a magnified photograph (X3000) of composite iron-silica particles. Jfc Figure 3 is a flowchart of the production process of this invention. Figure 4 is a doxorubicin binding curve for an iron-silica gel compound. Figure 5 is a doxorubicin binding curve for an iron-C18 compound. Figure 6 is a photograph of Microscopy of 0 ^ Electron Examination showing the morphology of particles ^^ of iron-hydroxyapatite. Figure 7 is the same frame as in Figure 6, with retro-dispersion monitoring to show iron in white and hydroxyapatite in black. Figure 8 is the spectra of the particle shown in figure 6, confirming that the white points are composed of iron. Figure 9 is the spectra of the particle shown in Figure 6, confirming that the black dots are composed of hydroxyapatite. Figure 10 is a particle size analysis of the hydroxyapatite particles using the light scattering technique. Figure 11 is a curve of magnetic susceptibility of a micro-particle of iron-hydroxyapatite using the magnetometer technique. Figure 12 is an isotherm tracing of Langmuir for iron-hydroxyapatite. Figure 13 is an Langmuir isotherm tracing for hydroxyapatite (without iron). Figure 14 is a desorption profile of doxorubicin for iron-hydroxyapatite. Figure 15 shows the labeling of iron-hydroxyapatite particles with indium 111 by direct incubation and stability in different media. Figure 16 shows the labeling of iron-hydroxyapatite particles with indium 111 / oxyquinoline and stability in different media. Details of the Invention The invention is a composite particle comprising from 1.0 to 95.0% of a ceramic (or a ceramic derivative) and 5.0 to 99.0% of iron, by mass. With compositions having less than 1.0% ceramic, the binding capacity of a particle is decreased to the point of being largely ineffective in carrying biologically active substances. With compositions of more than 95.0% ceramic, magnetic susceptibility is generally reduced beyond an effective level to objectify biologically active substances in vivo. The particles are disc-shaped and sphere-shaped, approximately 0.1 to 10.0 μm in diameter. The term "ceramic" means an adsorptive, porous, natural or synthetic material. It is usually, but not necessarily, a mixed oxide or oxide, where the oxide is metallic or non-metallic. It is usually, but not necessarily, inorganic. It is usually, but not necessarily, without a crystalline structure. Examples of synthetic ceramic materials include, but are not limited to, tricalcium phosphate, hydroxyapatite, aluminum hydroxide, aluminum oxide, aluminum calcium phosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, calcium phosphate, macro-porous, three-phase , calcium carbonates, hematite, bone meal, apatite, wollastonite, glass ceramics and other matrices of ceramics or glass. Also included are polymers that have a degree of crystallinity that will withstand pores and adsorption. Examples of such polymers include, but are not limited to, polyethylenes, polypropylenes, and polystyrenes.

Appropriate materials based on these parameters will be apparent to any technician in the field. An example table follows.

Non-metallic Oxide Amorphous Silica Yes Yes Yes Hydroxyapatite Yes No Yes Zeolites Yes No No Aluminas Yes No Yes Diamond No Yes No Also included in the definition of "ceramic" are silica and silica derivatives (including, but not limited to, octadecyl silane [C18] , octyl silane [C8], hexyl silane [C6], phenyl silane [C6], butyl silane [C4], aminopropylsilane [NH3C3], cyano nitril silane [CN], trimethylsilane [CJ, sulfoxyl propyl silane [S04C3], dimethyl silane [CJ, acid cation exchange coating [SCX], basic quaternary ammonium anion exchange coating [SAX], dihydroxypropyl silane [diol]), in a composite particle of 0.1 - 10.0 μm in diameter. By way of example, the following silicas are useful for forming the compounds of the invention.

