CN1287859C - Magnetic targeted carrier composed of iron and porous materials for targeted delivery of biologically active agents - Google Patents
Magnetic targeted carrier composed of iron and porous materials for targeted delivery of biologically active agents Download PDFInfo
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- CN1287859C CN1287859C CNB008173796A CN00817379A CN1287859C CN 1287859 C CN1287859 C CN 1287859C CN B008173796 A CNB008173796 A CN B008173796A CN 00817379 A CN00817379 A CN 00817379A CN 1287859 C CN1287859 C CN 1287859C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
The cross reference of related application
The application is the American National stage of the International Patent Application PCT/US00/__ of 2000-10-13 submission, and the priority of the U.S. Provisional Application sequence 60/160,293 of 1999-10-18 submission is enjoyed in requirement.
Preamble
The present invention relates to bio-compatible particle is delivered to compositions, its manufacture method and the delivering method at selected position in the body, more specifically to a kind of granule that can deliver bioactive compound, grain orientation magnetic transmission is provided and holds it in predetermined position, as to the locating therapy agent of disease, diagnosis supplementary means or can also can be as the difunctional compositions of therapeutic agent as diagnostic agent.
The locus specificity of bioactivator is sent and will chemotherapeutical therapeutic activity is improved, and greatly reduces systemic side effects simultaneously.The magnetic carrier of processing various diseases was advised in the past and was used, and was included in the compositions that externally-applied magnetic field guiding and control are made a response down in vivo.(referring to people such as Lieberman, United States Patent (USP) 4,849,209; People such as Schroder, United States Patent (USP) 4,501,726; Chang, United States Patent (USP) 4,652,257; And Mirell, United States Patent (USP) 4,690,130).
A kind of known this based composition, can pass through the intravascular injection administration, comprise by ferromagnetism composition outside and coat the microsphere that a kind of bioavailable polymer (albumin, gelatin and polysaccharide) is formed, wherein also comprise medicine, (Driscol, people such as C.F., Prog.Am.Assoc.Cancer Res., 1980, p.261).
Can produce a kind of magnetic material (magnetic iron ore Fe that contains
3O
4) and the albumin microsphere (Widder, people such as K., J.Pharm.Sci., 68:79～82,1979) of the maximum 3.0 μ m sizes of antitumor antibiotics amycin.This kind microsphere generates through overheated and/or chemical modification in emulsion (Water-In-Oil) by albumin, and wherein this emulsion is suspended in the medical solution by the decentralized photo that contains magnetic iron ore and constitutes.A kind of similar techniques once was used to the microcapsule of the magnetic control system of producing or guiding, and its outside is coating the ethyl cellulose (Fujimoto, people such as S., Cancer, 56:2404～2410,1985) that contains the antibiotic Mitomycin-C.
Know a kind of magnetic control system liposome again, 200nm～800nm size can carry the preparation that a kind of solubilized atherosclerosis forms thing.This method can produce closing membrane structure (Gregoriadis G., Ryman B.E., Biochem.J., 124:58,1971) based on phospholipid in the presence of water.
These previously known compositionss not proof are always actual and/or effective.Often be to render a service not enough to the drug level that target site is sent.The enough conveying capacitys of many shortages in this based composition showed the magnetic field that weak susceptibility and/or its control need high flux density.In some cases, do not reach the particulate real location that to realize accurate locating therapy.Other shortcomings comprise that the said composition that combines antibody and peptide has non-specificity binding ability and non-Target organ is had toxicity, and drug diffusion is to based on beyond the desired position of the technology of injecting in the tumor.Some compositions is difficult to make or be prepared into the performance that does not change its regulation in consistent quality, sterilization and the storage.
Therefore, still exist the needs to a kind of effective biologically compatible composition at present, it can transport by magnetic, and makes, stores and use than being easier to.
A kind of compositions of suggestion comprises ferrum carbon (ferrocarbon) granule, as the magnetisable material in the magnetic control compositions.The particulate key dimension of this kind (that is, maximum gauge) is about 0.2 μ m～about 5.0 μ m (preferred 0.5 μ m～5.0 μ m), comprises about 1.0%～about 95.0% (quality) carbon, and wherein carbon and ferrum link together securely.This granule is that the mixture crosslinking fastening deformation (that is, grinding) by ferrum and carbon dust is produced.Referring to United States Patent (USP) 5,549,915,5,651,989,5,705,195 and U.S. Patent Application Serial Number 09/003,286 and 09/226,818, for referencial use in these receipts.
Application before this technology comes from the motivation that will make a kind of alloy that can't obtain by melting method.Be not that all alloys that can imagine all can prepare by fusion because the solubility limit of a kind of motlten metal in another kind can obtain the concentration of mixture.The ferrum carbon granule that grinds is to derive and come according to a kind of method of using for reference from the alloy manufacturing technology.Grinding technique is used to produce a kind of permanent connection and does not make them closely be mixed into a kind of alloy again through meticulously revising between two kinds of materials, otherwise will cause the two reduction or the elimination of magnetic moment and/or medicine carrying capacity.The idea that ferrum and carbon are combined by grinding is subjected to the inspiration of their natural miscibilities, as fusion method forms alloy.
Summary of the invention
Have now found that ferrum-ceramic particle can be by Ginding process production.This discovery is why wondrous to be because use the alloy of these materials never to show before this.Therefore, do not expected and between ferrum and pottery, can form a kind of lasting interface unexpectedly.
Ferrum-ceramic composite particle shows the huge versatility in conjunction with various medicine; Because medicine can be adsorbed on particle surface, so the combination of activating agent is easy to.In addition, ferrum-ceramic particle adopts the susceptibility metallic iron higher than ferrum oxide, thereby promotes and the convenient migration that arrives therapentic part.Have, the biocompatibility of pottery then is well-known again.
Bio-compatible and biodegradable ceramic materials based on hydroxyapatite and other calcium phosphate derived materials have been used as the bone replacing material in dentistry and bone surgery.Yet, be brand-new as the notion of the magnetic orientation ceramic material of carrier.The invention provides a kind of magnetically responsive composition that carries bioactive substance.Usually, ferrum-ceramic composite particle can be used for the targeted delivery of multiple bioactivator, diagnostic agent or difunctional compositions.Its production and using method also are provided.
