Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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ORAL FORMULATIONS FOR PICOPLATIN
BACKGROUND
Cross Reference to Related Applications:
This application claims priority to U.S. Provisional Applications Serial
Nos. 60/950,033, filed July 16, 2007, and 61/043,962 filed April 10, 2008,
both
entitled "Oral Formulations for Picoplatin", both of which are incorporated by
reference in their entireties herein.
Background
Picoplatin is a new-generation organoplatinum drug that has promise for
treatment of various types of malignancies, including those that have
developed
resistance to earlier organoplatinum drugs such as cisplatin and carboplatin.
Picoplatin has shown promise in the treatment of various kinds of cancer or
tumor, including small cell lung cancer, colorectal cancer, and hormone-
refractory prostate cancer.
Structurally, picoplatin is:
H3N\ ,CI
Pt
N CI
/CH3
and is named cis-amminedichloro(2-methylpyridine)platinum(II), or
alternatively [SP-4-3]-ammine(dichloro)(2-methylpyridine)platinum(II). The
compound is a square planar complex of divalent platinum that is
tetracoordinate
and has three different ligand types. Two ligands are anionic, and two are
neutral; therefore as the platinum in picoplatin carries a +2 charge,
picoplatin is
itself a neutral compound and no counterions need be present. The name
"picoplatin", referring to the presence of a-picoline (2-methylpyridine) in
the
molecule, is the United States Adopted Name (USAN), the British Approved
Name (BAN), and the International Nonproprietary Name (INN) for this
material. Picoplatin is also referred to in the literature as NX473, ZD0473,
and
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AMD473, and is disclosed in U.S. Pat. Nos. 5,665,771, 6,518,428, and U.S.
Serial No. 10/276,503.
Picoplatin is been provided to patients in solution by intravenous (IV)
administration. Picoplatin under standard conditions is a solid, and has only
sparing solubility in water. The relatively low solubility of picoplatin in
water
(about 1 mg/mL) necessitates that substantial volumes of liquid be delivered
intravenously to provide a patient with total doses in the range of 100 mg and
more (i.e., at a concentration of 0.5 mg/mL, some 200 mL of liquid must be
introduced by IV infusion to provide a 100 mg dose). As typical human dosages
for cancer patients can be on the order of several hundred milligrams per
administration, and may be repeated every few weeks, substantial volumes of
liquid must be delivered to the patient for each administration of the
substance
by the IV route. Intravenous administration is thus undesirable due to the
need
for needle insertion into a vein, and the relatively prolonged periods over
which
the patient must be immobile to allow for infusion of the relatively large
volumes of the picoplatin solutions. Picoplatin is orally bioavailable, but
its low
solubility in water poses an obstacle to the preparation of effective oral
dosage
forms.
Picoplatin has also been found to be hydrolytically unstable, particularly
under certain storage conditions, undergoing conversion to two isomeric
species
designated Aquo 1 and Aquo 2, the structures of which are shown below:
CH3 \ CH3 + CICH3 + Cl
HO (::r"Pt PtCI Cl" /OH2 + /C I
H3N/ CI H3N/ CI HN OH2
Aquo I Aquo 2
Picoplatin
SUMMARY
The present invention provides formulations for picoplatin adapted for
oral administration to a cancer patient. The formulations comprise (a) a
self-emulsifying formulation containing picoplatin, (b) a plurality of
stabilized
picoplatin nanoparticles, (c) a picoplatin solid dispersion in a water-
dispersible
matrix material, (d) a nanoparticulate picoplatin suspension in a medium chain
triglyceride or a fatty ester, or any combination thereof. The formulation can
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provide improved oral availability of the picoplatin relative to an equivalent
dose
of solid picoplatin such as in a tablet, or to an equivalent dose of
picoplatin in a
simple solution such as in water or normal saline solution, that is orally
ingested.
An embodiment of the invention concerns a self-emulsifying formulation
of picoplatin. The self-emulsifying formulation includes picoplatin, an oil
and
an emulsifier, and, optionally, a first solvent. Examples of the oil include a
medium chain triglyceride, a fatty ester, or an edible vegetable oil, such as
peanut oil, cottonseed oil, or soybean oil. The emulsifier can be a lecithin,
a
polyethylene glycol (PEG), or a surfactant, or any combination thereof.
In another embodiment according to the invention, a method of preparing
a self-emulsifying formulation of picoplatin using a solvent method is
provided.
The method includes dissolving picoplatin in a first solvent other than DMSO
to
provide a picoplatin solution, then adding an oil, and an emulsifier
comprising a
lecithin, a PEG, or a surfactant, or any combination thereof; then, adding a
second solvent to dissolve the picoplatin solution, the oil, and the
emulsifier,
providing a substantially homogeneous second solution; then, evaporating at
least the second solvent and, optionally, the first solvent, from the
homogeneous
solution to provide the self-emulsifying formulation.
Another embodiment of the invention concerns a formulation that
includes a plurality of stabilized picoplatin nanoparticles. The picoplatin
nanoparticles, having an average particle diameter of less than about one
micron,
are stabilized to inhibit aggregation, and can be stabilized with casein, a
caseinate, or lecithin, or any combination thereof.
In another embodiment, a method of preparation of a formulation of
stabilized picoplatin nanoparticles is provided, the method comprising mixing
a
stabilizer and an aqueous medium under high-shear conditions or
microfluidization conditions to obtain a uniform dispersion, then adding solid
picoplatin, and then mixing until an average particle size of the solid
picoplatin
is less than about one micron or until crystalline particles are substantially
absent, or both, to provide a suspension of the stabilized picoplatin
nanoparticles. The suspension can further be dried, such as by freeze-drying,
to
obtain a substantially dry picoplatin formulation.
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Another embodiment of the invention concerns a picoplatin solid
dispersion in a water-dispersible matrix material. The water-dispersible
matrix
material can comprise a PEG-ylated mono- or diglyceride.
In another embodiment, a method of preparing a picoplatin solid
dispersion in a water-dispersible matrix material using a melt method is
provided, wherein the picoplatin is dissolved in a melt of the matrix
material,
which is then cooled to provide the solid dispersion.
In another embodiment, a nanodispersion of picoplatin in medium chain
triglyceride (MCT) oil or in a fatty ester, for example ethyl oleate, is
provided.
In an embodiment, a method of preparing the picoplatin nanodispersion in an
MCT oil or in a fatty ester is provided.
In another embodiment, an oral picoplatin formulation comprising a
substantially water-soluble capsule shell, the shell enclosing a formulation
comprising a substantially dry, finely particulate material comprising, in
admixture, about 10 to 60 wt% picoplatin, wherein the picoplatin is, in
physical
form, particulates of less than about 10 microns average particle diameter, in
admixture with a substantially water-soluble, water-dispersible, or water-
absorbing carbohydrate and an effective amount of up to about 5 wt% of a
lubricant (or "glidant"), is provided.
In another embodiment, an oral picoplatin formulation, wherein the
dosage form comprises a solid core comprising about 10 to 60 wt% particulate
picoplatin wherein the picoplatin is a particulate of less than about 10
microns
average particle diameter, about 40-80 wt% of a filler comprising a
substantially
water-soluble, water-dispersible, or water-absorbing carbohydrate, and an
effective amount of up to about 5 wt% of a lubricant, and optionally a
dispersant;
and a continuous coating on the outer surface of the core; wherein the core
and/or the coating are substantially free of redox-active metal salts, is
provided.
In various embodiments, the present invention provides a method of
treating cancer comprising administering an oral formulation of the invention
or
an oral formulation prepared by a method of the invention to a patient
afflicted
by cancer, in an amount, at a frequency, and for a duration of treatment
effective
to provide a beneficial effect to the patient. The patient can be chemotherapy-
naive or the patient can have previously received chemotherapy and/or
radiation
therapy.
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In various embodiments, the cancer can be lung cancer including small
cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), kidney
cancer, bladder cancer, renal cancer, stomach and other gastrointestinal (GI)
cancers, mesothelioma, melanoma, peritoneal lymphoepithelioma, endometrial
cancer, glioblastoma, pancreatic cancer, cervical cancer, testicular cancer,
ovarian cancer, colorectal cancer, esophageal cancer, uterine cancer,
endometrial
cancer, prostate cancer, thymic cancer, breast cancer, head and neck cancer,
liver
cancer, sarcomas, including Kaposi's sarcoma, carcinoid tumors, other solid
tumors, lymphomas (including non-Hodgkins lymphoma, NHL), leukemias,
bone-associated cancers and other cancers disclosed in the patents and patent
applications cited herein.
In various embodiments, an embodiment of the oral formulation can be
administered repeatedly to a patient suffering from cancer, at a dose, in a
frequency, and for a duration sufficient to provide a beneficial effect to the
patent. The oral picoplatin formulation can be administered in conjunction
with
a second anticancer agent or anticancer therapy. For example, the oral
formulation can be administered in conjunction with radiotherapy such as X-ray
or -y-ray irradiation, particle beam irradiation, brachytherapy, or
radioisotope
therapy, for treatment of the cancer.
In various embodiments, the oral formulation can be administered with a
second anticancer agent comprising a molecular entity such as a small molecule
or a protein. The second anticancer agent can be included in the oral
formulation
and thus administered in a combination with the picoplatin, or the second
anticancer agent can be administered separately from the picoplatin. If
administered separately, it can be administered substantially concurrently,
prior
to, or after administration of the oral formulation. The second anticancer
agent
can be administered orally or parenterally, for example intravenously.
Examples
are provided hereinbelow, and can be termed non-platinum containing anti-
cancer agents or platinum-containing anti-cancer agents. The second anticancer
agent can be provided at doses, frequencies of administration, and over a
duration of time in combination with picoplatin doses, frequencies of
administration, and over a duration of time effective to provide a beneficial
effect to the patient.
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In another embodiment of the invention, the present formulation is
provided as a kit; i.e., enclosed in packaging with instruction materials,
such as
paper labeling, a tag, a compact disk, a DVD, a cassette tape and the like,
regarding administration of the formulation to a patient. For example, the
instruction materials can comprise labeling describing/directing a use of the
formulation that has been approved by a government agency responsible for the
regulation of drugs.
Brief Description of the Figures
Figure 1 shows an HPLC calibration curve for picoplatin.
Figure 2 shows an HPLC trace of 0.5 mg/mL picoplatin standard solution
in normal saline.
Figure 3 shows an HPLC trace of 0.5 mg/mL picoplatin solution stored
in deionized water at 40 deg C for 2 days.
Figure 4 shows HPLC traces of, from the bottom up, 0.5 mg/mL
picoplatin solution in pH 2, 3, 4, 5, 6 buffers, normal saline and deionized
water,
each stored for 2 days at 40 C.
Figure 5 is a graph showing the solubility of picoplatin in neutral water
and in buffers of various pH values.
Figure 6 shows picoplatin recovery (% over initial) at 25 C after 0, 1 and
2 days.
Figure 7 shows picoplatin recovery (% over initial) at 40 C after 0, 1 and
2 days.
Figure 8 shows the stability over time of picoplatin in dimethylsulfoxide
(DMSO) with added buffers at various pH values.
Figure 9 shows representative chromatograms of picoplatin in N-methyl-
pyrrolidone (NMP) at 25 C for 4 hours. From top down: 0.5 mg/mL in 100%
NMP, 0.5 mg/mL in 80% NMP in normal saline, 0.5 mg/mL in 50% NMP in
normal saline, 0.5 mg/mL in 20% NMP in normal saline, and 0.5 mg/mL
standard in normal saline.
Figure 10 shows HPLC chromatograms of Picoplatin in reconstituted
solutions. The reconstituted solutions were obtained by adding normal saline
to
lyophilized picoplatin from various NMP solvents. From top down: from 100%
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"Miglyo1812" (Sasol Germany GmbH, Witten, Germany) refers to a
medium chain triglyceride wherein the acid moieties are caprylic and capric
acid. Miglyol is a trademark identifying the source of this and other
varieties of
MCT oil.
"Administering" or "administration" refers to providing a medicinal
compound to a patient in need thereof. A "dose" is the amount of the active
pharmaceutical ingredient (API), in this case picoplatin, that is provided in
a
single administration. A "frequency" of administration refers to how often the
medication is given when repeated doses are prescribed; for example, the
medication can be administered daily. A "duration" refers to the period of
time
over which repeated doses are administered; for example, the picoplatin can be
administered for a duration of two weeks.