Eka Nobel Kromasil Material Shape and Size Volu Area SuCharge Type of Phase Coverage Cover of Empa- Size of card size menu Final Phase per particle Poro Poro (pvVg) Bond Linked (μm) (A) (ml / g) (%) (μmol / m2) Kromasil S, 5, 7, 100 0.9 3 0 (analysis Silica 10, 13, ÍS elementary) Kromasil S, 5, 7, 100 0.9 340 4.7 Monomeric 4.3 Cl 10, 13, 16 Kromasil S, 5, 7, 100 0.9 340 Monomeric 3.7 If C4 10, 13, 16 Kromasil S, 5, 7, 100 0.! 340 1 Monomeric 3.6 S C8 10, 13, 16 Kromasil S, 5, 7, 100 0.9 340 19 Monomeric 3.2 Yes C18 10, 13, 16 EM Science Material of Form and Size Volume Area Su- Load Type of Coverage Packed Top Size of Pore of Carous Surface Pore- Phase of Final Phase Particle (?) (Ml / g) (mVg) Bonus Linked (μm) (%) ( μmol / m2) Lichrosorb I, 5, 10 60 550 No Yes 60 Lichrosorb I, 5, 10 100 420 No Yes 100 Lichrosorb I, 5, 10 60 150 16.0 Monomeric 1.55 No RP-18 Lichrosorb I, 5, 10 60 9.0 Monomeric 0.78 No RP-8 Lichrosorb I, 5, 10 60 0.7 550 12 2.5 If RP-select B Lichrospher S, 3, 5, 60 0.95 650 No Yes 60 10 Lichrospher S, 5, 10 100 1.25 420 No Yes 100 Lichrospher S, 3, 5, 60/100 1.25 350 12.5 RP-8 10 Lichrospher ?, 3, 5, 60/100 1.25 350 13 4.2 S RP-8 E / C 10 Lichrospher S, 3, 5, 100 1.25 350 21.4 3.9 No RP-18 10 Lichrospher S, 3, 5, 100 1.25 350 21.5 Yes RP-18 E / C 10 Lichrospher S, 3, 5, 100 1.25 350 CN 10 Lichrospher S, 3, 5, 100 1.25 350 4.5 3.Í NH2 10 Lichrospher S, 3, 5, 100 1.25 350 8.3 4.0 Diol 10 Lichrospher S, 3, 60 0. 9 360 12. 0 3. 2 If RP-select B 10 * Mt? Ammta atttl? É > i í.:. -.

Material Form and Size Volume Area Super- Load of Coverage Type Cover of Packaging- Size of Pore of Carbon Fiber Carbon Phase of Final Phase of Particle (Á) (ml / g) (m / g) < %) Linked (μm) (μmol / m2) Insert S, 5 ISO 320 S l ca Insert 18.5 Monomeric 3.23 ODS-2 Insert S, 3, S 15 Monomeric ODS-3 Insert S, 5 320 10.5 Monomeric 3.27 Yes C8 Insertill S , 5 10 Monomeric C8-3 Insert S, 5 10 Monomeric 2.77 5 Ph (Phenyl) Insertll 10 Monomeric Ph-3 (Phenyl) Insert 7.5 Monomeric 3.77 0 C4 Insert S, 5 16 Monomeric 80 Á Insert Prep ODS, 5 C8, Si • Vydac / T e Separations Group Material Form and Size Volu Area Your Load Type of Phase Coverage Cover of Empa Size of the end-of-phase Car of Final Phase cado Particle Poro Poro (m2 / g) Bonus Linked (μm) (Á) (ml / g) ( %) (μmol / m2) Vydac SD, 5, 10 300 0 6 90 Polyimage 4 16 Si 201TP C18 Vydac SD, 5, 10 300 0 6 Polymer 4 16 Yes 218TP 0i C18 Vydac SD, 5, 10 300 0 6 Polymer 4 89 Yes 214TP C4 Vydac SD, 5, 10 450 13 5 1 53 201HS 5 C18 • i < A - * ^ i? ..? - Waters Material of Form and Size Volume Area Load of Type of Phase Coverage Top Packed Size of Pore Pore Superf i - Carbon of Final Phase Particle (Á) (ml / g) cial. { %) Linked (μm) (mVg) (μmol / m2) μBondapak I, 10 125 1.0 330 10 Monomeric 1.46 Yes C18 μBondapak I, 10 125 1.0 330 2.08 Yes Phenyl μBondapak 10 125 1.0 330 3.5 1.91 No NH2 0 μBondapak I, 10 125 1.0 330 2.86 Yes CN μPorasil I, 10 125 1.0 330 No Silica Novapak S, 4 60 0.3 120 3.41 Yes 5 C18 Novapak 60 0.3 120 2.34 S • Phenyl Novapak CN S, 4 60 0 3 120 1.65 If Novapak S, 4 60 0.3 120 0 No 0 Silica Resolve S, 5, 10 90 0.5 175 10 2.76 No C18 Resolve C8 S, 5, 10 90 0. 5 175 5 2.58 Not Resolve CN S, 5, 10 90 0. 5 175 3 2.53 NO 5 Resolve S, 5, 10 90 0. 5 175 0 0 No Silica Sphepsorb S, 3, 5, 0.5 220 0 No Silica 10 Sphepsorb S, 3, 5, 0.5 220 Monomeric 1.47 Partial 0 ODS-1 10 r J ~ - .. ^ JuM • < * "*?" "Fr-fef _l JJ il i./t J __- J? ^ J .-« - »,. aé ^ tui í "? m? ^^? t YMC Material Shape and Size Volume Area Su- Coverage Type Load Packing Cap- Size of Pore Surface Carbono Final Phase Phase of Particle Pore (ml / g) (prVg) (%) Linked (μm) (A) (A) ( μmol / m2) S, 3, 5, Monomeric Si 7, 10, 15 S, 3, 5, Monomeric Si 7, 10, 15 • ODS-AQ S, 3, 5, Monomeric 7, 10, 15 S, 3, 5, Monomeric 7, 10, 15 Phenyl S, 3, 5, Monomeric 7, 10, 15 0 S, 3, 5, Monomeric 7, 10, 15 S, 3, 5, Monomeric 7, 10, 15 Note: The linked phase coverage calculated as by Sander, L. C, and Wise, S.A., Anal. Chern. , 56: 504 510, 1984. The characteristics of the material obtained from the literature published by the manufacturer of the material or his authorized representative.

