NZ621322B2 - Decitabine derivative formulations - Google Patents
Decitabine derivative formulations Download PDFInfo
- Publication number
- NZ621322B2 NZ621322B2 NZ621322A NZ62132212A NZ621322B2 NZ 621322 B2 NZ621322 B2 NZ 621322B2 NZ 621322 A NZ621322 A NZ 621322A NZ 62132212 A NZ62132212 A NZ 62132212A NZ 621322 B2 NZ621322 B2 NZ 621322B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- formulation
- dmso
- glycerin
- ethanol
- Prior art date
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- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
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- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MCZDHTKJGDCTAE-UHFFFAOYSA-M tetrabutylazanium;acetate Chemical compound CC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC MCZDHTKJGDCTAE-UHFFFAOYSA-M 0.000 description 1
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- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
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- 150000003624 transition metals Chemical class 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
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Abstract
Disclosed herein are formulations of 2-deoxyguanosine-decitabine derivatives also comprising a substantially anhydrous solvent comprising about 60% to 70% propylene glycol; about 20% to 30% glycerin; and about 5% to 15% ethanol (w/w/w). Also disclosed is the use of the formulations in the manufacture of medicaments for treating one or more myelodysplastic syndromes, leukemia, or solid tumours. e of medicaments for treating one or more myelodysplastic syndromes, leukemia, or solid tumours.
Description
DECITABINE DERIVATIVE FORMULATIONS
RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. §119 of United States Provisional
Patent Application 61/529,081, filed August 30, 2011, the contents of which is incorporated
herein by reference in its entirety.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are
herein incorporated by reference to the same extent as if each individual publication, patent,
or patent application was specifically and individually indicated to be incorporated by
reference.
BACKGROUND
Decitabine is currently being developed as a pharmaceutical for the treatment of
chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), non-small cell
lung (NSCL) cancer, sickle-cell anaemia, and acute myelogenous leukemia (AML).
Decitabine possesses multiple pharmacological characteristics. Decitabine can be
incorporated into DNA during the S phase of cell cycle, or can induce cell differentiation and
exert haematological toxicity. Despite having a short physiological half-life, decitabine has
an excellent tissue distribution.
Despite its proven antileukemic effects in CML, MDS, and AML, the potential
application of decitabine has been hampered by delayed and prolonged myelosuppression.
Lower doses of decitabine, given over a longer period of time, have minimized
myelosuppression to manageable levels without compromising its ability to suppress cancer
via its hypomethylation effect. At higher doses, the associated toxicity was prohibitive.
However, treatment of haematologic and solid tumours at maximally tolerated doses of
decitabine has been ineffective. The cause of myelosuppression is not clear. It is plausible
that since decitabine is randomly and extensively incorporated into the DNA of S phase cells,
including bone marrow cells that are involved in normal haematopoiesis, the severe DNA
damage due to the instability of decitabine leads to necrosis. Since incorporation of
decitabine is not restricted to only the CpG-rich sequences, the DNA can break, due to the
instability of decitabine, and require repair at numerous sites outside of the CpG islands.
Decitabine and azacitidine are unstable in aqueous media and undergo hydrolytic
degradation in aqueous media. The degradation is slowest at neutral pH.
Dinucleotide compounds derived from decitabine for the development of therapies for
similar indications had been described in U.S. Patent No. 7,700,567, which is incorporated by
reference in its entirety.
[0006A] In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that
such documents, or such sources of information, in any jurisdiction, are prior art, or form part
of the common general knowledge in the art.
[0006B] In the description in this specification reference may be made to subject matter that
is not within the scope of the claims of the current application. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the claims of this application.
SUMMARY OF THE INVENTION
In a first aspect of the present invention there is provided a formulation comprising:
(a) a compound of the formula:
O P OH
N NH
or a pharmaceutically-acceptable salt thereof; dissolved in (b) a substantially anhydrous
solvent comprising about 60% to about 70% propylene glycol; about 20% to about 30%
glycerin; and about 5% to about 15% ethanol.
In some embodiments, said solvent comprises about 65% to about 70% propylene
glycol; about 25% to about 30% glycerin, and 5% to about 10% ethanol.
It has been found that the use of a substantially anhydrous solvent in the formulations
of the invention produces a dramatic increase in the solubility (about 130 to about 150
mg/mL for the compound of formula I-1). This improves subcutaneous administration, since
such high concentrations lower the volumes of injection and increase the safety of the
compound as less amounts of excipients are needed compared to lower concentrations of the
same compound.
It has also been found that the use of substantially anhydrous solvents in the
formulations of the invention exhibit increased shelf life stability (see Example 2 herein). For
example, reconstituted dosage forms having a water content of 0.1% remain stable at 2-8˚C
for at least 12 months.
Ethanol can be incorporated as a thinning agent or can be eliminated while retaining
suitable handling/reconstitution characteristics.
In some embodiments, said solvent comprises about 65% propylene glycol; about
% glycerin; and about 10% ethanol, for example being 65% propylene glycol; 25%
glycerin; and 10% ethanol.
In some embodiments, said solvent comprises 65% to 70% propylene glycol and 25%
to 30% glycerin, any balance being ethanol.
In some embodiments, said solvent comprises about 70% propylene glycol and about
% glycerin, ethanol being absent.
Non-limiting embodiments of a pharmaceutically-acceptable salt include any salt
described herein. In some embodiments, said salt is a sodium salt. The compound can be
present at a concentration of about 80 mg/mL to about 110 mg/mL, for example about 100
mg/mL.
In some embodiments, the formulation further comprises dimethyl sulfoxide
(DMSO), optionally at a DMSO:compound ratio of about 2: about 1; about 1: about 1; about
0.5: about 1; about 0.3: about 1; or about 0.2 - about 0.3: about 1.
In some embodiments, a formulation disclosed herein is suitable for administration by
subcutaneous injection.
In another aspect, the invention provides a kit comprising: (a) a first vessel containing
a compound of formula I-1 as defined above or pharmaceutically-acceptable salt thereof; and
(b) a second vessel containing a substantially anhydrous solvent as defined above.
In some embodiments, the compound in the kit of the invention is present in the form
of a substantially anhydrous powder, for example a lyophilized powder. The compound can
be present in the first vessel in an amount of about 80 mg to about 110 mg, for example about
100 mg. In some embodiments, the kit further comprises instructions for administration by
subcutaneous injection.
In another aspect, the invention provides a process for preparing a pharmaceutical
composition, the process comprising dissolving a compound of formula I-1 as defined above
in a substantially anhydrous solvent as defined above.
In some embodiments, the process further comprises the steps of: dissolving said
compound in DMSO to produce a solution of said compound in DMSO; and lyophilizing said
solution to provide said compound as a substantially anhydrous powder.
Also described is a process for producing a compound of the formula:
O P OH
OH I-1,
or a pharmaceutically-acceptable salt thereof, in the form of a substantially anhydrous
powder, the process comprising dissolving said compound or salt thereof in DMSO to
produce a solution in DMSO, and then lyophilizing said solution to provide said compound
or salt thereof as a substantially anhydrous powder. Said substantially anhydrous powder can
comprise DMSO, for example, in an amount of up to about 2000 mg/g; up to about 1000
mg/g; up to about 600 mg/g; up to about 500 mg/g; up to about 400 mg/g; up to about 300
mg/g or about 200 – about 300 mg/g of said compound of formula I-1. In some
embodiments, the powder comprises up to about 200%, up to about 100%, up to about 60%,
up to about 50%, up to about 40%, up to about 30%, or about 20% – about 30% w/w
DMSO/compound of formula I-1.
Also described is a substantially anhydrous powder consisting essentially of a
compound of the formula:
O P OH
N NH
or a pharmaceutically-acceptable salt thereof, and DMSO, the DMSO being present in
an amount of up to about 200% w/w DMSO/compound of formula I-1. In one embodiment,
the DMSO is present in an amount of up to about 100%, up to about 60%, up to about 50%,
up to about 40%, or up to about 30% w/w DMSO/compound of formula I-1. In some
embodiments, the DMSO is present in an amount of about 20 – about 30% w/w
DMSO/compound of formula I-1. In some embodiments, the salt of the powder is a sodium
salt.
Also described is a pharmaceutical composition obtainable by the processes of the
invention.
Also described is a method for treating a cancer, myelodysplastic syndrome, leukemia
or solid tumour comprising administering the formulation or kit of the invention, or powder
or composition described to a subject in need or want thereof.
Also described is the formulation or kit of the invention or powder or composition
described for use in a method of treating a cancer, myelodysplastic syndrome, leukemia or
solid tumour, said method comprising administering said formulation, kit, powder or
composition to a subject.
In another aspect, the invention provides the use of the kit of the invention for the
manufacture of a medicament for use in a method of treating a cancer, myelodysplastic
syndrome, leukemia or solid tumour The method comprises administering said kit of the
invention to a subject.
In another aspect the invention provides the use of the formulation of the invention for
the manufacture of a medicament for use in a method of treating a cancer, myelodysplastic
syndrome, leukemia or solid tumour. The method comprises administering said formulation
of the invention to a subject.
The formulations, kits or uses of the invention and methods and compositions
described, find application in the treatment of a wide variety of diseases that are sensitive to
the treatment with decitabine, including those described herein as non-limiting examples.
In some embodiments, the administration is subcutaneous administration.
Any compound described herein is suitable for use in any formulation, powder, or kit
described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 illustrates the mean plasma concentrations of the compound I-1 in male
and female cynomolgus monkeys given weekly subcutaneous doses of compound I-1 in a
pahrmacokinetic study.
FIGURE 2 illustrates the mean plasma concentrations of decitabine in male and
female cynomolgus monkeys given weekly subcutaneous doses of decitabine in a
pharmacokinetic study.
FIGURE 3 illustrates the decrease in LINE1 methylation levels observed in blood
samples drawn from cynomolgus monkeys on various days (D) after pretest.
FIGURE 4 illustrates the change in total related substances of the sodium salt of a
compound of Formula I-1 in various DMSO and DMSO/water compositions.
DETAILED DESCRIPTION OF THE INVENTION
[0036A] The term “comprising” as used in this specification means “consisting at least in
part of”. When interpreting each statement in this specification that includes the term
“comprising”, features other than that or those prefaced by the term may also be present.
Related terms such as “comprise” and “comprises” are to be interpreted in the same manner.
In current clinical treatment with decitabine, to minimize decomposition, decitabine is
supplied as a lyophilized powder and reconstituted pre-administration in a cold solution
containing at least 40% water (v/v), such as water for injection (WFI). This method requires
refrigeration of decitabine in solution, but such storage is inconvenient and economically less
desirable than storage at ambient temperatures. Due to rapid decomposition of decitabine in
aqueous solution, the reconstituted decitabine solution can be infused only within hours of
reconstitution. Refrigeration after reconstitution is undesirable because infusion of cold fluid
can cause discomfort, pain, and subsequently, non-compliance in the subject. The inventions
described herein solve these problems by providing formulations of decitabine derivatives in
formulations that resist chemical decomposition and provide greater convenience and
versatility in a therapeutic regimen; and/or at least provide the public with a useful choice.
The inventions describe formulations of compounds derived from decitabine with
improved chemical stability and greater ability to deliver pharmaceutically-active agent to a
subject in need or want thereof. The compounds incorporate a 5-aza-cytosine group,
optionally in the form of a 5-aza-2'-deoxycytidine group (decitabine) or a 5-aza-cytidine
group. The compounds also incorporate a guanine group, optionally in the form of a 2'-
deoxyguanidine group or a guanidine group. The 5-aza-cytosine group and the guanine
group are linked by one of a variety of phosphorus-containing linkers.
A phosphorus-containing linker is a moiety comprising a phosphorus atom. In some
embodiments, the number of phosphorus atoms in the phosphorus-containing linker is 1.
