U.S. patent application number 16/199837 was filed with the patent office on 2019-06-27 for use of a reverse-micellar system for delivering chelators of radionuclides and metals.
The applicant listed for this patent is MEDESIS PHARMA. Invention is credited to Jaime Francisco ANGULO-MORA, Caroline BAUER, Elsa COMPTE, Olivier GREMY, Jean-Claude MAUREL, Laurent MICCOLI.
Application Number | 20190192420 16/199837 |
Document ID | / |
Family ID | 50231093 |
Filed Date | 2019-06-27 |
United States Patent
Application |
20190192420 |
Kind Code |
A1 |
BAUER; Caroline ; et
al. |
June 27, 2019 |
USE OF A REVERSE-MICELLAR SYSTEM FOR DELIVERING CHELATORS OF
RADIONUCLIDES AND METALS
Abstract
The present invention relates to reverse-micellar systems
comprising at least an active agent, an acylglycerol, a sterol,
lecithin, ethanol and water, for use in chelation and/or
sequestering of a radionuclide and/or a metal in a patient. The
invention also relates to the reverse-micellar systems and to
pharmaceutical compositions comprising said reverse-micellar
systems.
Inventors: |
BAUER; Caroline; (Rochefort
Du Gard, FR) ; COMPTE; Elsa; (Montpellier, FR)
; GREMY; Olivier; (Saint Germain Les Arpajon, FR)
; MICCOLI; Laurent; (Juvisy Sur Orge, FR) ;
ANGULO-MORA; Jaime Francisco; (Limours, FR) ; MAUREL;
Jean-Claude; (Castries, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MEDESIS PHARMA |
Baillargues |
|
FR |
|
|
Family ID: |
50231093 |
Appl. No.: |
16/199837 |
Filed: |
November 26, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15119678 |
Aug 17, 2016 |
10172954 |
|
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PCT/EP2015/053339 |
Feb 17, 2015 |
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16199837 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/006 20130101;
A61K 49/1809 20130101; A61P 39/04 20180101; A61K 47/6909 20170801;
A61K 49/103 20130101; A61P 39/02 20180101; A61K 47/547
20170801 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/69 20060101 A61K047/69; A61K 49/10 20060101
A61K049/10; A61K 49/18 20060101 A61K049/18; A61K 47/54 20060101
A61K047/54 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 18, 2014 |
EP |
14305217.3 |
Claims
1. A method for treating at least one disease linked to the
accumulation, overload, or accumulation and overload of at least
one radionuclide or metal comprising administering a
reverse-micellar system comprising at least an active agent, an
acylglycerol, a sterol, lecithin, ethanol and water to a patient in
need thereof, wherein the active agent chelates at least one metal,
chelates at least one radionuclide, sequesters at least one metal,
or sequesters at least one radionuclide.
2. The method according to claim 1, wherein the active agent is
DTPA, bisphosphonates, Prussian blue, EDTA, Trientine,
D-penicillamine, Deferoxamine, BAL, DMSA, DMPS, Phytic acid,
Hydroxypyridonates (HOPO), mercaptoacetyltriglycine (MAG3),
chelating peptides, derivatives thereof or combinations
thereof.
3. (canceled)
4. The method according to claim 1, wherein the disease is Wilson's
disease, haemochromatosis or a pathology or symptom due to a metal
accumulation from an external origin.
5. The method according to claim 1, wherein the reverse-micellar
system is administered transmucosally.
6. (canceled)
7. The method according to claim 1, wherein the sterol is
sitosterol.
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. The method of claim 1, wherein the active agent is pentetate
calcium trisodium (CaNa.sub.3 DTPA).
17. The method of claim 1, wherein the active agent has a
concentration of 1-124.4 mg/g.
18. The method according to claim 5, comprising administering said
reverse-micellar system through the buccal mucosal tissue.
Description
INTRODUCTION
[0001] The present invention relates to reverse-micellar systems
comprising at least an active agent, an acylglycerol, a sterol,
lecithin, ethanol and water, for use in chelation and/or
sequestering of a radionuclide and/or a metal in a patient. The
invention also relates to the reverse-micellar systems and to
pharmaceutical compositions comprising said reverse-micellar
systems.
BACKGROUND OF THE INVENTION
[0002] Exposure to radionuclides may have different origins, from
the involvement of a nuclear worker after breaking of the
containment of a glove box for example, to that of a multitude of
people contaminated by the widespread dissemination of
radionuclides in the environment: incident/accident or natural
disaster affecting facilities of research, production, operation or
storage of nuclear materials, military conflict with nuclear
weapons, radionuclide containing weapons, terrorist act aiming at
these facilities or characterized by an explosive device dispersing
radionuclides called "dirty bomb."
[0003] Internalized radionuclides are highly toxic and may cause
both acute and chronic radiation injuries. The nuclides the most
frequently encountered in these scenarios include americium,
cesium, iodine, plutonium, strontium, uranium. Plutonium (Pu) is an
example of highly toxic transuranic actinide alpha emitter. Once
internalized in the body, Pu is overwhelmingly and efficiently
distributed between the primary site of infection (e.g. the lungs
in the case of inhalation) and the two main secondary tissue
deposits (bone and liver), for very long periods.
[0004] To reduce the cumulative radiation dose delivered to the
tissues by the Pu atoms, and thus reduce the risk of developing
diseases, the only possibility is their decorporation by chelation
to facilitate their excretion by natural means.
[0005] Currently, the only recommended treatment for
actinide/lanthanide decorporation, such as Pu decorporation, is
chelator diethylene triaminopentaacetic acid (DTPA), which in its
dosage form solution benefits from a marketing authorization in
France (2008), Germany (2005) and the approval of the Food and Drug
Administration USA (2004). The marketed DTPA solution can be
injected or infused intravenously, applied on a contaminated wound,
or nebulized for inhalation.
[0006] DTPA is highly polar at neutral pH and is thus poorly
(<10%) or variably absorbed when delivered orally. Consequently,
DTPA is generally administered through more invasive routes, such
as intravenous injection for internal contamination routes.
Intravenous administration requires medical assistance and can thus
not be autonomously used by any contaminated person.
[0007] Nebulization administration and flush of a contaminated
wound are local and not optimal administration routes for
decorporation efficacy in patients and do not necessarily afford
systemic delivery. Wound flushing with a solution comprising DTPA
triggers spilling of contaminated DTPA solution and waste of a
great quantity of DTPA.
[0008] Reddy et al. Drug Development Research 2012, 73, 232-242 and
US 2013/0251815 disclose enteric-coated gelatin capsules
encapsulating DTPA that are safe and capable of decorporating
actinides. Said capsules can be administered orally.
[0009] Jay et al. U.S. Pat. No. 8,030,358 and WO 2013/109323
disclose oral and topical delivery of DTPA prodrug formulations
respectively.
[0010] However, there still exists a real need of new formulations,
which would allow simple and autonomous (i.e. without medical
assistance) administration of decorporating agents, such as DTPA.
Such formulations would be especially appropriate for large-scale
treatment of contaminated people and chronic treatments. In
addition, most described systems for oral or local delivery require
the use of high doses of DTPA, because these routes do not favor
the uptake of the active agent.
[0011] Metal poisoning is a serious health problem. It can occur in
different contexts, and potentially involves a wide variety of
metals. Metal can also be present in too high levels in specific
pathologies associated with metal accumulation in the body.
[0012] U.S. Pat. No. 5494,935 discloses the use of compositions
comprising partially lipophilic polyaminocarboxylic acids, for
chelating heavy metals in specific organs in the body. These
compositions are in particular capable of oral administration.
[0013] The described formulations for oral delivery of
decontaminating agents or of agents for treating metal intoxication
often require high doses, may be toxic and are usually not as
efficient as the corresponding formulations for intravenous
administration.
[0014] WO 2011/117333 discloses the use of a reverse-micellar
system based on acylglycerols, phospholipids or sphingolipids and
metal ions. Said reverse micellar systems are able to cross mucosa
and cellular membranes and thus allow vectorization of metal ions
to target sites. The reverse-micellar system allows the delivery of
the metal ions to many different organs.