• The powders are mixed in a planetary ball mill, or attrition mill, in the presence of a liquid, for example, ethanol, to inhibit the oxidation of iron. The liquid can also serve as a lubricant during grinding of the iron powder and ceramic, to produce the desired particle size distribution. It can also reduce the compaction of the ceramic during the process. As a result, the porosity of deposits • Ceramic in the composition is maintained so as to maximize the adsorption capacity of the particles. "The mixture is placed inside a planetary ball mill, or attrition mill, of the type used in powder metallurgy. iron and ceramic powders, ethanol, and metal or alloy balls • metal of various diameters. For example, the mill can have 6 mm diameter balls composed of hardened metal carbide. An appropriate amount of liquid (ie, ethanol) is added for lubrication. Depending on the type used, the mill runs between 2 and 14 hours at speeds of 100 to 1,000 rpm. It is believed that mill speeds above 1,000 rpm can create an undesirable amount of too small particles. Suitable liquids and grinding conditions are easily determined by one skilled in the art. After the joint deformation of the iron-ceramic mixture, the particles are removed from the mill and separated from the grinding balls, for example, by a sieve.

The particles can be resuspended in ethanol and homogenized to separate the particles from one another. The ethanol is removed, for example, by rotary evaporation, followed by drying in vacuo. Any suitable drying technique can be used, for example, in a vacuum oven (purging N2). The particles should be handled in such a way that they are protected against the oxidation of iron, for example, in a nitrogen environment. The resulting dry powder can then be screened or magnetically separated to obtain the desired fraction of product providing the desired magnetic susceptibility and therapeutic or diagnostic binding capacity. The product is then packaged in dosage units in a glove box purged with nitrogen and terminally sterilized. Any suitable sterilization technique can be used. For example, iron-ceramic particles can be sterilized using gamma irradiation and the aqueous solution of excipients can be sterilized by autoclaving. When ready for use, the biologically active agent or agents adsorb to or precipitate in the compound. The compound, with the active agent adsorbed, is administered to the patient in a suspension of the compound in a sterile diluent. The iron-ceramic particles are useful as a carrier to deliver one or more biologically active substances adsorbed to specific body sites under the control of an external magnetic field. As used herein, the term "biologically active substance" includes substances useful for diagnosis and / or in vivo medical treatment. Biologically active substances include, but are not limited to, anti-neoplastic, blood products, biological response modifiers, anti-fungal, antibiotics, hormones, vitamins, proteins, peptides, enzymes, dyes, antiallergics, anti-coagulants, agents circulatory, metabolic enhancers, anti-tuberculous, anti-viral, anti-anginal, anti-inflammatory, anti-protozoal, anti-rheumatic, narcotic, opiate, diagnostic imaging agents, cardiac glycosides, neuromuscular blockers, sedatives, anesthetics, as well as paramagnetic and radioactive particles. Other biologically active substances may include, but are not limited to, monoclonal or other anti-bodies, natural or synthetic genetic material and pro-drugs. As used herein, the term "genetic material" generally refers to nucleotides and polynucleotides, including nucleic acids, RNA and DNA of either natural or synthetic origin, including RNA and recombinant DNA, of sense and anti-DNA. sense. Types of genetic material may include, for example, genes carried in expression vectors, such as plasmids, phagemids, cosmids, yeast artificial chromosomes, and defective viruses (adjuvants), anti-sense nucleic acids, RNA and both simple strand DNA as _ ± _ + t Xí: t. + ¿, .. t > .__, s double, and its analogues. Also included are proteins, peptides and other molecules formed by the expression of the genetic material. For in vivo diagnostic imaging, the type of detection instrument available is a major factor in selecting a given radioisotope. The chosen radioisotope must have a type of spontaneous disintegration that can be detected by a given type of instrument. Generally, gamma radiation is required. Still another important factor in selecting a radioisotope is that the half-life is sufficiently long that it can still be detected at the time of maximum uptake by the target, but sufficiently short that the radiation harmful to the host is minimized. The selection of an appropriate radioisotope will be readily apparent to a technician in the material. Radioisotopes that may be employed include, but are not limited to, 99mTc, 142Pr, 161Tb, 186Re, and 188Re. Additionally, typical examples of other compounds useful in diagnostics are metal ions including, but not limited to, X11ln, 97Ru, 67Ga, 68Ga, 72As, 89Zr, and 201T1. Moreover, paramagnetic elements that are particularly useful in the formation of magnetic resonance imaging and electron gyration resonance techniques include, but are not limited to, 157Gd, 55Mn, ldDy, 52Cr, and 5dFe. It should also be noted that radioisotopes are also useful in radiation therapy techniques. Generally, alpha and beta radiation is considered useful for therapy. Examples of .í. É * & . k & & fc ^ i ^ .-. i «a.-t, i-."