U.S. patent application number 16/541504 was filed with the patent office on 2019-12-05 for pharmaceutical co-crystal composition and use thereof.
The applicant listed for this patent is SYN-NAT PRODUCTS ENTERPRISE LLC. Invention is credited to Xiaozhong LIU.
Application Number | 20190367547 16/541504 |
Document ID | / |
Family ID | 57586692 |
Filed Date | 2019-12-05 |
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United States Patent
Application |
20190367547 |
Kind Code |
A1 |
LIU; Xiaozhong |
December 5, 2019 |
PHARMACEUTICAL CO-CRYSTAL COMPOSITION AND USE THEREOF
Abstract
The current invention relates to series of co-crystals of
platinum analogues and their pharmaceutical use. The co-crystals of
the subject invention may be used in the treatment or prevention of
cancers and virus infections.
Inventors: |
LIU; Xiaozhong; (Potomac,
MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SYN-NAT PRODUCTS ENTERPRISE LLC |
Potomac |
MD |
US |
|
|
Family ID: |
57586692 |
Appl. No.: |
16/541504 |
Filed: |
August 15, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15736179 |
Dec 13, 2017 |
10428099 |
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PCT/US2016/039572 |
Jun 27, 2016 |
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16541504 |
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62184591 |
Jun 25, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 61/04 20130101;
A61K 9/0019 20130101; A61K 33/24 20130101; A61K 33/24 20130101;
A61K 31/282 20130101; A61K 47/26 20130101; C07B 2200/13 20130101;
A61K 9/08 20130101; A61K 47/542 20170801; A61P 35/00 20180101; A61K
45/06 20130101; C07F 15/0093 20130101; C07C 61/06 20130101; A61K
2300/00 20130101 |
International
Class: |
C07F 15/00 20060101
C07F015/00; A61P 35/00 20060101 A61P035/00; A61K 31/282 20060101
A61K031/282; A61K 45/06 20060101 A61K045/06; C07C 61/04 20060101
C07C061/04; C07C 61/06 20060101 C07C061/06 |
Claims
1-31. (canceled)
32. A co-crystal comprising a platinum analogue of formula Pt-02:
##STR00067## and a diacid selected from the group consisting of:
##STR00068##
33. The co-crystal of claim 32, wherein the diacid is selected from
the group consisting of formulas CF-01, CF-02, and CF-08.
34. The co-crystal of claim 32, which is a co-crystal comprising
the platinum analogue of formula Pt-02 and the diacid of formula
CF-02 and having an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 7.3.degree., 9.4.degree., 10.1.degree.,
12.5.degree., 13.6.degree. and 23.4.degree..+-.0.2, an XRPD pattern
comprising peaks as set forth in FIG. 14 or an XRPD pattern
substantially similar to the pattern as set forth in FIG. 14; or a
co-crystal comprising the platinum analogue of formula Pt-02 and
the diacid of formula CF-08 and having an XRPD pattern comprising
peaks at diffraction angles 2-Theta of 7.9.degree., 11.9.degree.,
14.5.degree., 15.8.degree., 17.0.degree., 17.4.degree. and
17.8.degree..+-.0.2, an XRPD pattern comprising peaks as set forth
in FIG. 17 or an XRPD pattern substantially similar to the pattern
as set forth in FIG. 17.
35. The co-crystal of claim 32, which is a co-crystal comprising
the platinum analogue of formula Pt-02 and the diacid of formula
CF-01 and having an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 7.1.degree., 9.2.degree., and
10.1.degree..+-.0.2.
36. The co-crystal of claim 32, which is a co-crystal comprising
the platinum analogue of formula Pt-02 and the diacid of formula
CF-08 and having an XRPD pattern comprising peaks as set forth in
FIG. 15 or an XRPD pattern substantially similar to the pattern as
set forth in FIG. 15.
37. A pharmaceutical composition comprising the co-crystal of claim
32.
