NZ714077B2 - Gel formulations for guiding radiotherapy - Google Patents
Gel formulations for guiding radiotherapy Download PDFInfo
- Publication number
- NZ714077B2 NZ714077B2 NZ714077A NZ71407714A NZ714077B2 NZ 714077 B2 NZ714077 B2 NZ 714077B2 NZ 714077 A NZ714077 A NZ 714077A NZ 71407714 A NZ71407714 A NZ 71407714A NZ 714077 B2 NZ714077 B2 NZ 714077B2
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- New Zealand
- Prior art keywords
- ray contrast
- ray
- gel
- saib
- peg
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Classifications
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- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
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- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
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- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0452—Solutions, e.g. for injection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0457—Semi-solid forms, ointments, gels, hydrogels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0476—Particles, beads, capsules, spheres
- A61K49/0485—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1806—Suspensions, emulsions, colloids, dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention describes an X-ray contrast composition for local administration, wherein the X-ray contrast composition exhibits contrast properties and wherein at least 60% of an administrated amount of said X-ray contrast composition remains more than 24 hours within 10 cm from an injection point when the X-ray contrast composition is administrated to a human or animal body. point when the X-ray contrast composition is administrated to a human or animal body.
Description
GEL FORMULATIONS FOR GUIDING RADIOTHERAPY
Field of the invention
The t invention relates to improved formulations for guiding
radiotherapy.
Technical Background
Every year more than 12 million people are diagnosed with cancer worldwide
and over 7.5 million people die from cancer each year. These numbers are ed
to increase e of population growth and due to the lifestyle in the Western
world. Radiotherapy is an important part of modern cancer ent and more
than 50% of cancer patients receive radiotherapy at least once. Modern
radiotherapy relies on advanced high precision planning, ent equipment and
imaging techniques (such as, e.g., computed tomography (CT), positron-emission
tomography (PET) and magnetic imaging resonance (M Rl)) in order to deliver high
radiation doses to a precisely defined target in patients.
One ofthe main difficulties in external beam radiotherapy is that both
tumors and the surrounding tissue move significantly and unpredictably during
radiotherapy; both within each single treatment, and during the whole course of
radiotherapy, lasting usually 5—7 weeks. These movements can be dramatic (e.g.
several cm within seconds) and may be caused by various factors such as respiration,
bladder- and bowel filling, air passing colon, tumor shrinkage and set-up variation of
the patient. One way of minimizing this problem is the implantation of markers in or
adjacent to the tumor allowing frequent imaging and treatment adaptation. So far,
markers have been inserted using long and thick needles, a complicated procedure
with a significant risk of complications, which is ng the practical usefulness of
markers in radiotherapy.
Ideally, a tissue marker should enable tracking of tumor movement; be
visible on several image ties; be visible for an extended period (e.g., at least 4
; be non-toxic; and be easy to insert.
Various attempts have been made for improvements within the field of
radiotherapy. 935 describes a composition for lled release of a
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substance WO9403155 describes a hydrogel composition prepared from a ne
bonded to a cross—linking agent. The hydrogels may be loaded with therapeutic
drugs and diagnostic labels, including X-ray contrast imaging agents for disease
diagnostics and treatment. U520120065614 discloses a hybrid system for bio
imaging. Gold is bound into a matrix comprising a hydrogel or polymer or similar. In
U520100297007 a substantially bi concave shaped nanoparticle is disclosed, the
nanoparticle comprising an aqueous inner core and a hydrophilic outer shell
comprising an hilic polymer.
Furthermore, U52009110644 discloses a nanoparticle consisting of a polymer
which is a metal chelating agent coated with a magnetic metal oxide, wherein at
least one active agent is covalently bound to the polymer. In the documents
U520100290995 and U52005036946, radio-opaque biodegradable compositions are
disclosed by ing terminal groups of synthetic and natural biodegradable
polymers such as polylactones with iodinated moieties and in SE403255 a contrast
agent is disclosed that comprises a polymer comprising hydroxy— and/or carboxy-
and/or amino groups further comprising X-ray contrast giving iodo-substituted
aromatic groups. Further yet, the document W09519184 discloses air ulating
micro particles formed by ionotropically gelling synthetic polyelectrolytes such as
poly(carboxylato—phenoxy)phosphazene, poly(acrylic acid), ethacrylic acid)
and rylic acid copolymers (Eudragit's) by contact with multivalent ions such
as m ions.
There are several drawbacks to the current al practice using solid
markers and the methods described in the documents above. Installation of solid
markers is invasive due to the large ion ofthe solid implant which may cause
severe complications limiting is usefulness in radiotherapy. By combining gel-
g, scosity solutions with solid particles and/or organic X-ray contrast
agents (or other imaging modalities) injectable gels can be ated with fine—
tuned properties as these can be modified by multiply parameters with t to
the gel forming solution and the contrast agents used. The solid particles can,
besides contributing to the overall contrast of the system, also carry pharmaceutical
substances and control their release in a controlled manner.
W0 2014!187962 2014/060673
One aim of the present ion is to provide new formulations comprising
rming, low-viscosity systems that are easy to administer parenterally, and
wherein the present invention provides good visualization by one or multiple
imaging modalities, including X—ray imaging.
Summary ofthe invention
X-ray imaging of a locally administered reference marker is achieved by use
of an X-ray contrast composition, wherein the X—ray contrast composition exhibits
contrast properties and n at least 60% of an administrated amount of said X-
ray contrast composition remains more than 24 hours within 10 cm from an
injection point when the X-ray contrast composition is administrated to a human or
animal body.
Detailed description of the invention
The formulation is preferably in the form adapted for parenteral
administration, and should preferably t of pharmaceutically acceptable
constituents. The formulation which as such has a comparable low viscosity is
intended for injection in the body of a human or animal, where after the formulation
becomes more viscous, e.g. it goes through a sol—gel transition (liquid to gel) or
forms a amorphous glass , due to the presence ofthe gel-forming system. It is
red that the viscosity of the formulation after injection in the body of a human
or animal increases by at least 50 %, such as at least 80 %, such as at least 100 %, or
at least 150 %, or at least 200 %, or at least 300 %, or at least 500 %, or at least 750
%, or at least 1000 %, or at least 10,000%, or that the formulation s
essentially solid (non-viscous).
The formulation is ably adapted for injection via a thin needle used for
injection into a body or surgical related procedures, such as but not limited to
biopsy. The viscosity of the hydrogel or gel-forming formulation before ion can
be any suitable viscosity such that the formulation can be parenterally administered
to a patient.
Exemplary formulations include, but are not limited to, those having a
viscosity (prior to administration/injection) lower than 10,000 centipoise (cP), e.g.
lower than 2,000 cP, such as 10 to 2,000 cP, such as 20 to 1,000 cP, such as 150 to
W0 2014!187962
350 cP, such as 400 to 600 cP, such as 600 to 1,200 cP or such as 1,000 to 2,000 cP,
or 10 to 600 cP, or 20 to 350 cP, at 20 °C.
Alternative formulations include, but are not limited to, those having a viscosity
(prior to administration/injection) lower than 10,000 centipoise (cP), e.g. lower than
2,000 cP, such as 10 to 2,000 cP, such as 20 to 1,000 cP, such as 150 to 350 cP, such
as 400 to 600 cP, such as 600 to 1,200 cP or such as 1,000 to 2,000 cP, or 10 to 600
cP, or 20 to 350 cP, at 5 °C.
When referred to herein, the (dynamic) viscosity is measured at the specified
temperature in accordance with the method described in ASTM D7483.
Hydrogels, gels or amorphous glass matrixes may be formed either through
covalent bond formation or ionic— or hydrophobic interactions. Physical (non-
covalent) cross-links may result from complexation, hydration, hydrogen bonding,
desolvation, Van der Waals ctions, ionic bonding, combinations thereof, and
the like, and may be initiated by mixing two precursors that are physically separated
until combined in situ, or as a consequence of a prevalent condition in the
logical environment, including ature, pH, ionic strength, combinations
thereof, and the like. al ent) cross linking may be accomplished by any
of a number of mechanisms, including free radical polymerization, condensation
polymerization, anionic or cationic polymerization, step growth polymerization,
electrophile-nucleophile reactions, combinations f, and the like. Figures 1-6
illustrate exemplary hydrogel and/or rming and/or amorphous glass matrix
systems that can be used in the present invention.
The hydrogel, gel or amorphous glass matrix forming compositions may be
loaded with organic x-ray agents such as iodinated polymers or sugars and
nanoparticles or submicron particles either prior to or during gel formation, such as
when the formulation is in a sol-state or in transition to the gel—state, e.g., by
diffusion into the el composition. These x—ray agents or les may either
be entrapped in the gel matrix without any chemical cross-linking, or they may be
, non—covalently or covalently, to the backbone or cross—linking agent of the
hydrogel, gel or amorphous glass matrix. The organic x-ray agents may be one
component in the gel and the particles r component, where the particles are
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either a contrast agent for imaging by x—ray, MRI, PET, SPECT, fluorescence or
ultrasound, and/or contain pharmaceutical agents. Pharmaceutical agents may be,
but not limited to, radiosensitzers, chemotherapeutics or hormones. MRI agents
such as gadolinium may be a component in the gel g systems. Pharmaceutical
agents can furthermore be covalent or non-covalently embedded in the el,
gel or amorphous glass matrix.
After ion, the formulation typically provides a well defined assembly of
x-ray contrast agents which provides contrast in e.g. X-ray imaging, and which may
serve as a marker, thus, enabling tracking of tumor movement during e.g.
radiotherapy or al procedures.
U52001/0142936 discloses covalently linked hydrogels particles in the
eter range (lOum — 500um) with/without radiopaque agents for use of
conformal filling of surgical sites with optional imaging in order to ensure that the
implants are oned correctly. The present invention offers several advantageous
features as it exploits organic x-ray contrast agents that may be in combination with
nano-sized particles combined with a gel forming able liquid. Nano—sized
particles exhibit low/no sedimentation rate due to the s of Brownian motion
which is problematic for micrometer sized particles. Furthermore, ng the
particles and the gel forming solution into two components enables control over
particle diffusion, release etc. within the gel which is advantageous for controlling
the overall properties of the formulation. U52011/0142936 is built on the invention
that swelling of the gel will increase the distance between normal and tumor tissue
by injecting into enic (”medically produced”) spaced. The present invention
aims at infiltrate tissue with minimal impact on the shape and position of the target
tissue typically being a cancer. Furthermore, the ion of the present invention is
to infiltrate tissue with minimal change in size and location why swelling is for this
invention a antage. This in contrast to USZOOl/0142936
In the context of the present invention, a ”marker” or ”tissue marker” is a
detectable agent or composition which does not move, or stays substantially in the
same position, for several days or weeks once it has been administered or implanted
into a specific site or tissue of a ian body. A tissue marker can, for example,
WO 2014!187962
comprise one or more X—ray contrast agents, ctive compounds, paramagnetic
compounds, fluorescent agents, or other detectable agents.
In the context of the present invention, a ”ge I” ‘ IS defined as a carrier matrix
in which the detectable agent (contrast agent) is dispersed and/or dissolved within.
The term ”gel” includes systems such as hydrogels, gels or amorphous glass matrixes
which upon injection into a human or an animal ses viscosity due to chemical
and/or physical stimulus.
An ”imageable tissue marker” or able marker” comprises a detectable
agent in a form and/or a sufficient amount to allow for detection of the tissue
marker by an external imaging modality if administered or implanted into a
mammalian body. ary external imaging modalities include, but are not
limited to, X-ray imaging, CT imaging, MRI, PET imaging, single photon emission
computed tomography (SPECT) imaging, nuclear scintigraphy imaging,
ultrasonography imaging, onic imaging, near—infrared imaging and/or
fluorescence imaging. Some examples ofthe brand names and types of different
image techniques are e.g. ExacTrac® (BrainLAB), Cone Beam (e.g. Vairan) and OBI
(e.g. On-Board ® Varian).
Contrast agents
Contrast may be ed using organic x—ray contrast agents, such as
radiopague agents such as iodinated nds, which may be combined with
chelators of MRI agents such as nium, and/or combined with chelators of PET
g agents such as copper-64, which may further be combined with solid
inorganic particles. Chelators may be DOTA, EDTA, or DTPA and chelators will be
non—covalently embedded or covalently conjugated to the gel—forming components.
The ed contrast agents should preferably be visible by at least CT imaging.
Preferred contrast agents are iodinated compounds such as rs or sugar
molecules such as derivatives ofglucose or sucrose or other oligosaccharides. Solid
particles may comprise, or t of, one or more X-ray contrast agents, i.e.,
compounds that are able to block or attenuate X—ray radiation. Such compounds
include transition metals, rare earth metals, alkali metals, alkali earth metals, other
metals, as defined by the periodic table. A metal or alkali metal may appear in non-
W0 2014!187962 2014/060673
oxidized or any of the ng oxidation states for the metal. These oxidation states
include monovalent cations, divalent cations, trivalent cations, tetravalent cations,
pentavalent cations, hexavalent cations and heptavalent cations.
In one embodiment, the one or more X—ray contrast agents are selected from
Iodine (I), gold (Au), bismuth (Bi), gadolinium (Gd), iron (Fe), barium (Ba), calcium
(Ca) and magnesium (Mg). In a particular embodiment, the detectable compound
comprises one or more compounds selected from the group of gold (Au) and
bismuth (Bi). The one or more X-ray contrast agents are typically present in metal
form, in alloy form, in oxide form or in salt form.
It should be understood that besides iodinated compounds which provides a
useful contrast for X-ray imaging, the formulation may also include solid particles
that are visible by X—ray imaging or other imaging modalities than X-ray imaging. In
one embodiment, the solid-particles are furthermore visible by MR and/or PET
imaging, or by other imaging ties.
In a particular ment, the gel-forming composition may further
se a radioactive or paramagnetic compound for one or more g
ties such as MRI, PET imaging, SPECT imaging, nuclear scintigraphy imaging,
ultrasonography imaging, ultrasonic imaging, near-infrared imaging and/or
fluorescence imaging.
In some interesting embodiments, the formulation according to any one of
the preceding claims, contain solid particles that comprise one or more radioactive,
paramagnetic or ferromagnetic particles.
Moreover, individual les may comprise two or more types of compounds
which are visible in different imaging modalities.
Said radioactive compounds may se isotopes of Copper (61Cu, 64Cu,
and 67Cu), Indium (lllln), Technetium (99mTc), Rhenium (186Re, 188Re), Gallium (67Ga,
68Ga), Strontium (89$r), Samarium ), Ytterbium (169Yb), Thallium (201Tl), Astatine
(211At), Lutetium (177Lu), Actinium (225Ac), Yttrium (90V), Antimony (1195b), Tin (117Sn,
113Sn), Dysprosium (159Dy), Cobalt , Iron (59Fe), Ruthenium (97Ru, ,
Palladium (103Pd), Cadmium (115Cd), Tellurium (118Te, 123Te), Barium (1318a, 140Ba),
nium (149Gd, 151Gd), m (160Tb), Gold (198Au, 199Au), num (140La),
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Zirconium (892r) and Radium (223Ra, 224Ra), wherein said isotope of a metal
radionuclide may appear in any of the existing oxidation states for the metal. These
oxidation states include monovalent cations, divalent cations, trivalent cations,
tetravalent cations, pentavalent cations, hexavalent cations and heptavalent cations.
Said paramagnetic or ferromagnetic compounds may also be selected from
the group of Scandium (Sc), Yttrium (Y), num (La), Titanium (Ti), Zirconium
(Zr), Hafnium (Hf), Vandium (V), Niobium (Nb), Tantalum (Ta); Chromium (Cr),
Molybdenium (Mo), en (W), Manganese (Mn), Technetium (Tc), Rhenium
(Re), Iron (Fe), Ruthenium (Ru), Osmium (Os), Cobalt (Co), Rhodium (Rh), Iridium (Ir),
Nickel (Ni), Palladium (Pd), Platinum (Pt), Copper (Cu), Silver (Ag), Gold (Au), Zinc
(Zn), Cadmium (Cd), Mercury (Hg), the lanthanides such as Lathanum (La), Cerium
(Ce), Praseodymium (Pr), ium (Nd), Promethium (Pm), um (Sm),
Europium (Eu), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho),
Erbium (Er), Thulium (Tm), Ytterbium (Yb), um (Lu)) and the actinides such as
Actinium (Ac), Thorium (Th), Protactinium (Pa), Uranium (U), Neptunium (Np),
Plutonium (Pu), Americium(Am), Curium (Cm), Berkelium (Bk), Californium (Cf),
Einsteinium(Es), Fermium (Fm), Mendelevium (Md), um (No) and Lawrencium
(Lr), wherein said paramagnetic or ferromagnetic nds may appear in any of
the existing oxidation states for the metal. These oxidation states include
monovalent cations, divalent cations, ent cations, tetravalent cations,
pentavalent cations, hexavalent cations and heptavalent cations.