The objective of the invention is to improve some parameter of the magnetic control compositions that is used for the directed transportation of bioactive substance, comprise: can in carrier granular, adopt the nature bone composition, expand applicable treatment of this technology and diagnostic area, improve relative absorbability and susceptibility, for example by the ionic group that can come binding compounds in a large number by ionic interaction is provided; Improve biocompatibility and biodegradable, strengthen diagnosis and therapeutical effect, simplify the manufacturing process of this magnetic control compositions, and guarantee that the condition of its characteristic that requires not changing is issued to the long-term storage performance of assurance.
This is by adopting a kind of suitable compound ferrum-ceramic particle to realize as the magnetisable material of magnetic control compositions.This granule is a disk and spheric, and about 0.1～10.0 μ m of diameter contains 1.0%～95.0% pottery (or deutero-pottery) and 5.0%～99.0% ferrum (by mass).They are to obtain by the uniting distortion (that is, grinding) of ferrum and ceramic powders.Absorption occurs in the surface of particle surface or modification, so medicine can utilize at any time and can be attached on the therapentic part.
Powder combines with solvent (for example, ethanol) in planetary ball (planetary ball) or grater.Subsequently, the composite powder of formation sieves and magnetic separation, thereby obtains the product fraction that requires and correspondingly obtain desired susceptibility.Bioactivator or diagnosis auxiliary agent are adsorbed or are deposited on this composite surface, and are taken by the patient with the suspended substance form of complex in sterile diluent.
Using method comprises interior level diagnosis of the body of disease or treatment,, provides a kind of magnetic response ferrum-ceramic monolith that is, is adsorbing a kind of bioactive substance according to its diagnosis or the selection of treatment disease effectiveness on it, then this vector injection is arrived in patient's body.For example, carrier can inject like this: be inserted into administration device in one section short distance of distance body part to be treated and be arranged in and lead to (preferably the most close) tremulous pulse to one or more bifurcation of the tremulous pulse network of this position blood supply.Carrier enters into blood vessel by administration device.Face before the injection, external, near the place at this position setting up magnetic field, its field intensity is enough to guiding and is injected in the carrier a large portion and this a large portion carrier is remained on this position.Preferably, magnetic field has to be enough to carrier is attracted to intensity in the soft tissue that closes on blood vessel network, thereby avoids these than the basic thromboembolism of any velamen carrier granular in the trunk.For example, for referencial use in these receipts referring to, U.S. Provisional Application sequence 60/160,293.
Therefore, the purpose of this invention is to provide a kind of high magnetically responsive composition, be used for randomly carrying bioactive substance, and production method and purposes.
Another object of the present invention provides a kind of magnetic response carrier that is used for bioactive substance, and it has high magnetic response degree (responsiveness), but and durable between storage and operating period.
Another object of the present invention provides a kind of magnetically responsive composition, and it comprises the granule of about 0.1～10.0 μ m of diameter, and each ferrum-ceramic particle contains 1.0%～95.0% pottery (or ceramic derivant) and 5.0%～99.0% ferrum, by mass.
Another object of the present invention provides a kind of compositions that is used for interior level diagnosis of disease body or treatment, it comprises the carrier with the compound ferrum-ceramic particle of about 0.1～10.0 μ m of diameter, each ferrum-ceramic particle contains 1.0%～95.0% pottery (or ceramic derivant) and 5.0～99.0% ferrum, by mass, and have and be adsorbed on its lip-deep optional bioactive substances that one or more are selected according to the effectiveness in disease specific diagnosis and/or the treatment.
These and other purpose, it is fully aware of to become after those skilled in the art have studied carefully hereinafter, therefore the invention reside in a kind of substantially such as hereinafter description, and more specifically by the neotectonics of claims regulation, combination and the arrangement and the method for each several part, wherein to know, still exist various variations in the disclosed invention specific embodiments here, these variations all should be included in the present invention, because they all drop within the scope of claim.
The accompanying drawing summary
Fig. 1 is the enlarged photograph (1000 times) of compound ferrum-silica dioxide granule.
Fig. 2 is the enlarged photograph (3000 times) of compound ferrum-silica dioxide granule.
Fig. 3 is the flow chart of production method of the present invention.
Fig. 4 is the binding curve of ferrum-silica gel compound to amycin.
Fig. 5 is the binding curve of ferrum-C18 complex to amycin.
Fig. 6 is the scanning electron microscope microphotograph of showing ferrum-hydroapatite particles form.
Fig. 7 is and the same photos of Fig. 6, but by backscatter ferrum is shown as white and hydroxyapatite is shown as black.
Fig. 8 is a particulate spectrum shown in Figure 6, and the confirmation white macula is made up of ferrum.
Fig. 9 is a particulate spectrum shown in Figure 6, and the confirmation black speck is made up of hydroxyapatite.
Figure 10 adopts light scattering technique to grain size analysis that hydroapatite particles is done.
Figure 11 is the ferrum-hydroxyapatite microparticle susceptibility curve that adopts the magnetometer technology to obtain.
Figure 12 is the langmuir isotherm of ferrum-hydroxyapatite.
Figure 13 is the langmuir isotherm of hydroxyapatite (iron-free).
Figure 14 is the amycin desorption curve of ferrum-hydroxyapatite.
Figure 15 displaying is carried out labelling by directly hatching with 111 pairs of ferrum-hydroapatite particles of indium, and the stability in different medium.
Figure 16 displaying is carried out labelling with indium 111/ oxyquinoline to ferrum-hydroapatite particles, and the stability in different medium.
Detailed Description Of The Invention
The present invention is a kind of composite particles, is made up of 1.0%～95.0% pottery (or ceramic derivative) and 5.0～99.0% iron, by mass. When composition have be less than 1.0% ceramic the time, the binding ability of particle will be reduced to the point that does not basically have ability to carry bioactivator. When the ceramic content of composition greater than 95.0% the time, magnetic susceptibility will be reduced to beyond the effective range that guides in vivo bioactivator usually. This particle is disk and sphere, diameter 0.1～10.0 μ m.