38. A pharmaceutical composition comprising the co-crystal of claim
34.
39. A pharmaceutical composition comprising the co-crystal of claim
35.
40. A pharmaceutical composition comprising the co-crystal of claim
36.
41. The pharmaceutical composition of claim 37, which is an aqueous
composition, wherein the co-crystal is dissolved or dispersed in a
pharmaceutically acceptable carrier or aqueous media.
42. The pharmaceutical composition of claim 37, further comprising
a therapeutic agent or adjuvant therapy agent selected from the
group consisting of folic acid, coenzyme Q10, curcumin, glutathione
(GSH), aloe vera, oryzanol, 5-fluorouracil, and bortezomib.
43. A method of treating cancer in a subject in need thereof,
comprising administering to the subject the pharmaceutical
composition of claim 37, wherein the co-crystal is in a
therapeutically effective amount.
44. A method of treating cancer in a subject in need thereof,
comprising administering to the subject the pharmaceutical
composition of claim 39, wherein the co-crystal is in a
therapeutically effective amount.
45. A method of treating cancer in a subject in need thereof,
comprising administering to the subject the pharmaceutical
composition of claim 40, wherein the co-crystal is in a
therapeutically effective amount.
46. The method of claim 43, wherein the cancer is prostate cancer,
colorectal cancer, or renal adenocarcinoma.
47. A method of preparing a co-crystal comprising: a) mixing a
platinum analogue and a diacid in water, b) slurrying or stirring
the mixture from step a) for a sufficient period of time to form a
co-crystal of the platinum analog and the diacid; and optionally c)
isolating the co-crystal, wherein the platinum analog is a platinum
analogue of formula Pt-02: ##STR00069## and the diacid is selected
from the group consisting of: ##STR00070##
48. The method of claim 47, wherein the molar ratio of the platinum
analogue to the diacid is in range of 1:0.1 to 1:20.
49. The method of claim 48, wherein the diacid is CF-01.
50. The co-crystal produced by the method of claim 47.
51. The co-crystal produced by the method of claim 49.
Description
FIELD OF THE INVENTION
[0001] The current invention relates to a series of co-crystals of
platinum analogues with diacids and the pharmaceutical use of these
co-crystals. The co-crystals of the current invention may be used
in the treatment or prevention of various diseases such as cancers
and virus infections.
BACKGROUND OF THE INVENTION
[0002] The interest in platinum-based antitumor drugs has its
origin in the 1960's, with the serendipitous discovery by Rosenberg
of the inhibition of cell division by platinum (Pt) complexes.
Since the approval of cisplatin for the treatment of testicular and
ovarian cancer in 1978, cisplatin has become one of the three most
widely utilized antitumor drugs in the world. Platinum-based
anticancer drugs have revolutionized cancer chemotherapy, and
continue to be in widespread clinical use, especially for
management of tumors of the ovary, testes, and the head and neck.
Thousands of Pt compounds have been synthesized and evaluated as
potential antitumor agents and over 28 have entered human clinical
trials. However, several types of dose limiting toxicities
associated with platinum drug use, partial anti-tumor response in
most patients, development of drug resistance, tumor relapse, and
other challenges have severely limited the patient quality of life.
Therefore, it is desirable to develop new strategies for improving
platinum therapy.
[0003] The search continues for an improved Pt antitumor agent. In
the years following the introduction of cisplatin, the design of
new Pt antitumor drugs focused mainly on direct cisplatin
analogues, which adhered to the set of structure-activity
relationships summarized by Cleare and Hoeschele in 1973. A number
of researchers have taken a completely different approach to Pt
drug design and have produced compounds that are inconsistent with
the traditional structure-activity relationships but still show
antitumor activities.
[0004] Carboplatin, one of the second generation platin analogues,
is less toxic than cisplatin and can be administered at a
significantly higher dose than cisplatin (up to 2000 mg/dose); it
has received worldwide approval and has achieved routine clinical
use. Unfortunately, the continued use of carboplatin is restricted
by severe dose limiting side effects and intrinsic or acquired drug
resistance.