Non-limiting examples of phosphorus-containing linkers include groups comprising a
phosphodiester, a phosphorothioate diester, a boranophosphate diester, and a
methylphosphonate diester.
The compounds are provided in formulations that preserve the efficacy of the
compounds by providing media wherein the compounds exhibit good chemical stability.
Compounds
Described herein is a formulation comprising: a) a compound of Formula I or a
pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; and b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient.
[0041A] The invention provides a formulation comprising:
(a) a compound of the formula:
O P OH
I-1,
or a pharmaceutically-acceptable salt thereof; dissolved in
(b) a substantially anhydrous solvent comprising about 60% to 70% propylene glycol;
about 20% to 30% glycerin; and about 5% to 15% ethanol (w/w/w).
In some embodiments, the invention provides a formulation comprising: a) a
compound of the formula:
O P OH
I-1: OH ,
or a pharmaceutically-acceptable salt thereof; b) a solvent comprising about 65% propylene
glycol; about 25% glycerin; and about 10% ethanol, wherein the solvent is substantially
anhydrous; and c) optionally, a pharmaceutically-acceptable excipient.
Described is a method of treating one or more myelodysplastic syndromes, leukemia,
or solid tumours, the method comprising administering a formulation to a subject in need or
want thereof, the formulation comprising: a) a therapeutically-effective amount of a
compound of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient.
Also described is a method of treating one or more myelodysplastic syndromes,
leukemia, or solid tumours, the method comprising administering a formulation to a subject
in need or want thereof, the formulation comprising: a) a therapeutically-effective amount of
a compound of the formula:
O P OH
N NH
I-1: ,
or a pharmaceutically-acceptable salt thereof; b) a solvent comprising about 65% propylene
glycol; about 25% glycerin; and about 10% ethanol, wherein the solvent is substantially
anhydrous; and c) optionally, a pharmaceutically-acceptable excipient.
Also described are formulations comprising a compound of Formula I or a
pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
L is a group suitable for linking the 5-azacytosine group with the guanine group. In
some embodiments, L comprises a carbohydrate. In some embodiments, L comprises more
than one carbohydrate. In some embodiments, L comprises two carbohydrates. When L
comprises more than one carbohydrate, the carbohydrates can be the same or different. A
carbohydrate can be a monosaccharide in the closed ring form, such as a pyranose or furanose
form. A carbohydrate can be substituted at any position or deoxygenated at any position that
would be oxygenated in a naturally-occurring form of the carbohydrate. In some
embodiments, the carbohydrate is ribose. In some embodiments, the carbohydrate is 2-
deoxyribose. The ribose or 2-deoxyribose can be substituted at any position.
The phosphate atom of L can be present in any naturally-occurring or synthetic
functional group containing a phosphorus atom. Non-limiting examples of such functional
groups include phosphodiesters, phosphorothioate diesters, boranophosphate diesters, and
methylphosphonate diesters.
In some embodiments, L comprises Formula II. In some embodiments, L is Formula
OR R (II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R together
with the oxygen atom to which R is bound forms an ether, an ester, a carbonate, or a
4 4 4
carbamate; R is H, or R together with the oxygen atom to which R is bound forms an ether,
an ester, a carbonate, or a carbamate; and X together with the oxygen atoms to which X is
bound forms a phosphodiester, a phosphorothioate diester, a boranophosphate diester, or a
methylphosphonate diester.
The 5-azacytosine group can be linked to either end of L, and the guanine group can
be linked to the other end of L as long as the compound contains one 5-azacytosine group and
one guanine group. Constitutional isomers can thus be prepared by exchanging the
connectivity of the 5-azacytosine group and the guanine group.
1 2 1 2
R and R can be the same or different. In some embodiments, R and R are
independently H, OH, OMe, OEt, OPh, OCH CH OMe, OCH CH OEt, OCH CH OBn,OBn,
2 2 2 2 2 2
OAc, OBz, OCOOMe, OCOOEt, OCOOBn, OCONH , OCONMe , OCONEt , OCONBn ,
2 2 2 2
OCONHMe, OCONHEt, OCONHBn, F, Cl, Br, or I. In some embodiments, R and R are
independently H, OH, OMe, OEt, OCH CH OMe, OBn, or F. In some embodiments, R and
2 1 2
R are independently H or OH. In some embodiments, R and R are H. In some
embodiments, R and R are OH.
R and R can be the same or different.
3 3 3
In some embodiments, R is H, or R together with the oxygen atom to which R is
bound forms OH, OMe, OEt, OPh, OCH CH OMe, OCH CH OEt, OCH CH OBn,OBn,
2 2 2 2 2 2
OAc, OBz, OCOOMe, OCOOEt, OCOOBn, OCONH , OCONMe , OCONEt , OCONBn ,
2 2 2 2
OCONHMe, OCONHEt, or OCONHBn. In some embodiments, R is H, or R together with
the oxygen atom to which R is bound forms OH, OMe, OEt, OCH CH OMe, or OBn. In
some embodiments, R is H.
4 4 4
In some embodiments, R is H, or R together with the oxygen atom to which R is
bound forms OH, OMe, OEt, OPh, OCH CH OMe, OCH CH OEt, OCH CH OBn,OBn,
2 2 2 2 2 2
OAc, OBz, OCOOMe, OCOOEt, OCOOBn, OCONH , OCONMe , OCONEt , OCONBn ,
2 2 2 2
OCONHMe, OCONHEt, or OCONHBn. In some embodiments, R is H, or R together with
the oxygen atom to which R is bound forms OH, OMe, OEt, OCH CH OMe, or OBn. In
some embodiments, R is H.
In some embodiments, X is P(O)OH, P(O)SH, P( O)BH , or P(O)Me. In some
embodiments, X is P(O)OH. In some embodiments, X together with the oxygen atoms to
which X is bound forms a phosphodiester.
Non-limiting examples of alkyl include straight, branched, and cyclic alkyl groups.
Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl,
hexyl, heptyl, octyl, nonyl, and decyl.
Branched alkyl groups include any straight alkyl group substituted with any number
of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl,
sec-butyl, and t-butyl.
Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also
include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems.
A cyclic alkyl group can be substituted with any number of straight or branched alkyl groups.
A halo-alkyl group can be any alkyl group substituted with any number of halogen
atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
An alkoxy group can be, for example, an oxygen atom substituted with any alkyl
group. An ether or an ether group comprises an alkoxy group. Non-limiting examples of
alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
An alkoxyalkoxy group can be, for example, an alkoxy group substituted at any
position with any alkoxy group. Non-limiting examples of alkoxyalkoxy groups include
methoxyethoxy, ethyoxyethoxy, ethoxyethoxyethoxy, groups derived from any order of
glyme, and groups derived from polyethylene glycol.
An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be
monocyclic or polycyclic. An aryl group can be substituted, for example, with any number of
hydrocarbyl groups, alkyl groups, and halogen atoms. Non-limiting examples of aryl groups
include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.
An aryloxy group can be, for example, an oxygen atom substituted with any aryl
group, such as phenoxy.
An aralkyl group can be, for example, any alkyl group substituted with any aryl
group, such as benzyl.
An arylalkoxy group can be, for example, an oxygen atom substituted with any
aralkyl group, such as benzyloxy.
A heterocycle can be any ring containing a ring atom that is not carbon. A
heterocycle can be substituted, for example, with any number of alkyl groups and halogen
atoms. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine,
piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan,
tetrahydrofuran, pyran, and tetrahydropyran.
An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl,
alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle. Non-
limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl,
methoxycarbonyl, and ethoxycarbonyl.
An acyloxy group can be an oxygen atom substituted with an acyl group. An ester or
an ester group comprises an acyloxy group.
A carbonate group can be an oxygen atom substituted with hydrocarbyloxycarbonyl,
alkoxycarbonyl, aryloxycarbonyl, or arylalkoxycarbonyl.
A carbamate group can be an oxygen atom substituted with a carbamoyl group,
wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosubstituted, or
disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the
nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form
a heterocycle.
Any functional group of a compound described herein can be optionally capped with
a capping group. For examples of capping groups, see GREENE’S PROTECTIVE GROUPS IN
ORGANIC SYNTHESIS, 4th Ed. (Wiley 2006) (1980) and PROTECTING GROUPS, 3d Ed. (Thieme
2005) (1994), each of which is incorporated by reference in its entirety.
Non-limiting examples of suitable capping groups for a hydroxyl group include alkyl,
haloalkyl, aryl, aralkyl, carbonate, carbamate, and acyl groups.
Non-limiting examples of suitable capping groups for nitrogen-functionalities include
alkyl, aryl, aralkyl, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, and
an aminocarbonyl group. A capping group together with the nitrogen atom to which the
capping group is bound can form, for example, an amide, a carbamate, a urethane, a
heterocycle, or an amine. Two capping groups bound to the same nitrogen atom can form
together with the nitrogen atom a heterocycle.
Also described are pharmaceutically-acceptable salts of any compound described
herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-
addition salts. The acid that is added to a compound to form an acid-addition salt can be an
organic acid or an inorganic acid. A base that is added to a compound to form a base-
addition salt can be an organic base or an inorganic base. In some embodiments, a
pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-
acceptable salt is an ammonium salt.
Acid addition salts can arise from the addition of an acid to a compound described
herein. In some embodiments, the acid is organic. In some embodiments, the acid is
inorganic. Non-limiting examples of suitable acids include hydrochloric acid, hydrobromic
acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,
nicotinic acid, isonicotinic acid, lactic acid, salicylic acid, 4-aminosalicylic acid, tartaric acid,
ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid,
benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid,
fumaric acid, succinic acid, citric acid, oxalic acid, maleic acid, hydroxymaleic acid,
methylmaleic acid, glycolic acid, malic acid, cinnamic acid, mandelic acid, 2-
phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, phenylacetic acid, N-
cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-
toluenesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, 4-
methylbenzenesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, 2-
phosphoglyceric acid, 3-phosphoglyceric acid, glucosephosphoric acid, and an amino acid.
Non-limiting examples of suitable acid addition salts include a hydrochloride salt, a
hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a
phosphate salt, a hydrogen phosphate salt, a dihydrogen phosphate salt, a carbonate salt, a
bicarbonate salt, a nicotinate salt, an isonicotinate salt, a lactate salt, a salicylate salt, a 4-
aminosalicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a
glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a
pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate
salt, a citrate salt, an oxalate salt, a maleate salt, a hydroxymaleate salt, a methylmaleate salt,
a glycolate salt, a malate salt, a cinnamate salt, a mandelate salt, a 2-phenoxybenzoate salt, a
2-acetoxybenzoate salt, an embonate salt, a phenylacetate salt, an N-cyclohexylsulfamate salt,
a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate
salt, a 2-hydroxyethanesulfonate salt, an ethane-1,2-disulfonate salt, a 4-
methylbenzenesulfonate salt, a naphthalenesulfonate salt, a naphthalene-1,5-disulfonate
salt, a 2-phosphoglycerate salt, a 3-phosphoglycerate salt, a glucosephosphate salt, and an
amino acid salt.
Metal salts can arise from the addition of an inorganic base to a compound described
herein. The inorganic base consists of a metal cation paired with a basic counterion, such as,
for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali
metal, alkaline earth metal, transition metal, or main group metal. Non-limiting examples of
suitable metals include lithium, sodium, potassium, cesium, cerium, magnesium, manganese,
iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, and zinc.
Non-limiting examples of suitable metal salts include a lithium salt, a sodium salt, a
potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a
calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a
cadmium salt, and a zinc salt.
Ammonium salts can arise from the addition of ammonia or an organic amine to a
compound described herein. Non-limiting examples of suitable organic amines include
triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine,
morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine,
dibenzyl amine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, pipyrazine,
ethylenediamine, N,N'-dibenzylethylene diamine, procaine, chloroprocaine, choline,
dicyclohexyl amine, and N-methylglucamine.