Term " pottery " refers to a kind of natural or synthesizing porous, sorptive material. It generally is but not necessarily oxide or mixed oxide that wherein oxide is metal or nonmetallic. It generally is but inorganic matter not necessarily. It generally is but non-crystalline structure not necessarily. The example of synthesize ceramic material includes but not limited to, tricalcium phosphate, hydroxyapatite, aluminium hydroxide, aluminium oxide, aluminum phosphate calcium, calcium phosphate dibasic dihydrate, tetracalcium phosphate, macropore three calcium phosphate phases, calcium carbonate, bloodstone, bone meal, apatite wollastonite glass ceramics and other potteries or glass matrix. Also comprise the polymer with the certain degree of crystallinity that can support hole and absorption. The example of this base polymer includes but not limited to polyethylene, polypropylene and polystyrene. The suitable material that meets these parameters will be apparent to those skilled in the art. The tabulation of example below.
| Oxide | Nonmetal | Amorphous | |
| Silica hydroxyapatite zeolite aluminium oxide diamond | Whether be | Whether noly be | Whether |
Also have silica and the silica derivative that are included in " pottery " definition (include but not limited to: octadecylsilane [C18], octyl group silane [C8], hexyl silane [C6], phenyl silane [C6], butyl silane [C4], γ-aminopropylsilane [NH3C
3], cyano group nitrile silane [CN], trimethyl silane [C1], sulphoxylic acid (sulfoxyl) propyl silane [SO4C
3], dimethylsilane [C1], acid cation-exchange coating [SCX], basic quaternary ammonium anion exchange coating [SAX], dihydroxypropyl silane [diol], make diameter between the composite particles of 0.1～10.0 μ m). As an example, following silica can be used for making composite of the present invention.
Eka Nobel Kromasil
| Filler | Grain shape and size (μ m) | Aperture () | Pore volume (ml/g) | Surface area (m2/g) | Carbon carrying (%) | Facies type | In conjunction with phase coverage rate (μ mol/m2) | End-block |
| Kromasil Silica Kromasil C1 Kromasil C4 Kromasil C8 Kromasil C18 | S，5，7，10，13，16 S，5，7，10，13，16 S，5，7，10，13，16 S，5，7，10，13，16 S，5，7，10，13，16 | 100 100 100 100 100 | 0.9 0.9 0.9 0.9 0.9 | 340 340 340 340 340 | - 4.7 8 12 19 | (elementary analysis) monomer monomer monomer monomer | 4.3 3.7 3.6 3.2 | -be |
EM Science
| Filler | Grain shape and size (μ m) | Aperture () | Pore volume (ml/g) | Surface area (m2/g) | Carbon carrying (%) | Facies type | In conjunction with phase coverage rate (μ mol/m2) | End- |
| Lichrosorb Si | ||||||||
| 60
| I，5，10 I，5，10 I，5，10 I，5，10 I，5，10 S，3，5，10 S，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S.5 S，5 S，3，5 S，5 S，5 S，5 S.5 S，5 S，5 S，10 | 60 100 60 60 60 60 100 60/100 60-100 100 100 100 100 100 60 150 150 100 150 100 150 100 150 80 100 | - - - - 0.7 0.95 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 0.9 - - - - - - - - - - | 550 420 150 - 550 650 420 350 350 350 350 350 350 350 360 320 320 450 320 450 320 450 320 450 350 | 0 0 16.0 9.0 12 0 0 12.5 13 21.4 21.5 - 4.5 8.3 12.0 0 18.5 15 10.5 10 10 10 7.5 16 14 | --monomer monomer------------the monomer monomer monomer monomer monomer monomer monomer monomer- | - - 1.55 0.78 2.5 0 0 4.1 4.2 3.9 - - 3.8 4.0 3.2 - 3.23 - 3.27 - 2.77 - 3.77 - - | Noly whether noly whether be---whether be-be- |
vydac/The Separations Group
| Filler | Grain shape and size (μ m) | Aperture () | Pore volume (ml/g) | Surface area (m2/g) | Carbon carrying (%) | Facies type | In conjunction with phase coverage rate (μ mol/m2) | End-block |
| Vydac 201TP C18 Vydac 218TP C18 Vydac 214TP C4 Vydac 201HS C18 | SD，5，10 SD，5，10 SD，5，10 S，5，10 | 300 300 300 80 | 0.6 0.6 0.6 0.8 | 90 90 90 450 | 8 8 3 13.5 | Polymer poly compound polymer- | 4.16 4.16 4.89 1.53 | Be- |
Waters
| Filler | Grain shape and size (μ m) | Aperture () | Pore volume (ml/g) | Surface area (m2/g) | Carbon carrying (%) | Facies type | In conjunction with phase coverage rate (μ mol/m2) | End-block |
| μBondapak C18 μBondapak Phenyl μBondapak NH2 μBondapak CN μPorasil Silica Novapak C18 Novapak Phenyl Novapak CN Novapak Silica Resolve C18 Resolve C8 Resolve CN Resolve Silica Spherisorb Silica Spherisorb ODS-1 Spherisorb ODS-2 Spherisorb C8 Spherisorb C6 Spherisorb Phenyl Spherisorb CN Spherisorb NH2 Spherisorb SAX Spherisorb SCX Symmetry | I，10 I，10 I，10 I，10 I，10 S，4 S，4 S，4 S，4 S，5，10 S，5，10 S，5，10 S，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，3，5，10 S，5，10 S，5，10 S | 125 125 125 125 125 60 60 60 60 90 90 90 90 80 80 80 80 80 80 80 80 80 80 100 | 1.0 1.0 1.0 1.0 1.0 0.3 0.3 0.3 0.3 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 - | 330 330 330 330 330 120 120 120 120 175 175 175 175 220 220 220 220 220 220 220 220 220 220 340 | 10 8 3.5 6 - 7 5 2 0 10 5 3 0 0 7 12 6 6 3 3.5 2 - - 19 | Monomer--------------the monomer monomer monomer monomer monomer monomer monomer--- | 1.46 2.08 - 1.91 2.86 - 3.41 2.34 1.65 0 2.76 2.58 2.53 0 0 1.47 2.72 2.51 2.27 1.08 2.37 1.58 - - 3.09 | That whether no no part is part is no no-be |
YMC
| Filler | Grain shape and size (μ m) | Aperture () | Pore volume (ml/g) | Surface area (m2/g) | Carbon carrying (%) | Facies type | In conjunction with phase coverage rate (μ mol/m2) | End-block |
| C18-A C18-AM ODS-AQ C8 Phenyl C4 Basic | S，3，5，7，10，15+ S，3，5，7，10，15+ S，3，5，7，10，15+ S，3，5，7，10，15+ S，3，5，7，10，15+ S，3，5，7，10，15+ S，3，5，7，10，15+ | 120 120 120 120 120 120 - | 1.0 1.0 1.0 1.0 1.0 1.0 - | ～300 ～300 ～300 ～300 ～300 ～300 - | 17 17 16 10 9 7 - | The monomer monomer monomer monomer monomer monomer monomer | - - - - - - - | Be |
Annotate: in conjunction with the calculating of phase coverage rate according to Sander, L.C. and Wise, S.A., Anal, Chem., 56:504～510,1984. Material behavior is obtained by the document that material maker or its authorised representative deliver.