[0015] The Applicant surprisingly evidenced that reverse-micellar
systems based on acylglycerols, sterols, lecithin, ethanol, water
and a chelating or sequestering agent are appropriate for efficient
chelation of radionuclides and/or metals in the whole body. Said
reverse-micellar system can be advantageously delivered by
transmucosal route, and favour the delivery and/or absorption of
the active agent into the desired cells or organs. The
reverse-micellar system acts both as a protecting shell around the
active agent, and as a vector for its delivery to the desired cells
and/or organs.
SUMMARY OF THE INVENTION
[0016] The first object of the invention is a reverse-micellar
system comprising at least an active agent, an acylglycerol, a
sterol, lecithin, ethanol and water, for use in chelation and/or
sequestering of a radionuclide and/or a metal, in a patient in need
thereof.
[0017] Another object of the invention is a reverse-micellar system
comprising at least an active agent, an acylglycerol, a sterol,
lecithin, ethanol and water, wherein the active agent is selected
from the group consisting of DTPA, bisphosphonates, Prussian blue,
EDTA (ethylene diamine tetraacetic acid), Trientine,
D-penicillamine, Deferoxamine, BAL (British Anti-Lewisite), DMSA
(DiMercaptoSuccinic Acid), DMPS (2,3-DiMercaptoPropane-1-Sulfonic
acid), Phytic acid, hydroxypyridonates (HOPO),
mercaptoacetyltriglycine (MAG3) or chelating peptides, or
derivatives thereof and combinations thereof.
[0018] Another object of the present invention is a
reverse-micellar system comprising at least an active agent, an
acylglycerol, a sterol, lecithin, ethanol, water, and at least one
radionuclide and/or metal, wherein the active agent is a compound
appropriate for chelating and/or sequestering said radionuclide
and/or metal.
[0019] Another object of the invention is a reverse-micellar system
comprising at least an active agent, an acylglycerol, a sterol,
lecithin, ethanol, water and a radionuclide and/or metal, wherein
the active agent is a compound appropriate for chelating and/or
sequestering said radionuclide and/or metal, for use as an imaging
agent and/or as a diagnosis agent.
[0020] Another object of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable support and a
reverse-micellar system comprising at least an active agent, an
acylglycerol, lecithin, ethanol and water, wherein the active agent
is appropriate for chelating at least one metal and/or
radionuclide.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1: Liver FIG. 1(a) and skeletal FIG. 1(b) retentions of
Pu (in % of administered Pu) in untreated rats and rats chronically
treated by two daily deposits on the rectal mucosa of DTPA in
reverse-micellar system at 3.6, 7.2 or 12.5 mgml.sup.-1,
corresponding respectively to cumulative DTPA doses of 44.3, 88.6
or 153.8 umolkg.sup.-1, or by four daily deposits at 12.5
mgml.sup.-1 corresponding to the cumulative DTPA dose of 307.6
umolkg.sup.-1.
[0022] FIG. 2: Decrease in retention of Pu in liver FIG. 2(a) and
bone FIG. 2(b) as a function of the administered DTPA cumulative
dose. The decrease in retention is expressed % of control (absence
of treatment). The cumulative dose is expressed in
logio,iumol/kg.
[0023] FIG. 3: Liver FIG. 3(a) and skeletal FIG. 3(b) retentions of
Pu in untreated and treated rats. The chronic treatment starting
from H+1, D+4 or D+7 post-contamination consists in four daily
deposits on the rectal mucosa of DTPA in reverse-micellar system at
12.5 mgml.sup.-1, yielding a cumulative DTPA dose of 307.6
itimolkg.sup.-1.
DETAILED DESCRIPTION OF THE INVENTION
[0024] A first object of the invention is a reverse-micellar system
comprising at least an active agent, an acylglycerol, a sterol,
lecithin, ethanol and water, for use in chelation and/or
sequestering of at least one radionuclide and/or metal in a patient
in need thereof
Components of the Reverse-Micellar System
Acylglycerols
[0025] Acylglycerols used in the reverse-micellar system according
to the invention can be isolated from the majority of animals, and
more preferably plants.
[0026] Acylglycerols used according to the invention include mono-,
di- and tri-acylglycerols of the following formula (1):
##STR00001##
in which: [0027] Ri is an acyl residue of a linear or branched
unsaturated fatty acid having between 14 and 24 carbon atoms;
[0028] R2 is an acyl. residue of a linear or branched unsaturated
fatty acid having between 2 and 18 carbon atoms, or a hydrogen
atom; [0029] R3 is an acyl residue of a linear or branched
unsaturated fatty acid having between 14 and 24 carbon atoms, or a
hydrogen atom.
[0030] According to a particular embodiment, Ri or R3, preferably
only one of Ri and R3, in particular only Ri, represents an acyl
residue of oleic acid (C18: l[cis]-9).
[0031] According to a particular aspect, R.sub.2 has 18 carbon
atoms, preferably R.sub.2 is an oleic acid residue (oleoyl group),
one of its positional isomers with respect to the double bond
(cis-6,7,911 and 13) or one of its iso-branched isomers.
[0032] According to another particular aspect, R.sub.1 represents
an oleoyl group.
[0033] According to another particular aspect, R.sub.3 is a
hydrogen atom.
[0034] According to another particular aspect, R.sub.2 and R.sub.3
are hydrogen atoms.
[0035] As a general rule, oil containing a high concentration of
oleic acid will be chosen as a useful source of acylglycerols
according to the invention. Such oil usually contains a high
proportion of acylglycerols useful according to the invention.
[0036] According to a particular aspect of the invention, the
preferred acylglycerols are glycerol 1-monooleate and glycerol 1,2
-dioleate.
[0037] A certain number of them, and more particularly those which
are found to be the most active in the applications sought after,
are also available commercially. For instance, glycerol monooleate
40 contains about 32 to 52% of monoacylglycerol, 30 to 50% of
diacylglycerol, 5 to 20% of triacylglycerol and is pharmaceutically
accepted (European Pharmacopeia (8.sup.th Edition), USP 25/N F20,
and Japanese Standard of food Additives). Such product is for
instance commercially available by Gattefosse Company under the
name Peceol.RTM.. In particular, Peceol.RTM. may comprise around
45.3 wt % of monoacyl glycerol, around 44.5 wt % of diacylglycerol
and around 8.6 wt % of triacyl glycerol (the acyl fraction of
Peceol.RTM. is mainly made of oleoyl--usually around 80% of the
acyl residue is oleoyl fraction).
[0038] According to the present description, the weight of
acylgylycerol corresponds to the total weight of the mixture
usually containing an acylglycerol, or a mixture of acylglycerols,
with glycerol and fatty acids derived from said acylglycerol(s),
such as Peceol.RTM. described above.
[0039] Acylglycerols are natural compounds, and may be extracted
and/or derived from renewable vegetable sources. Their use is thus
favoured in terms of biocompatibility and environmental concerns
when compared to synthetic compounds.
Sterol
[0040] The reverse-micellar system according to the invention
comprises at least one sterol, preferably natural sterol, such as
cholesterol or phytosterol (vegetable sterols). Sitosterol and
cholesterol are the preferred sterols that can be present in a
reverse-micellar system according to the invention. Preferably, the
reverse-micellar system comprises sitosterol.
[0041] Sitosterol and cholesterol are commercially available. More
particularly, commercial sitosterol, which is extracted from soya,
can be used. In such a product, the sitosterol generally represents
from 50 to 80% by weight of the product and is generally found in a
mixture with campesterol and sitostanol in respective proportions
in the order of 15% each. Commercial sitosterol, which is extracted
from a variety of pine called tall oil, can also be used.
Lecithin
[0042] In the present invention, the term "lecithin" designates
phosphatidylcholine.
[0043] Phosphatidylcholine is also known as
1,2-diacyl-glycero-3-phosphocholine or PtdCho.
[0044] Phosphatidylcholine is composed of a choline, a phosphate
group, a glycerol and two fatty acids. It is actually a group of
molecules, wherein the fatty acid compositions varies from one
molecule to another. Phosphatidylcholine may be obtained from
commercial lecithin that contains phosphatidylcholine in weight
fractions of 20 to 98%. The lecithin preferably used according to
the invention is Epikuron 200.RTM. and contains phosphatidylcholine
at a fraction of more than 90%. Preferably, the lecithin used
according to the invention comprises more than 92% wt
phosphatidylcholine.
Water
[0045] The water useful for the preparation of the reverse-micellar
system according to the invention is preferably purified water.
