WO2004071386A2 - Compositions comprising microcapsules containing magnetic nanoparticles and biologically active molecules, their preparation and use - Google Patents

Compositions comprising microcapsules containing magnetic nanoparticles and biologically active molecules, their preparation and use Download PDF

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Publication number
WO2004071386A2
WO2004071386A2 PCT/EP2004/001288 EP2004001288W WO2004071386A2 WO 2004071386 A2 WO2004071386 A2 WO 2004071386A2 EP 2004001288 W EP2004001288 W EP 2004001288W WO 2004071386 A2 WO2004071386 A2 WO 2004071386A2
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biologically active
compositions according
compositions
protein
microcapsules
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PCT/EP2004/001288
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French (fr)
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WO2004071386A3 (en
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Giovanni Baldi
Laura Niccolai
Marco Bitossi
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Colorobbia Italia S.P.A.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis

Definitions

  • the present invention pertains to the field of the intracellular administration of biologically active molecules, in particular compositions comprising microcapsules
  • micropcapsules or (microspheres) consisting of liposomes are indicated as useful vectors for the transport of molecules having pharmacological action to the inside of the cells to be treated.
  • Patent application WO 02/076428 provides a broad analysis of the problems associated with the preparation of compositions containing liposomes capable of acting as vectors of biologically active molecules for their transport inside cells, and in addition describes the various types of liposomes utilisable and the various techniques for their preparation and in addition cites broad literature which makes reference for the preparation of liposomes according to the present invention and for the loading techniques.
  • hyperthermia in which organs or tissues, in which tumour cells are present, are heated to a temperature comprised of between 41° - 47°C to kill said cells; if greater temperatures are used, up to 56°C, the technique is called "thermal ablation".
  • this liposome could also include cancer chemiotherapeutic agents without reporting any practical example.
  • Oxides in nanoparticle form have been amply described for example in the patents in the name of the same applicant FI2002A000038 and FI2002A000039.
  • microcapsules contain also a magnetic particle.
  • the present invention refers therefore to microcapsules (comprising in their structure liposomes, proteins, or biodegradable polymers) containing both a magnetic nanoparticle and a biologically active molecule.
  • the present invention allows the solving of the above mentioned problem thanks to microcapsule as above defined containing a magnetic nanoparticle and a biologically active molecule.
  • lipids formed by a membrane bilayer containing an aqueous phase.
  • They can be unilamellar particles i.e. constituted by a single, membrane bilayer or polylamellar particles having therefore a structure characterised by more membrane bilayers, superimposed into an "onion-like" structure, each of which is separated from the contiguous membrane by an aqueous layer.
  • the structure of the membrane is such that the hydrophobic part of the lipid molecule is oriented towards the centre of the bilayer whilst the hydrophilic part is oriented towards the aqueous phase.
  • lipids derivatised with polyethylene glycol can be included in the membrane bilayer.
  • the liposomial microcapsules can additionally be equipped with a ligand (for example an antibody) capable of interacting with a receptor on the cell towards which the liposome is directed.
  • a ligand for example an antibody
  • liposomes capable of fusing with a target cell.
  • the liposomes can be of the so called "pH-sensitive” type capable that is of being destabilised in weakly acidic conditions or "non pH-sensitive".