? ~ Á *. ~ - «-» - - ^. ^. ^ - •. ^^^^^^^^ - ^^^^ fc ^^. I¿ ^ «Á ^ aá A.t-fc ¿-Ki-.A I Therapeutic compounds include, but are not limited to, 32P, 186Re, 188Re, 13I, 125I, 90Y, 166Ho, 153Sm, 142Pr, 143Pr, 149Tb, 161Tb, ulIn, 212Bi, 2 3Ra, 210Po, 195Pt, 195mPt, 253Fm, 16SDy , 109Pd, 121Sn, 127Te, and 11At. The radioisotope usually exists as a radical within a salt, however, some tumors and the thyroid can take direct iodine. Useful therapeutic and diagnostic radioisotopes can be used alone or in combination. • The iron-ceramic composite particle exceeds previous inventions by using metallic iron that has a greater magnetic susceptibility than iron oxides that facilitates and expedites mobility to the treatment site. Advantages over current iron-carbon composite products include surface bond versatility, as well as biocompatibility and biodegradation properties of ceramics that are relatively well known. As a general principle, the amount of any biologically active, soluble, aqueous substance can be increased by increasing the proportion of ceramics in the particles to a maximum of about 50% by mass of the composite particles without loss of usefulness of the particles ^^ in the therapeutic treatment regimens described in this application. In many cases, it has been observed that an increase in the amount of biologically active substance adsorbed is approximately linear with the increase in ceramic content. However, as the ceramic content increases, the susceptibility, or responsiveness, of the composite particles to a magnetic field decreases, and thus the conditions for their control in the body worsen (although the capacity of adsorption increases). Therefore, it is necessary to achieve a balance in the ratio of iron: ceramic to obtain improved therapeutic or diagnostic results. To increase the amount of a given agent during a treatment regimen, a • Higher doses of particles can be administered to the patient, but the particles can not be made more magnetic by increasing the dose. The appropriate relationships can be determined by any person skilled in the art. It has been determined that the useful ratio of ^^ iron: ceramic ratio for proposed particles to the use of in vivo therapeutic treatments as described in the application is, 5 as a general rule, from around 99: 1 to around 5:95, for example, from around 80:20 to around 60:40. The maximum amount of biologically active substance that can be adsorbed on the iron-bearing particles: ceramics composed of any ceramic concentration will also differ depending on the nature of the biologically active substance, and, in some cases, the type of ceramic used in the composition. Any technician in the field will be able to determine the appropriate relationship for the desired application. Because it is convenient to prepare and sell carrier particles in a dry form, excipients can prepare in dry form, and one or more dry excipients are packaged together with a unit dose of the carrier particles. A wide variety of excipients may be used, for example, to improve adsorption or desorption, or to increase solubility. The type and amount of suitable dry excipients will be determined by a person skilled in the art depending on the chemical properties of the biologically active substance. More preferably, the package or assembly containing both the dry excipients and the dry carrier particles is formulated to be mixed with the contents of a bottle containing a unit dose of the medicament and a sufficient quantity of a biologically compatible aqueous solution, such as a saline solution. , as recommended by the drug manufacturer, to bring the drug to a pharmaceutically desirable concentration. Upon mixing the solution containing the diluted medicament with the contents of the set including the dry components (ie, the dry carrier particles and the dry excipients), the medicament is allowed to adsorb onto the carrier particles, forming a magnetically controllable composition. which contains a therapeutic amount of the biologically active substance adsorbed on the carrier particles which is suitable for therapeutic use or in vivo diagnosis. Alternatively, a liquid assembly can be used. In this, the carrier particles are contained as a unit, for example, in a bottle, while the aforementioned excipients are contained in another unit in the form of an aqueous solution. At the time of administration, the ferro-ceramic particles are mixed with the contents of a vial containing the unit dose of the medicament and sufficient quantity of a biologically compatible aqueous solution, such as a saline solution, as recommended by the manufacturer • of the drug, to bring the drug to a pharmaceutically desirable concentration. Subsequently, the resulting particles 0 having the biologically active substance adsorbed therein, are mixed with yet another unit containing the excipients in an aqueous solution. Any suitable sterilization technique can be used. For example, the ferro-ceramic particles can be sterilized using gamma irradiation and the aqueous solution of the excipients can be sterilized by autoclaving. The use of an autoclave undesirably oxidizes the ferro-ceramic particles. Also, when the biologically active agent to be adsorbed or deposited in the microparticles is soluble in an aqueous medium, the buffer used can have an impact on the overall bond. Any technician in the field will be able to determine the most appropriate shock absorber. A therapeutic or diagnostic amount of biologically active substance adsorbed to the carrier particles will be determined by a person skilled in the art as that amount. Í? .