Non-limiting examples of suitable ammonium salts include is a triethyl amine salt, a
diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a
morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an
N-ethylpiperidine salt, a dibenzyl amine salt, a piperazine salt, a pyridine salt, a pyrrazole
salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, a pipyrazine salt, an ethylene
diamine salt, an N,N'-dibenzylethylene diamine salt, a procaine salt, a chloroprocaine salt, a
choline salt, a dicyclohexyl amine salt, and a N-methylglucamine salt.
Non-limiting examples of compounds of Formula I include:
N NH
O P OH
O P OH
I-1: OH ; I-2: OH ;
N O N
N NH
HO HO
O P SH O P SH
I-3: ; I-4: OH ;
N NH
O P BH
3 O P BH
N NH
OH OH
I-5: ; I-6: ;
N NH
HO HO
O P Me O P Me
I-7: ; I-8: OH ;
O P OH
N NH
I-9: ;
N NH
O P OH
I-10: OMe ;
N O N
N NH
EtO EtO
O P OH O P OH
OEt OEt
I-11: ; I-12: ;
O P OH
I-13: OAc ;
N NH
O P OH
I-14: OAc ;
N NH
BnO BnO
O P OH O P OH
N N O
N NH
I-15: OBn ; I-16: OBn ;
N O N
N NH
BzO BzO
O P OH O P OH
N N O
N NH
OBz OBz
I-17: ; I-18: ;
EtOOCO
O P OH
I-19: OCOOEt ;
N NH
EtOOCO
O P OH
I-20: ;
OCOOEt
(Me) NOCO
O P OH
OCON(Me)
I-21: ;
N NH
(Me) NOCO
O P OH
OCON(Me)
I-22: ;
N NH
HO HO
O OH O OH
O P OH O P OH
N NH
OH OH OH
I-23: ; I-24: ;
N O N
N NH
HO HO
OMe O OMe
O P OH O P OH
OH OMe OH OMe
I-25: ; I-26: ;
N O N
N NH
O OEt O OEt
O P OH O P OH
N N O
OH OH OEt
I-27: OEt ; I-28: ;
N O N
N NH
O OQ
O OQ
O P OH
O P OH
N NH
OH OQ
OH OQ
OQ = OCH CH OMe OQ = OCH CH OMe
I-29: 2 2 ; I-30: 2 2 ;
N O N
N NH
HO HO
O OBn O OBn
O P OH O P OH
I-31: OH OBn ; I-32: OH OBn ;
N O N
N NH
O OAc O OAc
O P OH
O P OH
N N O
N NH
OH OAc OH
I-33: ; I-34: OAc ;
N NH
HO HO
O O OBz
OBz N
O P OH O P OH
N N O
OH OBz OH OBz
I-35: ; I-36: ;
N NH
N O OQ
O OQ N
O P OH
O P OH
N NH
OH OQ
OH OQ
OQ = OCOOEt OQ = OCOOEt
I-37: ; I-38: ;
N NH
N O OQ
O OQ N N
O P OH
O P OH
OH OQ
OQ = OCON(Me)
OQ = OCON(Me)
I-39: 2 ; I-40: ;
N O N
N NH
HO HO
F O F
O P OH O P OH
OH OH F
I-41: F ; I-42: ;
N O N
N NH
HO HO
O Cl O Cl
O P OH O P OH
N N O
OH Cl OH Cl
I-43: ; I-44: ;
and pharmaceutically-acceptable salts of any of the foregoing.
The compounds described herein can be synthesized by methods known in the art, for
example, solution phase or solid phase synthesis. For descriptions of the synthesis of
compounds useful in the invention, and for a description of the mechanism of action of
compounds of the invention, see U.S. Patent No. 7,700,567, which is incorporated by
reference herein in its entirety.
Formulations of the invention.
Formulations described herein provide pharmaceutically-useful compositions
comprising any compound described herein in a form with high solubility, low injection
volumes, and good chemical stability and shelf-life. These properties provide formulations
that retain a high percentage of the initial efficacy and deliver a therapeutically-effective
amount of the compound even after storage at or below room temperature for extended times.
In some embodiments, the invention provides a formulation comprising: a compound of
Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1. In some embodiments, described is a formulation comprising: a) a compound of Formula I
or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; and b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient. Non-limiting examples of compounds suitable for use in formulations
of the invention include compounds of Formula I wherein L is of Formula II. Non-limiting
examples of compounds suitable for use in formulations described include compounds I-(1-
44).
Formulations can be solutions or suspensions of a compound in a solvent or a mixture
of solvents. Non-limiting examples of suitable solvents include propylene glycol, glycerin,
ethanol, and any combination of the foregoing. The formulations can be prepared as non-
aqueous formulations. The formulations can be anhydrous or substantially anhydrous.
A mixture of solvents can contain a percentage of propylene glycol on either a mass
or a volume basis. In some embodiments, the percentage of propylene glycol can be at least
%, at least 20%, at least 30%, at least 40%, at least 50%, at least about 10%, at least about
%, at least about 30%, at least about 40%, or at least about 50%. In some embodiments,
the percentage of propylene glycol can be at most 90%, at most 80%, at most 70%, at most
60%, at most about 90%, at most about 80%, at most about 70%, or at most about 60%. In
some embodiments, the percentage of propylene glycol can be 30% to 90%, 45% to 85%,
55% to 75%, 60% to 70%, about 30% to about 90%, about 45% to about 85%, about 55% to
about 75%, or about 60% to about 70%. In some embodiments, the percentage of propylene
glycol can be 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,
about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about
65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
A mixture of solvents can contain a percentage of glycerin on either a mass or a
volume basis. In some embodiments, the percentage of glycerin can be at least 5%, at least
%, at least 15%, at least 25%, at least 30%, at least about 5%, at least about 10%, at least
about 15%, at least about 25%, or at least about 30%. In some embodiments, the percentage
of glycerin can be at most 70%, at most 60%, at most 50%, at most 40%, at most 30%, at
most about 70%, at most about 60%, at most about 50%, at most about 40%, or at most about
%. In some embodiments, the percentage of glycerin can be 0% to 50%, 5% to 45%, 15%
to 35%, 20% to 30%, 0% to about 50%, about 5% to about 45%, about 15% to about 35%, or
about 20% to about 30%. In some embodiments, the percentage of glycerin can be 0%, 5%,
%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, about 5%, about 10%, about 15%, about
%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.
A mixture of solvents can contain a percentage of ethanol on either a mass or a
volume basis. In some embodiments, the percentage of ethanol can be at least 1%, at least
3%, at least 5%, at least 10%, at least 15%, at least about 1%, at least about 3%, at least about
%, at least about 10%, or at least about 15%. In some embodiments, the percentage of
ethanol can be at most 30%, at most 25%, at most 20%, at most 15%, at most 10%, at most
about 30%, at most about 25%, at most about 20%, at most about 15%, or at most about 10%.
In some embodiments, the percentage of ethanol can be 0% to 30%, 0% to 25%, 0% to 20%,
% to 15%, 0% to about 30%, 0% to about 25%, 0% to about 20%, or about 5% to about
%. In some embodiments, the percentage of ethanol can be 0%, 1%, 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, about 1%, about 2%, about 3%, about
4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%,
about 13%, about 14%, or about 15%.
In some embodiments, a solvent or a mixture of solvents comprises 45% to 85%
propylene glycol, 5% to 45% glycerin, and 0% to 30% ethanol. In some embodiments, a
solvent or a mixture of solvents comprises about 45% to about 85% propylene glycol, about
% to about 45% glycerin, and 0% to about 30% ethanol. In some embodiments, a solvent or
a mixture of solvents consists essentially of 45% to 85% propylene glycol, 5% to 45%
glycerin, and 0% to 30% ethanol. In some embodiments, a solvent or a mixture of solvents
consists essentially of about 45% to about 85% propylene glycol, about 5% to about 45%
glycerin, and 0% to about 30% ethanol. In some embodiments, a solvent or a mixture of
solvents is 45% to 85% propylene glycol, 5% to 45% glycerin, and 0% to 30% ethanol. In
some embodiments, a solvent or a mixture of solvents is about 45% to about 85% propylene
glycol, about 5% to about 45% glycerin, and 0% to about 30% ethanol.
In some embodiments, a solvent or a mixture of solvents comprises 55% to 75%
propylene glycol, 15% to 35% glycerin, and 0% to 20% ethanol. In some embodiments, a
solvent or a mixture of solvents comprises about 55% to about 75% propylene glycol, about
% to about 35% glycerin, and 0% to about 20% ethanol. In some embodiments, a solvent
or a mixture of solvents consists essentially of 55% to 75% propylene glycol, 15% to 35%
glycerin, and 0% to 20% ethanol. In some embodiments, a solvent or a mixture of solvents
consists essentially of about 55% to about 75% propylene glycol, about 15% to about 35%
glycerin, and 0% to about 20% ethanol. In some embodiments, a solvent or a mixture of
solvents is 55% to 75% propylene glycol, 15% to 35% glycerin, and 0% to 20% ethanol. In
some embodiments, a solvent or a mixture of solvents is about 55% to about 75% propylene
glycol, about 15% to about 35% glycerin, and 0% to about 20% ethanol.
In some embodiments, a solvent or a mixture of solvents comprises 60% to 70%
propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol. In some embodiments, a
solvent or a mixture of solvents comprises about 60% to about 70% propylene glycol; about
% to about 30% glycerin; and about 5% to about 15% ethanol. In some embodiments, a
solvent or a mixture of solvents consists essentially of 60% to 70% propylene glycol; 20% to
% glycerin; and 5% to 15% ethanol. In some embodiments, a solvent or a mixture of
solvents consists essentially of about 60% to about 70% propylene glycol; about 20% to
about 30% glycerin; and about 5% to about 15% ethanol. In some embodiments, a solvent or
a mixture of solvents is 60% to 70% propylene glycol; 20% to 30% glycerin; and 5% to 15%
ethanol. In some embodiments, a solvent or a mixture of solvents is about 60% to about 70%
propylene glycol; about 20% to about 30% glycerin; and about 5% to about 15% ethanol.
In some embodiments, a solvent or a mixture of solvents comprises 65% propylene
glycol; 25% glycerin; and 10% ethanol. In some embodiments, a solvent or a mixture of
solvents comprises about 65% propylene glycol; about 25% glycerin; and about 10% ethanol.
In some embodiments, a solvent or a mixture of solvents consists essentially of 65%
propylene glycol; 25% glycerin; and 10% ethanol. In some embodiments, a solvent or a
mixture of solvents consists essentially of about 65% propylene glycol; about 25% glycerin;
and about 10% ethanol. In some embodiments, a solvent or a mixture of solvents is 65%
propylene glycol; 25% glycerin; and 10% ethanol. In some embodiments, a solvent or a
mixture of solvents is about 65% propylene glycol; about 25% glycerin; and about 10%
ethanol.
A formulation can be prepared, stored, transported, and handled in anhydrous or
substantially-anhydrous form. A solvent can be dried prior to preparing a formulation, and a
compound can be dried, for example, by lyophilization. A drying agent, or dessicant, can be
used during preparation, storage, transportation, or handling to regulate water content. Non-
limiting examples of drying agents include silica gel, calcium sulfate, calcium chloride,
calcium phosphate, sodium chloride, sodium bicarbonate, sodium sulfate, sodium phosphate,
montmorillonite, molecular sieves (beads or powdered), alumina, titania, zirconia, and
sodium pyrophosphate. A drying agent can contact a formulation directly, be inserted into
the formulation in the form of a packet with a permeable membrane, or be stored with the
formulation in a sealed environment, such as a dessicator, such that the drying agent and the
formulation are simultaneously exposed to the same controlled atmosphere. A drying agent
can be removed from a formulation, for example, by filtration or cannulation. Additionally, a
formulation can be stored in a sealed container within a controlled atmosphere consisting
essentially of, or enriched in, nitrogen or argon.