  • lipids used for the liposomes according to the invention are selected from the group constituted by: phosphatidylcholine (PC), dilauryl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyJphosphatidylcholine (DPPC), dioleoyl-phosphatidylcholine (COPC), dimyristoylphosphatidylglycerol (CMPG), dimyristoylphosphatidic acid (DMPA), dipalmtoyl phosphatidic acid (DPPA), dipalmitoylphosphatidylethanolamine (DPPE), phosphatidylserine (PS), sphyngomyelin (SM), dioleoylphosphatidyl ethanolamine (DOPE), possibly stabilised with
  • the biologically active molecules are those normally used in the various therapies, for example antitumour agents (such as anthracycline), antimicrobial agents, anti- inflammatory agents, immunomodulators, molecules acting on the central nervous system etc. or these destined to mark the cells so as to allow their identification with the normal means of diagnostic detection (for example fluorescent stains). Said molecules are absorbed inside the liposome during its formation together with the magnetic nanometric particles. Magnetic nanometric particles are known and described in the art, as are the various processes for their production (see for example the above mentioned patents in the name of the same applicant).
  • Examples of usable magnetic particles according to the invention are for example spinels of general formula
  • spinels always in nanoparticle form, reported herein as follows:
  • FePt, FeCo and other metal alloys having nanometric dimensions.
  • the magnetic nanoparticles are incorporated into the microcapsule together with the biologically active molecules as described hereinafter.
  • microcapsules are preferably intended particles having dimensions comprised between 10 "5 - 10 "8 m (therefore this definition comprises also particles which more appropriately could be defined nanocapsules).
  • microcapsules consisting or comprising in their structure a protein or mixture of proteins are both those for delivery of water-soluble compounds as those suitable for entrapping water insoluble ones.
  • These microcapsules can be prepared with methods known in literature for example by heat denaturation or by chemical crosslinking for example through the formation of disulfide bonds (see in this connection, for example, US 5,560,933 col. 2 last paragraph and US 5,439,686 col. 4 second half)
  • proteins preferably are intended human protein as for example albumin or those containing the aminoacid cysteine which allows the formation of the disulfide bonds when cross-linking is preferred.
  • the biodegradable polymers for the microcapsules according to the invention are preferably chosen in the group consisting of: poly(ester-carbonates) made of block copolymers of poly(lactic-glycoIlic acid) (PLGA) and poly(ethylene glycol) (PEG) [see International Journal of Pharmaceutics (2003), 261(1-2), p.
  • microcapsules comprising or consisting of a protein or a mixture thereof or of a biodegradable polymer or mixtures thereof, as above defined, loaded with the magnetic nanoparticles and the biologically active molecule which are also the object of a broad literature and the man skilled in the art can find a lot of possible ways for performing such preparations choosing the one most suitable for his purposes and necessities (available materials, working possibilities, etc.)
  • the action of the compositions according to the invention and the advantages connected with their use are easily understood.
  • the parts for treatment organs or tissues
  • a oscillating magnetic field for example micowave or RF
  • the nanometric particles under the action of the field produce heat which will provoke the collapse of the microcapsule therefore the release of the biologically active molecule, in this way, said molecule will act only in the cells in which its action is requested whilst in the cells not subjected to the action of the magnetic field they will remain absorbed within the liposome or the microcapsule, and therefore inert, thereby avoiding undesired side effects.
  • the nanoparticle rather than acting as the killer particle of the cells for treatment (as with the case of hyperthermia) acts as a detonator provoking the opening of the microcapsule and the escape of the biologically active molecule therefore enormously extending the spectrum of possible applications of the therapeutic technique which tends to only act on the cells for treatment.