á tí.j-i, -i,; f ___ necessary to make the diagnosis or treatment of a particular disease or condition, taking into account a variety of factors such as the weight, age, and general health of the patient, the diagnostic or therapeutic properties of the medication, and the nature or severity of the disease. A number of considerations are involved in determining the size of the carrier particles to be used for any specific therapeutic situation. The choice of particle size is determined in part by technological constraints inherent in producing the particles below 0.2 μm in size. Additionally, for particles less than about 1.0 μm in size, the magnetic control in the blood flow and the carrying capacity are reduced. Sizes of • Relatively large particles tend to cause desirable or undesirable embolization of blood vessels during injection either mechanically or by facilitating the formation of clots by physiological mechanisms. The dispersion can coagulate, which makes injections more difficult, and the rate at which biologically active substances get desorbed from particles in objective pathological zones may decrease. The method (as described below) of grinding together a mixture of iron and ceramic powders produces an irregular shape with a granular surface for the particles, and results in a particle population having a larger average dimension of about 0.1. to around 5.0 H. tt i? μm. Because the iron in the particles described in this invention is not in the form of an iron oxide, as is the case in certain previously disclosed magnetically controlled dispersions, the magnetic susceptibility, or response, of the ferro-ceramic particles is maintains at a high level. Iron: ceramic particles are characterized by iron particles and ceramic particles bonded together. The two components remain as individual entities. The characteristic sub-structure of the particles formed during the joint deformation process of the mechanical mixture of iron and ceramic powders also increases the magnetic susceptibility of the iron inclusions in ferroceramic particles, as compared to iron particles that They have other types of sub-structure. Because the large surface of the ceramic deposits in the particles, the biologically active substance adsorbed can comprise about 100 ± 50% by weight, relative to the ceramic fraction of the particle, it being variable from about 5 to 95% by weight of initial particle mass, and more preferably from 15 to 60%. In different terms, this can be up to about 200 mg of biologically active substance adsorbed per gram of particles. Therefore, in use, much less carrier is injected to l; Í..t -LikrA? A- r.-... i attaining a given dose of biologically active substance or, alternatively, a higher dose of biologically active substance per injection is obtained than in the case with some previously known carriers. The following describes a method for producing small amounts of the ferroceramic composition of this invention, it being understood that other means and mechanisms besides grinding can be designed to deform together iron and ceramic powders, which comprises the initial elements essential for the production of the carrier. The method used exerts mechanical pressure on a mixture of ceramic and iron particles to deform the iron particles and develop a substantial substructure, which captures the ceramic. The formation of ferroceramic particles is achieved without the addition of heat in the process (although the mixture is heated during the mechanical deformation step), and conducted in the presence of a liquid, for example, ethanol, to inhibit oxidation of iron and ensure that the particles produced are clean (sterile). The liquid can also serve as a lubricant during the grinding of the iron and ceramic powder, and can reduce the compaction of the ceramic during the process. As a result, the density of the ceramic deposits in the composition is maintained such that it maximizes the adsorption capacity of the particles. According to the joint deformation of the particles and ceramics continues, an interface of the two solids is developed, a third phase comprised of a molecular mixture of iron and ceramics. This interface stabilizes the particle such that it is durable to sterilization and in vivo use. This interface is expected to be formed with other types of iron particles, such as ferrocarbono, as molecular mixtures of iron and carbon exist in nature or can be formed by melting, for example, cementite and iron. Ferroceramic mixtures are not commonly known or manufactured such that a molecular mixture can be found at the interface between two substances. For example, to produce particles having an average of about 75:25 iron: ceramic ratio per mass, a part of substantially pure iron particles having average diameters of 0.1 to 5 μm in size are mixed with 0.1 to 1.0. parts by weight of substantially pure ceramic granules (typically from about 0.1 to 5.0 μm in diameter). The iron particles and the ceramic granules are mixed vigorously to achieve good distribution throughout the volume. Each biologically active substance should be evaluated individually with various types of ceramics to determine the optimum reversible ceramic bond. Factors such as pH, temperature, particle size, salts, viscosity of the solution and other potentially competing chemicals in the solution can influence the parameters of adsorption capacity, rate, and desorption. • ~ - ^ * á ^ Ba * f'ílill-Í ll 1 i ¿* * - - * * The mixture is placed inside a standard planetary, or attrition, laboratory ball mill of the type used in powder metallurgy. For example, the mill can have 6 mm diameter balls. An appropriate amount of a liquid, for example ethanol, is added for lubrication. The mixture is milled for 1 to 12 hours, or for the time necessary to produce the particles described below. Depending on the mill used, the mill speed can be anywhere in the range of about 100 to about 1,000 rpm (typically around 300 rpm). After the joint deformation of the iron: ceramic mixture, the particles are removed from the mill and separated from the grinding balls, for example, by a sieve.