A "second medicament comprising an anticancer medicament" can
include, without limitation, a taxane (e.g.: paclitaxel (Taxol ) or docetaxel
(Taxotere ), a tyrosine kinase and/or a growth factor receptor inhibitor such
as a
VEGFR inhibitor (e.g.: monoclonal antibodies such as: bevacizumab (Avastin'l-
),
trastuzumab (Herceptin ), panitumumab (Vectibixl) or cetuximab (Erbitux)); a
cephalotaxine analog (e.g.: topotecan (Hycamtin ); irinotecan; 9-
aminocamptothecin; Rubitecan ; Exatecari ; XR-5000, XR-11576); an anti-
metabolite (e.g.: capecitabine (Xeloda), gemcitabine, 5-FU with or without
leucovorin, S 1(gimeracil / oteracil /tegafur), tegafur/uracil, methotrexate,
or a
thymidylate synthease inhibitor (Tomudex , ZA933 1, LY231514
(pemetrexed))); a protein kinase inhibitor (e.g.: sorafenib (Nexavar),
dasatinib
(Sprycel ), gefitnib (ZD1839, Iressa ), imatinib (Gleevac ), lapatinib (Tykerb
), cediranib, also known as AZD2171 (Recentin ), erlotinib (Tarceva) or
sunitinib (Sutent )); an anthracyclin (e.g.: amrubicin, doxorubicin, liposomal
doxorubicin, epirubicin, idarubicin, Doxil ); a Vinca alkaloid (e.g.:
vinorelbine
(Navelbine ), vincristine, vinblastine, vindesine); a podophyllotoxin analog
(e.g.: etoposide, teniposide); a growth factor inhibitor (e.g.: inhibitor of
PDGF,
endothelial GF, VEGF, EGF, or hepatocyte GF; for example an GF-binding
antibody or a GF receptor-binding antibody); an inhibitor of cell cycle
kinases
(such as CDK-2, CDK-4, or CDK-6); a cytostatic agent (Tamoxifen,
Toremifene, Raloxifene, Droloxifene, Iodoxyfene; megestrol acetate; an
aromatase inhibitor such as Anastrozole (ZD1033), Letrazole, Vorazole,
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NMP, from 80% NMP in normal saline, from 50% NMP in normal saline, from
20% NMP in normal saline, and from normal saline.
Figure 11 shows a thermogravimetric / differential thermal analysis
(TG/DTA) scan of micronized picoplatin powder.
Figure 12 shows a thermogravimetric / differential thermal analysis
(TG/DTA) scan of TG/DTA of F50 Picoplatin nanoparticles in sodium caseinate.
Figure 13 shows representative HPLC chromatograms of picoplatin
nanoparticles. From the top down: 0.5 mg/mL nanoparticles in normal saline and
0.5 mg/mL picoplatin standard in normal saline. One unknown peak at 5.5 min
(not Aquo #1).
Figure 14 shows representative HPLC Chromatograms after hot melt in
Gelucire 50/15. From top down: 0.5 mg/mL picoplatin standard in normal saline
and 0.5 mg/mL F51 in normal saline.
Figure 15 shows a representative DSC for Picoplatin in Gelucire 50/15
hot melt. From top down: Gelucire 50/15, 5% picoplatin in Gelucire 50/15 hot
melt, and picoplatin API.
Figure 16 shows a representative DSC for Picoplatin in hot melt.
From top down: 5% picoplatin in Gelucire 50/15, 6% picoplatin in Gelucire
50/15 and 5% in Compritol 888 ATO.
Figure 17 shows HPLC traces, from the top down: 0.5 mg/mL standard
in neutral saline, F73- picoplatin in MCT, F74- picoplatin in MCT and PL90G,
and F75- picoplatin in MCT and Polysorbate 80.
Figure 18 shows zoomed-in views of the HPLC traces of Figure 17.
From the top down: 0.5 mg/mL standard in normal saline, F73- picoplatin in
MCT, F74- picoplatin in MCT and PL90G, and F75- picoplatin in MCT and
Polysorbate 80.
Figure 19 shows representative HPLC chromatograms
From top down: 0.5 mg/mL standard in normal saline, F77- picoplatin in Ethyl
Oleate and PL90, F80- picoplatin in MCT, PL90G and normal saline.
Figure 20 shows representative HPLC chromatograms, enlarged. From
top down: 0.5 mg/mL standard in neutral saline, F77- picoplatin in Ethyl
Oleate
and PL90, F80- picoplatin in MCT, PL90G and normal saline.
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Figure 21 shows representative HPLC Chromatograms. From top down:
0.5 mg/mL picoplatin standard in normal saline and 0.5 mg/mL F81-picoplatin
in PL90 and EO in normal saline.
Figure 22 shows representative HPLC chromatograms, enlarged. From
top down: 0.5 mg/mL picoplatin standard in normal saline and 0.5 mg/mL
F8 1 -picoplatin in PL90 and EO in normal saline.
Definitions:
As the term is used herein, "picoplatin" refers to the organoplatinum
anticancer drug, the structure of which is provided above, including any
solvate,
hydrate, or crystalline polymorph thereof, in solid form, or in solution or
dispersion.
A "formulation" as the term is used herein is a composition of matter
including picoplatin and other components, such as excipients, stabilizers,
dispersants, surfactants, and the like.
"Self-emulsifying" refers to a property of a formulation wherein upon
contacting the formulation with an aqueous medium, such as in the
gastro-intestinal tract of a patient, the formulation spontaneously forms an
emulsion.
"Nanoparticles" are solid particles of an average particle diameter of less
than about 1 micron (micrometer, pm). One micron is 1,000 nanometers (nm).
"Stabilized" nanoparticles are picoplatin nanoparticles coated with a
stabilizing material and having a reduced tendency for aggregation and loss of
dispersion with respect to nanoparticles of picoplatin without a stabilizing
coating.
"Casein" is a milk-derived protein that typically is globular in aqueous
dispersion, as is well known in the art. A "caseinate" is a salt form of
casein
wherein carboxylate groups in the protein are present in ionized form, such as
the sodium salts ("sodium caseinate").
"Microfluidization" is a technique for preparing dispersions of fine
particles in a liquid medium wherein coarser particles are comminuted in the
presence of the liquid medium.
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"High-shear mixing" is a technique for preparing dispersions of fine
particles in a liquid medium wherein high-shear conditions comminute coarser
particles into finer ones in the presence of the liquid medium.
A "solid dispersion" as the term is used herein refers to a dispersion of
solid picoplatin in a solid or semi-solid matrix. The solid dispersion can be
formed in a liquid or melt phase wherein the final mixture solidifies into the
solid or semi-solid form.
"Water-dispersible" means that a solid or semi-solid material can be
suspended in an aqueous medium and does not spontaneously phase separate
from the aqueous medium. "Water-dispersible" includes "water-soluble",
referring to a solid or semi-solid material that completely dissolves in the
aqueous medium to form a homogeneous solution. A "matrix" as the term is
used herein refers to an organic material, that is at least dispersible in
water, that
is solid at about room temperature or about human body temperature, in which
picoplatin can be dispersed.
An "oil" as the term is used herein refers to an organic liquid, which is
water-insoluble, or at least only partially water-soluble, that can form a
separate
phase in the presence of water. An example of an "oil" is a glyceride such as
a
medium chain triglyceride, or a medium chain mono- or di-glyceride, or castor
oil. Another example of an oil is a fatty ester. A fatty ester refers to an
alkyl
ester of a fatty acid. An example is ethyl oleate. "MCT oil" refers to medium
chain triglyceride oil. Examples include the MCT oil sold under the Miglyol
trademark, such as Miglyol 912, a caprylate/caprate ( octanoate/decanoate
triglyceride).
A "nanodispersion" is a dispersion of picoplatin particles of less than
1 m average particle diameter in a liquid, for example in MCT oil or in a
fatty
ester.
A "lecithin" as the term is used herein is a mixture of triglycerides,
glycolipids, and phospholipids such as phosphatidylcholine, as is well-known
in
the art. Lecithins can be derived from eggs or from soy beans. A high-
phosphatidylcholine lecithin is a lecithin with a relatively high phosphatidyl-
choline (PC) content. A low-phosphatidylcholine lecithin is accordingly a
lecithin with a relatively low PC content.
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A "surfactant" as the term is used herein is a substance that reduces
interfacial surface tension between immiscible liquids such as oil and water,
reduces surface tension of a water drop, and exhibits other surface-active
properties as are well known in the art.
The term "weight average molecular weight" is well known in the art and
characterizes an average molecular weight of a polydisperse sample of a
polymer.
A "PEG" or a "polyethyleneglycol" is a polymeric material composed of
repeating -CHZCH2O- units, wherein there are two or more units. Thus,
diethyleneglycol and all higher polymers are polyethyleneglycols within the
meaning herein. A polyethyleneglycol can have a free OH group at either
terminus or at both termini, or can alternatively include other groups such as
an
ether group at one or both ends, for example a methyl ether
CH3O-(CHZCH2O)õ-OCH3. Such an ether-terminated PEG can also be referred
to as a "polyethyleneglycol ether". PEG-400 is a PEG with a weight average
molecular weight of about 400 DA. PEG-8000 is a PEG with a weight average
molecular weight of about 8000 DA. A compound can be "PEG-ylated",
meaning that it bears at least one PEG group, which can be introduced in a
variety of ways, such as by polymerization of ethylene glycol initiated by the
compound, or coupling of the compound with a preformed PEG. For example,
Gelucire is a PEG-ylated fatty acid monoglyceride, meaning that a glycerol
moiety bears a single fatty acid moiety and PEG moieties on one or both of the
remaining free hydroxyl groups.
A "dipolar aprotic solvent" is a solvent not containing a source of protons
in aqueous solution (an example of a protic solvent is ethanol) that also is
polar
in character and is typically at least partially soluble in water. Examples of
aprotic solvents are DMF, NMP, DMSO, DMAC, and the like. "DMSO" is
dimethylsulfoxide. "NMP" is N-methylpyrrolidone. "DMF" is N,N-dimethyl-
formamide. "DMAC" is N,N-dimethylacetamide.
"Labrasol " is a mixture composed of about 30% mono-, di-, and
triglycerides of C8 and C 10 fatty acids, 50% of mono- and di-esters of
polyethyleneglycol (PEG 400), and 20% of free PEG 400. Labrasol has
surfactant properties.
CA 02693057 2010-01-12
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"Cremophor RH 40 " is a nonionic solubilizer and emulsifying agent
obtained by reacting 45 moles of ethylene oxide with 1 mole of hydrogenated
castor oil. The main constituent of Cremphor RH 40 is glycerol polyethylene
glycol oxystearate, which, together with fatty acid glycerol polyglycol
esters,
forms the hydrophobic part of the product. The hydrophilic part consists of
polyethylene glycols and glycerol ethoxylate.
"Cremophor ELP " is a nonionic solubilizer made by reacting castor oil
with ethylene oxide in a molar ratio of 1: 35.
"Gelucire " including Gelucire 44/14 (CAS RN 121548-04-7) and
Gelucire 50/13 (CAS RN 121548-05-8) are fatty acid glycerides bearing
polyethyleneglycol (PEG) groups. For example, Gelucire 44/14 is a PEG-ylated
glyceride of lauric acid; Gelucire 50/13 is a PEG-ylated glyceride of stearic
acid.
The numbers after the word Gelucire refer to the melting point in C and the
hydrophilic-lipophilic balance (HLB) value respectively. Gelucire compounds
are PEG-ylated with PEG 1500 (polyethyleneglycol of weight average molecular
weight 1500 DA).
"Polysorbate 80" refers to sorbitan mono-9-octadecanoate
poly(oxy-l,2-ethanediyl) derivatives; they are well known as complex mixtures
of polyoxyethylene ethers used as emulsifiers or dispersing agents in
pharmaceuticals.
"Phospholipon 90G" or "PL90G" (American Lecithin Products, Oxford,
CT) is a tradename for lecithin, minimum 94% phosphatidylcholine for the
manufacture of liposomes. "Phospholipon 90H" or "PL90H" is a hydrogenated
PL90G. The term "PL90" refers to either one of these materials.