[0005] In contrast to the 1970s and 1980s, the design of
third-generation Pt drugs in the recent years has clearly shifted
away from the early empirical structure-activity relationships and
the synthesis of mere cisplatin analogues. Instead, efforts have
been directed at the design of compounds capable of circumventing
specific mechanisms of resistance and at the design of
unconventional Pt compounds with radically different modes of
action. As the third-generation of compounds undergo clinical
trials, it is hoped that they will demonstrate significant clinical
advantages over the current drugs, particularly in the area of Pt
drug resistance.
[0006] Meanwhile co-crystallization has attracted great amount of
academic, industrial and therapeutic interests by
co-crystallization of two or more pure compounds with crystal
engineering to create a new functional material. Specifically,
pharmaceutical co-crystals are defined as "co-crystals in which the
target molecule or ion is an active pharmaceutical ingredient, API,
and it bonds to the co-crystal former(s) through hydrogen bonds."
Almarsson M. and Zaworotko J., Chem. Commun., 2004: 1889.
Pharmaceutical co-crystals are nonionic supramolecular complexes
and can be used to improve physiochemical properties such as
solubility, stability and bioavailability in pharmaceutical
development without changing the chemical composition of the active
pharmaceutical ingredient (API).
[0007] Therefore, it is desirable to improve the physiochemical and
therapeutic properties of cisplatin, carboplatin and other platin
with co-crystallization technology. In some cases, there is no need
to change the basic structure of the platin as the API, while
properties such as solubility, stability, permeability and
bioavailability can be improved. For example, it would be possible
to significantly enhance the bioavailabiltiy of a platin API with
co-crystallization, so that the co-crystal can be therapeutically
effective in certain environment of use and maintain the level for
a prolonged period of time.
[0008] The present invention provides a series of co-crystals
including a platinum analogue and a diacid as coformers. The
co-crystals of this invention may satisfy one or more of the
targeted objectives, such as but not limited to increased
solubility, stability and bioavailability and more versatility in
pharmaceutical use.
SUMMARY OF THE INVENTION
[0009] The present invention provides a series of co-crystals
comprising a platinum analogue and a diacid. In some embodiments,
co-crystals have a structure of Formula (I):
##STR00001##
[0010] In some embodiments, the platinum analogue
##STR00002##
is selected from the structures of formulas from Pt-00 to Pt-33 and
SPI-77 listed in Tables 1-5. In some embodiments, the diacid
##STR00003##
is selected from the structures of formulas CF-01, CF-02, CF-03,
CF-04, CF-05, CF-06, CF-07, CF-08, CF-10A, CF-10B, CF-10C and
CF-10D listed in Table 6.
[0011] In one aspect, the co-crystal of the present invention is
formed where the platinum analogue, the active pharmaceutical
ingredient (API), and the diacid, the co-crystal former, are bonded
together through hydrogen bonds. In some embodiments, other
non-covalent interactions may also be in the co-crystal. In one
embodiment, other non-covalent and covalent interactions may also
be present in the co-crystal.
[0012] In another aspect, the present invention provides a
pharmaceutical composition comprising the compounds of the
co-crystals of Formula I, wherein the co-crystal comprises a
platinum analogue and a diacid. In some embodiments of the
pharmaceutical composition, the platinum analogue is the API.
[0013] One aspect of the invention relates to platinum
analogue-based co-crystals which provide a sufficient level of
bioavailability to be therapeutically effective in pharmaceutical
use and maintains the level for a therapeutically effective period
of time.
[0014] Another aspect of the invention is to provide uses of the
compounds of the co-crystals (e.g. the co-crystals of Formal I) in
certain indications; in some embodiments the uses of the compounds
of the co-crystals extend beyond the uses of carboplatin by itself.