Other Components
[0046] The reverse-micellar system according tee the invention may
comprise any type of additional components. As example of
additional component, one can cite alcohols different from
ethanol.
[0047] The reverse-micellar system according to the invention may
comprise at least one alcohol in addition to ethanol as defined
above. The alcohols that may be used according to the invention are
preferably linear or branched mono-alcohols with two to four carbon
atoms. Examples of alcohols are 1-propanol, 2-propanol,
2-methyl-1-propanol, isopropanol, and any mixture thereof. Polyols
that may be used according to the invention are preferably glycerol
and propylene glycol.
[0048] The amounts of the components of the reverse-micellar system
can be adapted by anyone of ordinary skill in the art depending on
the desired properties for the system, such as visual appearance,
viscosity, and/or concentration of active agent for instance.
[0049] In a preferred embodiment, the reverse-micellar system does
not comprise liposomes.
[0050] In an embodiment of the invention, the amounts of the
components of the reverse-micellar system are adjusted so that the
reverse-micellar system is in the form of a gel.
[0051] A gel is sufficiently viscous and/or sticky for not flowing
and remaining in place when applied onto the skin or onto a mucosa.
Alternatively, the reverse-micellar system may be in the form of a
liquid. One of ordinary skill in the art can adapt the relative
amounts of active agent, acylglycerol, sterol, lecithin, ethanol
and water in the reverse-micellar system for obtaining a gel with
the desired properties, such as visual appearance, viscosity,
and/or concentration of active agent for instance.
[0052] Examples of amounts for the different components of the
reverse-micellar systems are the following:
[0053] The reverse-micellar system may comprise from 1 to 37%,
preferably from 1 to 30%, in particular from 5 to 20% lecithin.
[0054] The reverse-micellar system may comprise from 0.1 to 20%,
preferably from 1 to 20%, in particular from 5 to 15% water.
[0055] The reverse-micellar system may comprise from 5 to 20%,
preferably from 5 to 15% alcohols, including ethanol.
[0056] The reverse-micellar system may comprise from 0.82 to 4.5%
sterol.
[0057] The reverse-micellar system may comprise from 30 to 90%,
preferably from 50 to 90% acylglycerol.
[0058] Unless otherwise specified, the percentage values used in
the present invention are weight percentages with respect to the
total weight of the reverse-micellar system.
[0059] In the present invention, the term "reverse-micellar system"
relates to a reverse-phase system comprising an aqueous phase
dispersed in an oil phase. Preferably, the reverse-phase system
comprises reverse or reverse swollen micelles, but these may be
organized in higher ordered isotropic structures such as
water-in-oil microemulsion or anisotropic structures such as cubic,
hexagonal, lamellar organizations.
Active Agents
[0060] In the present invention, the term "active agent" refers to
a compound appropriate for chelating and/or sequestering at least
one metal and/or radionuclide. Said compound may be hydrophilic,
amphiphilic or hydrophobic. Preferably, the active agent is
hydrophilic.
[0061] According to the present invention, "chelation" and
derivatives of this term relate to the formation or presence of one
or more, preferably two or more, separate coordinate bonds between
a polydentate (multiple bonded) ligand and a single central
atom.
[0062] The term "sequestering agent" and derivatives of this term
relate to a substance that captures an ion from a solution system
by forming a ring, which does not have the chemical reactions of
the ion which is removed.
[0063] In an embodiment, the active agent is a compound that is
known to be useful for decorporating at least one radionuclide
and/or treating at least one metal intoxication. Such compounds are
well-known in the art and many prior art documents disclose
examples of such compounds. One may for instance refer to Varani et
al. Frontiers in Medicinal Chemistry 2009, 4, 130 or to Flora et
al. Int. J. Environ. Res. Public Health 2010, 7, 2745 for examples
of metal chelating and/or sequestering agents appropriate for
chelating metals.
[0064] The reverse-micellar system of the invention is appropriate
for encapsulating any active agent according to the present
invention, whatever its physical-chemical parameters, such as
molecular weight, chemical structure and/or charge. One of ordinary
skill in the art will be able to adapt the ratios of the components
of the reverse-micellar system and the amount of active agent to
encapsulate any active agent into the reverse-micellar system
according to the invention.
[0065] In an embodiment, the active agent is selected from the
group consisting of DTPA, bisphosphonates (such as tiludronate,
etidronate, or salt thereof), Prussian blue, EDTA, Trientine,
D-penicillamine, Deferoxamine, BAL, DMSA, DMPS, Phytic acid,
hydroxypyridonates (HOPO), mercaptoacetyltriglycine (MAG3) or
chelating peptides, derivatives thereof and combinations thereof.
Derivatives of the cited compounds include esters or salts thereof,
such as mesylate, calcium, sodium, or zinc.
[0066] A chelating peptide is according to the invention a natural
or synthetic peptide, which is able to chelate and/or sequester at
least one radionuclide and/or metal. Said chelating peptides mimic
either the active site or the metal-binding site of at least one
metalloprotein. Examples of peptides appropriate for chelating
metals are disclosed in WO 2011/145055, Pujol et al. 2009, Pujol et
al. 2011, Morris et al. 2013 and Zhang et al. 2013.
[0067] In particular, the active agent is a salt of DTPA, such as
the calcium or zinc salt of DTPA. In particular, the active agent
is pentetate calcium trisodium (CaNa.sub.3DTPA).
[0068] The term "decorporation" is used, in the present invention
in relation with a radionuclide to refer to the elimination of at
least some of said radionuclide from the patient body.
[0069] The term "agent for treating metal intoxication" refers in
the present invention to a compound appropriate for chelating and
preferably favor excretion of at least part of the metal comprised
in the patient's body. Said metal may come for instance from an
external intoxication (exposure to a metal) or to a pathology
triggering metal accumulation in the body.
[0070] In an embodiment, the reverse-micellar system for use
according to the invention is used for decorporating at least one
radionuclide and/or treating at least one metal intoxication from
the patient body. In this embodiment, decorporation or treatment of
intoxication comprises the chelation and/or sequestering of the
metal and/or radionuclide with a reverse-micelle system according
to the invention and the elimination and/or excretion of the
chelated and/or sequestered metal or radionuclide from the
patient's body. In a preferred embodiment, the excretion is through
natural routes, such as by urine or feces.
[0071] In an embodiment, the reverse-micellar system for use
according to the invention is used for decorporating at least one
radionuclide and/or treating at least one metal intoxication from
an external lesion of the body. In this embodiment, decorporation
or treating of the metal intoxication comprises the chelation
and/or sequestering of the metal and/or radionuclide with a
reverse-micelle system according to the invention and the
elimination of the chelated and/or sequestered metal and/or
radionuclide from the lesion, preferably by removal and/or washing.
For instance, when the reverse-micellar system is applied as a gel
on the lesion, the elimination can be performed by simple removal
of the gel after chelation and/or sequestering of the radionuclide
and/or metal.
[0072] DTPA is known to be appropriate for chelating plutonium,
americium, curium, iron, californium, cerium, lanthanum, manganese
and/or gallium. Bisphosphonates are known to be appropriate for
chelating uranium. Prussian blue is known to be appropriate for
chelating cesium and/or thallium. EDTA is known to be appropriate
for chelating lead, manganese, cadmium and/or zinc. Trientine is
known to be appropriate for chelating copper. D-penicillamine is
known to be appropriate for chelating copper, lead, gold, mercury
and/or zinc. Deferoxamine is known to be appropriate for chelating
iron and/or aluminium. BAL is known to be appropriate for chelating
lead, gold, mercury and/or arsenic. DMSA is known to be appropriate
for chelating lead, mercury, arsenic, copper and/or antimony. DMPS
is known to be appropriate for chelating lead, mercury, arsenic,
and/or copper. Phytic acid is known to be appropriate for chelating
uranium. Hydroxypyridonates (HOPO) are known to be appropriate for
chelating plutonium, americium, uranium and/or neptunium, depending
on members of HOPO. MAG3 is known for chelating technetium 99m.
Peptides are known for chelating, not always exclusively, arsenic,
cadmium, calcium, chromium, cobalt, copper, iron, lead, magnesium,
mercury, molybdenum, nickel, silver, selenium, tellurium, thallium,
tungsten, and/or zinc.