"Vitamin E TPGS" refers to the compound D-alpha-tocopheryl
polyethylene glycol 1000 succinate.
"Compritol 888" refers to glyceryl behenate. A "behenate" is an ester of
docosanoic acid, as is well known in the art.
"Poloxamer 188" (CAS RN 9003-11-6 ) is a Polyethylene-Polypropylene
Glycol copolymer of the formula HO(C2H4O)a(C3H60)b(C2H40)aH with a
weight average molecular weight of about 8400
"SPAN 60" refers to sorbitan monostearate.
"Kollidon K90" (Hoechst, Germany) refers to a polyvinylpyrrolidone
with a molecular weight of about 90,000.
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Exemestane; an antiandrogen such as Flutamide, Nulutamide, Bicalutamide,
Cyproterone acetate; an LHRH agonist or antagonist such as Foserelin acetate
or
Luprolide; an inhibitor of testosterone dihyhdroreductase such as Finasetide,
a
metalloproteinase inhibitor such as Marimastat or a uPAR inhibitor); an
alkylating agent (e.g.: melphalan, cyclophosphamide, ifosphamide, nitrosourea,
carmustine, lomustine); or radiation therapy (e.g.: X-ray, -y-ray, particle
beam,
brachytherapy, radioisotope).
Alternatively, the additional medicament is a non-platinum containing
agent, can be selected to treat a complication of the cancer, or to provide
relief to
a subject from at least one symptom of the cancer, for example, sirolimus or
rapamycin (Rapamune ), dexamethasone (Decadron), palonosetron HCl
(Aloxi), aprepitant (Emend), ondansetron (Zofran), or granisetron (Kytril).
Examples of anti-cancer medicaments that can be orally administered are
listed in Table 1, below.
Table 1. Orally Administrable Agents
altretamine exemestane lapatinib tamoxifen
anagrelide fadrozole lenalidomide tegafur/uracil
anastrozole finasteride letrozole temozolomide
(ZD1033)
bexarotene fludarabine osaterone thalidomide
bicalutamide gefitinib polysaccharide K topotecan
capecitabine GMDP prednimustine toremifene
clodronic acid HMPL 002 S 1 treosulfan
(gimeracil/oteracil/tegafur)
cytarabine hydroxycarbamide sobuzoxane trilostane
ocfosfate
dasatinib ibandronic acid sorafenib ubenimex
dutasteride idarubicin sunitinib vinorelbine
erlotinib imatinib tamibarotene vorinostat
Orally active anticancer agents that can be administered include
altretamine (Hexalen), an alkylating agent; capecitabine (Xeloda ), an anti-
metabolite; dasatinib (Sprycel), a TK inhibitor; erlotinib (Tarceva ), an EGF
receptor antagonist; gefitinib (Iressa ), an EGF inhibitor; imatinib (Gleevec
), a
TK inhibitor; lapatinib (Tykerb ), an EGFR inhibitor; lenalidomide,
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(Revlimid'), a TNF antagonist; sunitinib (Sutent'8), a TK inhibitor; S-1
(gimeracil/oteracil/tegafur), an anti-metabolite; sorafenib (Nexavar), an
angiogenesis inhibitor; tegafur/uracil (UFT , Uftoral'~, an anti-metabolite;
temozolomide (Temoda?), an alkylating agent; thalidomide (Thalomid"'), an
angiogenesis inhibitor; topotecan (Hycamtin for injection or Oral Hycamtin ),
vinorelbine (Navelbine ), an anti-mitotic; cediranib (AZD2171, Recentiri ), a
VEGF inhibitor; and/or vorinostat (Zolinza(o), a histone deacetylase
inhibitor.
As the tenn is used herein, "radiation" or "radiotherapy" refers to the
treatment of cancer patients with various forms of ionizing radiation, which
acts
to a great extent on dividing cells by interfering with DNA replication and
cell
division. The three main types of radiotherapy are external beam radiotherapy
(EBRT or XBRT) or teletherapy, brachytherapy or sealed source radiotherapy
and unsealed source radiotherapy. The differences relate to the position of
the
radiation source; external is outside the body, while sealed and unsealed
source
radiotherapy has radioactive material delivered internally. External beam
radiotherapy can involve beams of photons, such as X-rays, or beams of
particles, such as protons. External beam radiotherapy can involve either
total
body irradiation or the use of multiple focussed beams to concentrate the
energy
in a defined volume of body tissue. Brachytherapy involves implantation of
sealed sources of various radioisotopes within body tissues, such that the
sources
can be removed after a period of time. The type of radiation emitted depends
on
the identity of the radioisotope included in the sealed source, and can be
photon
(X-ray) or particle (e.g., beta particle). When unsealed sources are used,
e.g.,
radiolabeled antibodies or the like, the nature of the radiation again depends
on
the identity of the radioisotope used, but due to the fact that there is no
containment, particles of shorter range such as alpha particle and Auger
electrons can be used effectively. However, since unsealed sources typically
cannot be removed surgically, the radioisotopic form must be one that can be
excreted, or else decays, within an appropriate time frame. Examples of useful
isotopes include 90Y, 13 1I, and "'Lu.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns formulations of the anticancer drug
picoplatin adapted for oral administration to a cancer patient, and to methods
of
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preparation of the formulations. In an embodiment of the invention, a
self-emulsifying formulation provides the picoplatin dissolved in a one-phase
oleaginous vehicle, which forms an emulsion upon exposure to an aqueous
medium in the gastrointestinal tract, and delivers picoplatin in emulsified
oil
droplets with a potential for better intestinal absorption into the
bloodstream. A
self-emulsifying formulation can include an oil (oleaginous vehicle) along
with
dispersants and surfactants that assist in the self-emulsification properties
of the
formulation. Once orally ingested by a patient, the formulation can emulsify
in
the gastrointestinal tract. The formulation can provide improved oral
availability
of the picoplatin relative to an equivalent dose of solid picoplatin such as
in a
tablet, or to an equivalent dose of picoplatin in a simple solution such as in
water
or normal saline solution, that is orally ingested.
An embodiment of the self-emulsifying picoplatin formulation can
include an oil, and an emulsifier including a lecithin, a surfactant, a PEG,
or any
combination thereof. Preferably, the self-emulsifying formulation includes at
least about 10% w/w of the picoplatin, although it can include lesser amounts
of
picoplatin, for example, 5% w/w of the picoplatin. The inventive
self-emulsifying formulation can also include a first solvent in which
picoplatin
is at least sparingly soluble, provided that the first solvent is not DMSO. As
disclosed hereinbelow, picoplatin is unstable in DMSO, perhaps due to
oxidation
of the picoplatin by the DMSO. The first solvent can be a dipolar aprotic
solvent, a polyethylene glycol, or a polyethyleneglycol ether, a
polyethyleneglycol derivative of a mono- or a di-glyceride, or any combination
thereof. The dipolar aprotic solvent can be NMP. Preferably the dipolar
aprotic
solvent, particularly if it is NMP, is substantially free of amine
contaminants.
For example, the first solvent can be a polyethyleneglycol derivative of a
mono- or a di-glyceride, such as Gelucire 40/14 or Gelucire 50/13 . The
picoplatin can be dissolved in the Gelucire held above Gelucire's melting
point,
i.e., 40 C for Gelucire 40/14, or 50 C for Gelucire 50/13. The solution of the
picoplatin in the melted Gelucire can then be mixed with other components in
the second solvent to form a substantially homogenous second solution. The
Gelucire (polyethyleneglycol derivative of a mono-glyceride, i.e., a PEG-
ylated
monoglyceride) is itself a surfactant; thus mixing the Gelucire solution of
the
picoplatin with the oil in the second solvent, followed by removal of the
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solvent, can provide the self-emulsifying formulation of the invention,
wherein
the Gelucire serves both as the first solvent and as the emulsifier.
Alternatively,
lecithin, PEG, another surfactant, or any combination thereof, can also be
mixed
with the second solvent to provide a substantially homogeneous solution, from
which the second solvent is removed to provide the present self-emulsifying
formulation.
The self-emulsifying formulation includes an oil, wherein the oil is a
medium chain triglyceride, castor oil, a medium chain mono-glyceride, a
medium chain di-glyceride, an edible vegetable oil such as peanut oil,
cottonseed
oil, or soybean oil, or any combination thereof. Alternatively, the oil can be
other than a glyceride; for example, the oil can be a hydrocarbon oil or a
silicone
oil.
The self-emulsifying formulation includes an emulsifier. For example,
the emulsifier can contain a lecithin. The lecithin can be a high phosphatidyl-
choline content lecithin, a low phosphatidylcholine content lecithin, or any
combination thereof.
The emulsifier can also include a surfactant, such as Labrasol (a
mixture of glycerides and PEG-ylated materials), Cremophor RH40 (a
PEG-ylated glyceride), Cremophor ELP (a PEG-ylated glyceride), Gelucire
44/14 (a PEG-ylated glyceride), Polysorbate 80 HP (a PEG-ylated fatty ester
of sorbitan), or Vitamin E TPGS (a PEG-ylated tocopherol succinate), or any
combination thereof. Gelucire can be both the first solvent and the emulsifier
of
the inventive self-emulsifying formulation.
The present self-emulsifying formulation can contain a PEG, such as
PEG-400. PEG compounds are typically water-soluble, but also can stabilize
hydrophobic materials in aqueous media.
A method of preparation of the self-emulsifying formulation is likewise
provided as an embodiment of the invention herein. For example, the
formulation can be prepared by dissolving picoplatin in a first solvent other
than
DMSO to provide a picoplatin solution, then adding an oil, and an emulsifier
comprising a lecithin, a PEG, or a surfactant, or any combination thereof;
then,
adding a second solvent to dissolve the picoplatin solution, the oil, and the
emulsifier, providing a substantially homogeneous second solution; then,
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evaporating at least the second solvent and, optionally, the first solvent,
from the
homogeneous solution to provide the self-emulsifying formulation.
The first solvent can be a dipolar aprotic solvent, a polyethylene glycol,
or a polyethyleneglycol ether, a polyethyleneglycol derivative of a mono- or
di-glyceride, or any combination thereof. The dipolar aprotic solvent can be
NMP. Preferably the dipolar aprotic solvent, particularly if NMP, is
substantially free of amine contaminants. DMSO is not suitable as the first
solvent, due to the instability of picoplatin in DMSO. A solution of a
preselected amount of picoplatin for the batch formulation being prepared is
dissolved in the first solvent, then the emulsifier is added. The emulsifier
can
include a lecithin, a PEG, a surfactant, or any combination thereof. The oil
can
be a medium chain triglyceride, castor oil, a medium chain mono-glyceride, a
medium chain di-glyceride, or any combination thereof. The lecithin can be a
high phosphatidylcholine content lecithin, a low phosphatidylcholine content
lecithin, or any combination thereof. The PEG can be PEG-400. The surfactant
can be Labrasol, Cremophor RH40, Cremophor ELP, Gelucire 44/14,
Polysorbate 80 HP, or Vitamin E TPGS, or any combination thereof.
Then, a second solvent is added to provide a substantially homogenous
second solution, at or near room temperature, although some heating can be
used
to assist dissolution of all components. Then, the second solvent is removed
from the homogenous solution. A suitable second solvent is ethanol, which can
be removed under reduced pressure at or near room temperature, although
elevated temperatures can also be used. The evaporation can continue such that
the first solvent is also removed, although the first solvent or portions of
it can
remain in the formulation. The residue is a self-emulsifying formulation of
the
invention, which can be liquid, solid or semi-solid. This material can be
filled
into hard or soft gelatin capsules for administration to a patient. The
self-emulsifying formulation is adapted to aid in dissolution of the
picoplatin in
the gastrointestinal (GI) tract of the patient, and thus provide for enhanced
uptake into the bloodstream compared to the same dose of picoplatin
administered as a pure solid.
In another embodiment of the invention, a stabilized nanoparticle
preparation of picoplatin is provided that possesses a greatly increased
surface
area and thus an improved dissolution rate relative to solid crystalline
picoplatin.