• The particles can be re-suspended in ethanol and homogenized to separate the particles from each other. The ethanol is removed, for example, by rotary evaporation, followed by drying in vacuo. Any drying technique can be used. The particles must be handled in such a way that they are protected from the oxidation of iron, for example, in a nitrogen environment. 20 After drying, the particles should be collected ^^ according to the appropriate size. For example, the particles can be passed through a 20 μm screen and collected in a cyclone to remove particles larger than 20 μm. The cyclone only collects particles of a certain size and density, providing a method for removing fines and loose ceramics.

The screened particles can be packaged under nitrogen and stored at room temperature. The particles can be sub-aliquoted in dosage units, for example, between 50 and 500 mg per dose, and can be further bathed with nitrogen, for example. The dose units can be sealed, for example, with butyl rubber stoppers and aluminum seals. The dose units can then • sterilize by appropriate sterilization techniques, for example, gamma irradiation between 2.5 and 4.0 Mrads. Other sterilization techniques can also be used, for example, heat drying and electron beam sterilization. When ready for use, or before packing, if the carrier is to be prepared with a pre-selected biologically active substance already adsorbed on it, about 50 to 150 5 mg (about 75 to about 100 mg is preferred) to ensure absolutely no adsorption) of the biologically active substance in solution is added to 1 gram of the carrier. When ready for application to a patient, the combination is suspended (for example, in 5 or 10 ml) of a biologically compatible liquid such as water or saline solution using normal procedures. Example 1 A composite particle consisting of silica gel and iron was manufactured and a preliminary characterization was carried out. The characterization included analysis of dimensions of fcfejS ^^^ faith * particle (light scattering technique), surface area, pore size analysis, electron examination microscopy and doxorubicin binding. The tests showed that 95% of the fine product has particles that are less than 1.11 μm and that it has a mean (volume) diameter of 0.92 μm. The results of the surface area analysis showed that the iron-silica gel compound had a total surface area • 48 m2 / g and a total pore volume of 0.19 cc / g. The SEM images reveal discrete particles made of both iron and silica gel components (Figures 1 and 2). The preliminary doxorubicin binding assays (Figure 4) show correlation between the concentration of bound (Q) and unbound (C) doxorubicin. • Example 2 A composite particle consisting of silica-C18 and iron was manufactured and a preliminary characterization was carried out. The characterization included analysis of particle dimensions (light scattering technique) and doxorubicin binding. The tests showed that 95% of the final product has particles that are less than 1.60 μm and that have a diameter • medium (in volume) of 1.58 μm. The preliminary doxorubicin binding assays (Figure 5) show correlation between the concentration of bound doxorubicin (Q) and unbound (C).