In some embodiments, the present invention relates to treating or
preventing a disease in a subject in need thereof comprising
administering to the subject the pharmaceutical composition
comprising the compound of the co-crystal of Formula I, wherein the
compound is in a therapeutically effective amount. In some
embodiments, the disease is a cancer; in other embodiments, the
disease is a virus infection.
[0015] In one aspect, the present invention involves the use of a
pharmaceutical composition comprising the compounds of the
co-crystal of the current invention to induce cell death in cancer
cells by contacting the cancer cells with an effective amount of
the compound.
[0016] In some embodiments of the treatment of cancers, the
therapeutically effective amount of the compound is about 0.01 to
about 10 mg/kg body weight, and in some particular embodiments
about 0.01 to about 5 mg/kg body weight.
[0017] In some embodiments of treatment of virus diseases, the
therapeutically effective amount of the compound is about 0.01 to
about 10 mg/kg body weight, and in some particular embodiments
about 0.01 to 5 mg/kg body weight.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 shows the IC.sub.50 values of MD-39551 and the
control chemicals docetaxel and cisplatin in PC-3 prostate cancer
cell line.
[0019] FIG. 2 shows the IC.sub.50 values of MD-39551 and the
control chemicals docetaxel and cisplatin in LNCaP prostate cancer
cell line.
[0020] FIG. 3 shows the IC.sub.50 values of MD-39551 and the
control chemicals docetaxel and cisplatin in fetal hepatocytes
HL-7002.
[0021] FIG. 4 shows the IC.sub.50 values of MD-39551 and the
control chemicals docetaxel and cisplatin in human embryonic kidney
cell line HEK293.
[0022] FIG. 5 shows the IC.sub.50 values of MD-39703 and MD-39433
and the control chemicals oxaliplatin and 5-FU in colorectal cancer
cell line HCT-116.
[0023] FIG. 6 shows the IC.sub.50 values of MD-39703 and MD-39433
and the control chemicals oxaliplatin and 5-FU in colorectal cancer
cell line HT-29.
[0024] FIG. 7 shows the IC.sub.50 values of MD-39703 and MD-39433
and the control chemicals oxaliplatin and 5-FU in fetal hepatocytes
HL-7002.
[0025] FIG. 8 shows the IC.sub.50 values of MD-39703 and MD-39433
and the control chemicals oxaliplatin and 5-FU in human embryonic
kidney cell line HEK293.
[0026] FIG. 9 shows an X-ray powder diffraction (XRPD) pattern of
the co-crystal MD-36042.
[0027] FIG. 10 shows a scanning electron microscope (SEM) image of
the co-crystal MD-36042.
[0028] FIG. 11 shows an XRPD pattern of the co-crystal
MD-39551.
[0029] FIG. 12 shows a differential scanning calorimetry (DSC)
result of the co-crystal MD-39551.
[0030] FIG. 13 shows a SEM image of the co-crystal MD-39551.
[0031] FIG. 14 shows an XRPD pattern of the co-crystal
MD-39442.
[0032] FIG. 15 shows an XRPD pattern of the co-crystal
MD-39433.
[0033] FIG. 16 shows a SEM image of the co-crystal MD-39433.
[0034] FIG. 17 shows an XRPD pattern of the co-crystal
MD-39703.
[0035] FIG. 18 shows a DSC result of the co-crystal MD-39703.
[0036] FIG. 19 shows a SEM image of the co-crystal MD-39703.
[0037] FIG. 20 shows an XRPD pattern of the co-crystal HP-309.
[0038] FIG. 21 shows an XRPD pattern of the co-crystal MD3176.
DETAILED DESCRIPTION OF THE INVENTION
[0039] The following description of certain embodiment(s) is merely
exemplary in nature and is in no way intended to limit the
invention, its application, or uses. As used throughout, ranges are
used as shorthand for describing each and every value that is
within the range. Any value within the range can be selected as the
terminus of the range. In addition, all references cited herein are
hereby incorporated by referenced in their entireties. In the event
of a conflict in a definition in the present disclosure and that of
a cited reference, the present disclosure controls. Unless defined
otherwise, all technical and scientific terms used herein have the
same meaning as is commonly understood by one of skill in the art
to which this invention belongs. All patents and publications
referred to herein are incorporated by reference in their
entireties.