Radionuclides
[0073] The term "radionuclide", or radioactive nuclide, refers to
an atom with an unstable nucleus, characterized by excess energy
available to be imparted either to a newly created radiation
particle within the nucleus or via internal conversion. During this
process, the radionuclide is said to undergo radioactive decay,
resulting in the emission of gamma ray(s) and/or subatomic
particles such as alpha or beta particles.
[0074] In function of the active agent comprised in the
reverse-micellar system, said system is appropriate for
decorporation of any type of radionuclide. When the radionuclide is
a specific isotope of an element, the reverse-micellar system will
not necessarily more selectively chelate the radioactive isotope
than the other isotopes of the same element.
[0075] In embodiments, the radionuclide is selected from the group
consisting of plutonium, for instance .sup.238Pu, .sup.239Pu or
.sup.240Pu, americum, for instance .sup.241Am, uranium, for
instance .sup.234 U, .sup.234U, .sup.235U, or .sup.238U, cesium,
for instance .sup.134Cs, .sup.135Cs or .sup.137Cs, thallium, for
instance .sup.201Ti or .sup.204Tl, indium, for instance .sup.111In,
strontium, for instance .sup.85Sr, .sup.89Sr or .sup.90Sr,
molybdenum, for instance .sup.99Mo or .sup.100Mo, lead, for
instance .sup.210Pb, chromium, for instance .sup.51Cr, polonium,
for instance .sup.210Po, cobalt, for instance .sup.57Co, .sup.58Co
or .sup.60Co, copper, for instance .sup.64Cu or .sup.67Cu, gallium,
for instance .sup.67Ga, technetium, for instance .sup.99mTc, and
degradation products thereof.
[0076] In an embodiment, the radionuclide is used in nuclear
medicine.
[0077] In an embodiment, the radionuclide is used in at least one
of nuclear power plants and armament.
[0078] The selectivity of the reverse-micellar system according to
the invention for chelating or sequestering the radionuclides
and/or metals is linked to the selectivity of the active agent
comprised therein.
Metal
[0079] The metal that can be chelated and/or sequestered in the
reverse-micellar system according to the invention may be any
metal. For instance, the metal can be a transition metal, a heavy
metal, a lanthanide or an alkali metal.
[0080] In an embodiment, the metal is selected from iron, aluminum,
mercury, lead, arsenic, cadmium, copper, gold, beryllium, bismuth,
cobalt, chromium, nickel, protactinium, polonium, silver, platinum,
antimony, selenium, tin, technetium, titanium, zinc, manganese, and
thallium. In another embodiment, the metal is gadolinium.
[0081] The terms "radionuclides" and "metals" refer in the present
invention to any chemical form of said radionuclides and metals.
For instance, the radionuclides and/or metals to be chelated
according to the present invention may be in ionic form, optionally
with at least one counter-ion or complexed with at least one other
ligand, solvated or in the form of an oxide, before being
chelated.
Decorporation and Treatment
[0082] In the present invention, the terms treatment or
decorporation refer to any preventive and/or curative action that
is capable of suppressing or decreasing the duration or intensity
of any symptom due to the exposure to the radionuclide and/or
metal, or improving in any manner the state of health or comfort of
the patient.
[0083] In an embodiment, the metal or radionuclide is toxic for the
patient, or the amount of said metal or radionuclide present in the
patient in need of the treatment is toxic.
[0084] In an embodiment, the reverse-micellar system for use
according to the invention is used in the treatment of at least one
pathology linked to the accumulation and/or overload of at least
one metal in a patient in need thereof.
[0085] An overload refers to a concentration of said metal in the
patient body or in a specific organ or type of cells of the patient
body higher than the recommended concentration for the maintenance
of good health. In specific embodiments, the concentration is more
than 2 times, more than 3 times, more than 5 times, more than 10
times, more than 50 times or more than 100 times higher than the
recommended concentration. The recommended concentration may be
dependent on different parameters, such as the sex or the age of
the patient.
[0086] The pathology linked to the accumulation of at least one
metal may be either a pathology leading to said accumulation, such
as Wilson's disease or haemochromatosis, or a pathology or symptom
due to an accumulation from an external origin. For instance, the
accumulation may be due to a poisoning, preferably an unintentional
poisoning of the patient with said metal.
[0087] The poisoning may be due to ingestion or inhalation of said
metal by the patient.
[0088] Wilson's disease or hepatolenticular degeneration is an
autosomal recessive genetic disorder in which copper accumulates in
tissues; this manifests as neurological or psychiatric symptoms and
liver disease.
[0089] Mercury overload may be associated for instance with
anxiety, memory loss, depression, suicidal tendencies, loss of
strength and coordination, bleeding gums and tooth loss, abdominal
cramps, diarrhea or chronic constipation, abnormal heart rate or
blood pressure, repeated infections or cancer, chronic migraines,
allergies, dermatitis, heart palpitations, sinus congestion, loss
of appetite, chronic obesity and Alzheimer's disease.
[0090] Lead overload may be associated for instance with abdominal
pain, hypertension, kidney problems, loss of appetite, fatigue,
insomnia, hallucinations, headaches, tremors, arthritis, dizziness,
mental retardation, autism, psychosis, allergies, dyslexia,
hyperactivity, muscle weakness and paralysis.
[0091] Aluminium overload may be associated for instance with
memory loss, learning, difficulties, loss of coordination and
orientation, mental confusion, colic, "heartburn", flatulence and
headaches.
[0092] Arsenic overload may be associated for instance with nervous
and sensory changes (numbness, tingling), burning sensations in the
hands and feet, and progressive neuropathy (loss of nerve
function).
[0093] Cadmium overload may be associated with obstructive lung
disease, kidney disease, fragile bones, partial or total hair loss,
anemia, arthritis, learning difficulties, headaches, growth
retardation, osteoporosis, emphysema, loss of taste, smell,
frighten, and cardiovascular diseases.
[0094] Chromium overload may be associated with lung cancer, asthma
attacks in sensitive persons, stomach upsets and ulcers,
convulsions, kidney and liver damages and allergic
manifestations.
[0095] Iron overload (haemochromatosis, hemosiderosis,
polycythemia, and iron-loading anemias) may be associated with
cirrhosis of the liver, diabetes, cancer, cardiomyopathy, tanning
of the skin, arthritis (iron deposition in joints), joint pain and
bone pain.
[0096] Thallium overload may be associated with alopecia, memory
loss, ataxia and tremors.
[0097] In an embodiment, the pathology is linked to the
accumulation of at least one metal in at least one of liver,
kidneys, bowel, brain, nervous system, spleen and eye.
[0098] In another embodiment, reducing metal levels may be
necessary in neurologic pathologies in which some metals may
synergize the disease. This is the case for instance of Alzheimer
disease in which metal ions have been shown to increase the
(.beta.-amyloid plaque aggregation.
[0099] Another object of the present invention is a
reverse-micellar system comprising at least an active agent, an
acylglycerol, a sterol, lecithin, ethanol and water, wherein the
active agent is selected from the group consisting of DTPA
bisphosphonates, Prussian blue, EDTA, Trientine, D-penicillamine,
Deferoxamine, BAL, DMSA, DMPS, Phytic acid, hydroxypyridonates
(HOPO), mercaptoacetyltriglycine (MAG3) or chelating peptides, or
derivatives thereof and combinations thereof.
[0100] In an embodiment, the reverse-micellar system for use
according to the invention is used in the reduction of the
cumulative radiation dose delivered to the tissues by internalized
radionuclides. Indeed, the only possibility is decorporation of
radionuclides by chelation, as to facilitate their excretion by
natural means, such as urines or feces. According to a specific
embodiment, the reverse-micellar system of the invention is for use
in the reduction of the risk of developing diseases due to the
cumulative radiation dose delivered to the tissues by
radionuclides.
[0101] According to a specific embodiment, the reverse-micellar
system of the invention is for use in the treatment of at least one
disease linked to the accumulation and/or overload of at least one
radionuclide in a patient in need thereof.
[0102] The diseases (or pathologies) linked to the accumulation
and/or overload of at least one radionuclide may vary depending on
the radiation exposure (duration and/or amount), it can include
gastrointestinal disorders, such as nausea or vomiting, symptoms
related to falling blood counts, such as predisposition to
infection or bleeding, neurological disorders, or different types
of cancers (such as blood cancers or thyroid cancer).