Anhydrous or substantially-anhydrous conditions benefit the shelf-life of a
formulation disclosed herein at both ambient and reduced temperatures. This benefit reduces
the costs associated with the storage, transportation, and spoilage of a formulation, increases
the convenience of storage and handling, and avoids the need to administer cold
formulations, thereby improving subject tolerance and compliance to a regimen of a
formulation of the invention.
A formulation can further include a pharmaceutically-acceptable excipient. Non-
limiting examples of excipients include mannitol, sorbitol, lactose, dextrose, and
cyclodextrins. Excipients can be added to modulate the density, rheology, uniformity, and
viscosity of the formulation.
A formulation can include acidic or basic excipients to modulate the acidity or
basicity of the formulation. Non limiting examples of acids suitable to increase the acidity
of a formulation include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
phosphoric acid, nitric acid, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid,
formic acid, benzenesulphonic acid, benzoic acid, maleic acid, glutamic acid, succinic acid,
aspartic acid, diatrizoic acid, and acetic acid. Non limiting examples of bases suitable to
increase the basicity of a formulation include lithium hydroxide, sodium hydroxide,
potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium
phosphate, sodium acetate, sodium benzoate, tetrabutylammonium acetate,
tetrabutylammonium benzoate, and trialkyl amines. Polyfunctional excipients, such as
ethylene diamine tetraacetic acid (EDTA), or a salt thereof, can also be used to modulate
acidity or basicity.
A compound disclosed herein can be present in a formulation in any amount. In some
embodiments, the compound is present in a concentration of 1 mg/mL to 130 mg/mL, 10
mg/mL to 130 mg/mL, 40 mg/mL to 120 mg/mL, 80 mg/mL to 110 mg/mL, about 1 mg/mL
to about 130 mg/mL, about 10 mg/mL to about 130 mg/mL, about 40 mg/mL to about 120
mg/mL, or about 80 mg/mL to about 110 mg/mL. In some embodiments, the compound is
present in a concentration of 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60
mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130
mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, 200
mg/mL, about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50
mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100
mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, about
150 mg/mL, about 160 mg/mL, about 170 mg/mL, about 180 mg/mL, about 190 mg/mL, or
about 200 mg/mL. In some embodiments, the compound is present in a concentration of 100
mg/mL. In some embodiments, the compound is present in a concentration of about 100
mg/mL.
A formulation can be prepared by contacting a compound described herein with a
solvent or a mixture of solvents. Alternatively, the compound can be contacted with a single
solvent, and other solvents can be added subsequently, as a mixture, or sequentially. When
the final formulation is a solution, complete solvation can be achieved at whatever step of the
process is practical for manufacturing. Optional excipients can be added to the formulation at
whatever step is practical for manufacturing.
Preparation of the formulation can be optionally promoted by agitation, heating, or
extension of the dissolution period. Non-limiting examples of agitation include shaking,
sonication, mixing, stirring, vortex, and combinations thereof.
In some embodiments, a formulation is optionally sterilized. Non-limiting examples
of sterilization techniques include filtration, chemical disinfection, irradiation, and heating.
Formulations of the invention are effective for maintaining the therapeutic compound
and retarding decomposition during storage and handling, thereby sustaining the efficacy of
the compound and the formulation thereof.
One example of storage conditions is to store a formulation of the invention at
2-8 °C for a period of time, for example, a day, a week, a month, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months, about a year, or longer than a year. In some embodiments, the formulation
retains about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,
about 85%, about 90%, about 95%, or about 100% efficacy after storage for 3 months at 2-8
One example of storage conditions is to store a formulation of the invention at
°C and 60% relative humidity for a period of time, for example, a day, a week, a month, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, about a year, or longer than a year. In some
embodiments, the formulation retains about 50%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% efficacy
after storage for 3 months at 25°C and 60% relative humidity.
Dimethyl sulfoxide (DMSO) for use according to the invention
The use of DMSO as a solvent according to the invention can reduce bulk
solution and fill volumes (both bulk and fill volumes can be reduced to 1/5 of those used
with aqueous systems) and to remove time and temperature restrictions on scale-up.
Moreover, the use of substantially anhydrous DMSO greatly increases stability: increasing
water concentration is correlated with a decrease in stability (as shown in Figure 4, which
shows the % change in total related substances of the sodium salt of a compound of Formula
I-1 when stored in DMSO or DMSO/water (water for injection, “WFI”) at 25°C/60% RH for
24 hours).
Any source of DMSO can be used according to the invention. In some
embodiments, the DMSO source is suitable for healthcare and drug delivery applications, for
example, conforming to USP or Ph. Eur monographs, or manufactured under cGMP and API
guidelines. Grades such as anhydrous, analytical grade, HPLC grade, or Pharma Solvent can
be used according to the invention.
In some embodiments, the DMSO for use according to the invention has
impurities in low levels, for example <0.2% water by KF, <0.01% non-volatile residue,
and/or <0.1% of related compounds.
In some embodiments, the isosteres of DMSO can be used in place of DMSO.
In some embodiments, an isostere of DMSO is one in which one or more atom(s) is(are)
replaced by a cognate isotope, for example hydrogen by deuterium.
FURTHER EMBODIMENTS DESCRIBED
Embodiment 1. A formulation comprising: a) a compound of Formula I or a
pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; and b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient.
Embodiment 2. The formulation of embodiment 1, wherein L is Formula (II)
OR R (II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R together
with the oxygen atom to which R is bound forms an ether, an ester, a carbonate, or a
4 4 4
carbamate; R is H, or R together with the oxygen atom to which R is bound forms an ether,
an ester, a carbonate, or a carbamate; and X together with the oxygen atoms to which X is
bound forms a phosphodiester, a phosphorothioate diester, a boranophosphate diester, or a
methylphosphonate diester.
Embodiment 3. The formulation of embodiment 2, wherein R and R are
independently H, OH, OMe, OEt, OCH CH OMe, OBn, or F.
Embodiment 4. The formulation of any one of embodiments 2 and 3, wherein X
together with the oxygen atoms to which X is bound forms a phosphodiester.
Embodiment 5. The formulation of any one of embodiments 2-4, wherein R and R
are H.
Embodiment 6. The formulation of any one of embodiments 1-5, wherein the
compound of Formula I is any one of I-(1-44).
Embodiment 7. The formulation of any one of embodiments 1-6, wherein the
compound of Formula I is:
N NH
O P OH
O P OH
I-1: or I-2: OH .
Embodiment 8. The formulation of any one of embodiments 1-7, wherein the solvent
comprises: about 65% propylene glycol; about 25% glycerin; and about 10% ethanol.
Embodiment 9. The formulation of any one of embodiments 1-8, wherein the
formulation is substantially anhydrous.
Embodiment 10. The formulation of any one of embodiments 1-9, wherein the
compound is present in a concentration of about 10 mg/mL to about 130 mg/mL.
Embodiment 11. The formulation of any one of embodiments 1-10, wherein the
formulation is a solution.
Embodiment 12. The formulation of any one of embodiments 1-11, wherein the
formulation retains about 95% efficacy after storage for 3 months at 2-8 °C, or about 68%
efficacy after storage for 3 months at 25 °C and 60% relative humidity.
Embodiment 13. A formulation comprising: a) a compound of the formula:
O P OH
I-1: ,
or a pharmaceutically-acceptable salt thereof; b) a solvent comprising about 65% propylene
glycol; about 25% glycerin; and about 10% ethanol, wherein the solvent is substantially
anhydrous; and c) optionally, a pharmaceutically-acceptable excipient.
Embodiment 14. The formulation of embodiment 13, wherein the compound exists as a
sodium salt.
Embodiment 15. The formulation of any one of embodiments 13 and 14, wherein the
solvent is 65% propylene glycol; 25% glycerin; and 10% ethanol.
Embodiment 16. The formulation of any one of embodiments 13-15, wherein the
compound is present in a concentration of about 100 mg/mL.
Embodiment 17. A method of treating one or more myelodysplastic syndromes,
leukemia, or solid tumours, the method comprising administering a formulation to a subject
in need or want thereof, the formulation comprising: a) a therapeutically-effective amount of
a compound of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient.
Embodiment 18. The method of embodiment 17, wherein L is Formula (II)
OR R (II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R together
with the oxygen atom to which R is bound forms an ether, an ester, or a carbamate; R is H,
or R together with the oxygen atom to which R is bound forms an ether, an ester, or a
carbamate; and X together with the oxygen atoms to which X is bound forms a
phosphodiester, a phosphorothioate diester, a boranophosphate diester, or a
methylphosphonate diester.
Embodiment 19. The method of embodiment 18, wherein R and R are independently
H, OH, OMe, OEt, OCH CH OMe, OBn, or F.
Embodiment 20. The method of any one of embodiments 18 and 19, wherein X together
with the oxygen atoms to which X is bound forms a phosphodiester.
Embodiment 21. The method of any one of embodiments 18-20, wherein R and R are
Embodiment 22. The method of any one of embodiments 17-21, wherein the compound
of Formula I is any one of I-(1-44).
Embodiment 23. The method of any one of embodiments 17-22, wherein the compound
of Formula I is:
N NH
O P OH
O P OH
I-1: or I-2: OH .
Embodiment 24. The method of any one of embodiments 17-23, wherein the solvent
comprises: about 65% propylene glycol; about 25% glycerin; and about 10% ethanol.
Embodiment 25. The method of any one of embodiments 17-24, wherein the
formulation is substantially anhydrous.
Embodiment 26. The method of any one of embodiments 17-25, wherein the compound
is present in a concentration of about 10 mg/mL to about 130 mg/mL.
Embodiment 27. The method of any one of embodiments 17-26, wherein the
formulation is a solution.
Embodiment 28. The method of any one of embodiments 17-27, wherein the
myelodysplastic syndrome is acute myeloid leukemia (AML), acute promyelocytic leukemia
(APL), acute lymphoblastic leukemia (ALL), or chronic myelogenous leukemia (CML).
Embodiment 29. The method of any one of embodiments 17-28, wherein the
administration is subcutaneous.
Embodiment 30. A method of treating one or more myelodysplastic syndromes,
leukemia, or solid tumours, the method comprising administering a formulation to a subject
in need or want thereof, the formulation comprising: a) a therapeutically-effective amount of
a compound of the formula:
O P OH
I-1: ,
or a pharmaceutically-acceptable salt thereof; b) a solvent comprising about 65% propylene
glycol; about 25% glycerin; and about 10% ethanol, wherein the solvent is substantially
anhydrous; and c) optionally, a pharmaceutically-acceptable excipient.
Embodiment 31. The method of embodiment 30, wherein the myelodysplastic syndrome
is acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic
leukemia (ALL), or chronic myelogenous leukemia (CML).
Embodiment 32. The method of any one of embodiments 30 and 31, wherein the
compound exists as a sodium salt.
Embodiment 33. The method of any one of embodiments 30-32, wherein the solvent is
65% propylene glycol; 25% glycerin; and 10% ethanol.
Embodiment 34. The method of any one of embodiments 30-33, wherein the compound
is present in a concentration of about 100 mg/mL.
Embodiment 35. The method of any one of embodiments 30-34, wherein the
administration is subcutaneous.
Embodiment 36. A use of a compound in the preparation of a medicament for treating
one or more myelodysplastic syndromes, leukemia, or solid tumours, the medicament
comprising: a) a therapeutically-effective amount of a compound of Formula I or a
pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient.
Embodiment 37. The use of embodiment 36, wherein L is Formula (II)
OR R (II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R together
with the oxygen atom to which R is bound forms an ether, an ester, or a carbamate; R is H,
or R together with the oxygen atom to which R is bound forms an ether, an ester, or a
carbamate; and X together with the oxygen atoms to which X is bound forms a
phosphodiester, a phosphorothioate diester, a boranophosphate diester, or a
methylphosphonate diester.