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The picoplatin nanoparticles are stabilized with organic materials. For
example,
the picoplatin nanoparticles can be stabilized with casein, a caseinate, or
lecithin,
or any combination thereof. Casein and caseinates are proteins found in milk
that serve to stabilize butterfat droplets in the aqueous medium. In the
present
stabilized nanoparticle formulation, the casein or caseinates, or both, can
stabilize the sub-micron size picoplatin particles and inhibit re-aggregation
of the
particles. Also, lipid compositions such as lecithin can be used to stabilize
the
picoplatin nanoparticles. Preferably, the formulation contains at least about
10% w/w of the picoplatin on a dry weight basis, although the formulation can
include a lesser amount of picoplatin, for example, at least about 5% w/w of
picoplatin, on a dry weight basis, or an intermediate weight. The formulation
can provide improved oral availability of the picoplatin relative to an
equivalent
dose of solid picoplatin such as in a tablet, or to an equivalent dose of
picoplatin
in a simple solution such as in water or normal saline solution, that is
orally
ingested.
The picoplatin nanoparticles can be prepared by a process comprising
high-shear mixing or microfluidization. Solid picoplatin, for example
picoplatin
in crystalline form, can be mixed in an aqueous medium with a stabilizer such
as
casein, using microfluidization conditions or high-shear conditions, until the
average particle diameter of the solid picoplatin is less than about one
micron as
determined by laser light scattering spectroscopy, or, alternatively, until
crystalline picoplatin is observed to be largely absent using an optical
microscope with a polarized light filter lens. The average particle diameter
can
be even smaller; for example the picoplatin nanoparticles can have an average
particle diameter of less than about 0.5 micron; of less than about 0.25
micron;
or of less than about 0.15 micron.
An embodiment of the invention also provides a method of preparation of
the stabilized picoplatin nanoparticles. The method includes mixing a
stabilizer
and an aqueous medium under high-shear conditions or microfluidization
conditions to obtain a uniform dispersion, then adding solid picoplatin, and
then
continuing mixing under these conditions until an average particle size of the
picoplatin is less than about one micron or until crystalline particles are
substantially absent, or both, to provide a suspension of the stabilized
picoplatin
nanoparticles. The stabilizer can be casein, a caseinate, or a lecithin. The
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average picoplatin particle diameter can be less than about 1 micron, or less
than
about 0.5 micron, or less than about 0.25 micron, or less than about 0.15
micron.
The suspension of stabilized picoplatin nanoparticles can then be dried to
provide a solid material, for example by freeze-drying, to provide a
substantially
dry solid. By this method, a solid formulation that can be filled into gelatin
capsules for oral administration to a patient can be obtained. The picoplatin
content of the substantially dry solid can be at least about 10% w/w, or at
least
about 5% w/w.
In another embodiment of the invention, a dispersion of solid picoplatin
in a solid water-dispersible material (matrix) is provided. The inventive
solid
dispersion can be prepared by a process comprising dispersing of the
picoplatin
in a melt of the water-dispersible matrix material that then is cooled and
solidified. Preferably, the formulation contains at least about 10% w/w of the
picoplatin, although the formulation can include a lesser amount of
picoplatin,
for example, at least about 5% w/w of picoplatin. The water-dispersible matrix
material can include Gelucire 50/13, Gelucire 44/14, Poloxamer 188, SPAN 60,
PEG-8000, Kollidon K-90, Vitamin E TPGS, or Comprito1888, or any
combination thereof, definitions of which are provided herein. The Gelucire
and
Compritol materials are PEG-ylated glycerides of fatty acids. Poloxamer is a
polyethyleneglycol-polypropyleneglycol copolymer. Span is a monostearate
ester of sorbitan, and Kollidon is a poly-vinylpyrrolidone. Vitamin E TPGS is
a
PEG-ylated toxopherol succinate.
The water-dispersible matrix material is at least dispersible in water, not
phase-separating spontaneously, and can be completely water-soluble. The
matrix material is preferably a solid at about 20 C to about 37 C. The melt of
the water-dispersible matrix material can be held at a temperature of about 40
C
to about 160 C during dispersion of the solid picoplatin. The step of
dispersing
the picoplatin in the melt can involve dissolving the picoplatin in the melt
to
provide a homogenous melt. The homogeneous melt can include Gelucire
50/13, Gelucire 44/14, Compritol 888, or Vitamin E TPGS. The melt is then
cooled and solidified to provide the inventive solid dispersion. The
formulation
can provide improved oral availability of the picoplatin relative to an
equivalent
dose of solid picoplatin such as in a tablet, or to an equivalent dose of
picoplatin
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in a simple solution such as in water or normal saline solution, that is
orally
ingested.
In an embodiment of the invention, a nanoparticulate picoplatin
suspension in a medium chain triglyceride (MCT oil) or in a fatty ester is
provided. The nanoparticulate picoplatin comprises picoplatin particles of
less
than 1 micron average particle diameter, suspended in the MCT oil or fatty
ester.
The nanoparticulate picoplatin can make up about 20% up to about 70% by
weight of the composition. The MCT oil can be a triglyceride ester of a medium
chain fatty acid, or of a combination of different medium chain fatty acids.
For
example, the MCT oil can be tricaprylglyceride (trioctanoylglyeride) or can be
a
mixed caprylic / capric (octanoyl / decanoyl) glyceride. All three glycerin
hydroxyl groups are acylated in the MCT oil. An example of an MCT oil is a
Miglyol brand (Sasol) MCT oil, such as Miglyol 812). Alternatively, the
nanoparticulate picoplatin suspension can include a fatty ester. An example is
ethyl oleate. The suspension can further contain a lecithin, i.e., a
phospholipid.
An example is the brand Phospholipon 90G (American Lecithin). The
suspension can further contain a sugar ester surfactant, such as a sorbitan
ester.
An example is sorbitan mono-9-octadecanoate PEG ether (sold under the brand
name Sorbate 80).
An embodiment of the invention provides a method of preparation of the
nanoparticulate picoplatin suspension comprising contacting the picoplatin in
bulk form and the MCT oil or fatty ester, then mixing under high shear
conditions until the average picoplatin particle diameter is 1 micron or less.
A
lecithin, a Sorbate-type surfactant, or both can also be present during the
high
shear mixing, or can be added subsequently. In an embodiment, following the
high shear mixing, the solid picoplatin nanoparticulate form can be allowed to
settle, or can be settled by centrifugation, and a portion of the supernatant
liquid
removed to provide a nanoparticulate picoplatin suspension with a higher
picoplatin content than prior to removal of some of the supernatant liquid.
In another embodiment, an oral picoplatin formulation comprising a
substantially water-soluble capsule shell, the shell enclosing a formulation
comprising a substantially dry, finely particulate material comprising, in
admixture, about 10 to 60 wt% picoplatin, wherein the picoplatin is, in
physical
form, particulates of less than about 10 microns average particle diameter, in
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admixture with a substantially water-soluble, water-dispersible, or water-
absorbing carbohydrate and an effective amount of up to about 5 wt% of a
lubricant (or "glidant"), is provided. The capsule shell is preferably
composed of
a biodegradable and/or digestible material, such as hard or soft gelatin, PVA,
polylactides, polyglycolic acids, and the like. The picoplatin preferably is a
particulate having an average particle diameter of 1-5 microns. The picoplatin
particulate can be micronized, for example by jet-milling, or can be a
microcrystalline material, such as can be prepared by precipitation, or can be
a
particulate formed by a lyophilization process, or any combination of the
three
processes. The picoplatin particulate can be dispersed within substantially
every
particle of the powder of the formulation. The oral picoplatin formulation,
can
comprise a substantially dry powder comprising about 20 to 55 wt% picoplatin
wherein the picoplatin is particulates of less than about 10 microns average
particle diameter, a substantially water-soluble, water-dispersible, or water-
absorbing carbohydrate, and an effective amount of up to about 5 wt% of a
lubricant, enclosed within a substantially water-soluble capsule shell. The
formulation can also comprise an effective amount of a dispersing agent.
In another embodiment, an oral picoplatin formulation, wherein the
dosage form comprises a solid core comprising about 10 to 60 wt% particulate
picoplatin wherein the picoplatin is a particulate of less than about 10
microns
average particle diameter, about 40-80 wt% of a filler comprising a
substantially
water-soluble, water-dispersible, or water-absorbing carbohydrate, and an
effective amount of up to about 5 wt% of a lubricant, and optionally a
dispersant;
and a continuous coating on the outer surface of the core; wherein the core
and/or the coating are substantially free of redox-active metal salts, is
provided.
Preferably both the coating and the core are free of amounts of redox-active
metals that can be deleterious to the picoplatin in vivo or in vitro (e.g., in
storage). The coating forms a protective covering for the core, both
protecting
the contents from environmental degradation by oxygen, light, and reactive
chemicals, and protecting persons handling the dosage form from the cytotoxic
picoplatin. The coating can comprise gelatin, either hard or soft; a polymer,
for
example hydroxypropyl methyl cellulose; a sugar, for example sucrose; or any
other non-toxic, water soluble material suitable for human consumption. The
picoplatin particulate that has an average particle diameter of less than
about 10
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microns, preferably has an average particle diameter of less than about 7
microns, and more preferably has a particle size distribution such that about
90%
of the individual particulates have a diameter of less than about 5 microns.
In various embodiments, the present invention provides a method for
treating cancer comprising administering an inventive oral formulation or an
oral
formulation prepared by an inventive method to a patient afflicted by cancer,
in
an amount, at a frequency, and for a duration of treatment effective to
provide a
beneficial effect to the patient. The patient can be chemotherapy-naive or the
patient can have previously received chemotherapy.
The dose, dosage form, frequency, and duration of administration can be
detennined by the attending physician, based upon his or her knowledge and
experience, the body weight, skin area, disease state, and physical condition
of
the patient, and any other factors that the physician may decide are relevant
to
selection of a dose, frequency of administration, and duration of time over
which
the formulation is administered to the patient.
In various embodiments, the cancer can be lung cancer including small
cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), kidney
cancer, bladder cancer, renal cancer, stomach and other gastrointestinal (GI)
cancers, mesothelioma, melanoma, peritoneal lymphoepithelioma, endometrial
cancer, glioblastoma, pancreatic cancer, cervical cancer, testicular cancer,
ovarian cancer, colorectal cancer, esophageal cancer, uterine cancer,
endometrial
cancer, prostate cancer, thymic cancer, breast cancer, head and neck cancer,
liver
cancer, sarcomas, including Kaposi's sarcoma, carcinoid tumors, other solid
tumors, lymphomas (including non-Hodgkins lymphoma, NHL), leukemias,
bone-associated cancers and other cancers disclosed in the patents and patent
applications cited herein.
In another embodiment of the invention, the picoplatin compositions of
the invention used to prepare medicaments that are used in combination with an
effective amount of a second medicament, such as an non-platinum containing
anticancer agent. The latter agent can be co-administered to a patient in
conjunction with administration of an embodiment of the present oral
formulation
The anticancer drug can be a non-platinum based anticancer agent, or can
be a platinum-based anticancer agent. Examples of a second anticancer agent or
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therapy comprising a molecular entity are provided above in Table 1, above.
For
example, a second anticancer agent can be a non-platinum based anticancer
agent, or can be a platinum-based anticancer agent.
By "a non-platinum based anticancer agent" is meant a compound with
anticancer and/or anti-cell proliferation activity that does not contain
platinum,
for example, a compound or drug can be selected from one of the following
classes:
1. A compound of the camptothecin analogue class, i.e. any tumour cell
growth inhibiting compound which is structurally related to camptothecin, and
inhibits topoisomerase I; or a compound of the podophyllotoxin analogue class
which inllibits topoisomerase 11; or is a compound of the canlptotliecin
analogue
class which is an inhibitor of both topoisomerase I and II. Suitable compounds
of
the canlptothecin analogue class include, but are not limited to, pure
topoisomerase I inhibitors such as Topotecan, Irinotecan, 9-Aminocamptothecin,
Rubitecan and Exatecan (DX-8951 f); mixed topoisomerase I and topoisomerase
II inhibitors such as XR-5000 and XR-11576; and suitable compounds of the
podophyllotoxin analogue class which are pure topoisomerase II inhibitors
include, but are not limited to, Etoposide and Teniposide. Such compoLmds also
include, but are not limited to, any tumour cell growth inhibiting
camptothecin
analogue claimed or described in WO 93/09782 and the references cited therein
(which are hereby incorporated herein by reference). The preparation of
Topotecan (including pharmaceutically acceptable salts, hydrates and solvates
thereof) as well as the preparation of oral and parenteral pharmaceutical
compositions comprising topotecan and an inert, pharnlaceutically acceptable
carrier or diluent, is extensively described in U.S. Patent 5,004,758 and
European Patent Application Publication Number EP 0,321,122.