[0040] The term "effective amount" or "therapeutically effective
amount" refers to that amount of a compound or combination of
compounds as described herein that is sufficient to effect the
intended application including, but not limited to, prophylaxis or
treatment of diseases. A therapeutically effective amount may vary
depending upon the intended application (in vitro or in vivo), or
the subject and disease condition being treated (e.g., the weight,
age and gender of the subject), the severity of the disease
condition, the manner of administration, etc. which can readily be
determined by one of ordinary skill in the art. The term also
applies to a dose that will induce a particular response in target
cells and/or tissues (e.g., the reduction of cell proliferation
and/or morphological alteration of the tissue). The specific dose
will vary depending on the particular compounds chosen, the dosing
regimen to be followed, whether the compound is administered in
combination with other compounds, timing of administration, the
tissue to which it is administered, and the physical delivery
system in which the compound is carried.
[0041] A "therapeutic effect" as that term is used herein,
encompasses a therapeutic benefit and/or a prophylactic benefit. A
"prophylactic effect" (e.g. terms such as "prophylaxis," "prevent"
and "reducing the likelihood for developing") includes delaying or
eliminating the appearance of a disease or condition, delaying or
eliminating the onset of symptoms of a disease or condition,
slowing, halting, or reversing the progression of a disease or
condition, or any combination thereof by administering a drug
before the onset of the disease or condition. A "treatment effect"
(e.g. with terms such as "treatment" and "treat") includes reducing
or eliminating the appearance of a disease or condition, reducing
or eliminating the symptoms of a disease or condition, slowing,
halting, or reversing the progression of a disease or condition, or
any combination thereof by administering a drug after the onset of
the disease or condition.
[0042] A "subject" as the term is used herein, refers to a human or
non-human animal. In some embodiments, the subject is a mammal. In
some embodiments, the subject is human.
[0043] When ranges are used herein to describe, for example,
physical or chemical properties such as molecular weight or
chemical formulae, all combinations and subcombinations of ranges
and specific embodiments therein are intended to be included. Use
of the term "about" when referring to a number or a numerical range
means that the number or numerical range referred to is an
approximation within experimental variability (or within
statistical experimental error), and thus the number or numerical
range may vary. In some embodiments, the variation is from 0% to
15%; in some particular embodiments from 0% to 10%; and in other
embodiments from 0% to 5% of the stated number or numerical range.
The term "comprising" (and related terms such as "comprise" or
"comprises" or "having" or "including") includes those embodiments
such as, for example, an embodiment of any composition of matter,
method or process that "consist of" or "consist essentially of" the
described features.
[0044] Compounds used in the present invention also include
crystalline and amorphous forms of those compounds, including, for
example, polymorphs, pseudopolymorphs, solvates, hydrates,
unsolvated polymorphs (including anhydrates), conformational
polymorphs, and amorphous forms of the compounds, as well as
mixtures thereof. "Compound of the co-crystal" refers to
crystalline and amorphous forms made from the co-crystal, wherein
"made from" means left unaltered or processed with known methods
such as but not limited to dissolving, condensing, crystalline
disruption, drying, grinding, compaction, and polymer film coating.
"Crystalline form" and "polymorph" are intended to include all
crystalline and amorphous forms of the compound, including, for
example, polymorphs, pseudopolymorphs, solvates, hydrates,
unsolvated polymorphs (including anhydrates), conformational
polymorphs, and amorphous forms, as well as mixtures thereof,
unless a particular crystalline or amorphous form is referred
to.
[0045] The present invention relates to a series of co-crystals of
platinum analogues, and methods of making and using the same. The
co-crystal comprises a platinum analogue and a diacid as coformers.