Embodiment 38. The use of embodiment 37, wherein R and R are independently H,
OH, OMe, OEt, OCH CH OMe, OBn, or F.
Embodiment 39. The use of any one of embodiments 37 and 38, wherein X together
with the oxygen atoms to which X is bound forms a phosphodiester.
Embodiment 40. The use of any one of embodiments 37-39, wherein R and R are H.
Embodiment 41. The use of any one of embodiments 36-40, wherein the compound of
Formula I is any one of I-(1-44).
Embodiment 42. The use of any one of embodiments 36-41, wherein the compound of
Formula I is:
N NH
O P OH
O P OH
I-1: or I-2: OH .
Embodiment 43. The use of any one of embodiments 36-42, wherein the solvent
comprises: about 65% propylene glycol; about 25% glycerin; and about 10% ethanol.
Embodiment 44. The use of any one of embodiments 36-43, wherein the medicament is
substantially anhydrous.
Embodiment 45. The use of any one of embodiments 36-44, wherein the compound is
present in a concentration of about 10 mg/mL to about 130 mg/mL.
Embodiment 46. The use of any one of embodiments 36-45, wherein the medicament is
a solution.
Embodiment 47. The use of any one of embodiments 36-46, wherein the
myelodysplastic syndrome is acute myeloid leukemia (AML), acute promyelocytic leukemia
(APL), acute lymphoblastic leukemia (ALL), or chronic myelogenous leukemia (CML).
Embodiment 48. The use of any one of embodiments 36-47, wherein the medicament is
suitable for subcutaneous administration.
Embodiment 49. A use of a compound in the preparation of a medicament for treating
one or more myelodysplastic syndromes, leukemia, or solid tumours, the medicament
comprising: a) a therapeutically-effective amount of a compound of the formula:
O P OH
I-1: ,
or a pharmaceutically-acceptable salt thereof; b) a solvent comprising about 65% propylene
glycol; about 25% glycerin; and about 10% ethanol, wherein the solvent is substantially
anhydrous; and c) optionally, a pharmaceutically-acceptable excipient.
Embodiment 50. The use of embodiment 49, wherein the myelodysplastic syndrome is
acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic
leukemia (ALL), or chronic myelogenous leukemia (CML).
Embodiment 51. The use of any one of embodiments 49 and 50, wherein the compound
exists as a sodium salt.
Embodiment 52. The use of any one of embodiments 49-51, wherein the solvent is 65%
propylene glycol; 25% glycerin; and 10% ethanol.
Embodiment 53. The use of any one of embodiments 49-52, wherein the compound is
present in a concentration of about 100 mg/mL.
Embodiment 54. The use of any one of embodiments 49-53, wherein the medicament is
suitable for subcutaneous administration.
Embodiment 55. A compound for use in the treatment of one or more myelodysplastic
syndromes, leukemia, or solid tumours, the compound comprising: a therapeutically-effective
amount of a compound of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1, wherein the compound is provided in a solvent comprising: about 45% to about 85%
propylene glycol; about 5% to about 45% glycerin; and 0% to about 30% ethanol, and
optionally with a pharmaceutically-acceptable excipient.
Embodiment 56. The compound of embodiment 55, wherein L is Formula (II)
OR R (II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R together
with the oxygen atom to which R is bound forms an ether, an ester, or a carbamate; R is H,
or R together with the oxygen atom to which R is bound forms an ether, an ester, or a
carbamate; and X together with the oxygen atoms to which X is bound forms a
phosphodiester, a phosphorothioate diester, a boranophosphate diester, or a
methylphosphonate diester.
Embodiment 57. The compound of embodiment 56, wherein R and R are
independently H, OH, OMe, OEt, OCH CH OMe, OBn, or F.
Embodiment 58. The compound of any one of embodiments 56 and 57, wherein X
together with the oxygen atoms to which X is bound forms a phosphodiester.
Embodiment 59. The compound of any one of embodiments 56-58, wherein R and R
are H.
Embodiment 60. The compound of any one of embodiments 55-59, wherein the
compound of Formula I is any one of I-(1-44).
Embodiment 61. The compound of any one of embodiments 55-60, wherein the
compound of Formula I is:
N NH
O P OH
O P OH
I-1: or I-2: OH .
Embodiment 62. The compound of any one of embodiments 55-61, wherein the solvent
comprises: about 65% propylene glycol; about 25% glycerin; and about 10% ethanol.
Embodiment 63. The compound of any one of embodiments 55-62, wherein the solvent
is substantially anhydrous.
Embodiment 64. The compound of any one of embodiments 55-63, wherein the
compound is present in a concentration of about 10 mg/mL to about 130 mg/mL.
Embodiment 65. The compound of any one of embodiments 55-64, wherein the
compound forms a solution with the solvent.
Embodiment 66. The compound of any one of embodiments 55-65, wherein the
myelodysplastic syndrome is acute myeloid leukemia (AML), acute promyelocytic leukemia
(APL), acute lymphoblastic leukemia (ALL), or chronic myelogenous leukemia (CML).
Embodiment 67. The compound of any one of embodiments 55-66, wherein the
compound provided in the solvent is suitable for subcutaneous administration.
Embodiment 68. A compound for use in the treatment of one or more myelodysplastic
syndromes, leukemia, or solid tumours, the compound having the formula:
O P OH
I-1: ,
or a pharmaceutically-acceptable salt thereof; wherein the compound is provided in a solvent
comprising about 65% propylene glycol; about 25% glycerin; and about 10% ethanol,
wherein the solvent is substantially anhydrous, and optionally with a pharmaceutically-
acceptable excipient.
Embodiment 69. The compound of embodiment 68, wherein the myelodysplastic
syndrome is acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute
lymphoblastic leukemia (ALL), or chronic myelogenous leukemia (CML).
Embodiment 70. The compound of any one of embodiments 68 and 69, wherein the
compound exists as a sodium salt.
Embodiment 71. The compound of any one of embodiments 68-70, wherein the solvent
is 65% propylene glycol; 25% glycerin; and 10% ethanol.
Embodiment 72. The compound of any one of embodiments 68-71, wherein the
compound is present in a concentration of about 100 mg/mL.
Embodiment 73. The compound of any one of embodiments 68-72, wherein the
compound provided in the solvent is suitable for subcutaneous administration.
Dosing and Administration.
Doses of formulations of the invention can be administered to a subject by a
method known in the art. Non-limiting examples of methods of administration include
subcutaneous injection, intravenous injection, and infusion. In some embodiments, a subject
is in need or want of the formulation.
In some embodiments, described is a dosage form comprising: a compound of
Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1. In some embodiments, described is a dosage form comprising: a) a compound of Formula
I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; and b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient. Non-limiting examples of compounds suitable for use in dosage forms
of the invention include compounds of Formula I wherein L is of Formula II. Non-limiting
examples of compounds suitable for use in dosage forms of the invention include compounds
I-(1-44).
In some embodiments, described is a method of administering a dosage form
comprising: a compound of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1. In some embodiments, described is a method of administering a dosage form comprising:
a) a compound of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; and b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient. Non-limiting examples of compounds suitable for administration
include compounds of Formula I wherein L is of Formula II. Non-limiting examples of
compounds suitable for administration include compounds I-(1-44).
A dose of a formulation contains an amount that is therapeutically-effective
for an indication. In some embodiments, a subject is in need or want of therapy for the
indication.
A therapeutically-effective amount of a compound useful in the invention can
be expressed as mg of the compound per kg of subject body mass. In some embodiments, a
therapeutically-effective amount is 1-1,000 mg/kg, 1-500 mg/kg, 1-250 mg/kg, 1-100 mg/kg,
1-50 mg/kg, 1-25 mg/kg, or 1-10 mg/kg. In some embodiments, a therapeutically-effective
amount is 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 150 mg/kg, 200
mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg,
900 mg/kg, 1,000 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg,
about 75 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 250 mg/kg,
about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg,
about 800 mg/kg, about 900 mg/kg, or about 1,000 mg/kg.
In some embodiments, a therapeutically-effective amount can be administered
1-35 times per week, 1-14 times per week, or 1-7 times per week. In some embodiments, a
therapeutically-effective amount can be administered 1-10 times per day, 1-5 times per day, 1
time, 2 times, or 3 times per day.
Therapeutic Uses
The pharmaceutical formulations according to the present invention can be
used to treat a wide variety of diseases that are sensitive to the treatment with decitabine,
including those described herein.
Examples of indications that can be treated using the pharmaceutical
formulations of the present invention include those involving undesirable or uncontrolled cell
proliferation. Such indications include benign tumors, various types of cancers such as
primary tumors and tumor metastasis, restenosis (e.g. coronary, carotid, and cerebral lesions),
hematological disorders, abnormal stimulation of endothelial cells (atherosclerosis), insults to
body tissue due to surgery, abnormal wound healing, abnormal angiogenesis, diseases that
produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly
vascularized, and proliferative responses associated with organ transplants.
Generally, cells in a benign tumor retain their differentiated features and do
not divide in a completely uncontrolled manner. A benign tumor is usually localized and
nonmetastatic. Specific types benign tumors that can be treated using the present invention
include hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular
hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma,
fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative
hyperplasia, trachomas and pyogenic granulomas.
In a malignant tumor cells become undifferentiated, do not respond to the
body’s growth control signals, and multiply in an uncontrolled manner. The malignant tumor
is invasive and capable of spreading to distant sites (metastasizing). Malignant tumors are
generally divided into two categories: primary and secondary. Primary tumors arise directly
from the tissue in which they are found. A secondary tumor, or metastasis, is a tumor which
is originated elsewhere in the body but has now spread to a distant organ. The common
routes for metastasis are direct growth into adjacent structures, spread through the vascular or
lymphatic systems, and tracking along tissue planes and body spaces (peritoneal fluid,
cerebrospinal fluid, etc.)
Specific types of cancers or malignant tumors, either primary or secondary,
that can be treated using this invention include breast cancer, skin cancer, bone cancer,
prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gall bladder,
pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach,
bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and
papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing’s sarcoma, veticulum cell
sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor,
primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell
tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuronms,
intestinal ganglloneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor,
Wilm’s tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ
carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical
skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi’s sarcoma, osteogenic and other
sarcoma, malignant hypercalcemia, renal cell tumor, polycythermia vera, adenocarcinoma,
glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, epidermoid
carcinomas, and other carcinomas and sarcomas.
Hematologic disorders include abnormal growth of blood cells which can lead
to dysplastic changes in blood cells and hematologic malignancies such as various leukemias.
Examples of hematologic disorders include but are not limited to acute myeloid leukemia,
acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous
leukemia, the myelodysplastic syndromes, and sickle cell anemia.
Treatment of abnormal cell proliferation due to insults to body tissue during
surgery can be possible for a variety of surgical procedures, including joint surgery, bowel
surgery, and cheloid scarring. Diseases that produce fibrotic tissue include emphysema.
Repetitive motion disorders that can be treated using the present invention
include carpal tunnel syndrome. An example of cell proliferative disorders that can be
treated using the invention is a bone tumor.
The proliferative responses associated with organ transplantation that can be
treated using this invention include those proliferative responses contributing to potential
organ rejections or associated complications. Specifically, these proliferative responses can
occur during transplantation of the heart, lung, liver, kidney, and other body organs or organ
systems.
Abnormal angiogenesis that can be treated using this invention include those
abnormal angiogenesis accompanying rheumatoid arthritis, ischemic-reperfusion related
brain edema and injury, cortical ischemia, ovarian hyperplasia and hypervascularity,
(polycystic ovary syndrome), endometriosis, psoriasis, diabetic retinopaphy, and other ocular
angiogenic diseases such as retinopathy of prematurity (retrolental fibroplastic), muscular
degeneration, corneal graft rejection, neuroscular glaucoma and Oster Webber syndrome.