Abstract

Compositions containing magnetic nanoparticles and biologically active molecules useful for the intracellular administration of said biologically active molecules are described.

Description

COMPOSITIONS COMPRISING MICROCAPSULES CONTAINING MAGNETIC NANOPARTICLES AND BIOLOGICALLY ACTIVE MOLECULES, THEIR PREPARATION AND USE
Field of the invention
The present invention pertains to the field of the intracellular administration of biologically active molecules, in particular compositions comprising microcapsules
(or microspheres) containing magnetic nanoparticles and biologically active molecules.
State of the art
As is known, micropcapsules or (microspheres) consisting of liposomes are indicated as useful vectors for the transport of molecules having pharmacological action to the inside of the cells to be treated.
Patent application WO 02/076428 provides a broad analysis of the problems associated with the preparation of compositions containing liposomes capable of acting as vectors of biologically active molecules for their transport inside cells, and in addition describes the various types of liposomes utilisable and the various techniques for their preparation and in addition cites broad literature which makes reference for the preparation of liposomes according to the present invention and for the loading techniques.
In EP 243 947 liposomes containing biologically active substances which are released inside cells are described, after absorption of the liposomial microsphere by the cells, followed by the destruction of the microcapsule themselves by means of acoustic waves.
Furthermore, a curative technique is known, called hyperthermia, in which organs or tissues, in which tumour cells are present, are heated to a temperature comprised of between 41° - 47°C to kill said cells; if greater temperatures are used, up to 56°C, the technique is called "thermal ablation".
The use of magnetic materials in the hyperthermia of biological tissues is knownT at least at the theoretical level, for some decades.
Recent study developments have demonstrated that colloidal dispersions of iron oxide in nanoparticle form can be heated by the application of an electromagnetic field outside the patient thus allowing the inactivation of cells in which said nanoparticles have been absorbed [regarding this see IEEE Transaction of
Magnetics, Vol. 34, No. 5, September 1998 pp. 3745-3754 and J. of Magnetism and Magnetic Materials 201 (1999) pp. 413-419)].
WO 93/26019, although referring especially to liposome containing a nanoparticle
(and in particular to their preparation) and their use in the above said method of treatment of biological tissues by hyperthermia, suggests that this liposome could also include cancer chemiotherapeutic agents without reporting any practical example.
Oxides in nanoparticle form have been amply described for example in the patents in the name of the same applicant FI2002A000038 and FI2002A000039.
Moreover, a wide literature describes the possibilities of incorporating chemiotherapeutic agents in microcapsules consisting or comprising, for example, a protein, as albumin, or mixture thereof (see in this connection, for example, US
6,652,884).
None of such document, anyhow, describes or suggests the possibility that such microcapsules contain also a magnetic particle.
The growing demand for ever more refined techniques for intervention, in the most circumscribed ways possible, on the cells for treatment pushes the research towards new compositions which allow therapy to be more exactly targeted and at the same time applicable to the widest possible spectrum of treatments.
Summary of the invention
The present invention refers therefore to microcapsules (comprising in their structure liposomes, proteins, or biodegradable polymers) containing both a magnetic nanoparticle and a biologically active molecule.
Detailed description of the invention
The present invention allows the solving of the above mentioned problem thanks to microcapsule as above defined containing a magnetic nanoparticle and a biologically active molecule.
According to the invention, for liposomial microcapsules are meant, particles formed by a membrane bilayer containing an aqueous phase. They can be unilamellar particles i.e. constituted by a single, membrane bilayer or polylamellar particles having therefore a structure characterised by more membrane bilayers, superimposed into an "onion-like" structure, each of which is separated from the contiguous membrane by an aqueous layer. The structure of the membrane is such that the hydrophobic part of the lipid molecule is oriented towards the centre of the bilayer whilst the hydrophilic part is oriented towards the aqueous phase. As is known, lipids derivatised with polyethylene glycol can be included in the membrane bilayer.
The liposomial microcapsules can additionally be equipped with a ligand (for example an antibody) capable of interacting with a receptor on the cell towards which the liposome is directed.
Also suitable according to the invention are liposomes capable of fusing with a target cell.
The liposomes can be of the so called "pH-sensitive" type capable that is of being destabilised in weakly acidic conditions or "non pH-sensitive". Examples of lipids used for the liposomes according to the invention are selected from the group constituted by: phosphatidylcholine (PC), dilauryl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyJphosphatidylcholine (DPPC), dioleoyl-phosphatidylcholine (COPC), dimyristoylphosphatidylglycerol (CMPG), dimyristoylphosphatidic acid (DMPA), dipalmtoyl phosphatidic acid (DPPA), dipalmitoylphosphatidylethanolamine (DPPE), phosphatidylserine (PS), sphyngomyelin (SM), dioleoylphosphatidyl ethanolamine (DOPE), possibly stabilised with cholesteryl hemisuccinate (CHEMS), diacyl glycerol, phόsphatidyl ethanolamine, phosphatidyl glycerol. Other useful lipid types according to the invention are reported, for example in: Liposomes: From Physical structures to Therapeutic applications, Knight Ed Elsevier, North-Holland Biomedical Press, 1981.