2. A taxane, such as Taxol (Paclitaxel) or Taxotere (Docetaxel).
3. A growth-factor receptor inhibitor such as a growth :factor receptor -
protein-kinase inhibitor, including an epidermal growth factor receptor -
class I
tyrosine kinase inhibitor, for example, Iressa (ZD1839 or Gefitinib) or
Tarcevao (or Erlotinib)), and other inhibitors of growth factor function. Such
growth factors include, for example, platelet derived growth factor,
endothelial
growth factor, vascular endothelial growth factor (VEGF), epidermal growth
factor and hepatocyte growth factor and such inhibitors include growth factor
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antibodies and growth factor receptor antibodies, such as, e.g., Avastin or
Bevacizumab, and Erbituxt or Cetuximab, as well as serine/threonine kinase
inhibitors. Also included are inhibitors of cell cycle kinases such as CDK-2,
CDK-4 and CDK-6. Inhibitors of endothelial growth factor or vascular
endothelial growth factor may act, at least in part, by inhibiting tumor
angiogenesis.
4. An anti-metabolite such as 5-FU, S1, UFT, Capecitabine; a thymidylate
synthase inhibitor such as Tomudex or ZD933 1, or LY23151.4 (MTA,
pemetrexed disodium) or Gemcitabine, or an antifolate such as Methotrexate.
5. A Vinca alkaloid such as Vinolrebine (Navelbine), Vincristine,
Vinblastine or Vindesine.
6. An anti-angiogenic compound such as described in International Patent
Application Publication Nos. WO 97/22596, WO 97/30035, WO 97/32856, WO
98/13354, WO 00/21955 and WO 00/47212.
7. An alkylating agent such as Melphalan, Cyclophosphamide, Ifosphamide
or a nitroso-urea, such as Carmustine or Lomustine.
8. An Anthracyclin such as Doxrubicin, Epiribicin, Idarubicin, Amrubicin
or poxil .
9. An anti-HER-neu compound, such as Herceptin (Trastuzumab).
10. A cytostatic agent such as an antioestrogen (for example, Tamoxifen,
Toremifene, Raloxifene, Droloxifene, lodoxyfene), a progestogen (for example,
Megestrol Acetate), an aromatase inhibitor (for example, Anastrozole,
Letrazole,
Vorazole, Exemestane), an antiprogestogen, an antiandrogen (for example,
Flutamide, Nilutamide, Bicalutamide, Cyproterone Acetate), LHRH agonists and
antagonists (for example, Goserelin acetate, Luprolide), an inhibitor of
testosterone 5a-dihydroreductase (for exaniple, Finasteride) and an anti-
invasion
agent (for exainple, metalloproteinase inhibitors like Marimastat and
inhibitors
of urokinase plasminogen activator receptor function).
11. Antimitotics, natural and synthetic.
12. Interleukins and cytokines such as TNF.
13. Vaccines.
14. Uptake/efflux modulators such as mdr2.
15. Rescue agents.
16. Ca antagonists.
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Potentiation agents, e.g., Leucovorin, that do not possess anti-cancer
activity per se, can also be used in the present method.
A"platinum-based anticancer agent" can include other platinum agents,
such as BBR3464, Satraplatin, Cisplatin, Carboplatin, Nedaplatin, Heptaplatin
or
Oxaliplatin, with a different mode of action or useful profile, may also be
used
with picoplatin.
These categories are provided as a sum.inary of art-recognized classes of
anti-cancer agents or other classes of active agent or adjuvant and not meant
to
be exclusive.
The second anticancer agent can be administered in an effective amount
to the patient, concurrently with the oral picoplatin formulation, prior to
administration of the oral picoplatin formulation, or subsequent to the oral
picoplatin formulation, on a similar or diverse schedule of administration,
provided that the second anticancer agent is administered at a dose, in a
frequency, and for a duration of time sufficient to provide a beneficial
effect to
the patient when administered with the oral picoplatin formulation. The
picoplatin oral formulation can be administered with (before, after or
concurrently with) at least one platinum or non-platinum anticancer agent,
which
can be administered orally or parenterally. Preferably the picoplatin is
administered concurrently (simultaneously or overlapping) or prior to the
administration of the second anticancer agent. The second anticancer agent can
be administered prior to the picoplatin. If it is a taxane it is preferably
administered less than 10-20 hours to about 5 minutes prior to the picoplatin,
e.g., about 1 hour to 15 minutes prior to the picoplatin.
Additive effects between the picoplatin and the additional anticancer
agent can be observed, wherein the therapeutic effect of each agent is summed
to
provide a proportional increase in effectiveness. Synergistic effects between
the
picoplatin and the additional anticancer agent can be observed, wherein the
combined effectiveness of the treatment is greater than the summed
effectiveness
of the two agents.
In various embodiments of the present invention the ionizing radiation
employed may be X-radiation, 7-radiation, or (3-radiation. The dosages of
ionizing radiation will be those known for use in clinical radiotherapy. The
radiation therapy used will include, for example, the use of -y-rays, X-rays,
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
and/or the directed delivery of radiation from radioisotopes. Other forms of
DNA damaging factors are also included in the present invention such as
microwaves and UV-irradiation. It is most likely that all of these factors
effect a
broad range of damage to DNA, to the precursors of DNA, to the replication and
repair of DNA, and to the assembly and maintenance of chromosomes. For
example, X-rays may be dosed in daily doses of 1.8-2.0 Gy, 5 days per week for
5-6 weeks. Normally, a fractionaed dose will lie in the range 45-60 Gy. Single
larger doses, for example 5-10 Gy, may be administered as part of a course of
radiotherapy. Dosage ranges for radioisotopes vary widely, and depend upon the
half-life of the isotope, the type and energy of the radiation emitted, and
the rate
of uptake by cells.
This application is related to Application No. PCT/US2008/008076, filed
June 27, 2008, entitled "Stabilized Picoplatin Dosage Form"; Application No.
PCT/US2008/001746, filed Feb. 8, 2008, entitled "Encapsulated Picoplatin";
Application No. PCT/US2008/001752, filed Feb. 8, 2008, entitled "Stabilized
Picoplatin Oral Dosage Form"; U.S. Serial No. 10/276,503, filed September 4,
2003, entitled "Combination Chemotherapy"; U.S. Serial No. 11/982,841, filed
November 5, 2007, entitled "Use of Picoplatin to Treat Colorectal Cancer";
U.S.
Serial No. 11/935,979, filed November 6, 2007, entitled "Use of Picoplatin to
Treat Prostate Cancer"; U.S. Serial No. 11/982,839, filed November 5, 2007,
entitled "Use of Picoplatin to Treat Small Cell Lung Cancer"; WO/98/045331,
filed Apr. 3, 1998, entitled "Anti-VEGF Antibodies"; WO/96/040210, filed June
7, 1996, entitled "Antibody and Antibody Fragments for Inhibiting the Growth
of Tumors"; all of the above being incorporated by reference in their
entireties
herein.
This application is also related to U.S. Ser. No. 61/027,387, filed
February 8, 2008, entitled "Use of Picoplatin and Bevacizumab to Treat
Colorectal Cancer"; U.S. Ser. No. 61/027,382, filed February 8, 2008, entitled
"Use of Picoplatin and Cetuximab to Treat Colorectal Cancer"; U.S. Ser. No.
61/027,360, filed February 8, 2008, entitled "Picoplatin and Amrubicin to
Treat
Lung Cancer"; and U.S. Serial No. 61/034,410, filed Mar. 6, 2008, entitled
"Use
of Picoplatin and Liposomal Doxorubicin Hydrochloride to Treat Ovarian
Cancer"; all of the above being incorporated by reference in their entireties
herein.
26
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WO 2009/011861 PCT/US2008/008669
Furthermore, U.S. Pat. No. 7,060,808, issued June 13, 2006, entitled
"Humanized anti-EGF receptor monoclonal antibody"; and U.S. Pat. No.
4,673,668, issued June 16, 1987, entitled "Aminonaphthacene derivatives"; are
also incorporated herein by reference.
These patents and applications disclose, inter alia, useful agents for
administration with picoplatin, methods of treatment, dosing regimens, and
compositions.
EXAMPLES
Example 1: HPLC method for picoplatin.
Conditions:
Column: Luna 5u C18(2) 250x 4.6 mm
OOG-4252-E0
(Phenomenex)
Mobile phase A: 0.2% TFA (v/v) in deionized water
("di-water")
Mobile phase B: Methanol HPLC grade
Flow rate: 1.0 mL/min
Detection wavelength: 267 nm
Column temperature: 35 deg C
Sample temperature: 25 deg C
Run time: 25 min
Sample diluent: Normal saline
TABLE I - Gradient
Time (min) % B
0 5
4 5
13 35
14 100
18 100
19 5
5
27
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WO 2009/011861 PCT/US2008/008669
Example 2: Determination of the solubility of picoplatin at various pH
values.
The objective of this study was to determine the solubility of picoplatin
in aqueous solutions and to measure the effect of pH on picoplatin solubility.
TABLE II - pH Buffers
Vial pH Buffer
1 2 50 mM sodium phosphate
2 3 50 mM sodium phosphate
3 4 50 mM sodium acetate
4 5 50 mM sodium acetate
5 6 50 mM sodium citrate
6 7 50 mM sodium phosphate
7 8 50 mM sodium phosphate
8 9 50 mM sodium bicarbonate
9 10 50 mM sodium bicarbonate
Record di-water
Procedure:
Picoplatin (10 mg) was weighed into 0.5 mL Eppendorf vials, for a total
10 vials, then 250 L of buffer or water was added to the picoplatin. The
vials
10 were mixed for one minute. For each vial, the pH was measured. The vials
were
then placed on a shaker at 25 deg C for 16 hr in dark and the pH was measured
again. The solutions were filtered centrifugally through 0.45 uM Spin-X
filters,
then 50 mg of each filtrate was transferred into a respective HPLC vial. 1.5
mL
of 0.9% NaCI solution (normal saline) was added to the HPLC vials, then HPLC
analysis was performed immediately to determine the concentration of each
sample.
28
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WO 2009/011861 PCT/US2008/008669
TABLE III - pH of Picoplatin in Buffer Solutions
Buffer Initial pH Final pH Solubility
(filtrate) (mg/mL)
50mM sodium phosphate pH2 1.83 2.05 0.74
50mM sodium phosphate pH3 3.51 3.82 0.98
50mM sodium acetate pH4 3.81 4.01 0.77
50mM sodium acetate pH5 4.88 4.97 0.84
50mM sodium citrate pH6 6.29 6.54 0.78
50mM sodium phosphate pH7 7.02 6.80 1.10
50mM sodium phosphate pH8 8.28 7.81 0.97
50mM sodium bicarbonate pH9 8.92 8.76 0.67
50mM sodium bicarbonate pH10 10.45 10.07 0.60
Deionized H20 5.24 4.66 1.23
* Assuming the density of the saturated solution is 1 g/mL
Example 3: Determination of the pH-stability profile of picoplatin.
The objective of this study was to determine the effects of pH on stability
of picoplatin in aqueous solution and to assess the overall stability of
picoplatin
in an aqueous solution.
TABLE IV - pH Buffers
Vial pH Buffer/Solvent
1 2 50 mM sodium phosphate
2 3 50 mM sodium phosphate
3 4 50 mM sodium acetate
4 5 50 mM sodium acetate
5 6 50 mM sodium citrate
6 Record di-water
7 Record Normal Saline (NS)
Procedure:
Picoplatin (10 mg (+/- 0.1 mg) was weighed into a 5 mL volumetric
flask, then normal saline was added to the 5 mL volumetric mark and the sample
mixed by inversion to dissolve all solid and obtain a 2 mg/mL stock solution.
29
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
Then, to 1.125 mL buffer of specified pH or deionized water or normal saline
in
an HPLC vial was added 0.375 mL of the stock solution, which was mixed by
vortex for 10 sec to obtain a 0.5 mg/mL test solution. Two vials were made up
for each pH, which was checked.