[0103] Exposure to radionuclides and thus accumulation and/or
overload of radionuclides may have different origins, from the
involvement of a nuclear worker after breaking of the containment
of a glove box for example, to that of a multitude of people
contaminated by the widespread dissemination of radionuclides in
the environment, such as: incident/accident or natural disaster
affecting facilities of research, production, operation or storage
of nuclear materials, military conflict with nuclear weapons,
radionuclide containing weapons, terrorist act aiming at these
facilities or characterized by an explosive device dispersing
radionuclides called "dirty bomb."
[0104] Internalized radionuclides are highly toxic and may cause
both acute and chronic radiation injuries. The nuclides the most
frequently encountered in these scenarios include
actinides/lanthanides, such as americium, cesium, iodine,
plutonium, strontium, or uranium. Once internalized in the body,
the nuclide is distributed in several tissues (e.g. the lungs, bone
and/or liver).
[0105] According to a particular embodiment, the treatment for
actinide/lanthanide decorporation, such as Pu decorporation, is
chelator diethylene triaminopentaacetic acid (DTPA).
[0106] Another object of the present invention is a
reverse-micellar system comprising at least an active agent, an
acylglycerol, a sterol, lecithin, ethanol, water, and at least one
radionuclide and/or metal, wherein the at least one active agent is
a compound appropriate for chelating and/or sequestering said
radionuclide and/or metal.
[0107] The reverse-micellar system comprising at least one active
agent and at least one radionuclide and/or metal according to the
invention may be advantageously used for the delivery of the
radionuclide and/or metal chelated and/or sequestered by the active
agent to a patient.
[0108] Another object of the invention is a reverse-micellar system
comprising at least an active agent, an acylglycerol, a sterol,
lecithin, ethanol, water and a radionuclide and/or metal, wherein
the active agent is a compound appropriate for chelating and/or
sequestering said radionuclide and/or metal, for use as an imaging
agent and/or as a diagnosis agent.
[0109] Another object of the invention is a method of imaging at
least part of at least one organ of a patient, comprising the
administration of a reverse-micellar system comprising at least an
active agent, an acylglycerol, a sterol, lecithin, ethanol, water
and a radionuclide and/or metal, wherein the active agent is a
compound appropriate for chelating and/or sequestering said
radionuclide and/or metal. Said method of imaging advantageously
further comprises a step of detecting the emitted radiation and/or
signal, and preferably a step of forming an image therefrom.
[0110] Another object of the invention is the use of a
reverse-micellar system comprising at least an active agent, an
acylglycerol, a sterol, lecithin, ethanol, water and a radionuclide
and/or metal, wherein the active agent is a compound appropriate
for chelating and/or sequestering said radionuclide and/or metal,
in the preparation of a composition to be used in a method of
imaging and/or diagnosis.
[0111] The amount of reverse-micellar system to be administered for
implementing the imaging method can be easily adapted by anyone of
ordinary skill in the art in function of the amount of radionuclide
and/or metal in the reverse-micellar system, the area(s) to
visualize with this imaging method, and the imaging technique
used.
[0112] The method of imaging may be for instance scintigraphy or
Magnetic Resonance Imaging (MRI). In an embodiment, the method of
imaging is scintigraphy of bone, kidney, brain and/or lung. The
term "imaging agent" refers in the present invention to an agent
that can be advantageously used in a method of imaging to improve
the quantity and/or quality of the emitted radiation and/or signal
or of the image formed therefrom.
[0113] Another object of the invention is thus a reverse-micellar
system for use as an imaging agent according to the invention,
wherein the imaging agent is used in scintigraphy and/or MRI.
[0114] The imaging agent may also be used for studying the
perfusion of the renal and/or urinary tract function, or for
determining the glomerular filtration rate.
[0115] The method of imaging according to the invention may be part
of a diagnosis method for determining pathology, preferably
pathology of the visualized area, for instance bone, kidney, brain
and/or lung pathology. The term "diagnosis agent" refers in the
present invention to an agent that can be advantageously used to
help determining the existence of a pathology or of a risk of
pathology, for instance a pathology of the bones, kidneys, brain
and/or lungs.
[0116] In particular, the radionuclide comprised in the
reverse-micellar system is technetium 99m, and/or the active agent
is selected from the group consisting of bisphosphonates, DMSA,
DTPA and mercaptoacetyltriglycine (MAG3). In that context, the
radionuclide (such as technetium) with the active agent is in the
form of a complex or chelate in the reverse-micellar system (such
as Technetium (.sup.99mTc)-exametazime, Technetium
(99mTc)-sestamibi, Technetium (.sup.99mTc)-DTPA, or Technetium
(.sup.99mTc)-MAG3).
[0117] In particular, the metal comprised in the reverse-micellar
system is gadolinium, and/or the active agent is DTPA. In that
context, the metal with the active agent is in the form of a
metal-based contrast agent (such as a gadolinium-based contrast
agent) in the reverse-micellar system (such as Gd-HP-DO3A--also
named as Gadoteridol-, Gd-DTPA, Gd-DTPA-BMEA, Gd-EOB-DTPA, Gd-DOTA,
Gd-BOPTA).
[0118] The administration of the radionuclide and/or metal in the
form of a chelate with the active agent allows first that the
radionuclide and/or metal has no biological action in the organism,
for instance it does not settle in the tissues, and second it
affords an easy elimination of the radionuclide and/or metal after
imaging. In addition, the reverse-micellar system affords an
efficient delivery of the chelated and/or sequestered radionuclide
and/or metal via the transmucosal route, which highly favors
patient's compliance. In addition, the reverse-micellar system is
appropriate for efficiently delivering the chelated and/or
sequestered radionuclide and/or metal to any part of the body, such
as bone, kidney, brain and/or lung with the same transmucosal
administration route.
[0119] Comparatively, the administration of chelated technetium 99m
is nowadays performed intravenously for bone, kidney and/or brain
scintigraphy, but said chelated radionuclide is administered by
inhalation in the form of an aerosol for lung scintigraphy.
[0120] The administration of chelated gadolinium for MRI is
classically performed intravenously.
Administration of the Reverse-Micellar Systems
[0121] The reverse micellar-systems according to the invention are
able to be absorbed through mucosa and to vectorize active agents
under a protected form to any tissue of the organism.
[0122] The reverse-micellar system may be administered via
different routes. In a preferred embodiment of the invention, the
reverse-micellar system is administered by topical or transmucosal
route, preferably via transmucosal route.
[0123] As used herein, the terms "mucosa" and "mucosal" refer to a
mucous tissue such as of the respiratory, digestive, or genital
tissue. "Transmucosal delivery", "mucosal delivery", "mucosal
administration" and analogous terms as used herein refer to the
administration of a composition through a mucosal tissue.
"Transmucosal delivery", "mucosal delivery", "mucosal
administration" and analogous terms include, but are not limited
to, the delivery of a composition through bronchi, gingival,
lingual, nasal, oral, buccal, oesophageal, vaginal, rectal, and
gastro-intestinal mucosal tissue.
[0124] In a specific embodiment, the mucosal administration is
through buccal mucosal tissue.
[0125] The reverse-micellar system can be administered according to
the invention at any time with respect to the exposure to and/or
contamination with metal and/or radionuclide. In an embodiment, the
reverse-micellar system is administered preventively, that means
before the exposure to and/or contamination with the
radionuclide(s) and/or metal(s).
[0126] In another embodiment, the reverse-micellar system is
administered in the first day, preferably in the first hour, in
particular in the first 20 minutes, following the exposure to
and/or contamination with the radionuclide(s) and/or metal(s).
[0127] In another embodiment, the reverse-micellar system is
administered more than 24 hours, preferably more than 48 hours, in
particular more than 96 hours, after the end of the exposure to the
radionuclide(s) and/or metal(s).
[0128] The reverse micellar system of the invention has been shown
to be effective at decorporating a radionuclide when the treatment
is started immediately after 1 hour, 4 days after, and even 7 days
after the contamination, preferably the internal contamination.
[0129] The skilled practitioner will be able to adapt the number of
daily administrations, the amount to be administered, the frequency
of administration and/or the moment when the treatment is started
in function of the amount of active agent present in the
reverse-micellar system and the type and intensity of the
contamination with the metal or radionuclide.