Said one or more radioactive, paramagnetic or ferromagnetic compounds
may be covalently linked to gel-forming components or the ized particles or
non—covalently associated with the gel-forming components or nano-sized les.
In one embodiment, the gel-forming components or nano-sized particles
further comprise one or more fluorophore nds for near infrared
fluorescence imaging. Said nds may comprise a fluorescent proteins,
peptides, or fluorescent dye molecules. Common classes of fluorescent dyes e
xanthenes such as rhodamines, rhodols and fluoresceins, and their derivatives;
bimanes; coumarins and their derivatives such as umbelliferone and aminomethyl
coumarins; aromatic amines such as dansyl; squarate dyes; benzofurans; fluorescent
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cyanines; carbazoles; dicyanomethylene pyranes, polymethine, oxabenzanthrane,
xanthene, pyrylium, carbostyl, perylene, acridone, quinacridone, rubrene,
anthracene, coronene, phenanthrecene, pyrene, butadiene, stilbene, lanthanide
metal e complexes, rare-earth metal chelate complexes, and derivatives of
such dyes. Typical fluorescein dyes include 5-carboxyfluorescein, fluorescein-5—
isothiocyanate and oxyfluorescein; examples of other fluorescein dyes can be
found, for example, in US 6,008,379, US 5,750,409, US 5,066,580, and US 4,439,356.
The species may also include a ine dye, such as, for example,
ethylrhodamine-6—isothiocyanate, 5—carboxytetramethylrhodamine, 5—
y rhodol derivatives, tetramethyl and tetraethyl rhodamine, diphenyldimethyl
and diphenyldiethyl rhodamine, dinaphthyl rhodamine, rhodamine 101 yl
chloride (sold under the tradename of TEXAS RED), and other rhodamine dyes. The
species may alternatively include a e dye, such as, for example, Cy3, Cy3B,
Cy3.5, Cy5, Cy5.5, Cy. Or IRDye 800CW, IRDye 680LT, Qdot 800 nanocrystal, Qdot
705 nanocrystal or porphyrazine compounds
In another ment, the nano—sized particles further comprise or consist
of one or more gasses encapsulated in lipid, polymer or inorganic based particles for
ultrasonography imaging. Said gasses may comprise air, sulphur halides such as
sulphur hexafluoride or disulphur uoride; fluorocarbons such as
orocarbons; fluorinated (e.g. perfluorinated) ketones such as
perfluoroacetone; and fluorinated (e.g. perfluorinated) ethers such as
perfluorodiethyl ether. Representative perfluorocarbons, which may for example
contain up to 7 carbon atoms, include perfluoroalkanes such as perfluoromethane,
perfluoroethane, perfluoropropanes, perfluorobutanes (e.g. perfluoro—n—butane,
optionally in a mixture with other isomers such as perfluoro-iso—butane),
perfluoropentanes, perfluorohexanes and perfluoroheptanes; perfluoroalkenes such
as oropropene, perfluorobutenes (e.g. perfluorobut—Z-ene) and
perfluorobutadiene; perfluoroalkynes such as orobut-Z-yne;
perfluorocycloalkanes such as perfluorocyclobutane, perfluoromethylcyclobutane,
perfluorodimethylcyclobutanes, orotrimethylcyclobutanes,
perfluorocyclopentane, perfluoromethylcyclopentane,
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perfluorodimethylcyclopentanes, perfluorocyclohexane,
perfluoromethylcyclohexane and perfluorocycloheptane; and mixtures of any of the
foregoing, ing es with gases such as nitrogen, carbon dioxide, oxygen
etc, but not limited to those.
In another embodiment, contrast in achieved using small organic iodine
containing nds. Said small organic iodine containing compounds includes
commercial available iodinated contrast agents such as diatrizoate (marketed e.g.
under the trade name GastrografenTM), ionic dimers such as ioxaglate (marketed e.g.
under the trade name HexabrixTM), nonionic monomers such as iohexol (marketed
e.g. under the trade name Omnipaque‘”), iopamidol (marketed e.g. under the trade
name IsovueT'V'), iomeprol (marketed e.g. under the trade name lomeronTM) and the
non—ionic dimer iodixanol ted under the trade name and VisipaqueTM).
Additional examples of small organic iodine containing nds includes the
ones disclosed in W02009/071605
, EP1186305, EP686046, EP108638, EPOO49745,
992, W02003080554, W02000026179, W01997000240, WO9208691,
US3804892, US4239747, US3763226, 227 and U53678152, but not limited to
those. In another interesting ment, the said small c iodine ning
compounds includes iodinated derivates of sucrose acetate isobutyrate (SAIB). In
contrast to what is disclosed in for example EP1006935, where a ition for
controlled release of a substance is disclosed which composition ses SAIB,
this ic embodiment according to the present invention aims at providing a
stable contrast agent embedded in SAIB—gel. Examples of such iodinated derivates of
sucrose acetate isobutyrate (SAIB) are illustrated in figure 7, but not limited to
those. Such nds may be used alone or in combination with solid particles to
achieve an injectable gel visible by at least CT imaging. In one specific embodiment
of the invention the hydration sensitive gel forming component is sucrose acetate
isobutyrate (SAIB) a hydrophobic component composed of sucrose (the scaffold)
which has been acylated with isobutyrate and acetate. red scaffolds of this
invention are monosaccharides, disaccharides or trisaccharides. A particularly
preferred dissacharide scaffold is sucrose, however, the alcohol containing scaffold
may be derived from a polyhydroxy alcohol having from about 2 to about 20 hydroxy
W0 2014!187962 2014/060673
groups and may be formed by esterifying 1 to 20 polyol molecules. le alcohol
moieties include those derived by removing one or more hydrogen atoms from:
monofunctional C1-C20 alcohols, difunctional C1-C20 alcohols, trifunctional alcohols,
hydroxy—containing carboxylic acids, hydroxy-containing amino acids, phosphate—
ning alcohols, tetrafunctional alcohols, sugar alcohols, monosaccharides, and
disaccharides, sugar acids, and polyether polyols. More specifically, alcohol es
may include one or more of: dodecanol, hexanediol, more particularly, 1,6-
hexanediol, ol, glycolic acid, lactic acid, hydroxybutyric acid, hydroxyvaleric
acid, hydroxycaproic acid, , ATP, pentaerythritol, mannitol, ol, glucose,
galactose, se, maltose, lactose, glucuronic acid, polyglycerol ethers containing
from 1 to about 10 glycerol units, polyethylene glycols containing 1 to about 20
ethylene glycol units. Additionally, any oligosaccharide containing from 3 to about 6
monosaccharides may be used as the scaffold in the present invention. In general,
the scaffold esters of the invention can be made by reacting one or more ls, in
particular one or more polyols, which will form the alcohol moiety of the resulting
esters with one or more carboxylic acids, es, lactams, carbonates, or
anhydrides of the carboxylic acids which will form the acid moieties of the resulting
esters. The esterification reaction can be conducted simply by heating, although in
some instances addition of a strong acid or strong base esterification catalyst may be
used. Alternatively, an esterification catalyst such as stannous 2—ethylhexanoate or
activation reagents such as N-(3—Dimethylaminopropyl)—N’-ethylcarbodiimide (EDC),
N,N'—Dicyclohexylcarbodiimide (DCC), O-(7—azabenzotriazol-l-yl)—N,N,N’,N’-
tetramethyluronium hexafluorophosphate (HATU) and the like can be used.
The acyl groups forming the y substituents of the invention may be any
moiety derived from a ylic acid. More particularly, the acyl groups of the
compositions of the invention may be of the RC0—, where R is optionally oxy-
substituted alkyl of 2-10 carbon atoms which may be linear or branched
hydrocarbons with one or more functional groups present in the chain. Using
carboxylic acids and/or polyols of ent chain length and using carboxylic acids
having oxy-substitution allows control ofthe degree of hydrophilicity and of the
solubility of the resulting ester. Such materials are sufficiently resistant to
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dissolution in vivo that they are able to form stabile hydrophobic gels which may
encapsulate the said contrast agents of the present invention. The gels may further
comprise a ceutical agent in combination with the contrast agent.
Coating of solid particles
The solid particles may r comprise a variety of other components.
Useful solid particles include uncoated or coated metal particles, uncoated or coated
solid metal salts, as well as liposomes, polymersomes, dendrimers, water-soluble
cross-linked polymers, and micelles comprising such solid particles. As used herein, a
solid particle which is "coated” ses a shell or surface coating around a solid
core material. The shell or surface coating can be attached to the core material
covalently, non-covalently, or by a mixture of covalent and non—covalent bonds.
Exemplary shell or surface coatings are described herein. In one embodiment, the
solid particle comprises a r surface coating non-covalently or ntly
attached to the particle core surface. The polymer may be a homopolymer, a
copolymer, block copolymer, or a graft copolymer, or a dendrimer-type copolymer
of synthetic or natural origin, but not limited to those. lly, the polymer coating
ses polyethylene glycol (PEG), typically with a PEG molecular weight from
2,000 to 70,000 Daltons, such as 5,000 Daltons; dextrans, typically with a molecular
weight between 2,000 and 1,000,000 Daltons; and/or hyaluronic acid, typically with
a molecular weight between 2,000 and 1,000,000 Daltons. The polymers are
typically combined as block copolymers in such a way that the overall polymer
structure in negatively charged, allowing electrostatic ctions with a positively
charged nano-sized particle surface to achieve ent coating. In a particular
embodiment, the solid particles comprise ated o, PEGZOOO, PEG3000,
PEG5000 or PEGloooo, i.e., PEG preparations having an average molecular weight of
approximately 1,000, 2,000, 3,000, 5,000 and 10,000 Daltons, respectively, but not
limited to those. In an additional embodiment, the solid particles comprise
conjugated PNIPAMlOOO, ZOOO, PNIPAMgooo, PNIPAM5000 or PNIPAMlOOOO, i.e.,
PNIPAM preparations having an average molecular weight of approximately 1,000,
2,000, 3,000, 5,000 and 10,000 Daltons, respectively, but not limited to those. In one
embodiment, the solid les comprise a shell or surface coat comprising a lipid
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layer such as a lipid monolayer and/or one or more lipid bilayers, and a particle core
comprising an inorganic particle. Surface—coating lipids for the purpose of the
present invention, and include, for e, fatty acids, neutral fats, phosphatides,
glycolipids, ceramides, sphingoglipids, aliphatic alcohols, and steroids. Specific, non-
limiting examples of solid les are gold nano-sized particles synthesized with a
PEG coating or PEGylated gold nanorods as described in and Kim
et al 2007 [Invest. Radiol., 2007, 42, 797—806], polymer-coated bismuth sulphide
nano-sized particles as described in Rabin 2006 [Nat. Mater., 2006, 5, 188-122],
calcium phosphate me hell nanocomposites, dendrimers of PAMAM
with entrapped gold nano-sized particles for CT imaging as described in Haba et al.
2007 [Langmuir, 2007, 23, 5243—5246] and Kojima et al 2010 [Bioconjugate Chem.,
2010, 21, 1559-1564] and other solid particles comprising X-ray contrast agents
known in the art. In a specific embodiment ofthe present invention, the shell of the
nano—sized particle comprises stearoyl-sn—glycero—3—phosphocholine (DSPC)
”A”, cholesterol ”B”, and 1,2-distearoyl-sn-glycerophosphoethanolamine-N-
[methoxy (polyethylene glycol)—2000] (DSPE-PEG—2000) ”C”, and 1,2-distearoyl—sn-
glycero-3—phosphoethanolamine—N—[methoxy (polyethylene glycol)-2000]-TATE
PEGRGD) ”D” with the molar ratio A:B:C:D, wherein A is ed from
the interval 45 to 65, B is selected from the interval 35 to 45, C is selected from the
interval 5 to 13, D is selected from the interval 0 to 3, and wherein A+B+C+D = 100.
g of the solid particles can be exploited to introduce the desired
chemical and/or physical properties to the colloid particles. Properties such as
hydrophobicity/hydrophilicity, particle charge, hydrodynamic diameter and stability
in various environments such as high/low salt concentrations, organic solvents,
reductive environments and heat, among others, can be controlled by choosing the
t surface coating material. These properties, uced to the solid particles
by the surface coating, are ant factors to control in order to tune the overall
or of the X-ray contrast composition described here.
The amount of contrast agent comprised within the gel—forming composition
including an ed the nano—sized particles according to the present ion
may be quantified by the weight percent of the contrast agent relative to the total
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weight ofthe gel—forming system including an embedded nano—sized particle,
excluding any water comprised by the nano-sized particle, by defining the weight
percent of the contrast agent relative to the weight of the shell of the nano-sized
le, or by quantifying the size of the contrasting agent within the prepared
nano-sized particles. The latter can be measured by conventional methods in the art,
such as cryo-transmission electron microscopy or dynamic light scattering.
Shape and size
The nano-sized particles according to the present invention can be quasi
spherical, spherical or non—spherical such as rod—shaped. Suitable nanoparticles
e those having a size up to 50 um, preferably up to 5 pm.
Preferably, the nano-sized particles ing to the present ion are of a size
in the range of 1 to 1000 nm, such as 2 to 10 nm, or such as 10 to 100 nm, such as 10
to 80 nm, such as 10 to 50 nm, such as 10 to 20 nm, such as 10 to 15 nm, or such as
to 20 nm, or such as 20 to 50 nm, or such as 50 to 80 nm, or such as 80 to 110
nm, or such as 110 to 140 nm, or such as 140 to 170 nm, or such as 170 to 200 nm or
such as 200 to 220, or such as 220 to 250 nm, or such as 250 to 280 nm, or such as
280 to 310 nm, or such as 310 to 340 nm, or such as 340 to 370 nm, or such as 370
to 400 nm, or such as 400 to 420, or such as 420 to 450 nm, or such as 450 to 480
nm, or such as 480 to 500 nm, or such as 500 to 1000 nm. The size may according to
the present invention be measured in terms of the diameter, length or width,
ing the number average diameter, length or width. In a preferred
embodiment, the nano-sized particles in the composition of the present invention
have a number average diameter in the range of 10 nm to 150 nm, such as 10 to 100
nm, such as 10 to 80 nm, such as 10 to 50 nm, such as 10 nm to 30 nm, such as 10 to
20 nm, or such as 30 nm to 40 nm, or such as 40 nm to 50 nm, or such as 50 nm to
60 nm,
or such as 60 nm to 70 nm, or such as 70 nm to 80 nm, or such as 90 nm to 100 nm,
or such as 100 nm to 110 nm, or such as 110 nm to 120 nm, or such as 120 nm to
130 nm, or such as 130 nm to 140 nm, or such as 140 nm to 150 nm. Controlling the
shape and the size ofthe nano-sized particles may have significant nce on the
stability of the nano-scale colloidal suspensions as well as the in vivo fate of the
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particles. In a preferred embodiment, the nano—sized particles in the composition of
the present invention have a number average diameter in the range of 10 nm to 100
nm. Such nano-sized particles exhibit low/no sedimentation rate due to the effects
of an motion. In another preferred embodiment, the nano—sized particles in
the composition of the present invention have a number average diameter <10 nm.
Such particles may be cleared, after degradation ofthe hydrogel, by e.g. renal
filtration with uently excretion into the urine, which may prevent prolonged
tissue retention and/or thus lower the risk of toxicity.
The c gel-forming system
Suitable rming components include, but are not limited to, those
composed of organic tuents such as derivatized saccharides such as esterified
rides, derivatized polyols such as esterified polyols, polymers, lipids, peptides,
proteins, low lar weight gelators and non-water soluble high-viscosity liquid
carrier materials as well as ations hereof.
The saccharides and polyols gel g sysemts may be sucrose acetate
isobutyrate (SAIB) a hydrophobic component composed of sucrose (the scaffold)
which has been acylated with isobutyrate and acetate. Preferred scaffolds of this
ion are monosaccharides, disaccharides or trisaccharides. A particularly
preferred dissacharide scaffold is sucrose, however, the alcohol containing scaffold
may be derived from a polyhydroxy alcohol having from about 2 to about 20 hydroxy
groups and may be formed by esterifying 1 to 20 polyol molecules. le alcohol
moieties include those d by removing one or more hydrogen atoms from:
monofunctional C1-C20 alcohols, difunctional C1-C20 alcohols, trifunctional alcohols,
hydroxy—containing carboxylic acids, hydroxy-containing amino acids, phosphate—
containing ls, tetrafunctional alcohols, sugar alcohols, monosaccharides, and
disaccharides, sugar acids, and polyether polyols. More specifically, alcohol moieties
may include one or more of: dodecanol, diol, more particularly, 1,6-
hexanediol, glycerol, ic acid, lactic acid, hydroxybutyric acid, hydroxyvaleric
acid, hydroxycaproic acid, serine, ATP, pentaerythritol, mannitol, sorbitol, glucose,
galactose, fructose, maltose, e, glucuronic acid, polyglycerol ethers containing
from 1 to about 10 glycerol units, polyethylene glycols containing 1 to about 20
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ethylene glycol units. Additionally, any oligosaccharide containing from 3 to about 6
monosaccharides may be used as the ld in the present invention. In general,
the ld esters ofthe invention can be made by reacting one or more alcohols, in
ular one or more polyols, which will form the alcohol moiety of the resulting
esters with one or more carboxylic acids, lactones, s, carbonates, or
anhydrides of the carboxylic acids which will form the acid moieties of the resulting
esters. Such systems are known to form biodegradable, amorphous carbohydrate
glass matrixes upon hydration due to solvent induced phase separation.