At liquid, existence mixes powder down in planetary ball or grater such as ethanol, thereby has suppressed the oxidation of iron. This liquid also can be used as the lubricant during iron and the ceramic powders grinding, in order to produce appropriate size distribution. It also can reduce the compacting of pottery during processing. As a result, the porous of pottery in composition is maintained, thereby makes the adsorption capacity of particle reach maximum.
Mixture is put in the planetary ball of standard laboratory, in the grater of the sort of type of perhaps using in the powder metallurgy. Grinding-in is for the tank that the different metal or metal alloy ball of iron and ceramic powders, ethanol and diameter is housed. For example, this mill can have the 6mm diameter ball that is made of case-hardened metal carbides. Add an amount of liquid (such as, ethanol) lubricate. Decide on employed type, this mill is with speed running 2～14h of 100rpm～1000rpm. Be sure of when the speed of mill surpasses 1000rpm, will produce the not excessively granule of desired number. Suitable liquid and grinding condition can be determined easily by those skilled in the art.
Iron-ceramic mixture is united after the distortion, and particle takes out from mill and by separating with mill ball such as coarse filter. This particle can be re-suspended in the ethanol and homogenizing, in order to particle is separated from each other. Remove ethanol, for example by rotary evaporation, accept subsequently vacuum drying. Any suitable dry technology all can use, for example in vacuum drying oven (nitrogen blowing). In the particle operation, should note protecting its iron to avoid oxidation, for example in nitrogen environment, carry out.
Subsequently, the dry powder that is obtained is sieved or magnetic separation, so as to obtain to provide the susceptibility of requirement and treatment or diagnosis binding ability require the product fraction.Then, the glove box inner packing of product under nitrogen purging becomes various dosage units and finally sterilizes.Any suitable disinfection technology all can use.For example, ferrum-ceramic particle can adopt the gamma-radiation sterilization; The excipient aqueous solution can adopt the autoclave sterilization.
Face when using, allow one or more bioactivators absorption or be deposited on this composite.The composite that has adsorbed activating agent gives the patient with the suspended substance form in sterile diluent.
This ferrum-ceramic particle can be used as carrier from the control in magnetic field externally to particular body portion that send the bioactive substance of one or more absorption under.Here employed term " bioactive substance " comprises in the body with medical diagnosis and/or therapeutant.
Bioactive substance includes but not limited to, antineoplastic agent, blood products, biological respinse modifier, antifungal agent, antibiotic, hormone, vitamin, protein, peptide, enzyme, dyestuff, antiallergic agent, anticoagulant, circulation agent, metabolism reinforcing agent, antitubercular agent, antiviral agents, anti-anginal drug, antibiotic medicine, antiprotozoal, antirheumatic, anesthetis, Opiate, diagnostic imaging agent, cardiac glycoside, neuromuscular blocking agent, tranquilizer, anesthetis, and paramagnetic and radioactive granule.The other biological active substance can include but not limited to monoclonal or other antibody, natural or synthetic hereditary material and prodrug.
Term used herein " hereditary material " refers generally to nucleotide and polynucleotide, comprises the RNA and the DNA in nucleic acid, natural or synthetic source, comprises reorganization, meaningful (sense) and antisense RNA and DNA.The type of hereditary material for example can comprise the expression vector genes carried, for example plasmid, phasmid, cosmid, yeast artificial chromosome and defective (assisting) virus, antisensenucleic acids, list and double-stranded RNA and DNA and analog thereof.Also comprise protein, peptide and other molecules that forms by the expression of hereditary material.
For realizing the in-vivo diagnostic imaging, the detection instrument type of various available commercial is to select given radioisotopic principal element.Selected radiosiotope must be its attenuation type can given type instrument detect the sort of.Generally require gamma-radiation.Key factor during another selective emission isotope is that its half-life is answered long enough, so that maximum its still detectable the obtaining of the moment taken in of target, but should enough lack, so that as far as possible little to host's harmful radiation.Appropriate radioisotopic selection is easy to clear and definite to those skilled in the art.Spendable radiosiotope includes but not limited to
99mTc,
142Pr,
161Tb,
186Re and
188Re.In addition, the exemplary of other chemical compounds that can be used for diagnosing is metal ions, includes but not limited to
111In,
97Ru,
67Ga,
82As,
89Zr and
201TI.Have again, include but not limited at the paramagnetic element that is particularly useful aspect magnetic response imaging and the electronics rotation response technology
157Gd,
55Mn,
162Dy,
52Cr and
56Fe.
It should also be noted that radiosiotope also can be used for radiation therapy technology.Usually, α and β ray be considered to the treatment on be useful.The example of treatment chemical compound includes but not limited to
32P,
186Re,
188Re,
123I,
125I,
90Y,
166Ho,
153Sm,
142Pr,
143Pr,
149Tb,
161Tb,
111In,
77Br,
212Bi,
213Bi,
223Ra,
210Po,
195Pt,
195MPt,
255Fm,
165Dy,
109Pd,
121Sn,
127Te and
211At.Radiosiotope generally exists as the group in a kind of salt, however the direct ingestion of iodine of some tumor and thyroid.Useful diagnosis and radiotherapy isotope can uses also capable of being combined separately.
This ferrum-ceramic composite particle surpasses the metallic iron that invention part in the past is that its employing has the susceptibility that is higher than ferrum oxide, thereby promotes and convenient migration to therapentic part.The advantage of comparing with present ferrum carbon joint product comprises the multipurpose of surface combination, and the biocompatibility and the biodegradability of pottery, and the back has been well-known comparatively speaking a bit.