In some embodiments, the co-crystal formula is presented as Formula
(I):
##STR00004##
[0046] In some embodiments, the platinum analogue
##STR00005##
represents the platinum-based anticancer drugs which are approved
or already in marketing shown in Table 1.
TABLE-US-00001 TABLE 1 ##STR00006## Pt-00 ##STR00007## Pt-01
##STR00008## Pt-02 ##STR00009## Pt-03 ##STR00010## Pt-04
##STR00011## Pt-05 ##STR00012## Pt-06
[0047] In some embodiments, the platinum analogue
##STR00013##
represents lipoplatin and other platinum-based anticancer drugs
shown in Table 2.
TABLE-US-00002 TABLE 2 ##STR00014## Pt-07 ##STR00015## Pt-08
[0048] In some embodiments, the platinum analogue
##STR00016##
represents the platinum-based anticancer drugs in clinic phases
shown in Table 3.
TABLE-US-00003 TABLE 3 ##STR00017## Pt-09 ##STR00018## Pt-10
##STR00019## Pt-11 ##STR00020## Pt-12 ##STR00021## Pt-13
##STR00022## Pt-14 ##STR00023## Pt-15 ##STR00024## Pt-16
[0049] In some embodiments, the platinum analogue
##STR00025##
represents the platinum-based anticancer drugs in study as shown in
Table 4.
TABLE-US-00004 TABLE 4 ##STR00026## Pt-17 ##STR00027## Pt-18
##STR00028## Pt-19 ##STR00029## Pt-20
[0050] In some embodiments, the platinum analogue
##STR00030##
represents the platinum-based structures as shown in Table 5.
TABLE-US-00005 TABLE 5 ##STR00031## Pt-21 ##STR00032## Pt-22
##STR00033## Pt-23 ##STR00034## Pt-24 ##STR00035## Pt-25
##STR00036## Pt-26 ##STR00037## Pt-27 ##STR00038## Pt-28
##STR00039## Pt-29 ##STR00040## Pt-30 ##STR00041## Pt-31
[0051] In some embodiments, the platinum analogue
##STR00042##
represents the platinum-based anticancer drugs JM11 and iproplatin
as disclosed in Wheate, S. et al. Dalton Trans., 2010, Vol. 39,
8113-27. The structure of JM11 and iproplatin are shown below:
##STR00043##
[0052] In some embodiments of Formula (I), n is an integer selected
from 0 to 5; in some embodiments of Formula (I), n is an integer
selected from 2 to 5. In some embodiments, when n.gtoreq.2, the
carbon atoms on the diacid may be connected by single or double
bonds.
[0053] In some embodiments, the platinum analogue and the diacid
are bonded at a 1:1 ratio.
[0054] In some embodiments, R.sub.5 and R.sub.6 are the same as or
different from each other, and independently represent a hydrogen,
a halogen, an amino group, a C1-C6 alkyl group, a cyanide group, a
hydroxyl group, an acyl group, a phosphoryl group, a phosphoroamido
group, a hydroxylcarboxyl group, a phenyl group, or an aliphatic
group, or R5 and R6 are connected to form a substituted or
unsubstituted C3-C6 cycloalkyl group or phenyl group.
[0055] In some embodiments, the diacid
##STR00044##
may be selected from the group consisting of oxalic acid,
1,3-propanedioic acid, 1,4-butanedioic acid, 1,5pentanedioic acid,
cis-butenedioic acid, 2-hydroxy-1,4-butanedioic acid (malic acid),
2,3-dihydroxy-1,4-butanedioic acid (tartaric acid),
2-phenyl-1,3-propanedioic acid, 1,2-dicarboxycyclohexane,
3-hydroxy-3-carboxy-1,5-pentanedioic acid (citric acid), phthalic
acid, and 1,3,4-benzene-ticarboxylic acid.