The biologically active molecules are those normally used in the various therapies, for example antitumour agents (such as anthracycline), antimicrobial agents, anti- inflammatory agents, immunomodulators, molecules acting on the central nervous system etc. or these destined to mark the cells so as to allow their identification with the normal means of diagnostic detection (for example fluorescent stains). Said molecules are absorbed inside the liposome during its formation together with the magnetic nanometric particles. Magnetic nanometric particles are known and described in the art, as are the various processes for their production (see for example the above mentioned patents in the name of the same applicant).
Examples of usable magnetic particles according to the invention are for example spinels of general formula
M"M,π2 O4 with M(ll) = Mn, Fe", Zn, Ni, Co and M(lll) = Fe"1, Cr, Al.
Amongst these, particularly preferred are the spinels, always in nanoparticle form, reported herein as follows:
[Fe(ι.χ-y) CoxMny] tCr(1.Z)Fez]2O4 0<x<0.6 0<y<0.4 0<z<0.5
[Fe(1.x.y) CθχMnyZnw3 [Cr{i-Z)Fez]2O4 0<x<0.6 0<y<0.40<z<0.50<w<0.3
(Mn 0.01 Zn o.o4 NI 0,31, Co 0.64 )(Fe 0.41 Cr o.59 04
C0AI2O4
Fe3O4
Figure imgf000005_0001
FePt, FeCo and other metal alloys having nanometric dimensions.
Other useful products constituted by magnetic nanometric particles according to the invention are, for example, oxides of the type:
(Feι-χ,Crx)O3 wherein 0.07<x<0.5
FeO(OH), Fe(OH)3, Mn02
Preferred are magnetic particles having dimensions comprised between 2 - 300 nm, more preferred those having dimensions comprised between 3 - 30 nm.
According to the invention the magnetic nanoparticles are incorporated into the microcapsule together with the biologically active molecules as described hereinafter.
With the term "microcapsules" according to the invention are preferably intended particles having dimensions comprised between 10"5 - 10"8 m (therefore this definition comprises also particles which more appropriately could be defined nanocapsules).
The microcapsules consisting or comprising in their structure a protein or mixture of proteins are both those for delivery of water-soluble compounds as those suitable for entrapping water insoluble ones. These microcapsules can be prepared with methods known in literature for example by heat denaturation or by chemical crosslinking for example through the formation of disulfide bonds (see in this connection, for example, US 5,560,933 col. 2 last paragraph and US 5,439,686 col. 4 second half)
With proteins, or their mixture, preferably are intended human protein as for example albumin or those containing the aminoacid cysteine which allows the formation of the disulfide bonds when cross-linking is preferred. The biodegradable polymers for the microcapsules according to the invention are preferably chosen in the group consisting of: poly(ester-carbonates) made of block copolymers of poly(lactic-glycoIlic acid) (PLGA) and poly(ethylene glycol) (PEG) [see International Journal of Pharmaceutics (2003), 261(1-2), p. 69], sugar functionalised poly(amido-amines) (PPA), for example 2-methylpiperazine-2,2- bisacrylamido acetic acid [see Journal of Bioactive and Compatible Polymers (2001) 16(6) p. 479-491], water soluble functionalised polyesters containing fumarate or maleate units linked by polyethylene glycol segments by means of carbonate bonds [ Macromolecular Bioscience (2001) 1(4), 164-169 etc. The loading of the liposomial microcapsules with the biologically active molecules and with the magnetic nanometric particles takes place through well known procedures. Said methods include for example ultrasonication of the lipids, dialysis techniques, freeze/thawing methods, reswelling of the lipid layers in water. Seeing the broad literature available apropos, the expert in the art will not have difficulty preparing the liposomial microcapsules according to the invention using the most suitable process according to the use to which they are designated, the chosen method of administration, the dosage, the properties of the molecule, and so on.
The same applies to the preparation of microcapsules comprising or consisting of a protein or a mixture thereof or of a biodegradable polymer or mixtures thereof, as above defined, loaded with the magnetic nanoparticles and the biologically active molecule which are also the object of a broad literature and the man skilled in the art can find a lot of possible ways for performing such preparations choosing the one most suitable for his purposes and necessities (available materials, working possibilities, etc.) The action of the compositions according to the invention and the advantages connected with their use are easily understood.
Once they have been administered to the patient, according to the known therapeutic or diagnostic methodologies, it will be sufficient to subject the parts for treatment (organs or tissues) to the action of a oscillating magnetic field for example micowave or RF, the nanometric particles under the action of the field produce heat which will provoke the collapse of the microcapsule therefore the release of the biologically active molecule, in this way, said molecule will act only in the cells in which its action is requested whilst in the cells not subjected to the action of the magnetic field they will remain absorbed within the liposome or the microcapsule, and therefore inert, thereby avoiding undesired side effects. Therefore in the microcapsules according to the invention the nanoparticle, rather than acting as the killer particle of the cells for treatment (as with the case of hyperthermia) acts as a detonator provoking the opening of the microcapsule and the escape of the biologically active molecule therefore enormously extending the spectrum of possible applications of the therapeutic technique which tends to only act on the cells for treatment.
Furthermore, seeing the broad availability of magnetic nanoparticles, the possibility for choice as a function of the parts of the body for treatment and therefore of the magnetic fields which must be used, is enormously extended; in other words, thanks to the compositions according to the inventions it is achieved the double purpose of widening the possibility of intervention and limiting however the ever present damage following the vast scale administration of biologically active molecules.