As universal law, the adsorbance of any water-soluble biological active substance can be brought up to and is up to the about 50% of composite particles quality by improving the ratio of pottery in granule, and can not lose the effect of this granule in the described therapy of the application.Observe in many cases, the adsorbance of bioactive substance is along with the increase of ceramic content is linear increase substantially.Yet, along with the increase of ceramic content, the susceptibility of composite particles or the response in magnetic field descended, its in vivo controlled condition thereby worsen (although absorbability increase) thereupon.Therefore, need be at ferrum: obtain a kind of balance on the ceramic ratio, so that treatment that is improved or diagnosis effect.For increasing the amount of reagent that gives in the therapeutic scheme, can allow the patient take more heavy dose of granule, but these granules can't be stronger by increasing the dosage magnetic that becomes.Appropriate ratio can be determined by those skilled in the art.
Now confirm, as the described interior therapeutic granule of the application, its ferrum: the useful scope of ceramic ratio, generally speaking, and between about 99: 1～about 5: 95, for example about 80: 20～about 60: 40.Can be adsorbed on the compound ferrum of any given ceramic content: the maximum of the bioactive substance in the ceramic monolith granule will be along with the chemical property of bioactive substance, and in some cases, changes with the Types of Pottery that uses in the said composition.Those skilled in the art can determine the appropriate ratio of the purposes that requires.
Preparation and sale dried forms carrier granular are more convenient, so excipient can be made into dried forms, so one or more dried excipient will be packaging together with the unit dose carrier granular.There are various excipient to use, for example are used for improving absorption or desorbing, perhaps increase dissolubility.The type of appropriate dried excipient and consumption can be determined according to the chemical property of bioactive substance by those skilled in the art.Most preferably preparation comprises the form of the bag or the test kit of dried excipient and dried carrier granular, prepare to mix mutually with a content that unit dose drug and q.s bio-compatible aqueous solution such as brinish phial are housed, as pharmaceutical factory advise, thereby with modification of drug to medicinal desired concn.Contain the solution of this dilution medicine and comprise that dry ingredients (promptly, dried carrier granular and dried excipient) the test kit content mix after, medicine just is adsorbed onto on the carrier granular, thereby but forms a kind of magnetic control compositions that comprises the suitable interior therapeutic or the diagnostic uses of the therapeutic dose bioactive substance that is adsorbed on the carrier granular.
Alternatively, can use the liquid reagent box.Carrier granular is installed in as a unit, and for example in the phial, above-mentioned excipient then is contained in another unit with the aqueous solution form.When administration, the ferrum ceramic particle mixes mutually with the content that contains a unit dose drug and q.s bio-compatible aqueous solution such as brinish phial, as pharmaceutical factory's suggestion, thereby modification of drug is arrived medicinal desired concn.Subsequently, formed, surface adsorption the granule of bioactive substance, be mixed with each other with another unit that comprises aqueous solution form excipient.Any suitable disinfection technology all can use.For example, the ferrum ceramic particle can adopt the gamma-rays sterilization; The aqueous solution of excipient can adopt the autoclave sterilization.If use autoclave, undesirable oxidation can take place in the ferrum ceramic particle.
Also have, when preparing absorption or deposit to the bioactivator water soluble medium that microparticle gets on, the buffer agent of use may exert an influence to whole combination.Those skilled in the art can determine only buffer agent.
Being adsorbed onto the diagnosis of the bioactive substance that carrier granular gets on or therapeutic dose will be by those skilled in the art as to specified disease or situation reaches diagnosis or the needed amount of therapeutical effect is determined, to consider variety of factors therebetween, for example weight in patients, age and general health situation, the diagnosis of medicine or curative properties, and the character of disease and the order of severity.
When the employed carrier granular of definite any particular treatment situation is big or small, relate to many Considerations.Inherent various technical limitations in the particulate production of undersize 0.2 μ m are partly depended in the selection of granularity.In addition, magnetic control system and the carrying capacity of granule in blood flow less than about 1.0 μ m sizes will descend.May be tending towards causing during the injection than coarsegrain and wish or undesirable blood vessel embolism, both may because of mechanical reason also may be because of impelling by due to the physiological Mechanism formation grumeleuse.This dispersion may be solidified, thereby makes injection become more difficult, and bioactive substance might weaken from the desorbing on the granule in the target pathology school district.Ferrum produces the form on a kind of irregularly shaped particles surface with the mixture abrasive method (described for example) of ceramic powders, and generating a kind of average key dimension is the particle swarm of about 0.1 μ m～about 5.0 μ m.
Because the ferrum in the granule described in the invention is not the form of iron oxide as some previously disclosed magnetic control system dispersion situation, thus the susceptibility of ferrum ceramic particle, or response, remain on a high level.
This ferrum: ceramic particle available iron granule characterizes with combining of ceramic particle.These two kinds of compositions keep independent separately body.The particulate feature structure of this kind that forms in the associating deformation process of ferrum and ceramic powders mechanical impurity is compared the susceptibility that also can improve ferrum inclusion in the ferrum ceramic particle with the ferrum granule with other types structure.
Because ceramic deposit has huge surface in this granule, therefore with respect to particulate ceramic segment, adsorbed bioactive substance can account for about 100 ± 50wt%, or accounts for the about 5%～95% of primary particles quality, most preferably 15%～60%.Describe in another way, this can be the bioactive substance that is adsorbed up to the about 200mg of every gram granule.Therefore, in use, for reaching carrier that the given dose bioactive substance need inject with much less, perhaps alternatively, per injection can obtain to compare with the situation of some existing carrier the higher bioactive substance of dosage.
The method of producing a small amount of ferrum ceramic composition of the present invention is described below, but will knows, except grinding, also can imagine the distortion of uniting that reaches ferrum and ceramic powders with other means and mechanism, produce requisite initial element as long as comprised carrier.The program that is adopted applies mechanical pressure to pottery and ferrum granulate mixture, thereby makes the ferrum particle deformation and produce a kind of firm substructure that can catch pottery.The formation of ferrum ceramic particle is not heat to realize under the situation of (although during the mechanically deform step mixture heating) and implement in the presence of the liquid such as ethanol during processing, so that suppress the oxidation of ferrum and the particulate cleaning (aseptic) that assurance is produced.This liquid also can play lubricant during the grinding of ferrum and ceramic powders, and can reduce the compacting of pottery during the processing.As a result, ceramic sedimental density is maintained in the compositions, thereby obtains maximum granule absorbability.