The polymer may be a homopolymer, a copolymer, block copolymer, or a
graft copolymer, or a mer-type copolymer of synthetic or natural origin.
Specific examples of suitable monomers may include: Lactide, glycolide, N-vinyl
pyrrolidone, vinyl pyridine, acrylamide, methacrylamide, N-methyl acrylamide,
hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxymethyl methacrylate,
hydroxymethyl te, methacrylic acid and acrylic acid having an acidic group, and
salts of these acids, vinyl sulfonic acid, styrenesulfonic acid, etc., and derivatives
having a basic group such as N,N—dimethylaminoethyl methacrylate, N,N-
diethylaminoethyl methacrylate, N,N-dimethylaminopropyl acrylamide, salts of
these derivatives, etc. Other rs may include: acrylate derivatives and
methacrylate tives such as ethyl acrylate, methyl methacrylate, and glycidyl
methacrylate; N-substituted alkyl methacrylamide derivatives such as N-n-butyl
methacrylamide; vinyl chloride, acrylonitrile, styrene, vinyl acetate, lactones such as
s-caprolactone, es such as e—caprolactame and the like. Additional examples
of suitable monomers include alkylene oxides such as propylene oxide, ethylene
oxide and the like, but not restricted to any of these specific examples.
On the other hand, specific examples of polymeric blocks to be combined
with (or bonded to) the above-mentioned monomers may include: methyl cellulose,
dextran, polyethylene oxide, polypropylene oxide, polyvinyl l, poly N-vinyl
idone, polyvinyl pyridine, polyacrylamide, polymethacrylamide, poly N-methyl
mide, polyhydroxymethyl te, polyacrylic acid, polymethacrylic acid,
polyvinyl sulfonic acid, polystyrene sulfonic acid, and salts of these acids; poly N,N-
dimethylaminoethyl rylate, poly N,N-diethylaminoethyl methacrylate, poly
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N,N-dimethylaminopropyl acrylamide, and salts of these, poly lactic-co—glycolic acid,
prolactone and combinations hereof, but not limited to those.
The lipid may be any phospholipid including one or more of a sterol such as
cholesterol, and tanol, a fatty acid having a saturated or unsaturated acyl
group having 8 to 22 carbon atoms and an antioxidant such as tocopherol.
es of the phospholipids include, for example, phosphatidylethanolamines,
phosphatidylcholines, phosphatidylserines, atidylinositols, phosphatidyl—
glycerols, cardiolipins, sphingomyelins, ceramide phosphorylethanolamines,
ceramide phosphorylglycerols, ceramide phosphorylglycerol phosphates, 1,2—
dimyristoyl-1,2-deoxyphosphatidylcholines, plasmalogens, phosphatidic acids, and
the like, and these may be used alone or two or more kind ofthem can be used in
combination. The fatty acid residues of these phospholipids are not ularly
limited, and es thereof include a saturated or rated fatty acid residue
having 12 to 20 carbon atoms. Specific examples include an acyl group derived from
a fatty acid such as lauric acid, myristic acid, ic acid, stearic acid, oleic acid and
linoleic acid. Further, phospholipids derived from natural products such as egg yolk
lecithin and soybean lecithin can also be used. Also suitable are, for example, di— and
tri-glycerides, 1,2-bis(oleoyloxy)—3-(trimethylammonio)propane (DOTAP), 1-N,N-
dimethylaminodioleoylpropane (DODAP), 1—oleoyl—2-hydroxy-3—N,N-dimethylamino-
propane, 1,2-diacylN,N-dimethylaminopropane, 1,2-didecanoylN,N-
dimethylamino-propane, 3- beta—[n-[(N',N'-dimethylamino)ethane]—carbamoyl]—
cholesterol (DC-Chol), 1,2—dimyristyloxypropyl-3—dimethylhydroxyethylammonium
bromide (DMRIE), 1,2-dioleoyloxypropyldimethylhydroxyethylammonium
bromide , and the like, but not limited to those.
A ”peptide” or ”polypeptide” refers to a string of at least two a-amino acid
residues linked together by chemical bonds (for example, amide bonds). Depending
on the context, the term ”peptide” may refer to an individual peptide or to a
collection of peptides having the same or different sequences, any of which may
contain only naturally occurring a—amino acid residues, non-naturally occurring 0L—
amino acid residues, or both. The peptide may exhibit self-assembling properties, for
example, peptide amphiphiles, and peptides with B-sheet or cal forming
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ces. The peptides may include D—amino acids, L-amino acids, or combinations
thereof. Suitable, naturally—occurring hydrophobic amino acid residues which may
be in the self-assembling peptides include Ala, Val, Ile, Met, Phe, Tyr, Trp, Ser, Thr
and Gly. The hydrophilic amino acid residues may be basic amino acids (for example,
Lys, Arg, His, Orm); acidic amino acids (for example, Glu, Asp); or amino acids that
form hydrogen bonds (for example, Asn, Gln). ation of L—amino acids
produces amino acids that may be reused by the host . L-configured amino
acid residues occur naturally within the body, distinguishing es formed from
this class of compounds from numerous other patible substances. L-
configured amino acids contain biologically active sequences such as RGD adhesion
sequences. The amino acid residues in the self-assembling peptides may be naturally
occurring or non-naturally occuring amino acid es. Naturally occurring amino
acids may include amino acid residues encoded by the standard genetic code, amino
acids that may be formed by modifications of rd amino acids (for example
pyrrolysine or cysteine), as well as non-standard amino acids (for example,
amino acids having the D—configuration instead of the L—configuration). Although,
non—naturally occurring amino acids have not been found in nature, they may be
incorporated into a peptide chain. These include, for example, D-alloiso-
Ieucine(2R,3S)-2—amino—3—methylpentanoic: acid, L—cyclopentyl glycine (S)—2-amino-
2-cyclopentyl acetic acid. Self-assembling peptides used in accordance with the
disclosure may vary in length so long as they retain the ability to e.g. self-assemble
to an extent useful for one or more ofthe purposes described herein. Peptides
having as few as two OL-amino acid residues or as many as approximately 50 residues
may be suitable. In embodiments, OL—amino acid analogs can be used. In particular, 0L-
amino acid residues of the D-form may be used. Useful peptides may also be
branched. One or more of the amino acid residues in a self-assembling peptide may
be functionalized by the addition of a chemical entity such as an acyl group, a
carbohydrate group, a phosphate group, a farnesyl group, an isofarnesyl group, a
fatty acid group, or a linker for conjugation. This functional group may provide for
inter-peptide es, or linkages between the peptide and the hydrogel or
hydrogel sor. For example, the hydrophobic portion of an amphiphilic peptide
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may be onalized with acetylene groups. Alternatively, either or both ends of a
given peptide may be modified. For example, the carboxyl and/or amino groups of
the carboxyl- and amino-terminal residues, respectively, may be ted or not
ted. Examples of self assembling peptides include the ones disclosed by Nagai,
et al. [J. lled Release, 2006, 115, 18-25], der et al. [PLoS ONE, 2008, 1,
1—8] and rink et al. [PNAS, 2002, 99, 138].
The protein is not particularly limited and may have a molecular weight from
-500 kDa, such as 20-200 kDa. It may be of natural origin or human engineered
protein expressed in accessible biological expression systems such as e.g. yeast,
ian, and bacterial expression systems. Preferably, is has a responsive
domain such as o—helical coiled-coil or leucine zipper domain — but not limited to
those, which upon external or internal stimuli results in hydrogel formation which
structurally respond to changes in e.g. pH, temperature, and ionic strength.
Examples of such proteins include the ones disclosed by Banta et al. [Annu. Rev.
Biomed. Eng., 2010, 12, 167—86].
The low lar weight gelators include any molecule with molecular
weight from 100-4,000 s, such as 250-1,000 Daltons with an amphiphilic
structure capable of forming a hydrogel. Specific, miting examples of low
molecular weight rs as described in A2, Chem. Rev., 2004,
104, 1201—1217 and Eur. J. Org. Chem., 2005, 3615-3631.
The non-water soluble high-viscosity liquid carrier materials include, but are
not limited to, sucrose acetate isobutyrate, stearate esters such as those of
propylene glycol, glyceryl, diethylaminoethyl, and glycol, stearate amides and other
long—chain fatty acid amides, such as N,N'—ethy|ene distearamide, stearamide MEA
and DEA, ethylene bistearamide, cocoamine oxide, long—chain fatty alcohols, such as
cetyl alcohol and stearyl alcohol, long-chain esters such as myristyl ate,
behenyerucate, glyceryl phosphates, acetylated sucrose distearate (Crodesta A—IO),
and the like.
The gel of the present invention having biodegradability and sol—gel phase transition
which depends on pH, ature, ion—concentration, enzymatic activity, electric
field or hydration.
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The composition of the solvent (dispersion medium) should not be
particularly limited, and examples include, for example, a buffer such as phosphate
buffer, citrate buffer, and phosphate-buffered physiological saline, physiological
saline, a medium for cell culture and patible organic solvent such as ethanol,
ethyl lactate, propylene carbonate, glycofurol, N—methylpyrrolidone, 2-pyrrolidone,
propylene glycol, e, methyl acetate, ethyl acetate, methyl ethyl ketone,
benzyl l, triacetin, dimethylformamide, dimethylsulfoxide, ydrofuran,
caprolactam, decylmethylsulfoxide, oleic acid, cylazacycloheptanone and
the like. Although the formulation can be stably dispersed in these solvents
(dispersion media), the solvents may be further added with a saccharide (aqueous
on), for example, a monosaccharide such as glucose, galactose, mannose,
fructose, inositol, ribose and xylose, disaccharide such as lactose, e,
cellobiose, trehalose and maltose, trisaccharide such as ose and melezitose,
and polysaccharide such as OL-, [3—, or y-cyclodextrin, sugar l such as erythritol,
xylitol, sorbitol, mannitol, and maltitol, or a polyhydric alcohol (aqueous solution)
such as glycerin, diglycerin, polyglycerin, propylene glycol, polypropylene glycol,
ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, ethylene
glycol mono-alkyl ether, diethylene glycol lkyl ether and 1,3-butylene glycol.
Additives may furthermore be selected from the group consisting of bioavailable
materials such as amiloride, procainamide, acetyl-beta-methylcholine, ne,
dine, lysozyme, fibroin, albumin, collagen, transforming growth factor-beta
(TGF-beta), bone morphogenetic proteins (BM Ps), fibroblast growth factor ,
dexamethason, vascular elial growth factor (VEGF), fibronectin, fibrinogen,
thrombin, proteins, dexrazoxane, leucovorin, ricinoleic acid, phospholipid, small
intestinal submucosa, vitamin E, polyglycerol ester of fatty acid, Labrafil, Labrafil
M1944CS, citric acid, glutamic acid, hydroxypropyl, isopropyl myristate, Eudragit,
tego betain, dimyristoylphosphatidyl-choline, scleroglucan, and the like; organic
ts such as cremophor EL, ethanol, dimethyl sulfoxide, and the like;
preservatives such as methylparaben and the like; sugars such as starch and
derivatives thereof, sugar—containing s such as sucrose-mannitol, glucose—
mannitol, and the like; amino acids such as alanine, ne, glycine, and the like;
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polymer-containing s such as trehalose-PEG; sucrose-PEG, e—dextran,
and the like; sugar—containing amino acid such as sorbitol—glycine, sucrose-glycine,
and the like; tants such as poloxamer of various molecular weights, Tween 20
Tween 80, Triton X—100, sodium dodecyl sulfate(SDS), Brij, and the like; sugar—
ning ions such as trehalose—ZnSO4, maltose-ZnSO4, and the like; and bio-
acceptable salts such as silicate, NaCI, KCI, NaBr, Nal, LiCI, n-Bu4NBr, Br,
Et4NBr, Mg(OH)2, Ca(OH)2, ZnC03, Ca3(P04)2, ZnClz, (C2H302)ZZn, ZnC03, CdClz, HgClz,
CaClz, (CaN03)2, BaClz, MgClz, PbClz, AICIZ, FeClz, FeCI3, NiClz, AgCl, AuCl, CuClz,
sodium tetradecyl sulfate, ltrimethyl—ammonium bromide,
dodecyltrimethylammonium chloride, tetradecyltrimethyl-ammonium bromide, and
the like, but not limited to those.
In one ment of the present invention, the content of the additive is
from 1><10'6 -30 wt%, preferably 1><10'3 to 10 wt%, based on the total weight of the
gel forming component(s).
A preferred injectable medical gel-forming system can have one or more, preferably
all, of the following features:
(1) In order to be injectable, the system should be in a sol state before
administration. The sol state should be of sufficiently low viscosity — typically lower
than 10,000 cP, preferably lower than 2,000 cP, at 20 °C (or alternatively lower than
lower than 10,000 cP, preferably 2,000 cP, at 5 °C) - to allow for small needle head to
alleviate the patient discomfort and simplify insertion procedure.
(2) Gelation via either chemical cross-linking, physical association or
hydration starts to happen or is complete after injection.
(3) The gels should be radable or gradually dissolvable within a
controlled time period, and the products should be cleared/secreted through
normal pathways.
(4) The polymer itself and the degradable products should be biocompatible.
Likewise, if ves are added, such as cross-linking agents, initiators etc. these
should also be biocompatible.
(5) The gel could potentially have cell/tissue-adhesive properties.
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(6) The gel should not result in adverse effects such as immune response, e.g.
inflammation.
It should be understood, that the gel-forming system should preferably be
biocompatible, i.e. does not stimulate a severe, long-lived or escalating biological
se to the formulation when injected into a mammal, in ular a human. To
facilitate metabolism of the gel scaffold, degradable linkages can be included
through the use of polylactide, polyglycolide, poly(lactide—co-glycolide),
polyphosphazine, polyphosphate, polycarbonate, polyamino acid, polyanhydride,
and polyorthoester — based building blocks, among others. Additionally, small
molecule crosslinking agents containing similar hydrolyzable moieties as the
polymers such as carbonates, esters, urethanes, orthoesters, amides, imides,
imidoxy, hydrazides, thiocarbazides, and phosphates may be used as building .
Additionally, polyglycolide diacrylate, thoester diacrylate and acrylate-
substituted polyphosphazine, acrylate-substituted polyamino acid, or acrylate—
substituted polyphosphate polymers can be used as degradable building blocks.
rylate or acrylamide moieties can be employed instead of acrylate es
in the above examples. Similarly, small molecules containing a hydrolyzable segment
and two or more acrylates, methacrylates, or acrylamides may be used. Such
degradable rs and small molecule building blocks may be functionalized with
acrylate, methacrylate, acrylamide or similar moieties by methods known in the art.
In order to be injectability, the system should be in a sol state before
stration. The sol state should be of iently low viscosity to allow for small
needle head to alleviate the t discomfort and simplify insertion procedure.
Gelation via either chemical cross linking or physical association starts to happen or
is complete after injection.
Preferred properties of the rming system include one or more of the
following:
The gel-forming system may form a hydrogel. Hydrogels are comprised of
cross—linked polymer networks that have a high number of hydrophilic groups or
domains. These networks have a high affinity for water, but are prevented from
dissolving due to the al or physical bonds formed between the polymer
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. Water penetrates these networks causing swelling, giving the hydrogel its
form. Fully n hydrogels have some physical properties common to living
tissues, including a soft and y consistency, and low interfacial tension with
water or biological fluids. The elastic nature of fully swollen or hydrated hydrogels
can minimize irritation to the surrounding s after implantation. A low
interfacial n between the el surface and body fluid minimizes protein
adsorption and cell adhesion, which reduces the risk ofan adverse immune reaction.
Many polymers used in hydrogel preparations (e.g. polyacrylic acid (PAA), PHEMA,
PEG, and PVA) have mucoadhesive and bioadhesive characteristics that enhance
drug residence time and tissue permeability. This adhesive property is due to inter-
chain bridges between the hydrogel polymer's onal groups and the mucus
roteins, which can help enhance tissue specific g.