[0130] In the embodiment where the reverse-micellar system is used
in the treatment of a pathology linked to the accumulation of at
least one metal in a patient in need thereof, the pathology is not
necessarily initiated by exposure to said metal. The pathology may
also be linked to chronic exposure to a metal.
[0131] The reverse-micellar system may be formulated in a
composition further comprising a pharmaceutically acceptable
support.
[0132] Another object of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable support and a
reverse-micellar system comprising at least an active agent, an
acylglycerol, lecithin, ethanol and water, wherein the active agent
is a compound appropriate for chelating and/or sequestering at
least one metal and/or radionuclide.
[0133] The term "pharmaceutically acceptable support" refers to any
pharmaceutically acceptable excipient, vehicle or carrier,
well-known to the person skilled in the art. Other additives
well-known to the person skilled in the art such as stabilisers,
drying agents, binders or pH buffers may also be used. Preferred
excipients in accordance with the invention promote adherence of
the finished product to the mucosa.
[0134] According to particular embodiments, the pharmaceutical
composition is in the form of a capsule, a caplet, an aerosol, a
spray, a solution or a soft elastic gelatin capsule.
[0135] In an embodiment, the reverse-micellar system comprised in
the pharmaceutical composition further comprises at least one
radionuclide and/or metal, and the at least one active agent
comprised in the reverse-micellar system is a compound appropriate
for chelating and/or sequestering said radionuclide and/or
metal.
Preparation of the Reverse-Micellar Systems of the Invention
[0136] The reverse-micellar systems of the invention may be
prepared by any technique known in the art. They are more
particularly obtainable by the following method: [0137] (a)
Contacting (i) acylglycerol, preferably diacylglycerol, (ii)
lecithin, (iii) ethanol, (iv) water, preferably purified water, (v)
sterol, and (vi) at least one active agent, [0138] (b) Stirring
mixture obtained in step (a), at 40.degree. C. or less, and for a
time sufficient to obtain formation of the reverse-micellar
system.
[0139] The parameters of stirring, for instance duration and speed
of mechanical stirring, can be readily determined by any one
skilled in the art and depend on experimental conditions. In
practice, these parameters are such that a homogenous
reverse-micellar system is obtained; the speed is determined so as
to enable formation of a visually limpid formulation, and duration
of the stirring is such that the stirring may be stopped a few
minutes alter obtaining the visually limpid formulation.
[0140] In the embodiments where the reverse-micellar system further
comprises a radionuclide and/or metal, said radionuclide and/or
metal is preferably introduced in the system at step (a).
[0141] The following examples are provided as illustrative, and not
limitative, of the present invention.
EXAMPLES
Example 1: Reverse-Micellar Systems Comprising CaNa.sub.3DTPA
Sample A
[0142] 35.7 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 21.5 g of
absolute ethanol under magnetic stilling at 300 r/min at room
temperature. 5.9 g of phytosterol, containing more than 70% of
beta-sitosterol, were added to the mixture and stirred in the same
conditions. 144.6 g of Peceol.RTM. were added thereto and magnetic
stirring was carried out at 700 r/min at 37.degree. C. to form an
oil mixture.
[0143] 6.0 g of a solution containing 647.9 mg of CaNa.sub.3DTPA in
water were added to 41.5 g of the oil mixture at room temperature.
2.0 g of absolute ethanol were then added to the mixture by
vortexing few minutes to form microemulsion containing 13.1 mg/g or
12.5 mg/ml of CaNa.sub.3DTPA (density of 0.95).
Sample B
[0144] 3.0 g of a solution containing 187.6 mg of CaNa.sub.3DTPA in
water were added at room temperature to 20.7 g of the oil mixture
prepared for the sample A formulation. 1.0 g of absolute ethanol
were then added to the mixture by vortexing few minutes to form
microemulsion containing 7.6 mg/g or 7.2 mg/ml of CaNa.sub.3DTPA
(density of 0.95).
Sample C
[0145] 3.0 g of a solution containing 95.1 mg of CaNa.sub.3DTPA in
water were added at room temperature to 20.7 g of the oil mixture
prepared for the sample A formulation. 1.0 g of absolute ethanol
were then added to the mixture by vortexing few minutes to form
microemulsion containing 3.8 mg/g or 3.6 mg/ml of CaNa.sub.3DTPA
(density of 0.95).
Sample D
[0146] 21.4 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 12.8 g of
absolute ethanol under magnetic stirring at 300 r/min at room
temperature. 3.6 g of phytosterol, containing more than 70% of
beta-sitosterol, were added to the mixture and stirred in the same
conditions. 86.8 g of Peceol.RTM. were added thereto and magnetic
stirring was carried out at 700 r/min at 37.degree. C. to form an
oil mixture.
[0147] 12.1 g of a solution containing 1.3 g of CaNa.sub.3DTPA in
water were added to 83.0 g of the oil mixture at room temperature.
4.0 g of absolute ethanol were then added to the mixture by
vortexing few minutes to form microemulsion containing 13.1 mg/g or
12.5 mg/ml of CaNa.sub.3DTPA (density of 0.95).
Examples 2-4--Materials and Methods
[0148] The animals used were male rats of the Sprague-Dawley strain
of about 8 weeks of age upon arrival in the laboratory. Four to
five rats form a test batch.
[0149] Under gaseous isoflurane anesthesia, each rat received an
injection in a tail vein of 200 .mu.l of a citrate solution of
plutonium (9703-9778 Bq; composition: 99.4% .sup.238Pu+0.4%
.sup.239Pu+0.2% .sup.241Am (alpha activity), pH 6.5, 2 to 6.8 mM
citrate).
[0150] The active agent is CaNa.sub.3DTPA, being the trisodium
calcium salt form of the chelating agent DTPA, incorporated into
the reverse-micellar system according to the invention.
[0151] Using a micropipette and its cut blunt cone, each rat of the
treated groups received an intrarectal administration of 200 .mu.l
of reverse-micelle composition comprising CaNa.sub.3DTPA. (3.6, 7.2
or 12.5 mg CaNa.sub.3DTPA/ml reverse-micelles), at 2 or 4 times
daily for 5 consecutive days. This chronic repeated administration
protocol begins 1 hour (H+1), 4 days (D+4) or 7 days (D+7) after
contamination. For implementing the treatment, the rats were made
slightly sleepy with gaseous isoflurane anesthesia to ensure a more
reproducible deposition. Just before the deposition on the rectal
mucosa, feces that may be present in the rat rectum are removed
mechanically by palpation. Despite this precaution, the
introduction of the cone into the rectum can stimulate defecation.
If this takes place immediately after deposition (<few seconds),
a second deposit is made.
[0152] Euthanasia and tissue samples: Under deep pentobarbital
anesthesia, the rats are euthanized 12-14 days after the
contamination, by laparotomy, a section of the abdominal aorta and
the diaphragm. Liver and both femurs were removed.
[0153] Mineralization of biological samples: Tissue samples were
calcined in the oven and then mineralized in wet conditions
(H.sub.2O.sub.2+HNO.sub.32N). Mineralized samples are then
dissolved in 2N HNO.sub.3.
[0154] Physical measurements of alpha activity: The content of
alpha activity of each sample was measured by liquid scintillation
counting.
Example 2: Chronic Treatment with CaNa.sub.3DTPA Incorporated in a
Reverse-Micellar System According to the Invention
[0155] Four days after the Pu contamination, rats followed a
chronic treatment protocol consisting of two rectal administrations
of the reverse-micellar system comprising DTPA daily for 5 days,
each deposit being done at 3.6, 7.2 or 12.5 mg
CaNa.sub.3DTPA.ml.sup.-1 in reverse-micellar system, leading to
cumulative doses of 44.3, 88.6 or 153.8 .mu.molkg.sup.-1 (samples
A, B and C), or in 4 daily rectal deposits at 12.5 mgml.sup.-1,
leading to the cumulative DTPA dose of 307.6 .mu.molkg.sup.-1
(sample A).
[0156] At D+12 to14, the liver and hone retention of Pu were lower
for treated rats than those of the untreated control rats (see
FIGS. 1a and 1b). Chronic treatment with the reverse-micellar
system comprising CaNa.sub.3DTPA is therefore efficient for
decorporating Pu.
[0157] The efficacy of decorporation in liver or bone Pu deposits
is proportional to the administered dose cumulative of
CaNa.sub.3DTPA (see FIGS. 2a and 2b).