Link Doxorubicin for C18 Iron-Silica Compound 0 200 4G0 800 900 1000 C (unlinked) [ug DO iml solution) In order to be able to link a biologically active substance for objectified delivery, initially, the structure of the agent would be evaluated. Paclitaxiel, for example, contains three OH groups and three benzene rings. Using the information contained in Table 1, the link would be attempted using those derivatives for benzene rings and OH groups. First-line silica derivatives include silica alone, C8 and C18. Second line derivatives include phenyl, Cl, C2, C4 and C6. The additional silica derivatives would be tested based on the results of the experiments. The derivatives must be easily determinable by any technician in the material. Neoplastic agents can be especially useful with the particles of the invention. Examples of other useful neoplastic agents are exemplified in Table 2. Table 1: Examples of Functional Characteristics of Agents and Silica Derivatives j¿Í .Ar¡i.¿: ái.i¡át¿¿ - '«' > - "? ^ aa > ...- Jj¿. ^ .. ^ - j.

Table 2: Useful Agents in Neoplastic Disease . ^ »? ^ IaiMA? ^^^» .. ^ Mi ^ i.ia iM? Si ?? i. ^^ ¡í & j Agent Agent Name Commercial Name Abbreviation HORMONES AND INHIBITORS OF Estrogens Diethylbsbestrol DES HORMONES Conjugated Estrogens Premarin Estradiol Ethinyl Estinyl Androgens Testosterone Propionate TES Fluoxwpesterone Halotestine, Ora-testrilo, Utandran Progestins Caproate 17- Delautipa tiidroxiprogesterona Acetate Medroxyprogesterone Inetrose acetate Meeace Leuprolide Lupron Goserelin acetate Zoladex Adrenocorticosteroids Antiestrogens Synthesis inhibitors Aminoglutethimide Eliptene, Citadrene deHormone Antiadrogens • fcrf.jijfa- J-d- -i-J ..

Example 4 The adsorption capacities of the hydroxyapatite particles and the iron-hydroxyapatite composite particles were determined by a binding assay in doxorubicin. The Langmuir adsorption isotherms and the total drug loading capacities were calculated from the inverse of the slope of the isotherms. Figure 12 shows the isotherm for the iron-hydroxyapatite composite particles, which had a total capacity of 33 micrograms of doxorubicin per 0 milligram of particles. Figure 13 shows the isotherm for hydroxyapatite alone, which has a binding capacity of 53 micrograms of doxorubicin per milligram of particles. The The difference in the binding capacity of drugs between the hydroxyapatite and the iron-hydroxyapatite compound 5 is due to the difference in the compositions of these samples: the composite material of this example has -25% by weight of hydroxyapatite.

Isotherm of Langmuíi -J'i D.'JiarJi - 1"3 a7 is ¿u - ™ T3 is 18 -j 0 N 16 1 c •? • * O i t5 - 3 is 6 -. N is 5 - or * «4) 2 - u C? ^ C .ce -, &» • * Example 5 - Hydroxyapatite compound particles were loaded with doxorubicin by wetting the particles in a concentrated aqueous solution of the drug. The desorption profile was determined in a semi-dynamic assay by measuring the amount of doxorubicin released from the particles incubated in aliquots of human plasma at 37 ° C. Figure 14 shows that the drug is effectively released from the micro-particles as a function of time.

Amount Desoí ida vs. Time July 27, 1999 3S3S3 & ? ? sxr. 9 A s i 9 _ D a - O O M O w is 1 Ü 1 a I m • m * wrc; «< * 0i? ^ mU i w ptm? i MK Mß ^ to imWHHfl ln.RO it -matn.