Preferably, before in vivo stration, the gel-forming system according to
the invention is a flowable solution. The organic x—ray contrast agent, such as
iodinated SAIB derivatives as illustrated in figure 7 or other iodinated polymers, and
solid inorganic particles can, for example, be added to the gel-forming system simply
by mixing before injection. Once ed, the gel—forming system rapidly gels under
physiological conditions. An injectable matrix can thus be ted in the human
body with minimal surgical procedure. After gelation in situ, the matrix can provide a
reference marker for imaging and image—guided radiotherapy.
A number of activators or conditions can be used to trigger this transition
upon injection, either externally applied or in response to the tissue micro-
environment. Examples of this include gelation as a response to pH, temperature,
ion—concentration, enzymatic activity, electric field and hydration (Figure 1). In
relation to the invention it is relevant to be able to tune the mechanical stability
within the tissue to allow for single injections.
Gel—forming system in response to temperature change
In one embodiment, the gel-forming system undergoes gel-formation in
response to a temperature in the range of 10-65°C, preferably in the range C.
The favored thermosensitive material might exhibit an inverse sol—gel
transition. The term “inverse” here means that gelation occurs upon heating instead
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of cooling. Exemplary biodegradable or bioabsorbable thermogelling polymers are
shown in Figure 2. According to the origin of materials, gelling hydrogels can
be classified into l (or seminatural) polymeric systems and synthetic polymeric
systems. The polymers in the former system include cellulose, chitosan, ucan,
gelatin etc. and their derivatives. The rs in the latter class include some
polyethers, block copolymers of polyethers and biodegradable polyesters, synthetic
polypeptides, and other polymers (Figure 2).
Other examples of such gel-forming s are those described in; i) Eur. J.
Pharm. Biopharm., 2004, 57, 53—63, ii) Chem. Soc. Rev., 2008, 37, 1473—1481, iii) Adv.
Drug Deliv. Rev., 2010, 62, 83-99, iv) Macromol. Biosci., 2010, 10, 563-579, v) J.
Controlled Release, 2005, 103, 609-624, vi) Expert Opin. Ther. Patents, 2007, 17,
965—977, vii) Appl. Microbiol. Biotechnol., 2011, 427-443, viii) Science, 1998, 281,
389-392, ix) Eur. J. Pharm. Biopharm. 2008, 68, 34-45, x) Biomacromolecules, 2002,
4, 865-868, xi) Colloids and Surfaces B: Biointerfaces, 2011, 82, 196—202, xii)
Biomacromolecules, 2010, 11, 1082-1088, xiii) Adv. Eng. Mater., 2008, 10, 515—527,
xiv) Eur. J. Pharm. Biopharm., 2004, 58, 409-426, xv) Adv. Drug Deliv. Rev., 2002, 54,
37—51, xvi) Biomater., 2004, 25, 3005-3012, xvii) J. Biomed. Mater. Res., 2000, 50,
171-177, xviii) xix) WO 50651, xxi)
, xx) ,
xxii) WO 99/07416, xxiii) Park K., Shala by W.S.W., Park H., Biodegradable hydroge/s
for drug ry. Basel: Technomic Publishing Co., Inc., 1993. ISBN 1004-6,
Print, xxiv) Biomedical rs and polymers therapeutics, Ed. ini E.,
SunamotoJ., Migliaresi C., Ottenbrite R.M., Cohn D., New York, Kluwer Academic
Publishers, 2002, ISBN 01, Print - and references herein, but not limited
to those.
In one interesting embodiment the thermo sensitive r is
poly(ethylene glycol)-b-poly(propylene glycol)-b—poly(ethylene glycol) (PEG—PPG—
PEG, Pluronic® or Poloxamer) or derivates hereof. By controlling the PEG/PPG
composition, the molecular weight and the tration, reversible gelation can
occur at physiological temperature and pH.
In another interesting embodiment the thermo sensitive polymer is chitosan.
Chitosan can be a thermally ive, pH dependent, gel—forming system by the
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addition of polyol salts (e.g. B-glycerophosphate, GP). These formulations s a
neutral pH, remain liquid at or below room ature, and form monolithic gels
at body temperature. The stability of the sol at room temperature and the on
time increase as the chitosan degree of ylation decreases [Int. J. Pharm.,
2000, 203, 89-98]. The gelation for these chitosan-based systems occurs by the
combination of charge neutralization, ionic and hydrogen bonds and, as the main
driving force, hydrophobic interaction factors. Additionally, such systems are highly
compatible with biological compounds and can be used to inject in vivo biologically
active growth factors and cells [Biomater., 2000, 21, 161].
In one very interesting ment the thermo sensitive polymer is
poly(caprolactone—b-ethylene glycol-b-caprolactone) EG—PCL), poly(ethylene
glycol-b-caprolactone- ethylene glycol) (PEG-PCL—PEG) or poly(ethylene glycol-b—
caprolactone) (PEG-PCL). This family of block ymers can be tuned to be free
flowing solutions at room temperature and strong biodegradable gels at body
temperature. Such polymers are highly biocompatible having showed very little
toxicity with a maximum tolerance dose of 25g/kg body weight by subcutaneous
administration [J. Pharm. Sci., 2009, 98, 4684-4694] and have been found stabile in
vivo for more than 4 weeks [Tissue Eng. 2006, 12, 2863-2873].
In another interesting embodiment the thermo sensitive polymer is
poly(ethylene glycol-b-[DL-lactic acid-co—glycolic acid]—b—ethylene glycol) (PEG-PLGA-
PEG) triblock copolymers. PEG-PLGA-PEG (33 wt%) is a free-flowing sol at room
temperature and become a gel at body temperature. The gel showed good
mechanical strength and the integrity of gels ted longer than 1 month [J.
Biomed. Mater. Res., 2000, 50, 171—177]. Additional examples includes poly(N—
isopropylacrylamide)-g-methylcellulose copolymer as a reversible and rapid
temperature-responsive sol—gel hydrogel. By tuning the methylcellulose content
gelation temperature, gelation time and mechanical strength can be controlled
[Biomater., 2004, 25, 3005-3012].
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Gel—forming system in response to change in ion—strength
In another embodiment, wherein the gel—forming system undergoes gel—
formation in response to change in rength in the range of 1 uM-SOO mM —
preferably in the range of 1—50 mM or 50—200 mM.
miting examples of such gel-forming systems include those illustrated
in Figure 3 and those described in i) Int. J. Pharm. 1989, 57, 163—168, ii) J. Controlled
Release, 1997, 44, 201-208, iii) J. Am. Chem. Soc., 2001, 123, 9463-9464, iv) J.
Controlled Release, 2003, 86, 253-265, v) Biomater., 2001, 22, 511-521, xi) Park K.,
Shala by W.S.W., Park H., radable hydroge/sfor drug delivery. Basel:
Technomic Publishing Co., Inc, 1993. ISBN 1004—6, Print xii) Biomedical
polymers and polymers therapeutics, Ed. Chiellini E., Sunamoto J., Migliaresi C.,
Ottenbrite R.M., Cohn D., New York, Kluwer ic Publishers, 2002, ISBN 0—
30646472-1, Print; and references cited therein.
One intriguing example of such a gel—forming system is that of alginate.
Alginic acid is an unbranched binary copolymer of 1-4 glycosidically linked L-
guluronic acid (G) and its C-5 epimer D-mannuronic acid (M). The proportion as well
as the distribution of the two monomers ines to a large extent the
chemical properties of alginate.
In one embodiment, the gel—forming system is based on an aqueous solution
of an alginate. Alginates are a family of linear polysaccharides, which, in aqueous
solutions, can gel after addition of multivalent cations. The use of alginate as an
immobilizing agent in most applications rests in its ability to form heat—stable strong
gels which can develop and set at room temperatures. It is the alginate gel
ion with calcium ions which has been of interest in most applications.
r, te forms gels with most di- and multivalent cations. Monovalent
cations and Mg2+ ions do not induce gelation while ions like Ba2+ and Sr2+ will
produce er alginate gels than Ca2+. The gel strength depends on the guluronic
content and also ofthe average number of G-units in the G-blocks. Gelling of
alginate occur when divalent cations takes part in the interchain binding between G-
blocks giving rise to a three-dimensional network in the form ofa gel (Figure 1). The
alginate gel as an lization matrix is sensitive to ing compounds such as
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phosphate, lactate and citrate, presence of anti—gelling cations such as Na+ or Mg“.
To avoid this gel beads may be kept in a medium containing a few millimolar free
calcium ions and by g the Na+/Ca2+ ratio less than 25:1 for high G alginates
and 3:1 for low G alginates. An alternative is also to replace Ca2+ with other divalent
cations with a higher affinity for alginate. There has been found a ation
between mechanical gel th and affinity for cations. It has been found that gel
strength may se in the following orders: Pb2+ > Cu2+ = Ba2+ > Sr“ > Cd2+ > Ca2+
> Zn2+ > Co2+ > Ni2+ However, in applications involving lization of living cells
toxicity is a limiting factor in the use of most ions, and only Sr“, Ba“ and Ca2+ are
considered as nontoxic for these purposes. Alginate gels have been found stable in a
range of organic solvents.
Since the gel-inducing factor is added before injection, slow physical gelation
is required in order to avoid syringe jam. To combat this, calcium ions can be slowly
released from, e.g., CaSO4 powder after the powder has been added to a sodium
alginate aqueous solution [J. Biomater. Sci., Polym. Ed., 1998, 9, 475-487]. In another
sting embodiment co-injection of the gel-inducing factor and the s
alginate solution using a double e results in rapid gelation in the tissue of
st thus avoiding syringe jam. Another interesting embodiment is Gellan gum
(Gelrite®, Figure 3) — a high molecular weight polysaccharide (500kDa) produced by
the microbe Sphingomonas elodea. Gellan gum is consists of four linked
monosaccharides, including one molecule of rhamnose, one molecule ofglucuronic
acid and two les of glucose. It forms gels when positively charged ions (i.e.,
cations) are added. Thus, the properties ofthe gel can be lled by manipulating
the concentration of potassium, magnesium, calcium, and/or sodium salts.
In another interesting embodiment the ion-strength sensitive gel-forming
system is a peptide such as H-(FEFEFKFK)2-OH (FEK16) which is known to self-
assemble into 6-sheet structures in an ionic-strength dependent manner [J. Am.
Chem. Soc., 2001, 123, 9463-9464]. FEK16 has been found to be highly soluble in
pure H20 but form self-assembled hydrogels at concentrations >10 mg/mL in the
presence of mM concentrations of NaCl, KCI, and CaClz.
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Gel—forming system in se to change in pH
In still another embodiment, the gel-forming system undergoes gel-
formation in response to changes in pH. Optionally, the gel-forming system
undergoes gel-formation in response to a combined change in pH and ature,
such as a pH in the range of 6-8 and a ature in the range of 35 to 40 °C.
miting examples of such gel—forming systems are illustrated in Figure 4,
and e those described in i) Macromol. Biosci., 2010, 10, 9, ii) J.
Controlled Release, 2001, 73, 205-211, iii) Topics in tissue engineering — Smart
Polymers, Vol. 3, 2007, Chapter 6, iv) Adv. Drug Delivery Rev., 2010, 62, 83—99, v) J.
Controlled Release, 2003, 86, 253-265 vi) Biodegradable hydrogels for drug delivery.
Basel: Technomic hing Co., Inc., 1993. ISBN 1004-6, Print, vii)
Biomedical rs and polymers therapeutics, Ed. Chiellini E., Sunamoto J.,
Migliaresi C., Ottenbrite R.M., Cohn D., New York, Kluwer Academic Publishers,
2002, ISBN 0—30646472—1, Print, and references cited therein.
The pH of the formulation (before injection) is preferably in the range of pH =
2—10, optionally in a range selected from 4-6, 6-8 and 8—9.
The properties of pH responsive hydrogels are highly depending on the pKa of
the ionizable moiety, the hydrophobic moieties in the polymer ne, their
amount and distribution. When ionizable groups become neutral — non—ionized— and
electrostatic repulsion forces disappear within the r network, hydrophobic
interactions dominate. The introduction of a more hobic moiety can offer a
more compact conformation in the uncharged state and a more accused phase
transition. The hydrophobicity ofthese rs can be controlled by the
copolymerization of hydrophilic ionizable monomers with more hydrophobic
monomers with or without pH-sensitive moieties, such as 2-hydroxyethyl
methacrylate, methyl methacrylate and maleic anhydride.
An example of a gel—forming system responsive to pH changes is that which
employs the pH-sensitive property of chitosan solutions at low pH. Once injected
into the body, these polymer solutions face different environmental pH conditions
and form gels. One example is mucoadhesive pH—sensitive chitosan/glyceryl
monooleate (C/GMO) in situ gel system which consisted of 3% (w/v) chitosan and
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3% (w/v) GMO in 0.33 M citric acid. an is normally insoluble in neutral or
alkaline pH. However, in dilute acids (pHSS.0), it becomes e due to the
protonation of free amino groups on the chitosan chains (RNH3+). The solubility of
chitosan in acidic medium also depends on its molecular weight. Acidic solutions of
chitosan when exposed to alkaline pH or body ical pH lose this charge and
form viscous gels. Chitosan and GMO both own mucoadhesive property which has
been applied in drug delivery system. ve charges on the chitosan backbone
may give rise to a strong electrostatic interaction with mucus or a negatively charged
mucosal surface.
Gel-forming system in response to enzymatic ty
In still another embodiment, the gel-forming system undergoes gel-
formation in se to enzymatic activity.
Non-limiting es ofsuch rming systems are illustrated in Figure 5 and
include those described in i) Tissue Eng., 2006, 12, 1151—1168, ii) Biomater. 2001, 22,
453-462, iii) Biomater., 2002, 23, 2703—2710, iv) Colloids Surf., B, 2010, 79, 142—148,
v) Biomacromolecules, 2011, 12, 82-87, vi) Macromolecules 1997, 30, 5255-5264, vii)
Biodegradable hydrogelsfor drug delivery. Basel: Technomic Publishing Co., Inc.,
1993. ISBN 1004-6, Print, viii) Biomedical polymers and polymers
therapeutics, Ed. Chiellini E., Sunamoto J., Migliaresi C., Ottenbrite R.M., Cohn D.,
New York, Kluwer Academic hers, 2002, ISBN 0-30646472—1, Print, and
nces cited n.
The enzyme or its origin is not particularly limited. I can be added prior,
during or after injection of the gel forming system, thus function as a trigger
molecule to induce gel formation. It may be encapsulated in an e.g. liposomes etc.
which upon re to an internal or external stimuli releases the enzyme.
Additionally, the enzyme might be present in the injected tissue, either as a natural
tissue component, or as an up-regulated enzyme due to the pathophysiological
conditions at the site of injection.
In one embodiment, the enzyme triggered gel-forming system is based on
caseins, a group of phosphoproteins with a molecular weight in the range from 20
kDa to 30 kDa. Such system can be turned into a hydrogel by addition of microbial
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transglutaminase (MTGase), a natural tissue enzyme, at physiological temperature
and pH ids Surf., B, 2010, 79, 142-148].
Another interesting example of a gel forming system based on enzymatic activation
is based on Schiff base formation of lysine rich peptides clue to activation by either
lysyl e or plasma amine oxidase [Biomacromolecules, 2011, 12, 82-87].
ion of e-amino groups of lysine by either lysyl oxidase or plasma amine
oxidase results in de formation which readily forms a Schiff base with an
additional e-amino group of lysine resulting in hydrogel formation.
Gel—forming system in response to an initiator
In still another ment, the gel-forming system undergoes gel-
formation in response to contact with an initiator, e.g. a le or irradiation
which results in gel ion by cross linking the gel forming system by the means
of a covalent chemical bond.
Non—limiting examples of such gel—forming systems are described in i) US
5410016, ii) J. Controlled Release, 2005, 102, 619-627, iii) Macromol. Res., 2011, 19,
294-299, iv) Polym. Bull. 2009, 62—699-711, v) J. Biomater. Sci., Polym. Ed., 2004, 15,
895—904, and references cited therein.
In one embodiment the gel forming system is cross linked by photoinitiation
by free l generation, most preferably in the e or long wavelength
ultraviolet radiation. The preferred polymerizable regions are acrylates, lates,
crylates, methacrylates, dimethacrylates, oligomethoacrylates, or other
biologically acceptable photopolymerizable groups. Useful photoinitiators for the
above mentioned system which can be used to initiate by free radical generation
polymerization of the macromers without cytotoxicity and within a short time
frame, minutes at most and most preferably s. Preferred dyes as initiators of
choice for visible light initiation are ethyl eosin, 2,2-dimethoxy—2—phenyl
acetophenone, other acetophenone derivatives, and camphorquinone. In all cases,
cross linking are initiated among macromers by a light activated free-radical
polymerization initiator such as 2,2—dimethoxy—2—phenylacetophenone or a
combination of ethyl eosin and triethanol amine, for example.