The samples were then injected for HPLC analysis, analyzing each vial
once in the following sequence: pH 6, pH 5, pH 4, pH 3, pH 2, deionized water,
normal saline.
Then, one of each pair of vials for each solution was transferred to a 40 C
stability chamber, and the other to a 25 C chamber.
The injection sequence was repeated after the elapse of 1 and 3 days, or
until the samples were at least 20% degraded.
Results:
The results are shown below in TABLES V - XIII
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
N V') QN tn M --~ M
00 R N ~ 114:
~ ~ ~ ~ ~ ~ N
N
r~ 0~ q c~ oo oo
A cl~ 00 o M oc~
Q1 p O~ l- N N
~
0 ~o O O O O O O O
O O O O O O O
.-r .--.--~ ~ =--~ =--~ =--~
N ..,
cl ~
tt
=~ ~
> 00 00 M G~ O ~ G1
O G~ 00 N ~n v~
o ~+ N M M
I~I ~y
N a
o
U O
...
^l 4~-
O
cts Cd 0
' N rn ct
0 0
Y 03 U ~
H 'b "C~ "C 'd "d A
O
O O 0 0 0 w
r O ~ ~
E E E ~ ~ ~ 'b aa
(, O O O O O (A N ~t
0 W) v) vl
N M lq O
a. a a a. a 0
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
N tn M ~p N - ~ 00
CN 00 tn "O
A O O ~
~
N
3 ~ N kn 00 01 o0 I~ ON
M ON
~ cl M 4 -' en O
O A ~ ~ oo tn =--i ,~
~
U
o ,1
~ II
cd .F.~ O O O O O O O
N ~ O O O O O O O 0
z
c'
cl N
M
0
> x Q
0
o a' 00 ~ o o~o ~ i
r.^'+ N M M It O tn kn
> 0
0 U u
4-4
0
cl
4:~
Li
~ W Cd
, 0 0
Cl. 1:1. Cd cl U a
0
~ 0i 0 v0 i 0 0
0
p ~ 'd
cl
0 O O O O ~ N W
0 V~ tf) v') tn Vl
N
~ a a a a a 0 Q
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
~ o\ rn 00
~ ~ N
Cd
N
ON 00
~ CC (=) .-4 00 O~ ^ 01
t- oo N
U
0
C C O O O O
_. O O O O O O
C~ =--i .--i .-+ .--i .--i .-r .--i
N
~ oo oo M ON
O,, o0 N tn Ln
(D ~
7 a
N
,L,~= +
O w y 0
4
0-4
0-4
> a 0 0 ~
a ~. ~. 0 ~
H b b b b b
0 0 0 0 0
O O O N ~t
o v ) kn ~
d a. a. a a a Z Q
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
00 1,0 ~, O O l- M o0
oo M 00 M O .... oo W) M .-~ .--~
N
c~d ~ M 00 M N n 00 N
--~ 00 M Vj N 00 "D O\
O r+ O
01 G N
U
0 Cd ~ o O O o O O o
N ~ O O O O O O O N
N
..~'.
C7 a'
.--~ ¾
c~ .b
..., ~
.' M
0
x
0
cN oo w) `
0 0
C~ Q
O
cd
a
Cd
0 0
W ~. a ca m u
0
u
.. ..
o
0 0 0 0 0
~ cq3 ~
.. ~
~ b A
O O O O (D N W) W) N tn Cd .~
N M ~ v1 ~O ~ O
a a. a a a. Z A
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
N O l~ 1,0 - N 1,0
>"
0
A ~ ~ 0 N
00 ~ 00
N
.--~
o0 O N (7N N
ca
U
a~
cl
~ O~ 00 \O d 00 M G1
tr)
N ~= [~ l~ 00 00 00 tl~ 00
O~ a, O" O~ ON O-, O~
cd
cd
(D
c~
~ tn
CTS M
CL 00 00 M O~ O O~
O * O, 00 N tn v)
1~'.+ N M M ~O v~ ~
>
O ~ a
0
cts
4~-~ 4~=.~ y~ yõ~ ^
=~ ~ 4~-i 4~.-~ ~
O = =
CL.
Ll+ 0 0 y y N
~ cUd C Cd
a 'v b b b~c ~, a
pq 0 0 0 0 0 CA) b co
O O O O N
0 N t!1 V~ ~ N iF
a
tn
O
N
d a a o. a. o. 0 ~.1
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
N t~ t~ ~n o -~ ~
A rn ~ rn 06 ~,6 rn
03
b
N
.--~
~ (7N r- 0~ ~ ~
c~ A =--~
U
a~
0
q, 00 -,t 00 M 01
ON O,% 01 O,\ 1 O~ O~
c~ ~ Q
.
~ O
~ a ¾
o0 0o M rn o v o~
cl
O -~ ¾
o 0
F. F.
'D ~+N-+ cd
a 0 0
X a rs ~ ~ ~
b b b b b ~
0 0 0 0 0 ~
V o
N ~ 0 0 0 0
0 t/'~ N =~ iF
N N M v7 ~O O
a. a. o. a a z (D
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
W~ N
o~o WI) ~ a , N
N
r.
cd
.-r
N 'IO
o~ n ~ N o \o N
U
~
cd
W-, o~% 00 o v 00 m rn
~ ~ a , rn rn o O, rn rn rn
m
Cd M
0 cd r- CN
O
` ~ z
0
Cd
=~ w In.
4r 4r 4 r U
Cd
Cd cd
4-4
0 0
0 0 .~ .~
a ~ ~. A
O ~ O
0 0 0 0 0
"m b cl
(, O O O - M
0 tn W) tn tn v) m
O
d a a a a a 0
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
N ~O c=~ c,~ ~O r, O ,__
C:l
o0 CD
Cd
b
N
.--~
O
Ir ~ l!) Vl tn 01 lo M
00 M tI t 00
cl o~ rn 00 W) M rn
U
O
-d
cri
N a, 00 \G -~t 00 M 01
N
O'D
Cd O-, F Q-, F O~ O1
y
~ Cd 00
0
cl
0 ~ 00 ~ rn o~0 ~ i
N M M -t ~o tn
,
..
O C .~
o ~ 0
=~ 4r
0
4~"i 4~ F 4 Cd
= ~ 4~-i 4~-i ~+ c~
~
.. 0 0 cd ~
~ ~ u
o
~ 0 0 0 0 0 ~ ~ 0
v~ -d Cd
(, O O O O O
o tn tn tn tn tn Cd ia
N M ,:t _O
d a a a a o. 0
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WO 2009/011861 PCT/US2008/008669
Example 4: Determination of solubility of picoplatin in organic solvents.
The purpose of this study was to search for a solvent that can be used to
facilitate dissolution of picoplatin into self-emulsifying vehicles.
Solvent selection criteria:
- Dissolve picoplatin to > 20% w/w or 200 mg/mL
- Volatile - removable by vacuum drying
- Class 3 or injectable
- Chemically compatible with picoplatin
TABLE XIV - Composition
mg/g F-1 F-2 F-3 F-4 F-5 F-6 F-7
Acetonitrile 180
Tetrachloroethylene 180
Acetone 180
Methanol 180
THF 180
Isopropanol 180
Methylene chloride 180
Picoplatin 20 20 20 20 20 20 20
Total 200 200 200 200 200 200 200
Procedure:
Picoplatin (20+/-2 mg) was weighed into a series of 2 mL Eppendorf vials,
100 mg of each solvent was added respectively, then each sample was sonicated
to
mix and dissolve the picoplatin. If the picoplatin did not dissolve,
additional
aliquots of 100 mg solvent were added (to a maximum of 1.5 g), and the
suspensions sonicated, until all of the solid did dissolve. Each sample was
then
dried on a Speedvac on low heat overnight to evaporate the solvent, then 200
mg
deionized water was added to each vial. The supernatant (500 mg) was
transferred
from each vial into a respective HPLC vial, then 0.5 mL of the solvent used
was
added.
39
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
Results:
The results are shown below in TABLE XV.
TABLE XV
Solvent Solubility (mg/g)
Acetonitrile 1.30
Tetrachloroethylene 0.00
Acetone 0.14
Methanol 0.61
THF 1.81
Isopropanol 0.15
Methylene chloride 0.00
DMSO > 200 (degradation)
N-methylpyrrolidone > 200 (peak shifted)
Benzyl benzoate < 5
Benzyl alcohol < 5
Example 5: Determination of the solubility of picoplatin in.self-emulsifyin~
vehicles.
The purpose of this study was to find an oil: surfactant system(s) capable of
dissolving Picoplatin to 10% w/w. The composition of the various samples is
shown in TABLE XVI.
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WO 2009/011861 PCT/US2008/008669
,D o 0 0 0 o
~ 0 0
0 0 0 0 N o o 0 0 0 0
M
~ O O O O O
O C:)
N -- N en N
O O O O c:) c:)
.~
O
O
~
O O o 0
U O O
N --~ N en ~
~C O o
O O O O O 0
O O O O o
G=i N --N M N CD
00 O O O O O c:)
N r+ N M N c:)
O
0
00 a ~ ~ =~ =~ -d
0 0 ~ o o ~ o o o ~~
~ (2) w 0
U U t7 a> a ~ v(D) ~'E t~ ~~3 w" F -~
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Procedure:
Picoplatin was weighed out to within +/-5% of the target weight, then
solvent (e.g. DMSO USP) was added to dissolve. Then, oil, lecithin, PEG400 and
a
surfactant were mixed to within +1-5-10% of the target weight, then ethanol
was
added to homogeneity. The two solutions were combined, then vacuum dried until
the residual solvent was less than 1% of the dry weight. The dry formulation
was
examined under a microscope for crystals. If crystals were present, the sample
was
centrifuged to the pellet the crystals. Then 10 mg of the supernatant was
removed
and 5g normal saline added. The drug concentration was analyzed by HPLC.
42
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
b
O 00
~ N ~
a N O ~
;-~
(7~ ~, ~h M [~
G)
~
:-~..
00
4)
~
M ~ 0 [~ M M
~"i \O M
t:
U
C
0
N O b
ti -~e-~ =~ p~p M
'~ ~"~ 4) y M O~ M
o0 rr M
w
H
C*~
N 0 ~
00 ~ N
w a u1 O
00 r- ~
0
O O
~ ~ U a
U o U ~7
i; ( w a. a: .~. aQ.~
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Example 6: Degradation of picoplatin in DMSO and pH buffers at 25 C.
The purpose of this study was to obtain a profile of picoplatin in DMSO and
pH buffers or water.
TABLE XVIII - Materials
mg/mg F-28 F-29 F-30 F-31 F-32 F-33 F-34
Picoplatin 0.5 0.5 0.5 0.5 0.5 0.5 0.5
DMSO 950 950 950 950 950 950 500
glacial acetic acid 50
Normal saline 50 500
pH 2 buffer 50
pH 4 buffer 50
pH 6 buffer 50
Di-water 50
Total 1000 1000 1000 1000 1000 1000 1000
Procedure:
Picoplatin (0.5 mg +/- 0.01) was weighed out into a 1.5 mL HPLC vials for a
total of 7 vials. DMSO and the 2d solvent were weighed out in a separate 2 mL
Eppendorf vial and mixed well. Then, 1 mL of the DMSO mixture with solvent was
transferred into the HPLC vial containing picoplatin, then mixed by vortex for
10
sec to make sure all solid was dissolved.
The samples were then analyzed by HPLC, running the sequence 4-5 times,
or until at least 20% of the picoplatin had degraded
Example 7: Preparation of picoplatin nanoparticles
The purpose of this study was to generate nanometer sized and preferably
non-crystalline particles of picoplatin.
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TABLE XIX
Compound %w/w
Picoplatin 2.5
Soy lecithin 5
deionized water 92.5
Total 100
Procedure:
Soy lecithin and deionized water were weighed out, then mixed with a
high-shear mixer to obtain a uniform dispersion. Picoplatin was added and
mixed
well, the suspension being microfluidized until the particle size reached a
minimum
by laser light scattering or disappearance of crystalline particles. Then, the
nanosuspension was freeze-dried to obtain a dry powder.
Results:
The results are shown below in TABLE XX.
