Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-01-06
2002-11-19
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S443000, C424S448000, C424S445000, C424S447000
Reexamination Certificate
active
06482436
ABSTRACT:
FIELD OF INVENTION
This invention relates to compositions and methods for delivery of biocompatible particles to a selected location in a body, and, more particularly, relates to particles capable of carrying biologically active compounds, which provide for targeted magnetic transport of the particles and the maintenance of them in a predetermined place for localized diagnostic or therapeutic treatment of disease.
BACKGROUND OF THE INVENTION
Metallic carrier compositions used in the treatment of various disorders have been heretofore suggested and/or utilized (see, for example, U.S. Pat. Nos. 4,849,209 and 4,106,488), and have included such compositions that are guided or controlled in a body in response to external application of a magnetic field (see, for example, U.S. Pat. Nos. 4,501,726, 4,652,257 and 4,690,130). Such compositions have not always proven practical and/or entirely effective. For example, such compositions may lack adequate capacity for carriage of the desired biologically active agent to the treatment site, have less than desirable magnetic susceptibility and/or be difficult to manufacture, store and/or use.
One such known composition, deliverable by way of intravascular injection, includes microspheres made up of a ferromagnetic component covered with a biocompatible polymer (albumin, gelatin, and polysaccharides) which also contains a drug (Driscol C. F. et al.
Prog. Am. Assoc. Cancer Res
., 1980, p. 261).
It is possible to produce albumen microspheres up to 3.0 &mgr;m in size containing a magnetic material (magnetite Fe
3
O
4
) and the anti-tumoral antibiotic doxorubicin (Widder K. et al.
J. Pharm. Sci
., 68:79-82 1979). Such microspheres are produced through thermal and/or chemical denaturation of albumin in an emulsion (water in oil), with the input phase containing a magnetite suspension in a medicinal solution. Similar technique has been used to produce magnetically controlled, or guided, microcapsules covered with ethylcellulose containing the antibiotic mitomycin-C (Fujimoto S. et al.,
Cancer
, 56: 2404-2410,1985).
Another method is to produce magnetically controlled liposomes 200 nm to 800 nm in size carrying preparations that can dissolve atherosclerotic formations. 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).
The above compositions require extremely high flux density magnetic fields for their control, and are somewhat difficult to produce consistently, sterilize, and store on an industrial scale without changing their designated properties.
To overcome these shortcomings, a method for producing magnetically controlled dispersion has been suggested (See European Patent Office Publication No. 0 451 299 A1, by Kholodov L. E., Volkonsky V. A., Kolesnik N. F. et al.), using ferrocarbon particles as a ferromagnetic material. The ferrocarbon particles are produced by heating iron powder made up of particles 100 &mgr;m to 500 &mgr;m in size at temperatures of 800° C. to 1200° C. in an oxygen-containing atmosphere. The mixture is subsequently treated by carbon monoxide at 400° C. to 700° C. until carbon particles in an amount of about 10% to 90% by mass begin emerging on the surface. A biologically active substance is then adsorbed on the particles
This method of manufacturing ferrocarbon particles is rather complicated and requires a considerable amount of energy. Because the ferromagnetic component is oxidized due to the synthesis of ferrocarbon particles at a high temperature in an oxygen containing atmosphere, magnetic susceptibility of the dispersion obtained is decreased by about one-half on the average, as compared with metallic iron. The typical upper limit of adsorption of a biologically active substance on such particles is about 2.0% to 2.5% of the mass of a ferromagnetic particle.
The magnetically controlled particle produced by the above method has a spherical ferromagnetic component with a thread-like carbon chain extending from it and is generally about 2.0 &mgr;m in size. The structure is believed to predetermine the relatively low adsorption capacity of the composites and also leads to breaking of the fragile thread-like chains of carbon from the ferromagnetic component during storage and transportation.
Thus, there remains a need for an effective biocompatible composition which is capable of being transported magnetically, and which is relatively easy to manufacture, store and use.
SUMMARY OF THE INVENTION
This invention provides a magnetically responsive composition which may carry biologically active substances, or which may be used alone. Generally, any soluted substance can be carried, many of which have been heretofore suggested. For example, without limitation, alkylating agents, antimetabolites, antifungals, anti-inflammatory, antitumor, and chemotherapy agents, and suitable combinations thereof can be adsorbed on the particles. Other therapeutic agents and drugs, such as systemic toxicity inhibitors, antibiotics and hydrocortisone, or the like, can also be carried and administered in vivo by use of the magnetically controlled carrier particles of the invention. Methods of production and use thereof are also provided.
The aim of this invention is to improve some parameters of magnetically controlled compositions used for the targeted transport of biocompatible particles, including increasing relative adsorption capacity, increasing magnetic susceptibility, intensifying diagnostic and therapeutic effect and ease of use, as well as simplifying the technology of manufacturing the magnetically controlled composition and ensuring its guaranteed long storage without changing its desired characteristics.
This is achieved by using suitable composite,volume compounded ferrocarbon particles as a magnetically susceptible material for a magnetically controlled composition. These particles have a major dimension (i.e., largest diameter) of about 0.2 &mgr;m to about 5.0 &mgr;m (and preferably from 0.5 &mgr;m to 5.0 &mgr;m) and contain from about 1.0% to about 95.0% (by mass) of carbon, with the carbon strongly connected to iron. The particles-are obtained by jointly deforming (i.e., milling) a mixture of iron and carbon powders. In some cases the finished particles include trace amounts of the compound cementite (Fe
3
C).
The composition utilized for localized in vivo treatment of disease includes particles of about 0.5 &mgr;m and 5 &mgr;m in major dimension, each particle including carbon and iron and, optionally, a biologically active substance selected for its efficacy in diagnosing or treating the disease adsorbed on the particles.
The method of producing the composition includes the step of jointly deforming a mechanical mixture of iron and carbon powders for a time sufficient to bind the powders into a composite of iron:carbon particles having an average major dimension of less than 5 &mgr;m in size, and with a substantial portion of the particles including about 1.0% to 95.0% by mass of carbon distributed throughout the volume of each of the particles. The particles are preferably separated to select particles having a major dimension of from about 0.5 &mgr;m to about 5.0 &mgr;m, after which up to 20% by mass of the particles of a biologically active substance can be adsorbed onto the selected particles.
The methods of use include methods for localized in vivo diagnosis or treatment of disease comprising providing a magnetically responsive ferrocarbon carrier (such as the carrier of this invention) having adsorbed thereon a biologically active substance selected for its efficacy 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 to within a short distance from a body site to be treated and at a branch or branches (preferably the most immediate) to a network of arteries carrying blood to the site. The carrier is injected through the delivery means into the blood vessel. Just prior to inj
Allen Larry M.
Chernyakov Sergi V.
Dyuksherstnov Sergei D.
Kent Thomas B.
Volkonsky Viktor A.
FeRx Incorporated
Fish & Richardson P.C.
Page Thurman K.
Pulliam Amy E
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