Diseases associated with abnormal angiogenesis require or induce vascular
growth. For example, corneal angiogenesis involves three phases: a pre-vascular latent
period, active neovascularization, and vascular maturation and regression. The identity and
mechanism of various angiogenic factors, including elements of the inflammatory response,
such as leukocytes, platelets, cytokines, and eicosanoids, or unidentified plasma constituents
have yet to be revealed.
In some embodiments, the pharmaceutical formulations of the present
invention can be used for treating diseases associated with undesired or abnormal
angiogenesis. The method comprises administering to a patient suffering from undesired or
abnormal angiogenesis the pharmaceutical formulations of the present invention alone, or in
combination with anti-neoplastic agent whose activity as an anti-neoplastic agent in vivo is
adversely affected by high levels of DNA methylation. The particular dosage of these agents
required to inhibit angiogenesis and/or angiogenic diseases can depend on the severity of the
condition, the route of administration, and related factors that can be decided by the attending
physician. Generally, accepted and effective daily doses are the amount sufficient to
effectively inhibit angiogenesis and/or angiogenic diseases.
Pharmaceutical formulations of the present invention can be used to treat a
variety of diseases associated with undesirable angiogenesis such as retinal/choroidal
neuvascularization and corneal neovascularization. Examples of retinal/choroidal
neuvascularization include, but are not limited to, Bests diseases, myopia, optic pits, Stargarts
diseases, Pagets disease, vein occlusion, artery occlusion, sickle cell anemia, sarcoid,
syphilis, pseudoxanthoma elasticum carotid abostructive diseases, chronic uveitis/vitritis,
mycobacterial infections, Lyme’s disease, systemic lupus erythematosis, retinopathy of
prematurity, Eales disease, diabetic retinopathy, macular degeneration, Bechets diseases,
infections causing a retinitis or chroiditis, presumed ocular histoplasmosis, pars planitis,
chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser
complications, diseases associated with rubesis (neovascularization of the angle) and diseases
caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of
proliferative vitreoretinopathy. Examples of corneal neuvascularization include, but are not
limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic
keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea,
phylectenulosis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection,
Mooren ulcer, Terrien’s marginal degeneration, marginal keratolysis, polyarteritis, Wegener
sarcoidosis, Scleritis, periphigoid radial keratotomy, neovascular glaucoma and retrolental
fibroplasia, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial
ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan
infections and Kaposi sarcoma.
In some embodiments, the pharmaceutical formulations of the present
invention can be used for treating chronic inflammatory diseases associated with abnormal
angiogenesis. The method comprises administering to a patient suffering from a chronic
inflammatory disease associated with abnormal angiogenesis the pharmaceutical formulations
of the present invention alone, or in combination with an anti-neoplastic agent whose activity
as an anti-neoplastic agent in vivo is adversely affected by high levels of DNA methylation.
The chronic inflammation depends on continuous formation of capillary sprouts to maintain
an influx of inflammatory cells. The influx and presence of the inflammatory cells produce
granulomas and thus, maintains the chronic inflammatory state. Inhibition of angiogenesis
using the pharmaceutical formulations of the present invention can prevent the formation of
the granulosmas, thereby alleviating the disease. Examples of chronic inflammatory disease
include, but are not limited to, inflammatory bowel diseases such as Crohn’s disease and
ulcerative colitis, psoriasis, sarcoidois, and rheumatoid arthritis.
Inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis are
characterized by chronic inflammation and angiogenesis at various sites in the
gastrointestinal tract. For example, Crohn’s disease occurs as a chronic transmural
inflammatory disease that most commonly affects the distal ileum and colon but can also
occur in any part of the gastrointestinal tract from the mouth to the anus and perianal area.
Patients with Crohn’s disease generally have chronic diarrhea associated with abdominal
pain, fever, anorexia, weight loss and abdominal swelling. Ulcerative colitis is also a
chronic, nonspecific, inflammatory and ulcerative disease arising in the colonic mucosa and
is characterized by the presence of bloody diarrhea. These inflammatory bowel diseases are
generally caused by chronic granulomatous inflammation throughout the gastrointestinal
tract, involving new capillary sprouts surrounded by a cylinder of inflammatory cells.
Inhibition of angiogenesis by the pharmaceutical formulations of the present invention should
inhibit the formation of the sprouts and prevent the formation of granulomas. The
inflammatory bowel diseases also exhibit extra intestinal manifectations, such as skin lesions.
Such lesions are characterized by inflammation and angiogenesis and can occur at many sites
other the gastrointestinal tract. Inhibition of angiogenesis by the pharmaceutical formulations
of the present invention should reduce the influx of inflammatory cells and prevent the lesion
formation.
Sarcoidois, another chronic inflammatory disease, is characterized as a multi-
system granulomatous disorder. The granulomas of this disease can form anywhere in the
body and, thus, the symptoms depend on the site of the granulomas and whether the disease is
active. The granulomas are created by the angiogenic capillary sprouts providing a constant
supply of inflammatory cells. By using the pharmaceutical formulations of the present
invention to inhibit angionesis, such granulomas formation can be inhibited. Psoriasis, also a
chronic and recurrent inflammatory disease, is characterized by papules and plaques of
various sizes. Treatment using the pharmaceutical formulations of the present invention
should prevent the formation of new blood vessels necessary to maintain the characteristic
lesions and provide the patient relief from the symptoms.
Rheumatoid arthritis (RA) is also a chronic inflammatory disease
characterized by non-specific inflammation of the peripheral joints. It is believed that the
blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to
forming new vascular networks, the endothelial cells release factors and reactive oxygen
species that lead to pannus growth and cartilage destruction. The factors involved in
angiogenesis can actively contribute to, and help maintain, the chronically inflamed state of
rheumatoid arthritis. Treatment using the pharmaceutical formulations of the present
invention alone or in conjunction with other anti-RA agents can prevent the formation of new
blood vessels necessary to maintain the chronic inflammation and provide the RA patient
relief from the symptoms.
In some embodiments, the pharmaceutical formulations of the present
invention can be used for treating diseases associated with abnormal hemoglobin synthesis.
The method comprises administering the pharmaceutical formulations of the present
invention to a patient suffering from disease associated with abnormal hemoglobin synthesis.
Decitabine containing formulations stimulate fetal hemoglobin synthesis because the
mechanism of incorporation into DNA is associated with DNA hypomethylation. Examples
of diseases associated with abnormal hemoglobin synthesis include, but are not limited to,
sickle cell anemia and β-thalassemia.
In some embodiments, the pharmaceutical formulations of the present
invention can be used to control intracellular gene expression. The method comprises
administering the pharmaceutical formulations of the present invention to a patient suffering
from disease associated with abnormal levels of gene expression. DNA methylation is
associated with the control of gene expression. Specifically, methylation in or near
promoters inhibit transcription while demethylation restores expression. Examples of the
possible applications of the described mechanisms include, but are not limited to,
therapeutically modulated growth inhibition, induction of apoptosis, and cell differentiation.
Gene activation facilitated by the pharmaceutical formulations of the present
invention can induce differentiation of cells for therapeutic purposes. Cellular differentiation
is induced through the mechanism of hypomethylation. Examples of morphological and
functional differentiation include, but are not limited to differentiation towards formation of
muscle cells, myotubes, cells of erythroid and lymphoid lineages.
Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic
stem cell disorders associated with the presence of dysplastic changes in one or more of the
hematopoietic lineages, including dysplastic changes in the myeloid, erythroid, and
megakaryocytic series. These changes result in cytopenias in one or more of the three
lineages. Subjects afflicted with MDS typically develop complications related to anemia,
neutropenia (infections), or thrombocytopenia (bleeding). Generally, from about 10% to
about 70% of subjects with MDS develop acute leukemia. Representative myelodysplastic
syndromes include acute myeloid leukemia, acute promyelocytic leukemia, acute
lymphoblastic leukemia, and chronic myelogenous leukemia.
Acute myeloid leukemia (AML) is the most common type of acute leukemia
in adults. Several inherited genetic disorders and immunodeficiency states are associated with
an increased risk of AML. These include disorders with defects in DNA stability leading to
random chromosomal breakage, such as Bloom's syndrome, Fanconi's anemia, Li-Fraumeni
kindreds, ataxia-telangiectasia, and X-linked agammaglobulinemia.
Acute promyelocytic leukemia (APML) represents a distinct subgroup of
AML. This subtype is characterized by promyelocytic blasts containing the 15; 17
chromosomal translocation. This translocation leads to the generation of a fusion transcript
comprising a retinoic acid receptor sequence and a promyelocytic leukemia sequence.
Acute lymphoblastic leukemia (ALL) is a heterogenerous disease with distinct
clinical features displayed by various subtypes. Reoccurring cytogenetic abnormalities have
been demonstrated in ALL. The most common associated cytogenetic abnormality is the 9;
22 translocation leading to development of the Philadelphia chromosome.
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder
of a pluripotent stem cell, generally caused by ionizing radiation. CML is characterized by a
specific chromosomal abnormality involving the translocation of chromosomes 9 and 22,
creating the Philadelphia chromosome.
Compounds described herein and formulations thereof can be used to provide
therapy for a MDS. In some embodiments, a compound or formulation thereof can provide
therapy for more than one MDS in a single administration. In some embodiments, described
is a method of treating one or more myelodysplastic syndromes, leukemia, or solid tumours,
the method comprising administering a formulation to a subject in need or want thereof, the
formulation comprising a therapeutically-effective amount of a compound of Formula I or a
pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1. In some embodiments, described is a method of treating one or more myelodysplastic
syndromes, leukemia, or solid tumours, the method comprising administering a formulation
to a subject in need or want thereof, the formulation comprising: a) a therapeutically-effective
amount of a compound of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; and b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient. Non-limiting examples of compounds suitable for administration
include compounds of Formula I wherein L is of Formula II. Non-limiting examples of
compounds suitable for administration include compounds I-(1-44).
In some embodiments, described is a method for treating a myelodysplastic
syndrome (MDS). In some embodiments, described is a method for treating one or more
myelodysplastic syndromes, leukemia, or solid tumours. In some embodiments, described is
a method for treating acute myeloid leukemia (AML). In some embodiments, described is a
method for treating acute promyelocytic leukemia (APML) in a subject. In some
embodiments, described is a method for treating acute lymphoblastic leukemia (ALL). In
some embodiments, described is a method for treating chronic myelogenous leukemia
(CML).
In some embodiments, described is a use of a compound in the preparation of
a medicament for treating a myelodysplastic syndrome (MDS). In some embodiments,
described is a use of a compound in the preparation of a medicament for treating one or more
myelodysplastic syndromes, leukemia, or solid tumours. In some embodiments, described is
a use of a compound in the preparation of a medicament for treating acute myeloid leukemia
(AML). In some embodiments, described is a use of a compound in the preparation of a
medicament for treating acute promyelocytic leukemia (APML) in a subject. In some
embodiments, described is a use of a compound in the preparation of a medicament for
treating acute lymphoblastic leukemia (ALL). In some embodiments, described is a use of a
compound in the preparation of a medicament for treating chronic myelogenous leukemia
(CML).
In some embodiments, described is a compound for use in treating a
myelodysplastic syndrome (MDS). In some embodiments, described is a compound for use
in treating one or more myelodysplastic syndromes, leukemia, or solid tumours. In some
embodiments, described is a compound for use in treating acute myeloid leukemia (AML).
In some embodiments, described is a compound for use in treating acute promyelocytic
leukemia (APML) in a subject. In some embodiments, described is a compound for use in
treating acute lymphoblastic leukemia (ALL). In some embodiments, described is a
compound for use in treating chronic myelogenous leukemia (CML).
In some embodiments, described is a formulation comprising: a) a compound
of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; and b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient.