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In another embodiment the gel forming system is cross linked by — or
homo bifunctional linkers such as e.g. dithiothreitol, glutaraldehyde,
diphenylmethanebismaleimide, inimidyl suberate, bis(sulfosuccinimidyl)
suberate, dimethyl adipim and the like, but not limited to those. An example of such
a gel forming system is multiacrylate PEG-based polymers which have been reported
to form a hydrogel upon addition ofthe initiator DTT [J. Controlled Release, 2005,
102, 619-627]. The properties the gel could be fine tuned by controlling the size of
the polymer and the amount of initiator added and the gel could be formed under
physiological ature and pH. An additional example of such a system is
hydrogel formation by chemically cross-linking an hyaluronic acid (HA) derivative
with a hydrazide moiety and another HA derivative with an aldehyde, thus, forming
a slowly hydrolysable hydrazone bond [Eur. J. Pharm. Biopharm., 2008, 68, 57-66].
This method has the age of allowing in situ cross-linking without the use of
initiators, cross-linking chemicals, or extra equipment for cross—linking such as a light
source.
Gel—forming system in response to hydration
In still another embodiment, the gel-forming system undergoes gel-
formation in response to hydration. Example of such gel-forming systems are those
is selected from,- 1') , ii) Adv. Drug Delivery Rev., 2001, 47, 229—250,
iii) US 2007/0092560 - and references herein, but not limited to those.
Formulations composed of neutral diacyllipids and/or tocopherols and/or
phospholipids lized in biocompatible, oxygen containing, low viscosity organic
solvent may form a liquid crystalline phase structure upon ion, e.g. contact
with an s fluid such as vascular fluid, extracellular fluid, interstitial fluid
or plasma, but not limited to those. Other systems include ter soluble high-
viscosity liquid carrier materials such as sucrose acetate isobutyrate (SAIB). Such a
system may be mixed with solid particles described in the present invention
followed by parental ion, thus functioning as a injectable contrast agent which
that can be visualized by one or multiple imaging modalities, including X—ray
imaging.
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Gel—forming systems with cross linking groups
In still another embodiment, any of the afore mentioned rming
systems, are further functionalized by ucing one or more cross-linkable groups
such as acrylate, methacrylate, acrylamide, methacrylamide, vinyl ether, styryl,
e, maleic acid derivative, diene, substituted diene, thiol, alcohol, amine,
hydroxyamine, carboxylic acid, carboxylic anhydride, carboxylic acid halide,
aldehyde, ketone, isocyanate, succinimide, carboxylic acid hydrazide, glycidyl ether,
siloxane, alkoxysilane, alkyne, azide, 2'-pyridyldithiol, phenylglyoxal, iodo,
maleimide, imidoester, dibromopropionate, and halo acetates, such as
bromoacetate, but not limited to those.
Gel—forming systems with chelating groups
In an additional embodiment, the rming system is comprised of a
chelating agent that is known to chelate ions. Any ion chelating agent now known or
later discovered may be used in the articles of the t invention. Examples of
metal ion (e.g., Gd3+ or Cu“) chelating agents include, but are not limited to,
expanded porphyrins and rin-like derivatives, DOTA, DTPA, AngioMARKTM (a
backbone—functionalized DTPA chelate), DTPA-BMA (a neutral bis—methyl amide
derivative of DTPA), and HP-D03A (a DOTA-like macrocyclic compound wherein one
chelate arm is replaced with a hydroxylpropyl group). Additional chelates include,
but are not limited to, DPDP (TeslaScanT'V‘) and Deferoxamine (e.g. Fe3+ and Zr“).
Other constituents of the formulation
The ation may further e other constituents, such as (1-, [3-,
and/or y-cyclodextrins and any derivate hereof. Such constituents may form
guest/host complexes with the gel forming system and the nano—sized particles,
thus, both aiding in the gel formation and possible alter the le leakage profile
[Adv. Drug Delivery Rev., 2008, 60, 017]. In one very interesting embodiment
the gel forming system is based on PEG-PHB-PEG triblock copolymers, a—cyclodextrin
and PEG coated solid nano sized particles. In such a formulation, d-cyclodextrin may
form inclusion complexes with both the PEG blocks of the PEG—PHB-PEG triblock
copolymers and the PEG coated solid nano sized les which, combined with
hydrophobic interactions between the PHB middle block, forms a strong hydrogel
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with enhanced retention of solid nano sized particles due a-cyclodextrin interactions
which thus altering the particle leakage profile.
The formulation may further comprise compounds or polymers which are
visible in imaging modalities other than X—ray imaging.
In one embodiment, the formulation further comprises an iodine-containing
polymer, e.g. nylpyrrolidone-iodine (PVP-I), or one selected from i) Polym.
Chem., 2010, 1, 1467-1474, ii) US 3852341, iii) US 4406878, iv) US 5198136, v)
Biomedical polymers and polymers therapeutics, Ed. Chiellini E., Sunamoto J.,
resi C., Ottenbrite R.M., Cohn D., New York, Kluwer Academic hers,
2002, ISBN 01, Print, and references cited n. Such polymers can be
added to the gel forming components prior to gelation and on as contrast
agent in vivo. Such polymers may additionally or alternatively be covalently bound to
the one or more of the gel g components or adhered to the particles of the
present invention.
In one specific ment, the formulation consist of SAIB/6,6'-(2,4,6—
triiodophenoxy)acetoxy-isobutyric-Sucrose (8)/EtOH. The said combination enables
the formation of stabile injectable formulations with very high iodine content which
may be used to provide good visualization by one or multiple imaging modalities,
including X—ray imaging. High iodine contents (high HU—contrast) is especially
important for less ive imagining techniques such as e.g. fluoroscopy among
others. The iodine concentration of the said ation consisting of SAIB/6,6'—
(2,4,6-triiodophenoxy)acetoxy-isobutyric—Sucrose (8)/EtOH can be fine tuned by
varying the weight t (w%), as defined by the weight of the atom/molecule
giving x-ray contast such as iodoine divided by the total weight of the material
composition times 100, of 6,6'-(2,4,6-triiodophenoxy)acetoxy-isobutyric-Sucrose (8)
added to the . The elemental composition of 6,6'—(2,4,6-triiodophenoxy)—
acetoxy-isobutyric—Sucrose (8) is; C, 34.96; H, 3.61; I, 42.62; 0, 18.81, based on this,
the overall iodine content (w%) in various formulations can be calculated: SAIB/6,6'-
(2,4,6-triiodophenoxy)acetoxy-isobutyric—Sucrose (8)/EtOH (75:5:20) equals
2.13w%/2.67w% iodine before/after injection sion of EtOH out of the
formulation after injection causes an increases the w% of iodine); SAIB/6,6'-(2,4,6-
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triiodophenoxy)acetoxy-isobutyric-Sucrose (8)/EtOH (70:10:20) equals
4.26w%/5.33w% iodine before/after injection; SAlB/6,6'—(2,4,6-
triiodophenoxy)acetoxy-isobutyric-Sucrose (8)/EtOH (60:20:20) equals
8.52w%/10.66w% iodine before/after injection; ,6'—(2,4,6—
triiodophenoxy)acetoxy-isobutyric-Sucrose (8)/EtOH (55:25:20) equals
.65w%/13.32w% iodine before/after injection; SAIB/6,6'-(2,4,6—
triiodophenoxy)acetoxy-isobutyric—Sucrose (8)/EtOH (45:35:20) equals
14.92w%/18.65w% iodine before/after injection; SAIB/6,6'-(2,4,6-
ophenoxy)acetoxy—isobutyric—Sucrose OH (30:50:20) equals
21.30w%/26.64w% iodine /after injection.
An increase in iodine concentration of the ation can directly be
correlated to the observed contrast in Hounsfield units (HU). The following contrast
(HU) was observed at ent energies; 80-, 100-, 120- and 140kV, all 200mAs, 2
mm (col 40 x 0.6mm) for the following formulations; a) SAIB/6,6'—(2,4,6—
triiodophenoxy)acetoxy-isobutyric-Sucrose (8)/EtOH (70:10:20) (4.26w%/5.33w%
iodine before/after injection) 2500HU (80kV), 1800HU (100kV), 1500HU ) and
1300HU (140kV); b) SAIB/6,6'-(2,4,6-triiodophenoxy)acetoxy-isobutyric—Sucrose
(8)/EtOH (55:25:20) (10.65w%/13.32w% iodine before/after injection) 5000HU
(80kV), 4500HU (100kV), 3500HU (120kV) and 3000HU (140kV); c) SAIB/6,6'-(2,4,6-
triiodophenoxy)acetoxy-isobutyric-Sucrose OH (30:50:20) (21.30w%/26.64w%
iodine before/after injection) 10500HU (80kV), 8800HU (100kV), 6200HU (120kV)
and 5900HU (l40kV).
The gel-forming formulation may further comprise ceutical agents
including prodrugs (in short "drugs"; y interpreted as agents which are able to
modulate the biological processes of a mammal). Examples of pharmaceutical active
agents include small drugs, plasmid DNA (e.g. for gene therapy), mRNA, siRNA,
carbohydrates, peptides and proteins. Specific examples of ceutical agents
e; a) chemotherapeutic agents such as doxorubicin, cin, paclitaxel,
nitrogen mustards, etoposide, camptothecin, 5—fluorouracil, etc.; b) radiation
sensitizing agents such as gemcitabine and doranidazole, porphyrins for
photodynamic therapy (e.g. visudyne) or 108 clusters or 157Gd for neutron capture
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therapy; c) peptides or ns that modulate apoptosis, the cell cycle, or other
crucial signaling es; d) Anti matory drugs, such as methylprednisolone
hemisuccinate, B-methasone; e) Anti anxiety muscle relaxants such as diclofenac,
pridinol; f) Local anesthetics such as ine, bupivacaine, dibucaine, aine,
procaine; g) Analgesics such as opiods, non-steroidal anti-inflammatory drugs
(NSAIDs); h) Antimicrobial medications such as pentamidine, azalides; i)
Antipsychotics such as chlorpromazine, perphenazine; j) The antiparkinson agents
such as ne, prodipine, benztropine te, trihexyphenidyl, L-DOPA,
dopamine; k) Antiprotozoals such as quinacrine, chloroquine, amodiaquine,
chloroguanide, primaquine, mefloquine, quinine; l) Antihistamines such as
diphenhydramine, hazine; m) Antidepressants such as serotonin, imipramine,
ptyline, doxepin, desipramine; n) Anti anaphylaxis agents such as epinephrine;
o) Anticholinergic drugs such as atropine, decyclomine, methixene, propantheline,
physostigmine; p) Antiarrhythmic agents such as quinidine, propranolol, timolol,
pindolol; q) noids such as prostaglandins, thromboxane, prostacyclin, but not
limited to those. These drugs can be formulated as a single drug or as a combination
of two or more ofthe above mentioned drugs in its active form or as a prodrug.
Additional examples of antitumor agents include camptothecin derivatives
such as irinotecan hydrochloride, can hydrochloride, exatecan, 00,
lurtotecan, 50, Bay-383441, PNU—166148, IDEC-132, BN—80915, DB-38, DB-
81, DB-90, DB-91, CKD-620, T-0128, ST-1480, ST-1481, DRF-1042 and DE—310, taxane
derivatives such as docetaxel hydrate, IND—5109, EMS-184476, EMS-188797, T—3782,
TAX-1011, 31012, SBT-1514 and DJ-927, ifosfamide, nimustine hydrochloride,
carboquone, cyclophosphamide, dacarbazine, thiotepa, busulfan, melphalan,
ranimustine, estramustine phosphate sodium, 6—mercaptopurine riboside,
enocitabine, gemcitabine hydrochloride, carmofur, cytarabine, cytarabine
ocphosphate, tegafur, doxifluridine, ycarbamide, fluorouracil, methotrexate,
topurine, fludarabine phosphate, actinomycin D, aclarubicin hydrochloride,
idarubicin hydrochloride, epirubicin hloride, daunorubicin hydrochloride,
pirarubicin hydrochloride, bleomycin hydrochloride, zinostatin stimalamer,
neocarzinostatin, mytomycin C, bleomycin sulfate, peplomycin sulfate, vinorelbine
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tartrate, vincristine sulfate, vindesine e, vinblastine sulfate, amrubicin
hydrochloride, nib, exemestan, capecitabine, TNP-470, TAK—165, KW-2401, KW-
2170, 1, KT-5555, KT-8391, TZT-1027, S-3304, CS-682, YM-511, YM-598, TAT-
59, TAS-101, TAS—102, TA—106, FK—228, FK—317, E7070, E7389, KRN—700, KRN-5500, J-
107088, 4, SM-11355, ZD-0473 and the like.
Additional examples of radiation sensitizing agents include ium
,10,15,20—tetrakis(4-su|phophenyl)-porphine dodecahydrate, PYROA protein
(Emericella nidulans), photosan |||, lomefloxacin, azine, tiaprofenic acid and
the like, but not limited to those.
The drugs are included in the composition in an amount ient to achieve
a desired effect. The amount of drug or biologically active agent incorporated into
the composition depends upon the d release profile, the concentration of drug
required for a biological effect, and the d period of release of the drug. The
biologically active substance is typically present in the composition in the range from
about 0.5 percent to about 20 percent by weight relative to the total weight ofthe
composition, and more typically, between approximately 1 percent to about 15
t by weight. Another preferred range is from about 2 percent to about 10
percent by weight. For very active agents, such as growth factors, preferred ranges
are less than 1 % by weight, and less than 0.0001 %.
Viscosity of the ation
The viscosity of the formulation is before the injection preferably lower than
,000 cP, in particular lower than 2,000 cP, at 20 °C. Alternatively, the viscosity of
the formulation is before the injection typically lower than 2,000 cP at 5 °C.
The organic gel-forming system of the formulation is preferably one which,
after injection or under conditions ing those in a human body, forms a gel
having a viscosity at 37 °C in the range of 2,000 to 50,000,000 cP. More particularly,
the viscosity of the hydrogel can be about 2,000 cP, about 5,000 cP, about 10,000 cP,
about 20,000 cP, about 30,000 cP, about 50,000 cP, about 75,000 cP, about 100,000
cP, about 125,000 cP, about 150,000 cP, about 200,000 cP, about 30,000 cP, about
800,000 cP, about 1,000,000 cP, about 2,000,000 cP, about 5,000,000 cP, about
,000,000 cP, about 20,000,000 cP, about 30,000,000 cP, about 40,000,000 cP,
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about 50,000,000 cP, or ranges thereof. Preferably, the viscosity of the hydrogel
after injection (i.e. when present in the d location) is above 20,000 cP, e.g. in
the range of 20,000 cP to 1,000,000 cP. In particular, the formulation after injection
is preferably essentially solid.
Use of the formulation
The present invention also provides the formulation as defined hereinabove
for use in X—ray imaging as a marker of ic tissue, such as computer tomography
(CT), of the body of a mammal.
In one interesting embodiment, the formulation is parenterally administered
to a predetermined location of the body of a human or animal, and wherein an X-ray
image of at least a part ofthe body of the human or animal including the
predetermined location is ed.
A kit comprising the formulation
The present invention r comprises a kit comprising a syringe, a needle
used for injection into a body or surgical related ures, such as but not limited
to biopsy, adapted to the open end of said syringe, and a formulation as defined
above. In one embodiment, the formulation is held in the interior or said
syringe.
The gel forming system may be provided as a Iyophilized powder, a
suspension or a solution. Different components may be provided in one or more
dual vials or pre-mixed in the interior or said e. Exemplary different
components include, but are not limited to, the gel-forming system and the solid
particles, and the formulation and one or more initiators.
The syringe may consist of a single, a multiple barrel syringe (e.g. MEDMIX
SYSTEMS AG) or a double champer syringe (e.g. Debiotech SA.) and the like, but not
limited to those. Multiple barrel syringes and double champer syringes and the like
may be useful for e.g. two components formulations were one component is a
mixture of the gel forming system and the st agent(s) and the other
ent is an initiator or salt sion of e.g. Ca2+ in the case there the gel
forming system is based on alginate.
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The needle of the syringe can, in some embodiments, be one suitable for
fine—needle biopsies. Non—limiting examples of syringes and needles for such
embodiments are described in U.S. Patent No. 7,871,383, U.S. patent publication No.
20040162505, and references cited therein. Such syringes and needles can
advantageously be used in procedures where a biopsy of a tissue is to be taken in
conjunction with imaging of the same, using a formulation of the invention.
Preferably, the kit has a shelf-life of at least 6 months, such as at least 12 months
when stored at, e.g., room temperature (typically 18 to 25 °C) or lower
temperatures, such as, e.g., 2 to 10 °C, such as about 5 °C. The shelf-life can, for
example, be determined as the period wherein the kit can be stored at 25 °C, at 80
% RH and 1 atm. re, and where the viscosity is kept within 1r 5 % of the initial
viscosity.
A method of recording an X-ray image ofa body of animal or human
The present invention also provides a method of recording an X—ray image of
the body of a mammal, comprising the steps of:
(a) ing a formulation sing an organic gel-forming system that is a
nous liquid before injection that comprise an organic x-ray contrast
agent such as an iodinated compound detectable by X-ray imaging;
(b) administering the formulation to a t, and
(c) recording X-ray-based images, such as Computed Tomography (CT) s
or 2D X-ray images.