Along with granule and pottery unite distortion continue carry out, produce a kind of third phases of forming by ferrum and ceramic molecule mixture at two kinds of solid interfaces.This interface makes granule reach stable, stands to disinfect and in vivo use with activation.Estimate the ferrum granule of interface, form, because the molecule mixture of ferrum and carbon is present in occurring in nature or can for example cementite (cementite) and steel form by fusion as the ferrum carbon granule by other types.The ferrum ceramic mixture is not well-known or makes easily, and therefore a kind of molecule mixture may be present in the interface of two kinds of materials.
For example, for producing average ferrum: the granule of ceramic ratio about 75: 25 (quality), mix the ferrum granule of the substantially pure of a average diameter 0.1 μ m～5 μ m sizes with the ceramic particle (representative diameter is about 0.1 μ m～5.0 μ m) of the substantially pure of about 0.1～1.0 weight portion.The ferrum granule acutely mixes with the ceramic particle process, reaches the fine distribution along whole volume.Every kind of bioactive substance should be assessed one by one according to various dissimilar potteries, to determine best reversible ceramic combination.Such as other potential competition chemical substances in factors such as pH, temperature, granularity, salt, solution viscosity and the solution, all may influence absorbability, speed and desorbing parameter.
This mixture is put in the grater of the sort of type of using in planetary ball of standard laboratory or the powder metallurgy.For example, this mill can have the ball of 6mm diameter.Add appropriate amount of fluid, as ethanol, so that lubricated.Mixture grinds 1～12h, perhaps grinds one section and can produce the needed time of granule described above.Type on employed mill is decided, and the speed of mill can be between about 100rpm～about 1000rpm (representative value be about 300rpm).
Ferrum: ceramic mixture is united after the distortion, and granule takes out from mill and separates with mill ball, for example passes through coarse filter.This granule can be resuspended in the ethanol and carry out homogenize, so that granule is separated from each other.Drive ethanol out of, for example, carry out vacuum drying subsequently by rotary evaporation.Any suitable dry technology all can use.Granule should be subjected to protection against oxidation when operation, for example carry out in nitrogen environment.
After the drying, granule should be collected according to suitable size.For example, this granule can sieve by 20 μ m, and is collected in the air cyclone separator, to remove the granule greater than 20 μ m.Cyclone separator is only collected the granule of certain size and density, thereby a kind of method of removing tiny and loose pottery is provided.Room temperature can be packed and be stored in to granule after sieving under nitrogen protection.
Granule can carefully be divided into dosage unit again, and for example 50～500mg is every dose, and can, for example further cover with nitrogen.Each dosage unit can seal, and for example uses butyl rubber stopper and aluminum crimps.Then, these dosage units adopt suitable disinfection technology to carry out disinfection, and for example use the gamma-rays of 2.5～4.0Mrad.Other disinfection technologies also can use, and for example do the sterilization of heating and electron beam.
When preparing to use, perhaps if plan when preparing carriers is good the words of having adsorbed the bioactive substance of preliminary election on it, then before packing, the solution form of about 50mg～150mg (preferably about 75mg～about 100mg is so that definitely guarantee maximum adsorption) bioactive substance is added in the 1g carrier.When preparing to be used for the patient, combinations thereof adopts conventional program to put into becomes suspended substance (for example, 5～10ml) in bio-compatible liquid such as water or the saline.
Make a kind of composite particles of forming by silica gel and ferrum, and carry out Preliminary Identification.Evaluation comprises the combination of grain graininess analysis (light scattering technique), surface area, hole dimension analysis, scanning electron microscopy and amycin.Result of the test shows that the granule that 95% finished product has is less than 1.11 μ m, and average (by volume) diameter is 0.92 μ m.The surface area analysis result shows that the total surface area of ferrum-silica gel compound is 48m
2/ g; Total pore volume is 0.19cc/g.The SEM photo discloses the discontinuous granule (Fig. 1 and 2) that is become to be grouped into by ferrum and silica gel.Preliminary amycin shows in conjunction with (Q) and the relation that does not combine between (C) doxorubicin concentration in conjunction with test (Fig. 4).
Make a kind of composite particles of forming by silicon dioxide-C18 and ferrum, and carry out Preliminary Identification.Evaluation comprises the combination of grain graininess analysis (light scattering technique) and amycin.Result of the test shows that the granule that 95% finished product has is less than 1.60 μ m, and average (by volume) diameter is 1.58 μ m.Preliminary amycin shows in conjunction with (Q) in conjunction with test (Fig. 5) and has linear relationship with not combining between (C) doxorubicin concentration.
For the binding bioactive material to reach targeted delivery, at first the structure of medicament is assessed.For example, paclitaxel comprises three-OH group and three phenyl ring.Utilize the information in the table 1, will attempt to utilize those derivants come in conjunction with phenyl ring and-the OH group.One line silica derivative will comprise naked silicon dioxide, C8 and C18.The line derivant will comprise phenyl, C1, C2, C4 and C6.Other silica derivative will be checked according to these experimental results.These derivants can be determined easily by those skilled in the art.Oncology pharmacy cooperates with granule of the present invention and is particularly useful.The example of the oncology pharmacy that other are useful exemplifies in table 2.