In some embodiments, L is Formula (II)
OR R (II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R together
with the oxygen atom to which R is bound forms an ether, an ester, a carbonate, or a
4 4 4
carbamate; R is H, or R together with the oxygen atom to which R is bound forms an ether,
an ester, a carbonate, or a carbamate; and X together with the oxygen atoms to which X is
bound forms a phosphodiester, a phosphorothioate diester, a boranophosphate diester, or a
methylphosphonate diester.
In some embodiments, R and R are independently H, OH, OMe, OEt,
OCH CH OMe, OBn, or F.
In some embodiments, X together with the oxygen atoms to which X is bound
forms a phosphodiester.
In some embodiments, R and R are H.
In some embodiments, the compound of Formula I is:
O P OH
O P OH
I-1: or I-2: OH .
In some embodiments, the solvent comprises: about 65% propylene glycol;
about 25% glycerin; and about 10% ethanol.
In some embodiments, the formulation is substantially anhydrous.
In some embodiments, the compound is present in a concentration of about 10
mg/mL to about 130-150 mg/mL.
In some embodiments, the formulation is a solution.
In some embodiments, the formulation retains about 95% efficacy after
storage for 3 months at 2-8 °C, or about 68% efficacy after storage for 3 months at 25 °C and
60% relative humidity.
In some embodiments, the invention provides a formulation comprising: a) a
compound of the formula:
O P OH
I-1: OH ,
or a pharmaceutically-acceptable salt thereof; dissolved in b) a solvent comprising about 65%
propylene glycol; about 25% glycerin; and about 10% ethanol, wherein the solvent is
substantially anhydrous; and c) optionally, a pharmaceutically-acceptable excipient.
In some embodiments, the compound exists as a sodium salt.
In some embodiments, the solvent is 65% propylene glycol; 25% glycerin; and
% ethanol.
In some embodiments, the compound is present in a concentration of about
100 mg/mL.
In some embodiments, described is a method of treating one or more
myelodysplastic syndromes, leukemia, or solid tumours, the method comprising
administering a formulation to a subject in need or want thereof, the formulation comprising:
a) a therapeutically-effective amount of a compound of Formula I or a pharmaceutically-
acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in L is
1; b) a solvent comprising: about 45% to about 85% propylene glycol; about 5% to about
45% glycerin; and 0% to about 30% ethanol; and c) optionally, a pharmaceutically-
acceptable excipient.
In some embodiments, the myelodysplastic syndrome is acute myeloid
leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia
(ALL), or chronic myelogenous leukemia (CML).
In some embodiments, the administration is subcutaneous.
In some embodiments, described is a method of treating one or more
myelodysplastic syndromes, leukemia, or solid tumours, the method comprising
administering a formulation to a subject in need or want thereof, the formulation comprising:
a) a therapeutically-effective amount of a compound of the formula:
O P OH
N NH
I-1: ,
or a pharmaceutically-acceptable salt thereof; b) a solvent comprising about 65% propylene
glycol; about 25% glycerin; and about 10% ethanol, wherein the solvent is substantially
anhydrous; and c) optionally, a pharmaceutically-acceptable excipient.
In some embodiments, the myelodysplastic syndrome is acute myeloid leukemia (AML),
acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), or chronic
myelogenous leukemia (CML).
EXAMPLES
EXAMPLE 1: Inhibition of DNA Methylation by Compounds of the Invention.
The demethylating activity of compounds of the invention was tested in a cell-
based green fluorescent protein (GFP) assay. In the assay, a decrease in methylation resulting
from exposure to a methylation inhibitor led to GFP expression, and was readily scored.
The CMV-EE210 cell line containing the epigenetically silenced GFP
transgene was used to assay for reactivation of GFP expression by flow cytometry. CMV-
EE210 was made by transfecting NIH 3T3 cells with the pTR-UF/UF1/UF2 plasmid, which
contained pBS(+) (Stratagene, Inc.) with a cytomegalovirus (CMV) promoter driving a
humanized GFP gene adapted for expression in mammalian cells. After transfection, high-
level GFP expressing cells were initially selected by FACS analysis and sorting using a
MoFlo cytometer (Cytomation, Inc.).
Decitabine, a potent inhibitor of mammalian DNMT1, was used as a positive
control. To screen for reactivation of CMV-EE210, decitabine (1 M) or a test compound
(30-50 M) was added to complete medium (phenol red free DMEM (Gibco, Life
Technologies) supplemented with 10% fetal bovine serum (Hyclone)). Cells were then
seeded to 30% confluence (~5000 cell/well) in a 96-well plate containing the test compounds,
and grown for three days in at 37 °C in 5% CO .
The plates were examined under a fluorescent microscope using a 450-490
excitation filter (I3 filter cube, Leica, Deerfield Ill.). Wells were scored g1 positive, g2
positive, or g3 if GFP was expressed in 10%, 30%, >75% of viable cells, respectively.
Table 1 provides the results of the test for decitabine and the test compounds
as DNA methylation inhibitors. GFP is the concentration of an inhibitor at which the Green
Fluorescent Protein (GFP) expression level is reduced from g3 to g1/2. Table 1
demonstrates that the tested compounds inhibited DNA methylation effectively at low
concentrations, resulting in reactivation of GFP gene transcription.
TABLE1.
GFP Expression GFP
Compound
Level (nM)
Decitabine g3 500
g3 400
O P OH
I-1:
g3 700
O P OH
I-2: OH
EXAMPLE 2: Stability of a Representative Compound in Solvent Formulations.
The stability of a compound described in various formulations under various
storage conditions was investigated. Stability was determined by HPLC at the designated
time intervals. The results are summarized in Table 2 for formulations comprising a sodium
salt of compound I-1:
O P OH
TABLE 2.
Percent
Storage % decomposition
Formulation Time Point compound
Conditions per hour
detected
0 95.8%
water, pH 7.0 2-8 °C
hours 95.1% 0.14
0 95.8%
Room
water, pH 7.0
temperature
hours 90.4% 1.1
°C / 60% 0 93.7%
DMSO / water
relative
(1:1, w/w)
hours 90.1%
humidity 0.72
°C / 60% 0 96.6%
DMSO / water
relative
(3:1, w/w)
24 hours 94.2%
humidity 0.10
0 96.8% 0.021
Propylene glycol Room
/ Glycerin temperature
24 hours 96.3%
(70:30, v/v)
0 95.8%
Propylene
2-8 °C
Glycol /
3 months 95.1% 0.00032
Glycerin /
Ethanol
°C / 60% 0 95.8%
(65:25:10,
relative
3 months 67.6%
w/w/w)
humidity 0.013
Solution of compound I-1 in water at pH 7, the pH at which compounds of this
class are most stable, led to rapid decomposition in a few hours, even at lower temperatures.
Use of DMSO / water (1:1) gave slightly better results at higher temperatures. An
improvement was noted in using 3:1 DMSO / water formulation. The compound was stable
in anhydrous DMSO. This stability can facilitate a manufacturing process.
In regard to selection of pharmaceutically acceptable solvents for final
formulation ready for administration, the anhydrous propylene glycol / glycerin system
provided better stability. The final formulation was prepared by substituting small amounts of
propylene glycol and glycerin with ethanol, to provide propylene glycol / glycerin / ethanol
(65:25:10). This formulation provided a great improvement in the solubility and stability of
the compound at both higher and lower temperatures.
Based on the experiments conducted in water, a 10-fold improvement in
stability could have been expected upon changing from room temperature to colder (2-8 °C)
storage conditions. However, in the propylene glycol / glycerin / ethanol (65:25:10) system,
changing from warmer to colder storage conditions provided a 40-fold improvement in
stability. The combined effects of cooling plus the addition of ethanol to the propylene
glycol / glycerin system provided a 66-fold improvement in stability. Such great
improvements in the stability of compound I-1 during storage could not have been expected.
The propylene glycol / glycerin / ethanol (65:25:10) system provided
compound I-1 as a solution, which was smooth, free-flowing, and suitable for passage
through a 23-gague needle without complications or clogging. The maximum solubility of
the compound in this medium was determined to be about 130-150 mg/mL, which compares
favorably to the aqueous solubility of 20 mg/mL. The good chemical stability taken together
with the excellent solubility identified the glycol / glycerin / ethanol (65:25:10) system as a
formulation for use in animal experiments.
EXAMPLE 3: Animal Studies with the Formulation of EXAMPLE 2.
The glycol / glycerin / ethanol (65:25:10) formulation of EXAMPLE 2,
containing 100 mg/mL free base equivalent of the sodium salt of compound I-1 was
administered to live animals. An analogous decitabine formulation was used for comparison
(50 mg lyophilized decitabine powder vial reconstituted to 10 mg/mL with water for injection
and administered as infusions by diluting in infusion bags).
Administration of a single dose of the formulations to monkeys (10 mg/kg)
produced higher physiological concentrations of compound I-1 (C 1,130 ng/mL; AUC of
1,469 ng•hr/mL) than of decitabine (C 160 ng/mL; AUC of 340 ng•hr/mL).
In a repeat dose study, monkeys were dosed 3x weekly subcutaneously (3
mg/kg). At day 15, the systemic exposure to compound I-1 (C 181 ng/mL; AUC of 592
ng•hr/mL) was greater than that of decitabine (C 28 ng/mL; AUC of 99 ng•hr/mL). The
pharmacokinetic parameters of the compounds did not vary significantly over the 22-day
observation period, and minimal accumulation was detected. (FIGURES 1 and 2.)
Pharmacodynamic properties (not shown) were monitored and were acceptable. Blood
samples were drawn periodically to assay LINE-1 DNA methylation.
Decreases in LINE-1 DNA methylation, the indicator of biological activity,
were observed, and the decrease continued until termination of the study on day 22. The
observed LINE-1 methylation was significantly different (ρ < 0.05) from the methylation
level observed prior to initial dosing. (FIGURE 3.)
The formulation was well-tolerated in the species tested. Three regimens were
evaluated: a) once daily subcutaneous dose in rats and rabbits for 5 days; b) once weekly
subcutaneous dose in rabbits and cynomolgus monkeys for 28 days as tolerated; and c) twice
weekly subcutaneous dose in rats for 28 days as tolerated. Rabbits tolerated the 5-day
regimen well, up to a dose of 1.5 mg/kg/day, which is equivalent to 18 mg/kg/day in humans,
and the weekly regimen up to a dose of 1.5 mg/kg/week for 3 weeks.
Cynomolgus monkeys tolerated the weekly regimen well, up to a dose of 3.0
mg/kg/week for 3 weeks, which is equivalent to 36 mg/kg/week. Rats tolerated much higher
doses: 30 mg/kg/day over 5 days; and 20 mg/kg twice weekly for 4 weeks.
The main toxicity in all experiments was myelosuppression. However, the
subcutaneous formulation tested exhibited less myelosuppression and faster recovery.
EXAMPLE 4: Preparation of a kit according to the invention
First vessel: Compound of formula I-1 for Injection, 100 mg
The sodium salt of the compound of the formula:
O P OH
was prepared as described in US 7700567 (the content of which is hereby incorporated by
reference) by coupling 1s (where R = carbamate protective group) with phosphoramidite
building block 1d:
A protected 2’-deoxyguanosine-linked CPG solid support 1s (where R = tert-
butyl phenoxyacetyl) was coupled with 2-2.5 equivalents of phenoxyacetyl decitabine
phosphoramidite (1d, where R = phenoxyacetyl) in the presence of 60% of 0.3 M
benzylthiotetrazole activator (in acetonitrile) for 10 minutes. The CPG solid support
containing protected DpG dinucleotide was treated with 20 mL of 50 mM K CO in methanol
for 1 hour and 20 minutes. The coupled product was oxidized, the protective group was
removed, and the resultant compound was washed, filtered, and purified by the ÄKTA
Explorer 100 HPLC with a Gemini C18 preparative column (Phenomenex), 250x21.2 mm,
10μm with guard column (Phenomenex), 50x21.2mm, 10μm, with 50 mM triethylammonium
acetate (pH 7) in MilliQ water (Mobile Phase A) and 80% acetonitrile in MilliQ water
(Mobile Phase B), with 2% to 20/25% Mobile Phase B in column volumes.