In one ment, the method is forjoint herapy and X—ray imaging
of a target tissue in an individual, wherein the images in step (c) provides a
definition of the target tissue, and further comprises the step of:
(d) using the definition of the target tissue obtained in c) to direct external beam
radiotherapy to the target tissue.
The target tissue is typically one that comprises undesirably growing cells. In
one embodiment, the rably g cells are tumor cells, such as malignant
cells, and the individual is suffering from or at risk for cancer. In a particular
embodiment, the undesirable growth of cells is associated with lung cancer, prostate
cancer, cervix or n cancer. Other types of conditions or diseases associated
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with undesirable cell growth include extra uterine (ectopic) pregnancy, benign
tumors in brain, such as benign tumors located closely to the optical nerve, glandule
with overproduction of hormone, such as for example alamus, bone and
cartilage in relation with nerve compression, blood cells which may be killed prior to
transplantation, conditions associated with large tonsils such as acute tonsillitis or
ditis, ctive sleep apnoea, nasal airway obstruction, snoring, or
peritonsillar abscess or hyperplasic or angiogenic eye disorders.
In embodiments where the gel-forming system is one that gels upon the
addition of an initiator, the stration step (a) or (b) may further comprise
mixing with an initiator.
The formulation according to the present invention may be stered
parenterally, such as by intravenous, intramuscular, intraspinal, subcutaneous,
intraarterial, intracardiac, intraosseous, intradermal, intracisternal, intrathecal,
intracerebral, transdermal, transmucosal, inhalational, epidural, sublingual,
intravitreal, intranasal, intrarectal, intravaginal or intraperitoneal administration.
The parental administration may be performed by, e.g., infusion or injection.
Typically, the formulation is administered into, or adjacent to, a predetermined
location, such as a target tissue, optionally in conjunction with a biopsy of the target
tissue.
The amount of formulation to ster to the mammal or individual in step
(c) can be ined by one of skill in the art, taking into consideration the nature
ofthe investigation and the size ofthe area to be imaged. Typically, at least 100 uL
formulation is administered. In various specific embodiments, the method comprises
stration of between 100 uL and 20 mL, such as between 200 pL and 10 mL,
such as between 200 pL and 2 mL.
In step (c), an X-ray image is typically recorded of at least a part of the body
ofthe mammal including the predetermined location. In particular embodiments,
steps (c) and (d) may be performed simultaneously, so that image-recording and
execution of radiotherapeutic treatment is integrated and performed sequentially or
simultaneously.
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Use of the formulation as a tissue sealant
The present invention also provides the formulation as defined herein above
for use as a tissue sealant, e.g. for needle canals formed by biopsy in conjunction
with an imaging ure according to the invention.
The tissue sealant may e an effective amount of a hemostatic agent,
e.g. an agent selected from coagulation factors, coagulation tors, platelet
activators, vasoconstrictors and fibrinolysis inhibitors, e.g. hrine,
adrenochrome, collagens, thrombin, fibrin, fibrinogen, oxidized cellulose and
chitosan.
Specific embodiments of the invention
As said above, the present invention is in one embodiment an X—ray contrast
composition for local administration, wherein the X-ray contrast composition
ts contrast properties and wherein at least 60% of an administrated amount of
said X-ray contrast composition remains more than 24 hours within 10 cm from an
injection point when the X-ray contrast ition is administrated to a human or
animal body. There are various forms of injection forms and routes possible, such as,
but not limited to, utane injection, using a scope (bronchoscope, gastroscope,
or any other flexible wired systems used to navigate inside a body), spraying orjust
adding on a open wound, attached to another such system, intracranial injection,
inside air and fluent filled organs or cavities (e.g. bladder, stomach), or inside non
lly or medically created cavities.
Furthermore, there are various forms of dosing such as, but not limited to,
fast injections ('bolus’), pulling back to needle while injecting, slowly injection on the
site (e.g. less than 5 seconds, 60 seconds, 120 seconds, 5 minutes, 10 minutes or less
than 20 minutes), pulsating the injection, pushing the needle forward, and pump
giving a constant pressure for a defined period. Furthermore, there are various
devices that may be used such as, but not limited to, needle with 1 or more holes on
the side ofthe needle forming multiple smaller s, flexible, multiple chamber
s. In one embodiment, the present invention has gelating ties and is a
liquid before stration and has the ability to transform into a gel after
administration. In one specific ment, the present invention has gelating
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properties and is a homogeneous liquid before administration and has the ability to
transform into a gel after administration. Furthermore, in one ment the
present invention is a non-colloidal x-ray contrast agent as part of a homogeneous
liquid x-ray contrast composition that gels upon injection into a human or animal
subject. In yet another specific embodiment the X-ray contrast composition is a
liquid before administration into a human or animal body that increases in viscosity
by more than 100 centipoise (cP), such as e.g. more than 1,000, more than 2,000 or
more than 5,000 centipoise (cP), after administration into a human or animal body.
According to another specific embodiment of the present invention the X—ray
contrast composition is a liquid before administration into a human or animal body
that increases in viscosity by more than 10,000 centipoise (cP) after administration
into a human or animal body. In another ic embodiment the present invention
has a viscosity of less than 10,000 centipoise (cP) at 20°C.
Furthermore, from one perspective of the present invention, the X—ray
contrast composition comprises an X-ray contrast agent that is part of the X-ray
contrast ition and said X—ray contrast agent is an organic substance.
According to one specific embodiment, the organic substance is the contrast ”agent”
and the X-ray contrast composition ses alginate and chitosan. In another
specific embodiment the X—ray contrast agent comprises one or more natural
polymers, synthetic polymers, oligomers, lipids, saccharides, disaccharides,
polysaccharides, peptides or any combination thereof and as mentioned before
these may be the contrast ”agent”. In yet another specific ment of the
present invention the X-ray contrast agent comprises one or more iodinated
polymers, ers, lipids, saccharides, disaccharides, polysaccharides, peptides, or
a derivative or a combination f. Further, in one embodiment the X-ray
contrast agent is an inorganic acid or salt, such as auric acid.
The present ion may in one ment comprise particles for various
purposes. One purpose may be an additive contrast effect; another purpose may be
to potentiating the effect and a third e may be as a carrier of e.g. medication
or other substances. ing to one specific embodiment of the present ion,
the X-ray contrast composition comprises nanoparticles comprising gold (Au). In yet
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another embodiment the X-ray st composition also ses particles in the
size range from 1 — 1000 nm, such as nanoparticles in the size range from 2 to 500
nm and in one specific ment the nanoparticles comprises gold (Au) as the
prefered X—ray attenuating element. In yet another embodiment, the X—ray contrast
composition comprising nanoparticle that may be an MRI, PET, ultrasound,
fluorescence, radiofrequency, visible light contrast agent. Furthermore, in one
ic embodiment the nanoparticle is an MRI or PET contrast agent or a
ation of the above mentioned imaging modalities.
The present invention may in one embodiment comprise solid particles
coated with PAM (MW 3500). By choosing PNIPAM as the coating material
various interesting properties can be introduced to the particles. PNIPAM is more
hydrophobic compared to e.g. PEG but still water soluble, which enables efficient
and straightforward le coating in aqueous solution without prior tion to
organic solvents. Additionally, by having PNIPAM as the coating material results in a
nano ite which can be lyophilized into a powder without inducing particle
aggregation etc. which is not possible with other polymers e.g. PEG. Having the solid
particles in a powder form is advantageous from multiply perspectives in terms of
increased stability, easy storage and straight forward formulation procedures.
Furthermore, by having PNIPAM as the only polymer on the solid particles enables
the particles to be suspended in c solvents such as e.g. EtOH for a prolonged
period of time without aggregation due to the increased hydrophobicity of the
particle introduced by the PNIPAM polymer. By having PNIPAM attached to the solid
particles, as the only r in the formulation, the hydrophobic interactions with
the gel forming solution in terms of e.g. sucrose acetate isobutyrate (SAIB) is
sed resulting in a able system with very high particle retention. Choosing
a more hydrophilic coating material for the particles would induce the release of the
solid particles from the gel matrix which can be an advantage or a disadvantage
depending on the desired properties of the formulation.
As mentioned previously the present invention may have gelating properties
and the gelling may be initiated by various factors such as, but not limited to,
temperature, hydration, enzymatic activation, ion concentration and/or pH. In one
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embodiment the X—ray contrast ition ts gel—formation in se to a
temperature in the range of 35 to 40°C. In another embodiment the X-ray contrast
composition exhibits gel-formation in response to hydration. In yet another
ment the X—ray contrast composition exhibits gel—formation in response to an
ion-concentration in the range of 1 uM to 500 mM, such as in the range of 1 mM to
200 mM. In one embodiment the ions are divalent ions, such as calcium ions. In one
embodiment the X—ray contrast composition exhibits gel—formation in response to a
pH in the range of 6 to 8. In yet another embodiment, the X-ray contrast
composition exhibits gel—formation in response to contacting with an initiator and
here an initiator can be many different things such as, but not limited to, ions, or a
chemical reactive compound that cross link other molecules.
In one embodiment, the X—ray st composition ing to the present
invention may comprise radioactive compounds, paramagnetic compounds,
fluorescent compounds or ferromagnetic compounds, or any mixture thereof.
As mentioned previously, the X-ray contrast composition may also act as a
carrier of substances such as, but not limited to, pharmaceutical nces. The
nce may be in the composition or in or coated/linked to the nanoparticles.
The substance may also be other types of additives. Examples of substance could be,
but is not limited to, substances suitable for chemotherapy, gemcitabine, cisplatin,
doxorubicin, doranidazole, hormones or odies. In one embodiment the X—ray
composition comprise at least one pharmaceutical substance. In one specific
ment the X—ray contrast composition comprises particles in the size range
from 1 — 1000 nm, such as nanoparticles in the size range from 2 to 500 nm and
wherein the particle contains at least one pharmaceutical substance.
In one embodiment a polymer may be used to work as a stabilizer between
gel and biological surrounding and ore, the X-ray contrast composition may
also comprises a molecule that increase gel stability in the human or animal body,
such as an interfacially active molecule, such as an amphiphilic molecule, such as an
emulsifier. Therefore in one embodiment the X—ray contrast ition comprises
thylene glycol-b-caprolactone) (PEG-PCL), sucrose acetate isobutyrate (SAIB),
poly(D,L-lactic acid) (PLA), or actic—co-glycolic acid) (PGLA), or a combination
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f. In one embodiment of the present invention poly(D,L-lactic acid) (PLA) is
added to sucrose acetate isobutyrate (SAIB) gel causing a reduction of burst release
of said encapsulated contents e.g. particles drugs etc. Further, in one embodiment,
the X—ray contrast ition comprises sucrose e isobutyrate (SAIB) or a
derivative thereof and in one specific embodiment of the present invention, the X-
ray contrast composition comprises an iodinated derivate of sucrose e
isobutyrate (SAIB). Furthermore in another specific embodiment of the t
invention the X-ray contrast ition comprises an iodinated derivate of sucrose
acetate isobutyrate (SAIB) doped into sucrose acetate yrate . This has
been evaluated for stability and the amount of this iodo—SAIB/SAIB that can be
doped into SAIB, is at least 50 w/w%.
The iodo-SAIB provides high X-ray contrast. The iodo-SAIB compound is
poorly soluble in ethanol and is a white solid whereas SAIB is highly soluble in
ethanol and is a thick oil. However, a mixture of ethanol and SAIB can solubilize the
iodo-SAIB very nicely. This means that the SAIB helps solubility of iodo-SAIB, which is
an interesting e and which provides an injectable solution which forms a
biodegradable, amorphous carbohydrate glass matrix after administration (through
a thin needle, thinner than 20 gauge) that can function as a high st X-ray
marker. When injected into mice, the iodo—SAIB/SAIB provides high contrast and has
the desirable stability properties. rmore, the gel is homogeneous. In one
embodiment of the present invention the X-ray contrast composition comprises an
iodinated derivate of sucrose acetate isobutyrate (SAIB) solubilized in a mixture of
ethanol and sucrose acetate isobutyrate (SAIB).
One way of ning and also storing the composition may be, held in the
interior ofa syringe. This indicates a possible life of at least 6 months. One
embodiment of the present invention is a kit comprising a syringe, a needle used for
injection into a body or surgical related procedures such as but not limited to biopsy
adapted to the open end of said syringe, and a composition ing to the present
invention.
In one embodiment of the present invention, the X-ray contrast composition
comprises an iodinated derivate of sucrose acetate isobutyrate (SAIB) and contains a
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pharmaceutical substance. In another embodiment the X—ray contrast composition
ses an iodinated derivate of sucrose acetate isobutyrate (SAIB) and ns
particle that ns a pharmaceutical substance. In yet another embodiment, the
X—ray contrast composition ses an ted derivate of sucrose acetate
isobutyrate (SAIB) solubilised in a mixture of ethanol and sucrose acetate
isobutyrate (SAIB) and contains a pharmaceutical substance. Furthermore, in one
specific embodiment of the present invention, the X-ray contrast composition
comprises an iodinated derivate of sucrose acetate isobutyrate (SAIB) solubilised in a
mixture of ethanol and sucrose acetate isobutyrate (SAIB) and ns a particle
that contains a pharmaceutical substance.
The ed use of the present invention is for radio therapy or image—
guided radiation therapy, but not exclusively, other uses are thinkable such as, but
not limited to, 2D X-ray scans, for use in g, diagnostics, treatment and/or
quality rating of radiation therapy. The present invention may be used as a tissue
marker and/or for use as a controlled drug release ition.
In one embodiment the X—ray contrast composition according to the present
invention is for use in administration of an amount of 0.01 — 5.0 mL and in one
specific embodiment the X-ray contrast composition is for use in administration
wherein the amount is 0.1 — 1.0 mL. In one embodiment the present invention may
be used as a tissue sealant.
In one embodiment the X—ray contrast composition according to the present
invention, the X-ray st composition is erally administered to a
predetermined location of the body of a mammal, and wherein an X-ray image of at
least a part of the body of the mammal ing the predetermined location is
recorded. Further, an embodiment ofthe invention may comprise a method of
recording an X-ray image of the body of a mammal, comprising the steps of
a. providing an X-ray contrast composition comprising an organic X—ray
agent in a gel-forming system;
b. administering the X—ray contrast composition to a predetermined
location ofthe mammal, and
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C. recording X—ray-based images of at least a part of the body which
comprises the predetermined location.
In another ment, the invention comprise a method of joint herapy and
X—ray imaging of a target tissue in a mammal, comprising the steps of
a. providing an X-ray contrast ition comprising an organic X—ray
agent in a gel-forming system;
administering the X—ray contrast composition to a predetermined
target tissue of the mammal,
recording X—ray-based images, of at least a part of the body which
comprises the target tissue, thereby providing a definition of the
ta rget , a nd
d. using the definition of the target tissue obtained in c) to direct
external beam radiotherapy to the target tissue.
Steps (c) and (d) may potentially be performed simultaneously.
In another embodiment, the ion comprise a method for directing local
administration ofa pharmaceutical agent to a target tissue in a mammal, comprising
the steps of
a. providing an X-ray contrast composition comprising an organic X-ray
agent in a gel—forming system;
administering the X-ray contrast composition to a predetermined
target tissue of the mammal,
recording X—ray-based images, of at least a part of the body which
comprises the target , thereby ing a definition of the
ta rget tissue, a nd
d. using the X—ray contrast composition in b) to further comprise an
pharmaceutical agent for delivery of a pharmaceutical agent to a
predetermined target tissue of the mammal.
Steps (c) and (d) may potentially be med simultaneously.
In one specific embodiment of the present invention the target tissue
comprises undesirably growing cells and in another specific ment the target
tissue comprises tumor cells.
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Detailed description ofthe drawings
Figure 1. Illustrates various mechanisms of gel-formation including thermo-,
ion-, pH-, enzymatically-, tor— and hydration responsive gel-forming systems.
Figure 2. Illustrates various thermo responsive gel—forming systems which can
exhibit an inverse l transition.
Figure 3. Illustrates various ion ive gel-forming systems which form gels
in high salt concentration.
Figure 4. Illustrates various pH sensitive gel-forming systems which form
hydrogels at specific pH intervals.
Figure 5. Illustrates s enzymatically sensitive rming systems which
form hydrogels in presence of specific enzymes.
Figure 6. Illustrates the use of e acetate isobutyrate (SAIB) as a
hydration sensitive gel-forming system. SAIB dissolved in organic solvent such as
ethanol have a low viscosity suitable for injection trough thin needles. Upon
hydration the ethanol diffuses out of the matrix resulting in a highly viscous
hydrophobic gel le for ulation of contrast agents.