TABLE XX
In-process sample Particle size Purity by Crystalline
by LLS HPLC particles
Pre-microfluidization 10-20 micron 94.4% A lot
Post-microfluidization 643 nm 93.8% Not seen
Post-lyophilization 584 nm 95.1% A few
A significant size reduction from about 10 to 0.5 micron in diameter
corresponding to about 400-fold increase in particle surface area was obtained
by
microfluidization. It was found that picoplatin retains its integrity (purity)
after the
microfluidization and lyophilization process. Also, a reduction in
crystallinity was
apparent.
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Example 8: Determination of picoplatin stability in NMP.
The purpose of this study was to develop a profile of picoplatin in N-methyl-
pyrrolidone at 25 C and at 5 C
TABLE XXI - Composition
mg/g F-45 F-46 F-47 F-48 F-49
Picoplatin 0.5 0.5 0.5 0.5 0.5
NMP 1000 800 500 200
NS 200 500 800 1000
Total 1000.5 1000.5 1000.5 1000.5 1000.5
TABLE XXII - Composition
mg/g F-45 F-46 F-47 F-48 F-49
Stock 200 200 200 200 HPLC Std
NMP 800 600 300
NS 200 500 800
Total 1000 1000 1000 1000
Procedure:
In a 2 mL Eppendorf vial, 2.000 mg picoplatin was weighed out, 800 mg
NMP added, and the mixture vortexed to dissolve picoplatin to obtain a stock
solution, of which 200 mg was transferred into Eppendorf vials for total of 4
vials.
An appropriate amount of normal saline was added and mixed well by vortex for
approximately 10 seconds, then 500 mg was transferred into an HPLC vial, and
an
HPLC analysis run. Then, the remainder of the solution was dried in a
lyophilizer
until all the liquid was gone and 500 mg normal saline was added to each vial
and
mixed well by vortex for 20 seconds, transferred 500 mg into an HPLC vial. Ran
HPLC with a 0.5 mg/mL standard.
46
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Results:
Representative HPLC chromatograms are shown in Figures 9 and 10.
Example 9: Optimization of picoplatin nanoparticle formulations.
The purpose of this study was to prepare and compare stability of
nanoparticles using various stabilizers by microfluidization.
TABLE XXIII - Composition (%w/w)
Composition (% w/w)
Compound F-37 F-38 F-39 F-40 F-41 F-42 F-43
Picoplatin 2.5 2.5 2.5 2.5 2.5 2.5 2.5
Soy lecithin S-45 5
Soy lecithin S-75 5
Soy lecithin PL-90 5
Soy lecithin PL-90H 5
itamin E Succinate, pH7 97.5
5% pre-made dispersion in
S
Oleic acid (Croda), pH 7, 5% 97.5
re-made dispersion in water
Sodiumcaseinate, pH 7, 5% 97.5
re-made dispersion in water
Di-water 92.5 92.5 92.5 92.5
otal 100 100 100 100 100 100 100
Composition (mg/10 g)
Compound F-37 F-38 F-39 F-40 F-41 F-42 F-43
Picoplatin 25 25 25 25 25 25 25
S-45 50 0 0 0 0 0 0
S-75 0 50 0 0 0 0 0
IPL-90 0 0 50 0 0 0 0
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PL-90H 0 0 0 50 0 0 0
VES pH7 5% pre-made 0 0 0 0 975 0 0
dispersion in water
Oleic acid (Croda), pH 7, 5% 0 0 0 0 0 975 0
re-made dispersion in water
Sodium caseinate, pH 7, 5% 0 0 0 0 0 0 975
re-made dispersion in water
Di-water 925 925 925 925 0 0 0
otal 1000 1000 1000 1000 1000 1000 1000
*Added additional 10 g of di-water to each.
Procedure
Lecithin PL, picoplatin and deionized water were weighed out into a 50 mL
falcon tube and mixed by high-shear mixer at 8000 RPM for 2 minutes until all
of
the solid was uniformly dispersed. A micro fluidizer with a Z-chamber was set
up
and the sample was processed for about 1100 strokes. 1 g each was transferred
into
3 mL glass vial for a total of - 15 vials, which were freeze-dried to obtain a
"lyophilizate".
One vial of the lyophilizate was reconstituted by adding di-water and
mixing well to form a suspension. "Post-lyo"
For all samples, the following tests were performed at (T=0):
Micrograph at 200 x, laser light scattering (LLS),
HPLC (dilute to 0.5 mg/mL with NS) for post lyophilization sample only
Results
The results are shown below in TABLE XXIV.
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CA 02693057 2010-01-12
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a~
M 'y p.
~ + + + + + + $
Q..
~
+r y ++ +-+
o o., o r. O O
; r+ O~,
z z zm rn
z
O O O O + O }+
+ zrn z; z z; z;
+ +
rn 18
0 ooo o~ o
~ w z~ z~ ~ ~ z~
~
00 o o o
~ w t z~ zrA ~
0
~.
U
0 0 0 0 O
~ r-
Q, to to rA
0 0 ~
N
ed c's m m
N
o O O O O ~ O 0 cn
= .r = "=~ N = .. ^' ir ^ ^'
o ~" o r.+' 44 4r vl ~ U
.. ~ 4. ~+~ .. ~ r+ O ~+
U U
~ c~d o ~ o cd kr) E ~ Cd . ~.
x N tn GX) W) ~ N N N N U U ~ U cd U ~ U cts U rn
O O 0 O 0 O 0 O 0 O O O o ~~~
~ h7 y W 0 W y ~ y ~ y ~
O O~ O~ O~ O y O G) O N Cd a)
cn~~ o
:C~n ~ +
tf)
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TABLE XXV - Particle diameter by Laser Light Scattering (LLS) in nm
Sample ID F-37 F-40 F-43
After 1100 passes 746 3386 136
After keeping the suspension 844 1630 188
at 5 C for 24 hr
After keeping the suspension 1406 758 228
at 25 C for 24 hr
Reconstituted suspension 1126 1740 1104
at 25 C for 72 hr
TABLE XXVI - HPLC anal siy s for picoplatin in nanoparticles
Sample ID Concentration Purity
(mg/mL)*
F37 reconstituted suspension (fresh) 0.36 97.3
F40 reconstituted suspension (fresh) 0.48 94.8
F43 reconstituted suspension (fresh) 0.59 94.5
Based picoplatin peak only
Sample ID Concentration Purity
(mg/mL)*
F37 reconstituted suspension (fresh) 0.36 100.0
F40 reconstituted suspension (fresh) 0.50 100.0
F43 reconstituted suspension (fresh) 0.60 97.7
Based on combination of pico, Aquo 1 and Aquo 2 peaks
* The target concentration is 0.5 mg/mL
Example 10: Preparation of a second batch of picoplatin nanoparticles in 5%
Sod. Caseinate dispersion.
The purpose of this study was to reproduce the results from the previous
experiment and to try using a rotary evaporator to remove water.
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TABLE XXVII - Composition:
Composition (% w/w)
Compound F-50
Picoplatin 1.25
Sodiumcaseinate, pH 7, 5% 2.5
pre-made dispersion in water
Di-water QS
Total 100
Composition (mg/40 g)
Compound F-50
Picoplatin 500
Sodiumcaseinate, pH 7, 5% 19500
pre-made dispersion in water
Di-water 20000
Total 40000
Procedure
100 g of a 5% sodium caseinate dispersion and 100g of deionized water
were weighed into an Erlenmeyer flask, and the pH adjusted to 6 using
HC1/NaOH.
The solution was sparged with Nitrogen gas for 10 minutes, then 39.5g of the
dispersion transferred into a 100 mL Erlenmeyer flask. 500 mg picoplatin was
added and mixed under high shear conditions at 8000 RPM for 5 minutes. A 500
mg sample was processed in a microfluidizer with a Z-chamber for 2200 strokes
and
the pH recorded. The remainder of the sample was dried at 40 C on a rotary
evaporator for 2 hr, then vacuum dried at 25 C and 150 mTorr for 16 hr. The
residue was ground into a fine powder, then the moisture content determined by
TG/DTA along with a picoplatin standard. A moisture uptake study was performed
by placing 10 mg in 3 HPLC vials and keeping them at 25 deg C/60%RH, 30 deg C
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/65%RH and 40 deg C/75%RH respectively, exposed overnight. An HPLC
analysis and a microscopic examination were performed.
Results
Figure 11 shows a thermogravimetric / differential thermal analysis
(TG/DTA) scan of micronized picoplatin powder.
Figure 12 shows a thermogravimetric / differential thermal analysis
(TG/DTA) scan of TG/DTA of F50 Picoplatin nanoparticles in sodium caseinate.
Particle size in the reconstituted suspension could not be measured due to
presence of large non-crystalline caseinate agglomerates, which interfered
with the
laser light scattering measurement. However, microscopic examination revealed
that there was few crystalline particles in the micron size range, indicating
that
picoplatin remained in nanometer size (possibly less than 300-400 nm).
TABLE XXVIII - Hygroscopicity Data
Temperature/Humidity Conditions % Weight Gain
25 C/60% RH overnight 0.36
30 C/65% RH overnight 0.73
40 C/75% RH overnight 3.6
TABLE XXIX - HPLC Results
Lot: 69-1-68 Assay (mg/g) * % Peak area
Picoplatin 569.0 93.9
Aqua 1 761.7 1.7
Aqua 2 848.4 1.15
Total 573.7 96.75
*Theoretical assay value = 333.3 mg/g or 33.3% w/w. The higher-than-
theoretical
assay value may be due to presence of volatile components (e.g. water) in the
sodium caseinate starting material.
Figure 13 shows a representative HPLC chromatogram of picoplatin
nanoparticles. From the top down: 0.5 mg/mL picoplatin nanoparticles in normal
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WO 2009/011861 PCT/US2008/008669
saline and 0.5 mg/mL picoplatin standard in normal saline. One unknown peak at
5.5 min (not Aquo #1).
Example 11: Solid dispersion of picoplatin using hot melt method.
The purpose of this study was to determine if it is possible to dissolve
picoplatin in a molten solution of a solid matrix excipient without
decomposition of
picoplatin. The second purpose of this study is to verify the solid matrix
form for
crystallinity by DSC.
TABLE XXX - Composition (mg)
Component, grade MP F-51 F-52 F-53 F-54 F-57
Gelucire 50/13 45 950
poloxamer 188 52 950
PEG 8000 60 950
Sorbitan monostearate (SPAN 60) 57 950
Kollidon K-90 150 950
Picoplatin 50 50 50 50 50
Procedure:
The selected excipient was weighed out into a 3 mL glass vial, then warmed
up to a temperature of about 5-10 C above the melting point of the matrix
material
using a hot plate. Picoplatin was added and the mixture stirred at about 100 C
for 1
hr, or for the sorbitan monostearate sample, at about 150 C. The samples were
then
cooled quickly on a chilled metal block.
Observations:
Picoplatin dissolved in molten Gelucire 50/13 and in SPAN 60, but not in
PEG, poloxamer or Kollidon, suggesting picoplatin is more soluble in lipids.
The
Gelucire 50/13 picoplatin mixture appeared to contain intact picoplatin, but
the
SPAN 60 picoplatin mixture turned brown on heating
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Example 12-1: Solid dispersion of picoplatin using hot melt method.
The purpose of this study is to determine the solubility of picoplatin in
Gelucire 50/13 and to try two more low MP lipids
TABLE XXXI - Composition (mg)
Component,
supplier, grade MP F-59 F-60 F-61 F-62 F-63 F-64 F-65 F-66
Gelucire 50/13 45 90 80 70 60 50 40
Gelucire 44/14 44 70
Vitamin E TPGS 40 70
Picoplatin 10 20 30 40 50 60 30 30
Procedure
The selected excipient and the picoplatin (+/- 2 mg) were weighed into a
HPLC glass vial, and vortexed to mix. The mixture was heated to 60 C to form a
complete melt, and stirred and observed to determine if complete dissolution
of the
picoplatin occurred. The sample was heated at 60 deg C for 1 hour for F-59 to
F-66,
and F-61 to F-66 received additional 30 min heating at 80 deg C. The samples
were
then cooled immediately by placing the vial in a chilled metal block.
Example 12-2: Solubility of picoplatin in Gelucire 50/13.