Table 1: the sense feature of medicament and the example of silicon derivative
| The sense feature | Be used for bonded potential silica derivative |
| -OH group | Naked silicon dioxide |
| Open-chain structure | Naked silicon dioxide |
| Phenyl ring | C8，C18 |
| Long-chain alkane | C8，C18 |
| Positive charge | Cation exchange (that is sulfoxyl (SO, 4) carboxyl, SCX) |
| Negative charge | Anion exchange (that is, quaternary ammonium (SAX), diethyllaminoethyl) |
| The mixture of ring and-OH group | Phenyl, C1, C2, C4, C6 |
Table 2: the medicament that tumor disease uses
| Medicament | The medicament title | Trade name | Abbreviation | |
| Alkylating agent | Chlormethine | Machlorathamine cyclophosphamide ifosfamide phenyalamine mustard chlorambucil | Mustargen，nitrogen mustard Cytoxan，Endoxan Ifex Melphalan，AIkeran Lukeran | HN 2 CTX IFS L-PAM CLR |
| Aziridine derivative | Triethylene thiophosphoramide | Thiotepa | T-TEPA | |
| Alkyl sulfonic ester | Busulfan | Myleran | MYL | |
| Nitroso ureas | Cyclohexyl-chlorethylnitrosourea 1, two [2-chloroethyl] the nitroso ureas streptozotocin semustines of 3- | Lomustine，CEENU Carmustiue，BiCNU Zanosar | CCNU BCNU STZC | |
| Triazenes | Dimethyl triazenyl Imidazole carboxamide | Dacarbazine | DTIC | |
| Antimetabolite | Folacin | Methotrexate | Amethopterin | MTX |
| Pyrimidine analogue | 5-fluoro-2-uracil deoxyriboside 5-fluorouracil cytosine arabinoside | Floxuridine Cytarabine.Cytosar | FUDR 5-FU ARA-C | |
| Purine analogue | Ismipur 6-thioguanine Deoxycofomycin | Purinethol Thioguanine Pentostatin | 6-MP 6-TG VM-26 | |
| Natural or semi-synthetic product | Vinblastine | The vincaleucoblastine vincristine | Velban Oncovin | VLB VCR |
| Antibiotic | Adriamycin mitoxantrone Baunombicin bleomycin dactinomycin D mithramycin mitomycin C | Adriamycin Novantrone Daunomycin Blenoxane Actinomycin D，Cosmegen Mithracin Mutamvcin | ADR NDV DNR BLEO - - MITO-C MMC | |
| Taxane | Paclitaxel | Taxol | TXL | |
| Enzyme | The altheine enzyme | Elspar | L-ASP | |
| Epipodophyllotoxin | The etoposide teniposide | Vepesid Vumon | VP-16 VM-26 | |
| Other | Platinum coordination complex | Suitable-diamidogen dichloro network platinum II Carboulatin | Cisplatin，Platinol Paraplatin | CDDP CBP |
| The urea that replaces | Hydroxyurea | Hydrea | HXU | |
| The methyl hydrazine derivant | Procarbazine | Matulane | PROC | |
| Acridine derivatives | Amsacrine | Emcyt Amsidyl | m-AM | |
| Medicament | The medicament title | Trade name | Abbreviation | |
| Hormone and hormone inhibitors | Estrogen | Diethylstilbestrol conjugated estrogen hormone class ethinylestradiol | Premarin Estinyl | DES |
| Androgen | The testosterone propionate fluoxymesterone | --- Halotestin，Ora-Testryl， Utandran | TES | |
| Prohormone | 17-hydroxyprogesterone alkyl caproate acetic acid medroxyprogesterone acetic acid Meeestrol | Delalutin Provera Meeace | ||
| Leuprorelin | Goserelin acetate | Lupron Zoladex | ||
| The thyroliberin class | Prednisone | |||
| Anti-estrogens | Tamoxifen | Nolvadex | ||
| The hormone synthetic inhibitor | Aminoglutethimide | Elipten，Cytadren | ||
| Anti-androgens | Flutamide | Eulexin | ||
Embodiment 4
By amycin in conjunction with test determine hydroapatite particles and ferrum-hydroxyapatite composite particles absorbability.Determined langmuir isotherm according to amycin binding data under several concentration, and calculated total medicine bearing capacity by the inverse of isothermal line slope.Figure 12 shows the isothermal line of ferrum-hydroxyapatite composite particles, and particulate total capacity is every milligram of granule 33 μ g amycin.Figure 13 shows the isothermal line of independent hydroxyapatite, and its binding ability is every milligram of granule 53 μ g amycin.Medicine binding ability difference between hydroxyapatite and the ferrum-hydroxyapatite composite material is because due to the difference of forming in these samples: the composite of present embodiment has about 25wt% hydroxyapatite.
Langmuir isotherm
Ferrum-hydroxyapatite composite particles loads amycin by granule is immersed in the medicine fortified aqueous.Desorption curve is in half-dynamic test, and the amycin quantity that granule discharged after hatching in 37 ℃ the five equilibrium human plasma sample determines by being determined at.Figure 14 shows that as the function of time, medicine is by discharging effectively on the microparticle.
The desorption quantity vs. time
On July 27th, 1999
Embodiment 6
Ferrum-hydroxyapatite microparticle is hatched 30min with indium 111 in 37 ℃ of PBS (phosphate-buffered saline), under the 1400rpm condition.By radioactive size in hatching and with twice bonded radioactive comparison afterwards of PBS washing, determine labeling effciency.Illustration among Figure 15 shows the labeling effciency that obtains, through it is approximately 60% after twice washing.The particulate stability of labelling is all tested in 37 ℃ PBS and human plasma.Compare the gross activity of each moment sample and the activity in the supernatant.After 12 days, the ferrum among the PBS-hydroxyapatite microparticle has kept the indium 111 more than 95%; Particulate stability in the blood plasma then is about 90%.These results prove that microparticle is used indium cation labelling easily, and label is highly stable in human plasma.
Embodiment 7
Repeat the test of front, but adopt indium complex to replace indium salt.After the method preparation of knowing, indium-111-oxyquinoline complex is used to hatch in the step.By top described definite efficient and stability, the results are shown in Figure 16.Labeling effciency after second time washing is increased to and surpasses 90%.Very near direct labelling, wherein keep bonded radioactivity after 12 days in PBS is more than 95% to the stability of the microparticle of this indium-oxyquinoline labelling; And still keep bonded radioactivity after 12 days in blood plasma is about 90%.Therefore, the direct labelling of mode that indium complex also can be highly stable is to granule.
Claims (17)
1. particulate magnetically responsive composition that comprises that is used for to intravital selected position targeted delivery bioactivator, this granule comprises ferrum and pottery, wherein said ferrum and pottery at random are distributed in whole described granule, wherein said pottery: the ratio of ferrum according to the quality of final composition between 1%～95% pottery: 5%～99% ferrum, wherein each particulate diameter is 0.1～10.0 μ m.