Figure 7. Illustrates various iodo-SAIB derivates which may be used for x—ray
attenuation.
Figure 8. rates a tic scheme for the synthesis of 2-(2,4,6-
triiodophenoxy)acetic acid (3)
Figure 9. Illustrates a synthetic scheme for the synthesis of 6,6'—(2,4,6-
triiodophenoxy)acetoxy-isobutyric—Sucrose (8)
Figure 10. Illustrates CT-contrast of iodinated gels with 10-, 25-, or 50w% (8)
((w% is the weight of the atom/molecule (in this case iodine) divided by the total
weight of the material times 100)) and a negative control containing MQ-HZO were
ized in a clinical CT—scanner at different energies; 80-, 100—, 120- and 140kV, all
ZOOmAs, 2 mm (col 40 x 0.6mm).
Figure 11. Illustrates AuNP synthesis and characterization. A) Synthetic
scheme for the synthesis of PNIPAM-coated AuNPs using a seeding approach,- B)
AuNP characterization by UV-Vis; C) AuNP terization by DLS; D) AuNP
characterization by Z—potential.
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Figure 12. Illustrates the enhanced stability of PNIPAM coated AuNPs. A) UV-
Vis of PNIPAM coated AuNPs before(stock)/after lization and re-suspension in
ous EtOH (concentration of AuNP in the range of 1.0-5.0 mg Au/mL); B) DLS
of PNIPAM coated AuNPs before(stock)/after lyophilization and re—suspension in
anhydrous EtOH (concentration of AuNP in the range of 1.0-5.0 mg .
Figure 13. rates the accumulative release of PNIPAM3500- and PE65000
coated AuNPs from gels composed of SAIB/EtOH/PLA (75:20:5) + 3.0w% PNIPAM3500
or PE65000 coated AuNPs.
Figure 14. Illustrates a ultrasonography imagee of Formulation B
(SAIB/8/EtOH (55:25:20)) (250pL) in vitro. Gel present at the bottom ofa glass
beaker under water.
Figure 15. Illustrates MicroCT images of Formulation B (SAIB/8/EtOH
(55:25:20)) (200pL) administered by aneous injection to healthy NMRI mice.
A) CT—image recorded 24h p.i.; B) CT—image recorded 48 p.i.
Figure 16. A) MicroCT image of SAIB/8/EtOH (65:15:20) injected sq. in
immunocompetent mice; B) MicroCT image of SAIB/8/EtOH (50:30:20) injected sq.
in immunocompetent mice; C) Ex vivo visualization of SAIB/8/EtOH (50:30:20)
present in the s.q. compartment 14w p.i. and D) Gel implants composed of
SAIB/8/EtOH (50:30:20) removed after 14w implantation in immunocompetent
mice.
Figure 17. A) Series of MicroCT images of SAIB/8/EtOH (50:30:20) injected
sq. in mice. MicroCT scans recorded with short time intervals to monitor the
gelation kinetics of the iododinated gel; B) Gelation kinetics of SAIB/8/EtOH
(50:30:20) (50uL) implanted sq. in immunocompetent mice and C) 14w ation
profiles of iododinated gels composed of SAIB/8/EtOH (65:15:20) or SAIB/8/EtOH
(50:30:20) after s.q. tation (50uL).
Figure 18. Illustrates a CT—image of Formulation B (SAIB/8/EtOH (55:25:20))
administrated intratumoral to a companion dog can Staffordshire terrier, 9
years, 34kg) with a mast cell tumor t between the front legs.
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Examples
Example 1 — lodo—SAIB gel formation and CT-contrast in vitro
Materials
Chemicals were purchased from Sigma—Aldrich Inc. (Br¢ndby, k)
unless otherwise stated. 2-(2,4,6—triiodophenoxy)acetic acid (3) and 6,6'-(2,4,6—
triiodophenoxy)acetoxy-isobutyric-Sucrose (8) was synthesized in two and four
steps, respectively, as outlined in Figure 7 and Figure 8.
Synthesis
,6—triiodophenoxy)acetic acid (3). 2,4,6—triiodophenol (1) (10.00g,
21.2mmol) was dissolved in dry DMF (75mL) under Nz-atmosphere. To this solution,
tert—butyl bromoacetate (4.20mL, 28.46mmol) and K2C03 (8.79g, 63.6mmol) were
added and the stirred ght at rt. The solvent was removed in vacou and the
remaining yellow oil re-dissolved in EtOAc (150mL) and washed with MQ-HZO
(3x150mL). The organic phase was dried with MgSO4, filtrated and concentrated in
vacou to give tert—butyl 2—(2,4,6-triiodophenoxy) acetate (2) as a light yellow oil
which was used in the next step without further purification. 2 was dissolved in
CHzClz (60mL) and trifluoroacetic acid (30mL) was added. The mixture stirred for 1h
at rt after which the t was removed in vacou to give a white solid. The crude
product was re-crystallized from EtOH to give 2—(2,4,6-triiodophenoxy)acetic acid (3)
as fine white needles (9.58g, 85% (2 ). 1H-NMR (300MHz, MeOD): 5 6.58 (s,
2H), 2.95 (s, 2H). TOF MS (DHB+Na): Chemical Formula: C8H5|3Na03,
calculated mass; 552.83; found: 553.08 (M+Na+).
6,6'-TBDP$-Sucrose (5). Sucrose (4) (3.00g, 8.76mmol) was dissolved in dry
pyridine (54.0mL) under Nz—atmosphere. To this solution tert-butyldiphenylchloro—
silane (TBDPS-Cl) (2.51mL, ol) and a catalytic amount of DMAP (107.5mg,
0.88mmol) were added and the mixture heated at 70°C for 3h. After cooling to rt,
TBDPS-Cl (2.51mL, ol) was added and the mixture stirred overnight at rt. The
solvent was removed in vacou and the crude product purified by flash chromato-
graphy using a stepwise gradient starting from,- i) EtOAc, ii) EtOAc/Acetone/HZO
(100:100:1) and iii) EtOAc/Acetone/HZO (10:10:1) as eluent to give BDPS-
Sucrose (5) as a white solid (4.66g, 65%). Rf = 0.40 (EtOAc/Acetone/HZO (100:100:1)).
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MALDI-TOF MS a): Chemical Formula: Na011Si2, calculated mass;
841.08; found: 841.81 (M+Na+).
6,6'-TBDPS-isobutyric-Sucrose (6). 6,6'-TBDPS-Sucrose (5) (3.00g, 3.66mmol)
was dissolved in dry pyridine (45.0mL) under Nz—atmosphere. To this solution
isobutyric anhydride (15.00mL, 90.4mmol) was added and the e stirred at rt
overnight. Additional isobutyric anhydride (5.0mL, 15.06mmol) and a catalytic
amount of 4-dimethylaminopyridine (DMAP) (50mg, 0.41mmol) were added and the
mixture heated to 70°C for 6h. The solvent was removed in vacou and the crude
product purified by flash chromatography using hexanezEtOAc (5:1) as eluent to give
6,6'-TBDPS-isobutyric-Sucrose (6) as clear viscous oil (4.54g, quantitative). Rf = 0.48
(hexane:EtOAc (5:1). MALDI-TOF MS (DHB+Na): Chemical Formula: C68H94Na017Si2,
calculated mass; 1262.62; found: 2 ).
6,6'-OH-isobutyric-Sucrose (7) 6,6'-TBDPS-isobutyric-Sucrose (6) (217.2g,
0.175mmol) was dissolved in THF (940mL) and stirred at RT. Glacial acetic acid
(42.1g, 0.701mol) was added to the flask followed by addition of tetrabutyl-
ammonium fluoride trihydrate 3H20) g, 0.701mol) in THF (692mL). The
solution was d at RT for 15h after which heptanes (2085mL) and phosphate
buffer (0.5M, 2111mL) (HZKPO4 (177.2g) and HK2P04 (343.3g) in MQ-HZO L)),
pH 7.0) was added. The organic phase was collected and washed with additionally
two portions of phosphate buffer (0.5M, 2111mL). The crude product purified by
flash chromatography using a gradient starting from hexanes:EtOAc (7:3) then
hexanes:EtOAc (6:4) as eluent to give 6,6'—OH-isobutyric—Sucrose (7) as clear viscous
oil (106.1g, 79%). Rf = 0.21 (hexane:EtOAc (3:1). 1H-NMR (300MHz, DMSO-de): 6 5.75
(d,J = 6.1 Hz, 1H), 5.50 (d,J = 3.6 Hz, 1H), 5.40 (d, J = 7.7 Hz, 1H), 5.31 (t,J = 7.4 Hz,
1H), 5.18 (t, J = 9.8 Hz, 1H), 4.87 (t, J = 5.5 Hz, 1H), 4.70 (dd, J = 10.4, 3.7 Hz, 1H), 4.29
(d,J = 11.9 Hz, 1H), 4.11 (dd, J = 12.0, 5.5 Hz, 1H), 3.69—3.44 (m, 4H), 2.64—2.49 (m,
6H), 1.13—0.96 (m, 36H). MALDI-TOF MS (DHB+Na): Chemical Formula: C36H53Na017,
calculated mass; 785.83; found: 785.82 (M+Na+).
6,6’-(2,4,6—triiodophenoxy)acetoxy—isobutyric-Sucrose (8) H—isobutyric-
Sucrose (7) (800mg, 1.05mmol) was dissolved in dry DMF L) under N2-
atmosphere. To this solution a pre-mixed mixture of 2-(2,4,6-triiodophenoxy)acetic
W0 2014!187962
acid (3) (1.67g, 3.15mmol), EDC-HCI (622mg, 3.15mmol) and DMAP (769mg,
6.29mmol) in dry DMF (10.0mL) were added and the reaction stirred at rt overnight.
The solvent was removed in vacou and the remaining yellow oil re-dissolved in
CH2C|2 (40mL) and washed with MQ—HZO (3x40mL). Organic phase was dried with
MgSO4, filtrated and reduced in vacou to give light yellow oil. Final purification was
achieved by flash tography using hexanezEtOAc (5:1) as eluent to give 6,6'-
(2,4,6-triiodophenoxy)acetoxy-isobutyric—Sucrose (8) as white foamy solid (1.56g,
83%). Rf = 0.31 (hexane:EtOAc (5:1). 1H-NMR (300MHz, MeOD): 6 8.05 (s, 2H), 8.04
(s, 2H), 5.68 (d,J= 3.7 Hz, 1H), 5.56 (d, J = 7.3 Hz, 1H), 5.54— 5.48 (m, 1H), 5.43 (t,J =
7.2 Hz, 1H), 5.37 (t,J = 9.8 Hz, 1H), 5.03 (dd,J = 10.2, 3.7 Hz, 1H), 4.70—4.06 (m, 12H),
2.73—2.45 (m, 6H), 1.36—1.04 (m, 36H). MALDI-TOF MS (DHB+Na): Chemical
Formula: C52H64|6Na021, calculated mass; 1809.47; found: 1809.59 (M+Na+).
Gel preparation
Three sucrose e isobutyrate (SAIB)—based formulations (600mg each)
with increasing amounts of 6,6'-(2,4,6-triiodophenoxy)acetoxy-isobutyric-sucrose
were prepared as ed in the table below.
6,6'—(2,4,6-triiodophenoxy)—
ation SAIB EtOH
acetoxy-isobutyric-sucrose (8)
SAIB/8/EtOH
420mg 60mg 120mg
(70:10:20)
SAIB/8/EtOH
330mg 150mg 120mg
:20)
SAIB/8/EtOH 180mg 300mg 120mg
(30:50:20)
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SAlB-solution (90w/w in EtOH) was weighted off and mixed with 8 and
anhydrous EtOH (see table above). The mixtures were nized on a ball-mill
homogenizer for 60min (30s'1) and centrifuged for 20s at 5000RPM to remove air
bubbles from the formulations. All formulations were homogenous clear solutions
with sing viscosity as a on of the concentration of 8 — all injectable
trough 256 hypodermic s.
Iodinated gels (500pL) from formulation A—C were prepared by injection into
MQ-HZO (5.0mL) containing plastic vials at 37°C. The aqueous solutions were
replaced three times and the gels stored at 37°C for 12 days prior to ualization
and HU-contrast measurements in a clinical CT-scanner.
CT—contrast of iodinated gels in vitro
The three formed iodinated gels with 10—, 25-, or 50w% 8 and a negative
control containing MQ-HZO were visualized in a clinical CT-scanner at different
energies; 80—, 100—, 120— and 140kV, all 200mAs, 2 mm (col 40 x 0.6mm). The
obtained contrast in Hounsfield unit (HU) plotted as a function of energy is
illustrated in Figure 10 and listed in the table below. Excellent contrast g from
1.300-10.500HU was observed dependent on the w% of8 and the applied energy.
w% iodine
Formulation (before 80kV 100kV 120kV l40kV
injection)
A 4.26w% 2500HU 1800HU 1500HU 1300HU
B 10.65w% 5000HU 4500HU 3500HU 3000HU
C 21.30w% 10500HU 8800HU 6200HU 5900HU
As may be understood from above, according to one specific embodiment of
the present invention, the X-ray st composition is a liquid before administra-
tion into a human or animal body and having an iodine concentration of more
than 1.5 w% before injection, such as 2-30 w%, such as 3-25 w%, such as 4-25 w%.
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Example 2 — Synthesis and improved properties of PNIPAM-coated AuNP
Materials
Chemicals were sed from Sigma-Aldrich Inc. (Br¢ndby, Denmark)
unless otherwise stated. x3H20 was purchased from Wako Chemicals GmbH
(Neuss, Germany) and SH—PNIPAM (MW 3500, PDI = 1.24) was purchased from
Polymer Source (Dorval, Canada).
AuNP synthesis, PNIPAM coating and particle characterization
All glassware was cleaned with aqua regia prior to use. Trisodium citrate
(10mL, 38.8mM) was rapidly injected into a refluxing solution of HAuCl4*3H20
(100mL, 1.0mM) under vigorous stirring. An immediately color change from light
yellow to wine red was observed and the reflux was continued for 15min after which
the solution was cooled to rt. The ed AuNP—seeds (20mL) were added to a
boiling on of *3HZO (2500mL, 0.296mM) under vigorous stirring.
Subsequently, trisodium citrate L, 38.8mM) was added and the mixture
refluxed for 30min resulting in a clear color change from wine red to purple.
Additional trisodium citrate (100mL, 38.8mM) was added as stabilizer and the
mixture heated for additional 1h. The AuNP solution was cooled to rt and SH-
PNIPAM3500 (40mg, 11.4pmol) (6 molecules pr/nm2 AuNP e area) dissolved in
EtOH (5.0mL) was added. The reaction mixtures d overnight at rt (Figure 11a).
The PNIPAM-coated AuNPs was extensively washed with MQ-HZO and up-
concentrated to approx. 2.3mL etically 65mg AuNP/mL) by centrifugation
(4.500RPM, 45min/cycle). The AuNP-seeds, the citrate stabilized AuNPs and the
purified up-concentrated PNIPAM-coated AuNP were all terized by UV-Vis
(Figure 11b), DLS (Figure 11c) and the ntial was measured (Figure 11d). The
[Au]-concentration of the up-concentration PNIPAM-coated AuNPs were
ined by ICP—MS using a Au3+'standard (1000mg/mL) in 5% HCl spiked with
0.5ppt Ir as internal standard. Up—concentrated PNIPAM—coated AuNPs were
dissolved in aqua regia and diluted with 5% HCl to theoretically 666ppt Au3+. The
concentration of the PNIPAM-coated AuNPs was determined to 64mg Au/mL. The
PNIPAM coated AuNPs were stored at 5°C until further use.
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Lyophilization of PNIPAM coated AuNP and stability in organic solvent
PNIPAM coated AuNPs (see synthesis above) were d to 1.0—, 2.5- or 5.0
mg Au/mL (500uL each) with MQ—HZO and snap-frozen in liquid nitrogen for 2
minutes. The samples were lyophilized overnight (p < 6.0x10'2 mbar) to form dark
colored shiny s. The lyophilized PNIPAM coated AuNPs were re—dissolved in
EtOH (0.50 mL) and ed for a few seconds. The particles tely re-
dispersed within s to give dark colored solutions. The particle morphology
was evaluated by UV-Vis (figure 12a) and DLS (figure 12b). No sign of aggregation or
instability was observed for the PNIPAM—coated AuNPs neither during lyophilization
or EtOH solubilization. The lyophilized powder could easily be stored and weighted
off at a later time—point.
Example 3 — Controlling particle retention in SAIB gels based on particle
hydrophobicity
Chemicals were purchased from Sigma—Aldrich Inc. (Brondby, Denmark)
unless otherwise stated. HAuCl4x3HZO was purchased from Wako Chemicals GmbH
(Neuss, Germany), SH-PNIPAM (MW 3500, PDI = 1.24) was purchased from Polymer
Source (Dorval, Canada) and MeO—PEGgooo—SH was purchased from Rapp Polymere
GmbH (Tuebingen, Germany).