The ESI-MS (-ve) of DpG dinucleotide 2b:
where X = triethylammonium (calculated exact mass for the neutral compound
C H N O P is 557.14), exhibited m/z 556.1 [M-H] and 1113.1 for [2M-H] (see mass
18 24 9 10
spectrum in Figure 31 of US 7700567).
The sodium salt of the compound of formula I-1, i.e. DpG dinucleotide 2b,
where X = sodium, was obtained by re-dissolving the triethylammonium salt in 4 mL water,
0.2 mL 2M NaClO solution. When 36 mL acetone was added, the dinucleotide precipitated.
The solution was kept at -20°C for several hours and centrifugated at 4000 rpm for 20
minutes. The supernatant was discarded and the solid was washed with 30 mL acetone
followed by an additional centrifugation at 4000 rpm for 20 minutes. The precipitate, which
was dissolved in water and freeze dried, exhibited m/z 556.0 [M-H] (see mass spectrum in
Figure 36 of US 7700567).
Compounding and filling of bulk formulation
1. Based on the assay value of the lot of the sodium salt of the compound of
formula I-1, needed quantities the salt and DMSO were calculated and weighed appropriately
for the intended batch scale.
2. The sodium salt of the compound of formula I-1 was dissolved in DMSO
utilizing an overhead mixer in an appropriately sized stainless steel (SS) vessel.
3. Upon complete solubilization of the drug in DMSO, samples of the bulk
solution were tested using a UV or HPLC in-process method to determine that the amount of
the sodium salt of the compound of formula I-1 was within 95-105% of the target
concentration.
4. Bulk solution was filtered through a series of two pre-sterilized 0.2 micron
sterilizing filters that were DMSO compatible, and collected into a 2L SS surge vessel.
5. Filtration rate was continuously adjusted by visual monitoring of quantity
available for filling in the surge vessel.
6. One gram of the filtered bulk solution was filled into each of the 5 cc
depyrogenated, clear glass vials and the operation was continued with until all of the filtered
bulk solution was filled.
7. Each vial was automatically and partially stoppered on the fill line with a
fluoropolymer coated, chlorobutyl rubber lyo stopper that was pre-sterilized.
8. Product vials were transferred to lyophilizer under aseptic transfer
conditions for initiation of lyophilization cycle.
Lyophilization and capping of vials
1. Vials were lyophilized using the cycle parameters as below.
Freezing Primary/Secondary Drying Final Set
point
(stoppering
conditions)
Temperature -40° C -5° C 10° C 30° C 60° C 25° C
Ramp time (min) 133 117 50 67 100 -
Time (min.) 360 1440 1440 1440 1440 hold
Vacuum (mTorr) - 100 100 50 50 50 mT
(note:100 before back
mT for fill
evacuation
-50°C)
2. Upon completion of the lyophilization cycle, the lyophilizer was back filled
with nitrogen, and the vials were completely and automatically stoppered.
3. Vials were aseptically transferred to an isolator where each of the vials was
automatically capped with a blue aluminum flip-off cap.
4. Vials were visually inspected before proceeding with sampling for release
testing, and the labeling and packaging operation. Vials were kept at 2-8°C until ready.
Labeling and Packaging
Each vial was labeled per approved content, and packaged individually into a
heat-sealed aluminum foil pouch with a desiccant under vacuum. The foil pouch was labeled
outside with the same label as was used for the product vial. Labeled and packaged vials were
stored at 2-8°C until further distribution.
Residual DMSO
Four batches of the same scale of 3000 vials/batch were prepared using the
same process as described above. DMSO was consistently removed to the following residual
levels to yield a solid white powder, demonstrating that lyophilization of the sodium salt of
the compound of formula I-1 out of DMSO as described above yielded a safe and chemically
stable sodium salt of the compound of formula I-1 as a powder:
# DMSO in
mg/vial
Batch 1 25
Batch 2 28
Batch 3 27
Batch 4 29
Second vessel: Diluent for reconstitution of the sodium salt of the compound of formula I-1,
3 mL
Compounding and filling of bulk formulation
1. Calculated quantities (see table below) of propylene glycol, ethanol, and
glycerin in the aforementioned order were added into an appropriately sized stainless steel
vessel equipped with an overhead mixer.
% of each Grade Function
ingredient
Propylene glycol 65 NF, PhEur Solvent
Glycerin 25 NF, PhEur Solvent
Alcohol/Ethanol 10 USP, PhEur Thinning agent
2. Intermittent mixing during addition of components was followed by at least
minutes of mixing to yield a well-mixed solution.
3. Bulk solution was filtered through a series of two pre-sterilized 0.2 micron
compatible sterilizing filters, and collected into a 2L SS surge vessel.
4. Filtration rate was adjusted by visual monitoring of quantity available for
filling in the surge vessel.
5. At least 3.15 g, equivalent to 3.0 mL, of the filtered bulk solution was filled
into each of the 5 cc depyrogenated, clear glass vials followed by automatic stoppering using
fluoropolymer coated chlorobutyl rubber closures.
6. Stoppered vials were capped with sterilized white aluminum flip-off caps.
7. Vials were visually inspected prior to sampling for the release testing and
labeling operation and were stored at 2-30°C until ready.
Labeling and Packaging
Each diluent vial was labeled per approved content. Labeled vials were stored
at 2-30°C until further distribution.
Claims (51)
1. A formulation comprising: (a) a compound of the formula: O P OH N NH I-1, or a pharmaceutically-acceptable salt thereof; dissolved in (b) a substantially anhydrous solvent comprising about 60% to 70% propylene glycol; about 20% to 30% glycerin; and about 5% to 15% ethanol (w/w/w).
2. The formulation of claim 1, wherein said solvent comprises 60% to 70% propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol (w/w/w).
3. The formulation of claim 1, wherein said solvent consists essentially of about 60% to 70% propylene glycol; about 20% to 30% glycerin; and about 5% to 15% ethanol (w/w/w).
4. The formulation of claim 1, wherein said solvent consists essentially of 60% to 70% propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol (w/w/w).
5. The formulation of claim 1, wherein said solvent is about 60% to 70% propylene glycol; about 20% to 30% glycerin; and about 5% to 15% ethanol (w/w/w).
6. The formulation of claim 1, wherein said solvent is 60% to 70% propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol (w/w/w).
7. The formulation of claim 1, wherein said solvent comprises about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
8. The formulation of claim 1, wherein said solvent comprises 65% propylene glycol; 25% glycerin; and 10% ethanol (w/w/w).
9. The formulation of claim 1, wherein said solvent consists essentially of about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
10. The formulation of claim 1, wherein said solvent consists essentially of 65% propylene glycol; 25% glycerin; and 10% ethanol (w/w/w).
11. The formulation of claim 1, wherein said solvent is about 65% propylene glycol; about 25% glycerin; and about 10% ethanol (w/w/w).
12. The formulation of claim 1, wherein said solvent is 65% propylene glycol; 25% glycerin; and 10% ethanol (w/w/w).
13. The formulation of any one of the preceding claims, wherein said salt is a sodium salt.
14. The formulation of any one of the preceding claims, wherein the compound is present at a concentration of about 80 mg/mL to about 110 mg/mL
15. The formulation of any one of the preceding claims, wherein the compound is present at a concentration of about 100 mg/mL.
16. The formulation of any one of the preceding claims, further comprising DMSO.
17. The formulation of claim 16, wherein the DMSO:compound ratio is about 2: about 1.
18. The formulation of claim 16 or 17, wherein the DMSO:compound ratio is about 1: about
19. The formulation of any one claims 16-18, wherein the DMSO:compound ratio is about 0.5: about 1.
20. The formulation of any one of claims 16-19, wherein the DMSO:compound ratio is about 0.3: about 1.
21. The formulation of any one of claims 16-20, wherein the DMSO:compound ratio is or about 0.2 - about 0.3: about 1.
22. The formulation of any one of the preceding claims, suitable for administration by subcutaneous injection.
23. A kit comprising: (a) a first vessel containing a compound as defined in claim 1 or claim 13; (b) a second vessel containing a substantially anhydrous solvent as defined in any one of claims 1-12.
24. The kit of claim 23, wherein the compound is in the form of a substantially anhydrous powder.
25. The kit of claim 24, wherein the compound is lyophilized.
26. The kit of any one of claims 23-25, wherein the first vessel contains about 80 mg to about 110 mg of said compound.
27. The kit of any one of claims 23-26, wherein the first vessel contains about 100 mg of said compound.
28. The kit of any one of claims 23-27, further comprising instructions for administration by subcutaneous injection.
29. The kit of any one of claims 24-28 wherein the substantially anhydrous powder consists essentially of said compound and DMSO, the DMSO being present in an amount of up to about 200 % w/w.
30. The kit of claim 29, wherein the DMSO is present in an amount of up to about 100% w/w DMSO/compound.
31. The kit of claim 29 or 30, wherein the DMSO is present in an amount of up to about 60% w/w DMSO/compound.
32. The kit of any one of claims 29-31, wherein the DMSO is present in an amount of up to about 50% w/w DMSO/compound.
33. The kit of any one of claims 29-32, wherein the DMSO is present in an amount of up to about 40% w/w DMSO/compound.
34. The kit of any one of claims 29-33, wherein the DMSO is present in an amount of up to about 30% w/w DMSO/compound.
35. The kit of any one of claims 29-34, wherein the DMSO is present in an amount of about 20 – about 30% w/w DMSO/compound.
36. A process for preparing a pharmaceutical composition comprising dissolving a compound as defined in claim 1 or claim 13 or a substantially anhydrous powder as defined in any one of claims 24 and 29-35 in a substantially anhydrous solvent as defined in any one of claims 1-12.
37. The process of claim 36, further comprising the steps of: (a) dissolving said compound in DMSO to produce a solution of said compound in DMSO; and (b) lyophilizing said solution of step (a) to provide said compound as a substantially anhydrous powder.
38. The formulation of any one of claims 1-22 or kit of any one of claims 23-35 for use as a medicament.
39. The formulation of any one of claims 1-22 or kit of any one of claims 23-35 for treating a cancer, myelodysplastic syndrome, leukemia or solid tumour.
40. Use of the kit of any one of claims 23-35 for the manufacture of a medicament for treating a cancer, myelodysplastic syndrome, leukemia or solid tumour.
41. The use of claim 40 wherein said medicament is for treating a disease selected from those described herein.
42. The use of claim 40 or 41 wherein said medicament is for subcutaneous administration.
43. Use of the formulation of any one of claims 1-22 for the manufacture of a medicament for treating a cancer, myelodysplastic syndrome, leukemia or solid tumour.
44. The use of claim 43 wherein said medicament is for treating a disease selected from those described herein.
45. The use of claim 43 or 44 wherein said medicament is for subcutaneous administration.
46. The use of claim 43, wherein said medicament is a formulation of any one of claims 2-
47. A formulation of any one of claims 1-22 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
48. A kit of any one of claims 23-35 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
49. A process of claim 36 or 37 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
50. The formulation of any one of claims 1-22 or kit of any one of claims 23-35 for use according to any one of claims 38 or 39 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
51. Use of any one of claims 40-46 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161529081P | 2011-08-30 | 2011-08-30 | |
US61/529,081 | 2011-08-30 | ||
PCT/US2012/052816 WO2013033176A1 (en) | 2011-08-30 | 2012-08-29 | Decitabine derivative formulations |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ621322A NZ621322A (en) | 2016-07-29 |
NZ621322B2 true NZ621322B2 (en) | 2016-11-01 |
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