2. the compositions of claim 1, wherein pottery comprises silicon dioxide.
3. the compositions of claim 2, wherein silicon dioxide is macro porous silica gel, has the hole of 0.2nm～50nm.
4. the compositions of claim 2, wherein silicon dioxide carries out derivatization with octadecylsilane, has the hole of 0.2nm～50nm.
5. the compositions of claim 1, wherein pottery is a hydroxyapatite.
6. the compositions of claim 5, wherein hydroxyapatite has the hole of 25nm～120nm.
7. the compositions of claim 1 further comprises the bioactivator that is selected from chemotherapeutics, radiosiotope, hereditary material, contrast agent, dyestuff or its combination.
8. the compositions of claim 1, wherein said compositions adopts gamma-ray method sterilization by comprising.
9. one kind is used for the test kit that in patient's body position gives bioactive substance, and it comprises the ferrum ceramic particle of unit dose claim 1.
10. one kind is used for the test kit that in patient's body position gives bioactive substance, and it comprises a kind of container, and this container comprises:
A) the dried ferrum ceramic particle of unit dose claim 1; And
B) one or more dried excipient.
11. one kind is used for the test kit that in patient's body position gives bioactive substance, it comprises:
A) first container comprises the ferrum ceramic particle of unit dose claim 1; And
B) second container comprises the aqueous solution that contains one or more excipient.
12. claim 9,10 or 11 test kit, wherein excipient comprises bioavailable polymer, and it combines the back at granule and plays Stabilization with aqueous solution.
13. claim 9,10 or 11 test kit, wherein excipient comprises mannitol, sorbitol, sodium carboxymethyl cellulose, polyvinyl pyrrolidone or its combination.
14. the test kit of claim 10 or 11 also comprises a kind of preparation of biological active agents of commercial preparation.
15. the test kit of claim 11, wherein aqueous solution comprises at least a buffer agent.
16. claim 9,10 or 11 test kit, wherein unit dose ferrum ceramic particle has adopted gamma-rays, has done heating or electron beam is sterilized.
17. the test kit of claim 11, the aqueous solution that wherein comprises excipient has adopted autoclave to sterilize.
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| GB9808052D0 (en) | 1998-04-17 | 1998-06-17 | Secr Defence | Implants for administering substances and methods of producing implants |
| US20060204442A1 (en) * | 2003-09-12 | 2006-09-14 | Bankruptcy Estate Of Ferx, Inc. | Magnetically targetable particles comprising magnetic components and biocompatible polymers for site-specific delivery of biologically active agents |
| JP2007001865A (en) * | 2003-09-16 | 2007-01-11 | Ltt Bio-Pharma Co Ltd | Fine particle enclosing fat-soluble medicine, method for producing the same and preparation containing the same |
| JP4982084B2 (en) * | 2004-02-09 | 2012-07-25 | 株式会社サンギ | Antitumor agent |
| PL1735013T3 (en) * | 2004-02-20 | 2012-07-31 | Algeta Asa | Alpha- and beta-emitting hydroxyapatite particles |
| GB0403856D0 (en) * | 2004-02-20 | 2004-03-24 | Algeta As | Composition |
| JP2006199810A (en) * | 2005-01-20 | 2006-08-03 | Yokohama National Univ | Composite particle and method for producing the same |
| JP5097540B2 (en) * | 2005-04-06 | 2012-12-12 | 株式会社サンギ | Antitumor agent for intestinal absorption |
| JP5858906B2 (en) | 2009-05-04 | 2016-02-10 | シヴィダ・ユーエス・インコーポレイテッドＰｓｉｖｉｄａ Ｕｓ， Ｉｎｃ． | Porous silicon drug eluting particles |
| IN2013MN00758A (en) | 2010-11-01 | 2015-06-12 | Psivida Inc | |
| KR101365737B1 (en) * | 2012-08-28 | 2014-02-20 | 한정헌 | Porous solid matter for rapid isolation of biological molecule for nucleic acid amplification reaction from biological sample and uses thereof |
| JP2016512839A (en) | 2013-03-15 | 2016-05-09 | シヴィダ・ユーエス・インコーポレイテッドＰｓｉｖｉｄａ Ｕｓ， Ｉｎｃ． | Biodegradable silicon-based compositions for the delivery of therapeutic substances |
| JP6443907B2 (en) * | 2014-02-17 | 2018-12-26 | 浩文 山本 | Accumulation promoter for promoting accumulation of contrast agent in tumor |
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| US4243652A (en) * | 1978-07-14 | 1981-01-06 | The Procter & Gamble Company | Gastrointestinal scanning agent |
| ES2066851T3 (en) * | 1988-05-24 | 1995-03-16 | Anagen Uk Ltd | MAGNETICALLY ATTRIBUTABLE PARTICLES AND METHOD OF PREPARATION. |
| US5928958A (en) * | 1994-07-27 | 1999-07-27 | Pilgrimm; Herbert | Superparamagnetic particles, process for their manufacture and usage |
| WO1997001304A1 (en) * | 1995-06-29 | 1997-01-16 | Mallinckrodt Medical, Inc. | Radiolabeled apatite particles containing a paramagnetic ion |
| JP3735990B2 (en) * | 1997-01-28 | 2006-01-18 | 東ソー株式会社 | Method for producing magnetic silica gel |
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| JP2003512336A (en) | 2003-04-02 |
| EP1221974A2 (en) | 2002-07-17 |
| IL149004A0 (en) | 2002-11-10 |
| AU1090501A (en) | 2001-04-30 |
| JP2003321348A (en) | 2003-11-11 |
| DE1221974T1 (en) | 2003-02-06 |
| BR0014877A (en) | 2002-06-11 |
| NZ518311A (en) | 2003-10-31 |
| WO2001028587A3 (en) | 2002-01-03 |
| HK1045110A1 (en) | 2002-11-15 |
| CZ20021357A3 (en) | 2002-11-13 |
| AU772755B2 (en) | 2004-05-06 |
| ES2182731T1 (en) | 2003-03-16 |
| CZ293919B6 (en) | 2004-08-18 |
| JP2005200426A (en) | 2005-07-28 |
| KR20020064299A (en) | 2002-08-07 |
| CN1420787A (en) | 2003-05-28 |
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