The purpose of this study was to determine the solubility of picoplatin in
Gelucire 50/13 at less than 10% and to test one more lipid (Compritol 888 ATO)
at 5%
TABLE XXXII - Composition (mg)
Component, supplier, MP F-67 F-68 F-69 F-70 F- 71
grade
Gelucire 50/13 45 95 94 93 92
Compritol 888 ATO 70 95
Pico 5 6 7 8 5
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Procedure:
The lipid and picoplatin (+/- 2mg) were weighed into a HPLC glass vial,
then vortexed to mix. Then, a glass beaker with Miglyol oil and placed it on a
hot
plate set to 100 C. All mixtures were heated for 2 hours (100 deg C) and
vortexed
from time to time. After heating, all samples were cooled rapidly by placing
the
vial in a chilled metal block.
Observations:
All turned clear. The solutions of F-67 and F-68 appeared slightly clearer
than the others. The results of Samples F-51 to F-71 are shown below in Tables
XXXIII and XXXIV.
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~ U
a
~ U
0 0
N
N
tn
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.-r r
a -d cd
U
4-4 a~ w ' azz
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O o ~ ~WOU
~ 00 ~ a ~ ~
~ o
'n
~ ~ ~ o 0 G U
. u k O
C7 a aW. ~~ C7 > U
CA 02693057 2010-01-12
WO 2009/011861 PCT/US2008/008669
-+ O
~
O
O
N
N
'-' o O
b H
cC .--N
.-.
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cl
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~ ~
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o ~ u
tn
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00 U
C7 ri) C C7 > U
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TABLE XXXV - Concentration of Picoplatin in
Gelucire 50/15 hot melt (F-51, 5% load)
Concentration (mg/g)* Purity (% peak area)
5% picoplatin in 68.7 96.95
Gelucire 50/15
* Theoretical concentration is 50 mg/g (5% w/w)
Figure 14 shows a representative HPLC trace of picoplatin in Gelucire
50/15.
Figure 15 shows a representative DSC for Picoplatin in Gelucire 50/15 hot
melt. From top down: Gelucire 50/15, 5% picoplatin in Gelucire 50/15 hot melt,
and picoplatin API.
Figure 16 shows a representative DSC for Picoplatin in hot melt.
From top down: 5% picoplatin in Gelucire 50/15, 6% picoplatin in Gelucire
50/15
and 5% in Compritol 888 ATO.
TABLE XXXVI - Heat of Fusion for 5% picoplatin in Gelucire 50/15, 6%
picoplatin in Gelucire 50/15 and 5% picoplatin in Compritol 888 ATO.
Sample Heat of Fusion (mJ/mg) for the
endothermic peak at 220-250 C
Picoplatin API 54.9
F51- 5% picoplatin in Gelucire 50/15 10.0
F68- 6% picoplatin in Gelucire 50/15 31.7
F71- 5% picoplatin in Compritol 888 ATO 36.3
Example 13: Preparation of 50% w/w picoplatin suspension in medium chain
triOyiceride (MCT) oil.
Objective:
To prepare 50% w/w picoplatin nano-suspension in MCT oil
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TABLE XXXVII - Materials
Composition (% w/w)
Compound F-73 F-74 F-75
Picoplatin 5 5 5
Miglyol 812 95 90 90
Phospholipon 90G 5
Polysorbate 80 5
Total 100 100 100
Composition (g/30 g)
Compound F-73 F-74 F-75
Picoplatin 1.5 1.5 1.5
Miglyol 812 28.5 27 27
Phospholipon 90G 1.5 1.5
Polysorbate 80
Total 30 30 30
Procedure:
Picoplatin was weighted out into a 50 mL Falcon tube, MCT oil was added
to the tube (final picoplatin concentration was 5% w/w). PL-90 or Polysorbate
80
was then added, and mixed using a high shear mixer (IKA @ 5 setting for 3
minutes), then microfluidized using M 110EH at 25000 psi and a Z-chamber to
obtain submicron particles. Chill the chamber with ice. Maintain the
suspension
during processing at below 40-50 deg C.
Samples were removed and average size determined by laser light scattering.
Allow the suspension settle down and remove supernatant to obtain about 50%
w/w
suspension. Store at 2-8 C. Observe under microscope and measure size at T-0
and
Day-1. Run HPLC (diluted in normal saline to 0.5 mg/mL) at Day-7
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Results
TABLE XXXVIII - Process and Size
F-73 F-74 F-75
Passes 200 200 200
Size at TO 430 nm 482.33 807 nm
Size at Day 1 638 nm 602.7 nm 576 nm
SizeatDay7 474nm 485nm 186nm
Observation under Aggregated Uniformly Aggregated
microscope particles separated particles particles and
phase separated
TABLE XXXIX - HPLC (Method #1)
Peak Area RT Std F-73 F-74 F-75
(% of total) (min) (0.5 mg/mL
in NS)
Picoplatin 91.7 90.18 88.98 80.13
Aqua 1 4.6 4.9 5.59 6.12 9.81
Aqua 2 9.09 3.4 4.23 4.70 9.62
Unk# 1 5.7 0 0 0.24 0
Unk#2 6.2 0 0 0 0.88
Total 100.0 100.01 100.03 100.43
*Oil phase (supematent) contained no picoplatin, as determined by HPLC.
Figure 17 shows HPLC traces, from the top down: 0.5 mg/mL standard in
normal saline, F73- picoplatin in MCT, F74- picoplatin in MCT and PL90G, and
F75- picoplatin in MCT and Polysorbate 80.
Figure 18 shows zoomed-in views of the HPLC traces of Figure 17 From
the top down: 0.5 mg/mL standard in NS, F73- picoplatin in MCT, F74-
picoplatin
in MCT and PL90G, and F75- picoplatin in MCT and Polysorbate 80.
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Example 14: Preparation of 50% w/w picoplatin suspension in MCT and oils.
Objective:
%To prepare final concentration of 50% w/w picoplatin suspension in oils.
To compare microfluidization efficiency in oils with different viscosity
TABLE XL - Materials
Composition (% w/w)
Compound F-76 F-77 F-78 F-79
Picoplatin 10 10 10 10
Miglyol MCT 85
Ethly oleate 85
Capmul MCM 85
Soybean oil, super refined 85
PL-90 5 5 5 5
Normal saline 10
Total 110 100 100 100
Composition (g/tube)
Compound F-76 F-77 F-78 F-79
Picoplatin 3 3 3 3
Miglyol MCT 25.5 0 0 0
Ethyl oleate 0 25.5 0 0
Capmul MCM 0 0 25.5 0
Soybean oil, super refined 0 0 0 25.5
PL-90 1.5 1.5 1.5 1.5
Normal saline 3 0 0 0
Total 33 30 30 30
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Procedure:
Weigh out Picoplatin into a 50 mL Falcon tube. Record weight. Add oil and
PL90. Record weight. Mix using a high shear mixer, IKA @ 5 setting for 3
minutes
Microfluidize using Z-chamber for 200 passes. Record the pass# and final
particle size. Let the sample settle down and remove 90% of sample weight of
supernatant to obtain 50% w/w suspension. HPLC for purity. Store at 2-8 C.
Results:
F76 formed large aggregates and was not able to be microfludized.
However, small amount of sample with additional amount of PL90 added (double
amount) was tested and it appeared to have smaller particle size and possibly
can be
microfludized. It will be tested in the next study.
F79 formed large aggregates and was not able to be microfludized.
F78 became a waxy semi-solid and therefore, could not be processed by
either high-shear or microfluidization.
F77 was the only formulation that could be microfludized. The particle size
after microfluidization for 200 passes is 919 nm by LLS.
TABLE XLI - Purity% by HPLC (Method #1) for F77
Peak Area RT Std F-77
(% of total) (min) (0.5 mg/mL in NS)
Picoplatin 7.6 91.9 77.1
Aqua 1 4.7 3.5 10.6
Aqua 2 10.3 4.4 10.8
Unk#l 4.3 0.2 1.5
Total 100.0 100.0
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Example 15: Preparation of 50% w/w picoplatin suspension in MCT oil.
Objective
To prepare final concentration of 50% w/w picoplatin suspension in oil. To
test microfluidization efficiency with normal saline
TABLE XLII - Materials:
Composition (% w/w)
Compound F-80
Picoplatin 10
Miglyol MCT 80
PL-90 10
Normal saline 10
Total 110
Composition (g/tube)
Compound F-80
Picoplatin 3
Miglyol MCT 24
PL-90 3
Normal saline 3
Total 33
Procedure:
Weigh out Picoplatin into a 50 mL Falcon tube. Record weight.
Add oil, PL90, and N.S. Record weight.
Mix using a high shear mixer, IKA @ 5 setting for 3 minutes
Microfluidize using Z-chamber for 200 passes. Record final particle size
Let the sample settle down and remove 90% of sample weight of supematant
to obtain 50% w/w suspension.
HPLC for purity
Store at 2-8 C.
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Results:
F80 was able to be microfluidized. The particle size after microfluidization
for 200 passes is 554 nm by LLS.
TABLE XLIII - Purity% by HPLC (Method #1) for F80
Peak Area RT Std F-80
(% of total) (min) (0.5 mg/mL in NS)
Picoplatin 7.6 91.9 72.6
Aqua 1 4.7 3.5 12.2
Aqua 2 10.3 4.4 13.1
Unk# 1 4.3 0.2 2.0
Total 100.0 99.9
Figure 19 shows representative HPLC chromatograms. From top down:
0.5 mg/mL standard in normal saline, F77- picoplatin in Ethyl Oleate and PL90,
F80- picoplatin in MCT, PL90G and normal saline.
Figure 20 shows representative HPLC chromatograms, enlarged. From top
down: 0.5 mg/mL standard in normal saline, F77- picoplatin in Ethyl Oleate and
PL90, F80- picoplatin in MCT, PL90G and normal saline.
Example 16: Preparation of 50% w/w picoplatin suspension in Ethyl Oleate.
Objective
To prepare final concentration of 50% w/w picoplatin suspension in ethyl
oleate at pico:PL90 ratio of 1:1 (wt).
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TABLE XLIV - Materials
Composition (% w/w)
Compound Supplier Grade F-81
Picoplatin 10
Ethyl oleate 80
PL-90 10
Total 100
Composition (g/tube)
Compound lot F-81
Picoplatin 3
Ethyl oleate 24
PL-90 3
Total 30
Procedure:
Weigh out Picoplatin into a 50 mL Falcon tube. Record weight. Add oil and
PL90. Record weight. Mix using a high shear mixer, IKA @ 5 setting for 3
minutes.
Microfluidize using Z-chamber for 2000 strokes. Record the pass# and
final particle size. Let the sample settle down and remove 21 g (90% of sample
weight) of supernatant to obtain 50% w/w suspension. HPLC for purity Store at
2-8 C.
Results:
F81 can be microfluidized. The particle size after microfluidization for 200
passes is 586 nm by LLS.
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TABLE XLV - Purity% by HPLC for F81
Peak Area RT Std F-81
(% of total) (min) (0.5 mg/mL in NS)
Picoplatin 7.8 94.8 86.5
Aqua 1 4.7 2.2 6.7
Aqua 2 10.3 2.9 6.6
Unk#l 4.3 0.0 0.3
Unk#2 16.5 0.1 0.0
Total 100.0 100.01
Figure 21 shows representative HPLC Chromatograms. From top down:
0.5 mg/mL picoplatin standard in normal saline and 0.5 mg/mL F81-picoplatin in
PL90 and EO in normal saline.
Figure 22 shows representative HPLC chromatograms, enlarged. From top
down: 0.5 mg/mL picoplatin standard in normal saline and 0.5 mg/mL
F81-picoplatin in PL90 and EO in normal saline.
TABLE XLVI - Picoplatin Oil Nano-Suspension Summary
PL90:Pico Pass# Size (nm) Observation
F74 in MCT 1:1 200 482 Uniformly separated
particles
F77 in EO 1:2 200 919 Uniformly separated
particles.
F80 in MCT 1:1 200 554 Uniformly separated
w/ NS particles
F81 in EO 1:1 200 586 Uniformly separated
particles.
All publications, patents and patent applications are incorporated herein by
reference. While in the foregoing specification this invention has been
described in
relation to certain preferred embodiments thereof, and many details have been
set
forth for purposes of illustration, it will be apparent to those skilled in
the art that
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the invention is susceptible to additional embodiments and that certain of the
details
described herein may be varied considerably without departing from the basic
principles of the invention.
67