Claims

1. A composition comprising microcapsule containing a magnetic nanoparticle and a biologically active molecule.
2. The composition according to claim 1 wherein the microcapsule consists or comprises a liposome
3. Composition according to claim 2 wherein said liposome is formed from non "pH-sensitive" lipids.
4. The composition according to claim 2 wherein said liposome is formed from pH- sensitive lipids.
5. Compositions according to claims 1. - 4 wherein the lipids constituting the liposome are selected from the group constituted by: phosphatidylcholine (PC), dilauryl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), dioleoyl phosphatidylcholine (COPC), dimyristoylphosphatidylglycerol (CMPG), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), dipalmitoylphosphatidylethanolamine (DPPE), phosphatidylserine (PS), sphyngomyelin (SM), dioleoylphosphatidyl ethanolamine (DOPE), possible stabilised with cholesteryl hemisuccinate (CHEMS), diacyl glycerol, phosphatidyl ethanolamine, phosphatidyl glycerol,
6. Compositions comprising microcapsules, comprising or consisting of a protein or a mixture of proteins, and containing a magnetic nanoparticle and a biologically active molecule.
7. Compositions according to Claim 6 wherein said microcapsules are suitable for delivery of water-soluble compounds or for entrapping water insoluble ones.
8. Compositions according to Claim 7 wherein said protein is a human protein.
9. Compositions according to Claim 8 wherein such protein is albumin.
10. Compositions according to Claim 8 wherein said protein is a protein containing the aminoacid cysteine.
11. Compositions comprising microcapsules, comprising or consisting of a biodegradable polymer or mixture thereof, and containing a magnetic nanoparticle and a biologically active molecule.
12. Composition according to claim 11 wherein such biodegradable polymer is chosen in the group consisting of : poly(ester-carbonates) made of block copolymers of poly(lactic-glycollic acid) (PLGA) and poly(ethylene glycol) (PEG), sugar functionalised poly(amido-amines) (PPA), for example 2-methylpiperazine- 2,2-bisacrylamido acetic acid, water soluble functionalised polyesters containing fumarate or maleate units linked by polyethylene glycol segments by means of carbonate bonds.
13. Compositions according to claim 1 - 12 in which the nanometric particle is selected from the group constituted by M"Mnι 2 O4 wherein:
M(ll) = Mn, Fe", Zn, Ni, Co and M(lll) = Fe'", Cr, Al.
14. Compositions according to claim 13 selected from the group constituted by: [Fe(i_x.y) CoxMny] [Cr(i.Z)Fez]2O wherein 0<x<0.6 0<y<0.4 0<z<0,5; [Fe(i-x.y) CoxMnyZnw] [Cr(i-Z)Fez]2O4 wherein 0<x<0.6 0<y<0.4 0<z<0.5 0<w<0.3;
(Feι-x,Crχ)O3 wherein 0.07<x<0.5;
(Mn o.oι Zn 0.04 Ni 0.31, Co 0.β4 )(Fe 0.41 Cr 0.59 )2θ4, CoAI2O4, Fe3O4, FeO(OH),
Fe(OH)3, MnO2.
CoFe2O4
Figure imgf000009_0001
FePt, FeCo and other metal alloys having nanometric dimensions.
15. Compositions according to claims 13 and 14 wherein the biologically active molecule is selected from the group constituted by: antitumour agents, antimicrobial agents, anti-inflammatory agents, immunomodulators, molecules acting on the central nervous system.
16. Compositions according to claim 15 wherein said biologically active molecule is an anthracycline.
17. Compositions according to claims 13 and 14 wherein the biologically active molecule is a marker for diagnostic identification.
18. Compositions according to claim 17 wherein said marker is a fluorescent stain.
19. A method for the introduction of biologically active molecules inside the cells of tissues or organs in which compositions according to claims 1 - 18 are used.
20. The method according to claim 19 wherein said biologically active molecules have pharmacological action.
21. The method according to claim 19 wherein said biologically active molecules are markers for diagnostic identification.
PCT/EP2004/001288 2003-02-13 2004-02-12 Compositions comprising microcapsules containing magnetic nanoparticles and biologically active molecules, their preparation and use WO2004071386A2 (en)

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