AuNP synthesisI PEGM g and particle characterization
PEGylated AuNPs (PEG5000) were prepared as outlined for the PNIPAM coated
AuNP in Example 2 using SH—PEGSOOO as particle coating r. PEGylated particles
were characterized by UV—Vis (A = 539nm) and DLS (59.7i0.9nm) and the
tration determined by ICP—MS (82.6mg Au/mL).
In vitro release of AuNP from SAIB EtOH PLA els
ations (1000mg each) consisting of SAIB/EtOH/PLA (7522025) + 3.0w%
PNIPAM3500 or PE65000 coated AuNP was prepared as outlined in the table below.
PNIPAM3500' PEGSOOO'
Formulation SAIB EtOH PLA
AuNP AuNP
D 750mg 200mg 50mg 30mg -
E 750mg 200mg 50mg — 30mg
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The gel components were mixed and nized by a ball homogenizer
(45min, 30s'1) to give a clear homogenous solution. AuNPs (PNIPAM3500 or PEGsooo)
were erred into ous EtOH, mixed with the gel solution and vortexed.
In vitro release study was carried out by injection of the formulations (3x200uL
each) into MQ-HZO (10.0mL for PNIPAM—AuNP) or PBS-containing (for PEG-AuNP)
glass vial at 37°C. Small aliquots ) were removed as a function of time and
replaced with fresh aqueous solutions. The amount of released AuNPs was measu-
red by correlating the UV-Vis absorbance with a standard curve based on the corre-
sponding particles (figure 13). A burst release (20%) of the encapsulated hydrophilic
PEGylated particles was observed within the first few hours whereas the more
hydrophobic PNIPAM coated AuNP remained encapsulated in the SAIB— amorphous
glass matrix due to the enhanced hydrophobic interactions with the gel matrix.
Example 4 — AIB gel formation with PNIPAM-coated AuNP in vitro
Materials
Chemicals were purchased from Sigma-Aldrich Inc. (Brondby, k)
unless otherwise stated. HAuCl4x3HZO was purchased from Wako Chemicals GmbH
(Neuss, Germany) and PAM (MW 3500, PDI = 1.24) was purchased from
Polymer Source l, Canada). 6,6'-(2,4,6-triiodophenoxy)acetoxy-isobutyric-
sucrose (8) was synthesized as described in e 1.
AuNP synthesisI PNIPAM coating and particle characterization
PNIPAM coated AuNPs were prepared as described in Example 2.
Gel preparation
A formulation consisting of SAIB/8/EtOH (55:25:20) + 3.0w% PNIPAM-AuNP
was prepared as outlined in the table below.
6,6'-(2,4,6-triiodophenoxy)- PNIPAM-
Formulation SAIB EtOH
acetoxy—isobutyric-sucrose (8) AuNPs
/EtOH
165 mg 75mg 60mg 9mg
(55:25:20)
+ 3.0w% PNIPAM-AuNP
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olution (90w/w% in EtOH) was weighted off and mixed with 8 (see
table above). The e were homogenized on a ball-mill homogenizer for 60min
(30s‘1) and centrifuged for 205 at 5000RPM to remove air bubbles from the
formulations. PNIPAM coated AuNPs (141uL, 64mg L) was diluted with MQ-
H20 (1659uL) and lyophilized to give a shinny powder. The lyophilized PNIPAM—
coated AuNPs was re-dispersed anhydrous EtOH (52.8uL) and mixed with the other
gel components.
In vitro release of AuNP in MQ-HZQ
An iodinated gel (200uL) with 3.0w% PNIPAM-coated AuNPs (Formulation F)
were prepared by injection into a MQ-HZO (10.0mL) containing glass vial at 37°C.
Small aliquots (1.0mL) were removed as a function of time and replaced with fresh
MQ-HZO. The amount of released AuNPs was measured by correlating the UV-Vis
absorbance with a standard curve based on the PNIPAM—coated AuNPs. No release
of PNIPAM-coated AuNPs was observed throughout the experiment. Formulation F
was a homogenous dark colored solution injectable trough 256 hypodermic needles.
Example 5 — Visualization of iodo—SAIB gels using onography in vitro
Materials
Chemicals were purchased from Sigma—Aldrich Inc. by, Denmark) unless
otherwise stated. 6,6'-(2,4,6-triiodophenoxy)acetoxy-isobutyric—Sucrose (8) was
synthesized as described in Example 1.
Gel preparation
A formulation consisting of /EtOH (55:25:20) (350mg) was prepared as
bed in Example 1 (Formulation B). The iodo—SAIB gel (250uL) was injected into
MQ—HZO (500mL) in a glass beaker and the gel was allowed to set for 5 days prior to
visualization by ultrasonography. ound imaging ofthe iodo-SAIB gel was
ted by an Ultrasound Scanner (BK Medical, Herlev, k) with the
following settings: Res/Hz 2/21Hz, B Gain 83%, Dynamic range 80dB, Noise reject 10,
Noise cutoff 32. The iodo—SAIB gel was clearly visible using ultrasonography as
illustrated in Figure 14.
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Example 6 — Iodo—SAIB gels as iniectable CT-contrast agent in vivo — Visibility study in
immunocompetent mice
Materials
als were sed from Sigma—Aldrich Inc. (Br¢ndby, Denmark)
unless otherwise . 6,6'-(2,4,6-triiodophenoxy)acetoxy-isobutyric-sucrose (8)
was synthesized as described in Example 1. Healthy female NMRI (Naval Medical
Research Institute) mice were purchased from Taconic (Borup, Denmark).
Gel preparation
A formulation consisting of SAIB/8/EtOH (55:25:20) (900mg) was ed as
described in e 1 (Formulation B).
Animal setup
Formulation B 8/EtOH (55:25:20)) was strated to healthy female
NMRI mice (n = 3) by subcutaneous injection (200uL each) under anaesthesia.
MicroCT imaging of iniectable iodo—SAIB gels
The iodinated gels were visualized over time by computed tomography (CT).
Images were acquired with a MicroCAT® II system (Siemens Medical solutions,
Malvern, USA). Excellent CT-contrast was achieved using Formulation B
(SAIB/8/EtOH :20)) as illustrated in Figure 15A-B (CT-images recorded 24h pi
and 48 pi.)
Example 7 — Iodo—SAIB gels as able CT-contrast agent in vivo — long term
ity and visibility study in immunocompetent mice
Materials
Chemicals were purchased from Sigma-Aldrich Inc. (Br¢ndby, Denmark)
unless otherwise stated. 6,6'-(2,4,6—triiodophenoxy)acetoxy-isobutyric—Sucrose (8)
was synthesized as described in Example 1. Healthy female NMRI (Naval Medical
Research Institute) mice were purchased from Taconic (Borup, Denmark).
Gel preparation
Formulation consisting of a) SAIB/8/EtOH (65:15:20) (750mg) and b)
SAIB/8/EtOH (50:30:20) (750mg) were prepared as described in Example 1.
W0 2014!187962
Animal setup
Both formulations; a) SAIB/8/EtOH (65:15:20) and b) SAIB/8/EtOH (50:30:20)
were administrated to healthy female NMRI mice (n = 2><8mice) by subcutaneous
injection (50uL each) under anesthesia.
MicroCT imaging of iniectable iodo-SAIB gels and mplantation visualization
The iodinated gels were visualized over time by computed tomography (CT).
Images were acquired with a MicroCAT® II system (Siemens Medical ons,
Malvern, USA). Excellent CT-contrast was achieved using both formulations: a)
SAIB/8/EtOH (65:15:20) and b) SAIB/8/EtOH (50:30:20) as rated in Figure 16A—B.
The obtained CT- contrast was found the scale with the formulated amount of iodo-
SAIB (8) in the formulation. After 14w of implantation the animals were sacrificed
and the gels removed from the s.q. compartment (Figure 16C-D). The iodinated gels
were well-defined gels that could easily be removed and transferred without
disruption of the gels. They were furthermore soft enough to be deformed using a
scalpel.
Gelation kinetics of iniectable iodo-SAIB gels
The gelation kinetics of the ted gels composed of SAIB/8/EtOH
(50:30:20) was monitored by running multiply micro-CT scans within the first few
hours of ion (Figure 17A). Based on these images the total volume ofthe
iodinated gel as a function of time was calculated as illustrated in Figure 178.
Gelation of the iodinated gel is caused by efflux of EtOH from the gel matrix which
takes place within the first two hours p.i. causing a rapid increase in hte viscosity of
the iodinated gel and an increase of CT-contrast by approximately 35% due to
contraction of the gel.
Degradation profile of iniectable iodo-SAIB gels over 14w
The degradation profile of iodinated gels composed a) /EtOH
(65:15:20) and b) SAIB/8/EtOH (50:30:20) were monitored by microCT scanning over
a period of 14w. Based on these images the total volume of the iodinated gels as a
on of time were calculated as illustrated in Figure 17C. No difference in
degradation e between the two ations was ed and a steady—state
degradation e was observed for both formulations. A volume loss, with a 95%
W0 2014!187962
confidence interval, of -0.09176uL/day was observed for both formulations after the
initial EtOH efflux phase.
Example 8 — |odo-SA|B gels as iniectable CT-contrast agent in vivo — visibility study in
canine with spontaneous tumor
Materials
Chemicals were purchased from Sigma-Aldrich Inc. (Br¢ndby, k)
unless otherwise stated. 6,6'-(2,4,6-triiodophenoxy)acetoxy-isobutyric-Sucrose (8)
was synthesized as described in e 1.
Gel preparation
A formulation consisting of SAIB/8/EtOH :20) (350mg) was prepared as
described in Example 1 (Formulation B).
Animal setup
Formulation B (SAIB/8/EtOH (55:25:20)) was administrated to a ion
dog (American Staffordshire r, 9 years, 34kg) with a mast cell tumor present
between the front legs. The iodo—SAIB gel was administrated by intratumoral
injection (SOOuL) using a 256 needle.
CT imaging of iniectable iodo-SAIB gels in canine
The iodo-SAIB gel was visualized computed tomography (CT). Images were
ed with a Single slice Siemens CT—scanner (Siemens Medical solutions,
Malvern, USA). Excellent CT-contrast was achieved using Formulation B
(SAIB/8/EtOH (55:25:20)) as illustrated in Figure 18 (CT—image recorded 24h p.i.).
Claims (18)
1. An X-ray contrast composition for local administration, n the X-ray contrast composition exhibits st properties and wherein at least 60% of an 5 administrated amount of said imaging contrast composition remains more than 24 hours within 10 cm from an injection point when the X-ray contrast composition is strated to a human or animal body, wherein the X-ray st composition is a liquid before administration and has the ability to transform into a gel after administration, and wherein the X-ray st composition comprises an iodinated 10 derivate of sucrose acetate isobutyrate (SAIB) or an ted derivate of sucrose acetate isobutyrate (SAIB) doped into sucrose acetate isobutyrate (SAIB), and wherein the X-ray contrast composition also comprises a rming component comprising poly(ethylene -b-caprolactone) (PEG-PCl), e acetate isobutyrate (SAIB), poly(D,L-lactic acid), poly(lactic-co-glycolic acid) (PLGA), chitosan, 15 PEG-PPG-PEG, PLGA-g-PEG, PEG-PLGA-PEG, PNIPAM, PEG/PLLA mulitiblock copolymer, PLGA-PEG-PLGA, multi-arm PLGA-PEG, poly(1,2-propylene phosphate, P(NIPAM-co-AA), poly[(Val-Pro-Gly-Val-Gly)-co-(Pro-Hyp-Gly)10], cyclotriphosphazenes, cellulose (MC), hydroxyl propyl methylcellulose (HPMC), PCL-PEG, PAA-g-pluronic, PCL-PEG-PCL, PEG-PCL-PEG, te, FEK16, PVA, 20 gelrite, OSM-PCLA-PEG-PCLA-OSM, PAA-PEG-PAA, or PAE-PCL-PEG-PCL-PAE, or a combination thereof.
2. The X-ray contrast composition according to claim 1, wherein the X-ray contrast composition increases in viscosity by more than 1,000 centipoise (cP) after 25 administration into a human or animal body.
3. The X-ray contrast composition according to claim 1, wherein the X-ray contrast composition has a viscosity of less than 10,000 centipoise (cP) at 20°C.
4. The X-ray st composition according to claim 1, wherein the X-ray contrast composition ses an X-ray contrast agent that is part of the X-ray contrast composition and said X-ray contrast agent is an organic substance.
5 5. The X-ray contrast agent according to claim 4, wherein the X-ray contrast agent comprises one or more natural polymers, synthetic polymers, oligomers, lipids, saccharides, disaccharides, polysaccharides, peptides or any combination thereof, or wherein the X-ray contrast agent comprises one or more iodinated polymers, oligomers, , saccharides, disaccharides, polysaccharides, peptides, or 10 a tive or a combination thereof.
6. The X-ray contrast composition according to claim 1, wherein the X-ray st composition exhibits gel-formation in response to a temperature in the range of 35 to 40°C, in response to hydration, in response to an ncentration in 15 the range of 1 uM to 500 mM, in response to a pH in the range of 6 to 8 and/or in response to contacting with an initiator.
7. The X-ray contrast composition according to claim 1, wherein the X-ray st composition also comprises, radioactive compounds, paramagnetic 20 compounds, fluorescent compounds or ferromagnetic compounds, or any mixture thereof, and/or wherein the X-ray contrast composition also comprises at least one pharmaceutical nce.
8. The X-ray contrast composition according to claim 1, wherein the gel-forming 25 component ses poly(ethylene glycol-b-caprolactone) (PEG-PCl), sucrose acetate isobutyrate (SAIB), ,L-lactic acid), or actic-co-glycolic acid) (PGLA), or a combination thereof.
9. The X-ray contrast composition according to claim 1, wherein the X-ray 30 contrast composition comprises an iodinated derivate of sucrose acetate isobutyrate (SAIB) solubilized in a mixture of ethanol and sucrose acetate isobutyrate (SAIB).
10. The X-ray contrast composition according to claim 1, wherein the X-ray contrast composition comprises an ted derivate of sucrose acetate isobutyrate (SAIB) and contains a pharmaceutical nce or particle that contains a 5 pharmaceutical substance.
11. The X-ray contrast composition ing to claim 1, wherein the X-ray contrast composition comprises an iodinated derivate of e acetate isobutyrate (SAIB) solubilised in a mixture of ethanol and sucrose acetate isobutyrate (SAIB) and 10 contains a pharmaceutical substance or a particle that ns a pharmaceutical substance.
12. The X-ray contrast composition according to claim 1, for use in radio therapy, for use in imaging, diagnostics, treatment and/or quality rating of radio therapy, for 15 use as a tissue marker and/or for use as a controlled drug e composition.
13. The X-ray contrast ition according to claim 1, wherein the composition is formulated for parenteral stration to a human or animal body. 20
14. A kit comprising a syringe, a needle used for injection into a body or surgical related procedures, such as but not limited to biopsy adapted to the open end of said syringe, and an X-ray contrast composition ing to any one of the previous claims. 25
15. A method of recording an X-ray image of the body of a non-human mammal, comprising the steps of a. providing an X-ray contrast composition as claimed in any one of claims 1 – 13, b. administering the X-ray contrast composition to a predetermined 30 location of the mammal, and c. recording X-ray-based images of at least a part of the body which comprises the predetermined location.
16. A method of joint radiotherapy and X-ray imaging of a target tissue in a non- 5 human , comprising the steps of a. providing an X-ray contrast composition as claimed in any one of claims 1 – 13, b. administering the X-ray st composition to a predetermined target tissue of the mammal, 10 c. recording X-ray-based images, of at least a part of the body which ses the target tissue, thereby providing a definition of the target tissue, and d. using the definition of the target tissue obtained in c) to direct external beam radiotherapy to the target .
17. A method for directing local administration of a pharmaceutically active agent to a target tissue in a non-human mammal, comprising the steps of a. providing an X-ray contrast composition as claimed in any one of claims 1 – 13, 20 b. administering the X-ray contrast ition to a predetermined target tissue of the , c. recording X-ray-based images, of at least a part of the body which comprises the target tissue, thereby providing a definition of the target tissue, and 25 d. using the X-ray contrast composition in b) to further comprise an active pharmaceutical agent for delivery of an active pharmaceutical agent to a predetermined target tissue of the mammal.
18. The method according to any one of claims 16 or 17, wherein the target 30 tissue comprises undesirably growing cells.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE1350637-3 | 2013-05-24 | ||
SE1350637 | 2013-05-24 | ||
PCT/EP2014/060673 WO2014187962A1 (en) | 2013-05-24 | 2014-05-23 | Gel formulations for guiding radiotherapy |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ714077A NZ714077A (en) | 2020-12-18 |
NZ714077B2 true NZ714077B2 (en) | 2021-03-19 |
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