Example 3: Influence of the Moment of the Initiation of the
Treatment
[0158] One hour, four days or seven days after the Pu
contamination, rats followed a chronic treatment protocol
consisting in 4 rectal administrations of the reverse micellar
system comprising CaNa.sub.3DTPA daily for 5 days, each deposit
being done at 12.5 mg CaNa.sub.3DTPA per ml of reverse-micellar
system, leading to a cumulative dose of 307.6 .mu.molkg.sup.-1
(sample D). On D+12 to 14, treated rats have lower liver and bone
deposits of Pu than those of untreated control rats, regardless of
the time of initiation of chronic treatment protocol (see FIGS. 3a
and 3b).
[0159] This decorporation of systemic Pu deposits in liver and bone
by a protocol of chronic treatment with the reverse-micellar system
comprising CaNa.sub.3DTPA is more effective if the protocol begins
early after Pu contamination (see FIGS. 3a and 3b).
Example 4: Influence of the Frequency of Rectal Deposits on the
Efficacy of the Treatment
[0160] The cumulative doses of 44.3, 88.6 and 153.8
.mu.molkg.sup.-1 result from two daily administrations for 5 days
of 3.6, 7.2 and 12.5 mg of CaNa.sub.3DTPA per ml of
reverse-micellar system (samples A, B and C). The cumulative dose
of 307.6 .mu.molkg.sup.-1 CaNa.sub.3DTPA results from 4 daily
administrations for 5 days of 12.5 mg of CaNa.sub.3DTPA per ml of
reverse micellar system (sample A). The point corresponding to the
efficacy of decorporation of the Pu deposits for the cumulative
dose of 307.6 .mu.molkg.sup.-1 aligns with the linear regression
performed for lower cumulative doses (see FIGS. 1 and 2).
[0161] This strongly suggests the absence of influence of daily
dosing frequency on the efficacy of chronic treatment protocol, the
dosage seeming to be the determining factor for the effectiveness
of the chronic protocol in the range of dosages tested.
Examples 2-4, Conclusions
[0162] The overall results show the effectiveness of CaNa.sub.3DTPA
incorporated in the reverse-micellar system for decorporating
systemic and tissue Pu deposits.
[0163] The undeniable advantage of this dosage form is its
potential for simple, fast and autonomous administration, including
making repeated undemanding treatment.
[0164] As the chemical structure of CaNa.sub.3DTPA is not altered
by the formulation, any element for which the CaNa.sub.3DTPA is
recommended or suspected to be effective could also be formulated
similarly.
Example 5: Reverse-Micellar Systems Comprising PEG-Amine Stabilized
Nanoparticles of Ferric Hexacyanoferrate (II) (Prussian Blue)
Sample E
[0165] 7.1 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 4.3 g of absolute
ethanol under magnetic stirring at 300 r/min at room temperature.
1.2 g of phytosterol, containing more than 70% of beta sitosterol,
were added to the mixture and stirred in the same conditions. 28.9
g of Peceol.RTM. were added thereto and magnetic stirring was
carried out at 700 r/min and 37.degree. C. to form an oil
mixture.
[0166] 244.7 mg of a solution containing 4.1 mg PEG-amine
stabilized nanoparticles of prussian blue in water were mixed with
1.7 g of the oil mixture by vortexing a few minutes to form a
microemulsion containing 2.1 mg/g or 2.0 mg/ml of PEG-amine
stabilized nanoparticles of prussian blue (density of 0.95).
Sample F
[0167] 3.8 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 2.3 g of absolute
ethanol under magnetic stirring at 300 r/min and room temperature.
0.5 g of phytosterol, containing more than 70% of beta-sitosterol,
were added to the mixture and stirred in the same conditions. 9.5 g
of Peceol.RTM. were added thereto and magnetic stirring was carried
out at 700 r/min and 37.degree. C. to form an oil mixture.
[0168] 297.2 mg of a solution containing 7.9 mg of PEG-amine
stabilized nanoparticles of prussian blue in water were mixed with
1.6 g of the oil mixture by vortexing a few minutes to form a
microemulsion containing 4.2 mg/g or 4.0 mg/ml of PEG-amine
stabilized nanoparticles of prussian blue (density of 0.95).
Example 6: Reverse-Micellar Systems Comprising Tiludronate
Sample G
[0169] 28.4 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 17.1 g of
absolute ethanol under magnetic stirring at 300 r/min and room
temperature. 4.8 g of phytosterol, containing more than 70% of
beta-sitosterol, were added to the mixture and stirred in the same
conditions. 115.7 g of Peceol.RTM. were added thereto and magnetic
stirring was carried out at 700 r/min and 37.degree. C. to form an
oil mixture.
[0170] 120.3 mg of a solution containing 1.0 mg of tiludronate in
water were mixed with 829.8 mg of the oil mixture by vortexing a
few minutes to form a microemulsion containing 1.1 mg/g or 1.0
mg/ml of tiludronate (density of 0.95).
Sample H
[0171] 19.0 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 11.4 g of
absolute ethanol under magnetic stirring at 300 r/min and room
temperature. 2.4 g of phytosterol, containing more than 70% of
beta-sitosterol, were added to the mixture and stirred in the same
conditions. 47.2 g of Peceol.RTM. were added thereto and magnetic
stirring was carried out at 700 r/min and 37.degree. C. to form an
oil mixture.
[0172] 212.3 trig of a solution containing 8.3 mg of tiludronate in
water were mixed with 1.4 g of the oil mixture by vortexing a few
minutes to form a microemulsion containing 5.1 mg/g or 4.8 mg/ml of
tiludronate (density of 0.95).
Example 7: Reverse-Micellar Systems Comprising CaNa.sub.3DTP
Sample I
[0173] 56.4 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 24.4 g of
absolute ethanol under magnetic stirring at 300 r/min and room
temperature. 4.7 g of phytosterol, containing more than 70% of
beta-sitosterol, were added to the mixture and stirred in the same
conditions. 62.5 g of Peceol.RTM. were added thereto and magnetic
stirring was carried out at 700 r/min and 37.degree. C. to form an
oil mixture.
[0174] 16.2 g of a solution containing 2.4 g of CaNa.sub.3DTPA in
water were mixed with 59.9 g of the oil mixture by vortexing a few
minutes to form a microemulsion containing 31.4 mg/g or 30.5 mg/ml
of CaNa.sub.3DTPA (density of 0.97).
Sample J
[0175] 28.5 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 8.6 g of absolute
ethanol under magnetic stirring at 300 r/min and room temperature.
2.4 g of phytosterol, containing more than 70% of beta-sitosterol,
were added to the mixture and stirred in the same conditions. 35.6
g of Peceol.RTM. were added thereto and magnetic stirring was
carried out at 700 r/min and 37.degree. C. to form an oil
mixture.
[0176] 401.2 mg of a solution containing 4.1 mg of CaNa.sub.3DTPA
in water were mixed with 1.5 g of the oil mixture by vortexing a
few minutes to form a gel containing 2.1 mg/g of
CaNa.sub.3DTPA.
Example 8: Reverse-Micellar Systems Comprising Deferoxamine
Mesylate
Sample K
[0177] 4.7 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 8.6 g of absolute
ethanol under magnetic stirring at 300 r/min and room temperature.
2.4 g of phytosterol, containing more than 70% of beta-sitosterol,
were added to the mixture and stirred in the same conditions. 73.4
g of Peceol.RTM. were added thereto and magnetic stirring was
carried out at 700 r/min and 37.degree. C. to form an oil
mixture.
[0178] 119.8 mg of a solution containing 12.0 mg of deferoxamine
mesylate in water were mixed with 1.8 g of the oil mixture by
vortexing a few minutes to form a microemulsion containing 6.3 mg/g
or 5.9 mg/ml of deferoxamine mesylate (density of 0.94).
Sample L
[0179] 14.3 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 8.6 g of absolute
ethanol by magnetic stirring at 300 r/min and room temperature. 2.4
g of phytosterol, containing more than 70% of beta-sitosterol, were
added to the mixture and stirred in the same conditions. 57.8 g of
Peceol.RTM. were added thereto and magnetic stirring was carried
out at 700 r/min and 37.degree. C. to form an oil mixture.
[0180] 239.8 mg of a solution containing 24.0 mg of deferoxamine
mesylate in water were mixed with 1.7 g of the oil mixture by
vortexing a few minutes to form a microemulsion containing 12.6
mg/g or 12.0 mg/ml of deferoxamine mesylate (density of 0.95).