US * S f »tßß SJS nt Time (minutes) 6 micro-particles of iron-hydroxyapatite were incubated with indium-111 in PBS for 30 min at 37 ° C and 1,400 rpm. The labeling efficiency was determined by comparing the amount of radioactivity in the incubation with bound radioactivity after two washes with PBS. The insertion in Figure 15 shows the resulting labeling efficiencies, which are approximately • 60% after the second wash. The stability of the labeled particles was tested in both PBS and human plasma at 37 ° C. For 0 each time point, the total activity of the sample was compared to the activity in the supernatant. After 12 days, the iron-hydroxyapatite microparticles in PBS retained more than 95% of indium-111 and the stability of the particles in • Plasma was around 90%. These results demonstrated that 5 microparticles are easily labeled with indium cation and that labeling is very stable in human plasma.

Time (h) *. laugh -. l Example 7 The previous experiment was repeated using an indium complex instead of the indium salt. The indium-111-oxyquinoline complex was used in the incubation step after being prepared by well-known methods. The efficiency and stability were determined as previously described and the results are shown in Figure 16. The labeling efficiency was increased over 90% after the second wash. The stability of the labeled micro-particles of indium-oxyquinoline is very similar to direct labeling, with more than 95% of the radioactivity still bound after 12 days in plasma. Thus, the indium complex can also be labeled directly in a very stable manner in the particles.

Time (h)

Claims

CLAIMS 1. A magnetically responsive composition comprising composite particles including iron and ceramic or their derivatives, where the ratio of ceramic: iron is in the range of about 1 to 95% ceramic to 5 to 99% iron, and where the diameter of each particle is from about 0.1 to 10.0 μm. • The composition of claim 1, wherein the ceramic comprises silica. The composition of claim 2, wherein the silica is a macroporous silica gel, having pores in the range of from about 2 to about 500 A. The composition of claim 2, wherein the • silica is derived with octadecylsilane, having pores in the range of from about 2 to about 500 A. The composition of claim 1, wherein the ceramic is hydroxyapatite. The composition of claim 5, wherein the hydroxyapatite has pores in the range of about 25 to about 1,200 Á. ^^ 7. The composition of claim 1, further comprising a biologically active agent selected from the group consisting of chemotherapy agents, radioisotopes, genetic materials, contrast agents, dyes, and their derivatives or combinations. 8. A set for administering a biologically active substance to a site in vivo in a patient comprising a unit dose of composite ferroceramic particles, where each particle has an iron to ceramic ratio in the range of about 99: 1 to 5:95. . 9. A set for administering a biologically active substance to a site in vivo in a patient who • comprises a receptacle containing: a) a unit dose of composite ferroceramic particles, each particle having an iron to ceramic ratio in the range of about 99: 1 to 5:95; and b) one or more dry excipients. (10. A set for administering a biologically active substance to an in vivo site in a patient comprising: a) a first receptacle comprising a unit dose of composite ferroceramic particles, each particle having an iron to ceramic ratio in the range from about 99: 1 to 5:95; and ^^ b) a second receptacle comprising an aqueous solution comprising one or more excipients. The assembly of claim 8, 9 or 10, wherein the excipients include a biologically compatible polymer for stabilization after the particles are combined with the aqueous solution. JsS-a-t - S ¿.5 12. The assembly of claim 8, 9 or 10, wherein the excipients include mannitol, sorbitol, carboxymethyl cellulose sodium, polyvinyl pyrrolidone or combinations thereof. The assembly of claim 8, 9 or 10, wherein the contents of the pool are combined with a commercially prepared formulation of a biologically active substance. 14. The assembly of claim 10, wherein the • aqueous solution comprises at least one buffer. 15. The assembly of claim 8, 9 or 10, wherein the unit dose of ferroceramic particles has been sterilized by means of gamma irradiation, dry heat or electron beam. 16. The assembly of claim 10, wherein the aqueous solution comprises that the excipients have been sterilized by autoclave means. The composition of claim 1, wherein the composition is sterilized by a method comprising the use of gamma irradiation. 18. A method for localized in vivo delivery of a biologically active agent, comprising: a) adsorbing a biologically active agent into a magnetically responsive carrier composition comprising composite iron and ceramic particles; b) injecting the carrier having the biologically active agent adsorbed into a patient; Y i.?.? r thdM ?? ^ Ét, c) establishing a magnetic field outside the patient and adjacent to the desired site, where the magnetic field is strong enough to guide and retain a portion of the carrier at the site. 19. The method of claim 18, wherein the step of injecting is intra-arterial. 20. The method of claim 18, wherein the desired site is a tumor. 21. The method of claim 18, wherein the biologically active agent 0 is selected from the group consisting of a diagnostic agent, a therapeutic agent, a bifunctional agent, and combinations thereof. •