Example 9: Reverse-Micellar Systems Comprising CaNa.sub.2EDTA
Sample M
[0181] 301.3 mg of a solution containing 37.2 mg of CaNa.sub.2EDTA
in water were mixed with 1.6 g of the oil mixture described in
sample H formulation by vortexing a few minutes to form a
microemulsion containing 19.4 mg/g or 18.4 mg/ml of CaNa.sub.2EDTA
(density of 0.95).
Sample N
[0182] 28.5 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 11.4 g of
absolute ethanol under magnetic Mining at 300 r/min and room
temperature. 2.4 g of phytosterol, containing more than 70% of
beta-sitosterol, were added to the mixture and stirred in the same
conditions. 32.8 g of Peceol.RTM. were added thereto and magnetic
stirring was carried out at 700 r/min and 37.degree. C. to form an
oil mixture.
[0183] 400.8 mg of a solution containing 41.9 mg of CaNa.sub.2EDTA
in water were mixed with 1.5 g of the oil mixture by vortexing a
few minutes to form a micro emulsion containing 22.0 mg/g 21.1
mg/ml of CaNa.sub.2EDTA (density of 0.96).
Example 10: Reverse-Micellar Systems Comprising D-Penicillamine
Sample O
[0184] 120.8 mg of a solution containing 10.2 mg of D-penicillamine
in water were mixed with 1.8 g of the oil mixture described in
sample K formulation by vortexing a few minutes to form a
microemulsion containing 5.3 or 5.0 mg/ml of D-penicillamine
(density of 0.94).
Sample P
[0185] 244.9 mg of a solution containing 20.4 mg of D-penicillamine
in water were mixed with 1.7 g of the oil mixture described in
sample L formulation by vortexing a few minutes to form a
microemulsion containing 10.5 mg/g or 10.0 mg/ml of D-penicillamine
(density of 0.95).
Example 11: Reverse-Micellar Systems Comprising Trientine
Sample Q
[0186] 120.0 mg of a solution containing 18.8 mg of trientine in
water were mixed with 837.4 mg of the oil mixture described in
sample L formulation by vortexing a few minutes to form a
microemulsion containing 19.6 mg/g or 18.6 mg/ml of trientine
(density of 0.95).
Example 12: Reverse-Micellar Systems Comprising Dimercaprol
(BAL)
Sample R
[0187] 11.8 mg of dimercaprol were mixed with 828.9 mg of the oil
mixture described in sample L formulation and to 108 mg of water by
vortexing a few minutes to form a microemulsion containing 12.4
mg/g or 11.8 mg/ml of dimercaprol (density of 0.95).
Sample S
[0188] 118.5 mg of dimercaprol were mixed with 830.8 mg of the oil
mixture described in sample L formulation by vortexing a few
minutes to form a microemulsion containing 124.4 mg/g or 120.6
mg/ml of dimercaprol (density of 0.97).
Example: 13: Reverse-Micellar Systems Comprising Phytic Acid
Sample T
[0189] 239.5 mg of a solution containing 10.0 mg of phytic acid in
water were mixed with 1.7 g of the oil mixture described in sample
L formulation by vortexing a few minutes to form a microemulsion
containing 5.2 mg/g or 4.9 mg/ml of phytic acid (density of
0.95).
Sample U
[0190] 400.0 mg of a solution containing 20.1 mg of phytic acid in
water were mixed with 1.5 g of the oil mixture described in sample
by vortexing a few minutes to form a gel containing 10.5 mg/g of
phytic acid.
Example 14: Reverse-Micellar System Comprising Etidronate
Disodium
Sample V
[0191] 1.5.0 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 9.0 g of absolute
ethanol under magnetic stirring at 300 r/min and room temperature.
2.5 g of phytosterol, containing more than 70% of beta-sitosterol,
were added to the mixture and stirred in the same conditions. 60.9
g of Peceol.RTM. were added thereto and magnetic stirring was
carried out at 700 r/min and 37.degree. C. to form an oil
mixture.
[0192] 5.1 g of a solution containing 72 mg of etidronate disodium
in water were mixed with 34.9 g of the oil mixture by vortexing a
few minutes to form a microemulsion containing 1.8 mg/g of
etidronate disodium.
Example 15: Reverse-Micellar System Comprising Gadolinium-DTPA
(Gd-DTPA) Complex
Sample W
[0193] 141.0 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 122 g of absolute
ethanol under magnetic stirring at 300 r/min and room temperature.
23.5 g of phytosterol, containing more than 70% of beta-sitosterol,
were added to the mixture and stirred in the same conditions. 533.4
g of Peceol.RTM. were added thereto and magnetic stirring was
carried out at 700 r/min and 37.degree. C. to form an oil
mixture.
[0194] 240.8 mg of a solution containing 10.9 mg of Gd-DTPA in
water were mixed with 1.7 g of the oil mixture by vortexing a few
minutes to form a microemulsion containing 5.7 mg/g of Gd-DTPA.
Example 16: Reverse-Micellar System Comprising Gadolinium-HP-DO3A
(Gadoteridol) Complex
Sample X
[0195] 34.9 g of commercially available lecithin, containing more
than 90% of phosphatidylcholine were dissolved in 5.8 g of absolute
ethanol under magnetic stirring at 300 r/min and mom temperature.
30.2 g of phytosterol, containing more than 70% of beta-sitosterol,
were added to the mixture and stirred in the same conditions. 131.8
g of Peceol.RTM. were added thereto and magnetic stirring was
carried out at 700 r/min and 37.degree. C. to form an oil
mixture.
[0196] 1.2 g of a solution containing 294.8 mg of Gadoteridol in
water were mixed with 8.8 g of the oil mixture by vortexing a few
minutes to form a microemulsion containing 29.5 mg/g of
gadoteridol.
[0197] Table 1 shows the amounts (w/w %) of individual components
in the different samples.
TABLE-US-00001 TABLE 1 Leci- Phytos- Aqueous Sam- API thin terol
Ethanol Peceol solution ples (%) (%) (%) (%) (%) (%) A
CaNa.sub.3DTPA 14.4 2.4 12.7 58.3 12.2 (1.31) B CaNa.sub.3DTPA 14.4
2.4 12.7 58.3 12.2 (0.76) C CaNa.sub.3DTPA 14.4 2.4 12.7 58.3 12.2
(0.38) D CaNa.sub.3DTPA 14.4 2.4 12.7 58.3 12.2 (1.31) E Prussian
Blue 15.0 2.5 9.0 60.9 12.6 (0.21) F Prussian Blue 19.9 2.5 12.0
49.8 15.8 (0.42) G Tiludronate 15.0 2.5 9.0 60.9 12.6 (0.11) H
Tiludronate 20.0 2.5 12.0 49.7 15.8 (0.51) I CaNa.sub.3DTPA 30.0
2.5 13.0 33.2 21.3 (3.14) J CaNa.sub.3DTPA 30.0 2.5 9.0 37.5 21.0
(0.21) K Deferoxamine 5.0 2.5 9.0 77.2 6.3 mesylate (0.63) L
Deferoxamine 15.0 2.5 9.0 60.9 12.6 mesylate (1.26) M
CaNa.sub.2EDTA 20.0 2.5 12.0 49.7 15.8 (1.94) N CaNa.sub.2EDTA 30.0
2.5 12.0 34.5 21.0 (2.20) O D-penicillamine 5.0 2.5 9.0 77.2 6.3
(0.53) P D-penicillamine 15.0 2.5 9.0 60.7 12.8 (1.05) Q Trientine
15.0 2.5 9.0 60.9 12.6 (1.96) R Dimercaprol 15.0 2.5 9.0 60.8 11.4
(1.24) S Dimercaprol 15.0 2.5 9.0 60.8 0.0 (12.4) T Phytic acid
15.0 2.5 9.0 60.9 12.6 (0.52) U Phytic acid 30.0 2.5 9.0 37.5 21.0
(1.05) V Etidronate 15.0 2.5 9.0 60.8 12.7 disodique (0.18) W
Gd-DTPA 15.0 2.5 13.0 56.9 12.6 (0.57) X Gd-HP-DO3A 15.0 2.5 13.0
57.2 12.0 (2.95)
* * * * *