[0056] In some embodiments, the diacid
##STR00045##
may be selected from formulas CF-01, CF-02, CF-03, CF-04, CF-05,
CF-06, CF-07, CF-08, CF-10A, CF-10B, CF-10C and CF-10D in Table
6.
TABLE-US-00006 TABLE 6 CF-09 ##STR00046## CF-10 ##STR00047##
##STR00048## CF-01 ##STR00049## CF-02 ##STR00050## CF-03
##STR00051## CF-04 ##STR00052## CF-05 ##STR00053## CF-06
##STR00054## CF-07 ##STR00055## CF-08 ##STR00056## CF-10A
##STR00057## CF-10B ##STR00058## CF-10C ##STR00059## CF-10D
[0057] When the platinum analogue is carboplatin (Pt-01),
co-crystals disclosed in U.S. Pat. App. Pub. No. 20050160931 and
U.S. Pat. No. 6,699,901 are not included in the co-crystals of the
present invention. In particular, when the platinum analogue is
carboplatin (Pt-01), the diacid does not have the structure of
CF-01, CF-04, CF-10A, CF-10B, CF-10C, CF-10D as shown in Table
6.
[0058] In some embodiments, the co-crystal of the present invention
comprises a platinum analogue selected from the group consisting of
formulas Pt-01, Pt-02, Pt-03 and Pt-05.
[0059] In some embodiments, the co-crystal of the present invention
comprises a diacid selected from the group consisting of formulas
CF-01, CF-02, CF-08.
[0060] In some embodiments, the co-crystal of the present invention
comprises a platinum analogue selected from the group consisting of
formulas Pt-01, Pt-02, Pt-03 and Pt-05 and a diacid selected from
the group consisting of formulas CF-01, CF-02, CF-08.
[0061] In some embodiments, the co-crystal of the present invention
comprises the platinum analogue of formula Pt-01 and the diacid of
formula CF-02 bonded at 1:1 ratio. In some embodiments, the
co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 8.821.degree., 8.961.degree., 11.998.degree.,
13.160.degree., 17.681.degree., 18.001.degree., 19.101.degree. and
20.837.degree. (round to 8.8.degree., 9.0.degree., 12.0.degree.,
13.2.degree., 17.7.degree., 18.0.degree., 19.1.degree. and
20.8.degree., respectively) (corresponding to d-spacing of 10.0166
.ANG., 9.8604 .ANG., 7.3703 .ANG., 6.7219 .ANG., 5.0120 .ANG.,
4.9237 .ANG., 4.6427 .ANG. and 4.2595 .ANG., respectively) .+-.0.2.
In some embodiments, the co-crystal has an XRPD pattern comprising
peaks at diffraction angles 2-Theta of 8.821.degree.,
8.961.degree., 11.998.degree., 13.160.degree., 17.681.degree.,
18.001.degree., 19.101.degree. and 20.837.degree..+-.0.1. In some
embodiments, the co-crystal has an XRPD pattern comprising peaks at
diffraction angles 2-Theta of 8.821.degree., 8.961.degree.,
11.998.degree., 13.160.degree., 17.681.degree., 18.001.degree.,
19.101.degree. and 20.837.degree..+-.0.05. In some embodiments, the
co-crystal has an x-ray diffraction pattern comprising peaks as set
forth in FIG. 9. In some embodiments, the co-crystal has an x-ray
diffraction pattern substantially similar to the pattern as set
forth in FIG. 9.
[0062] In some embodiments, the co-crystal of the present invention
comprises the platinum analogue of formula Pt-01 and the diacid of
formula CF-08 bonded at 1:1 ratio. In some embodiments, the
co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 6.338.degree., 14.437.degree., 14.860.degree.,
15.281.degree., 19.958.degree., 22.682.degree. and 24.600.degree.
(round to 6.3.degree., 14.4.degree., 14.9.degree., 15.3.degree.,
20.0.degree., 22.7.degree. and 24.6.degree., respectively)
(corresponding to d-spacing of 13.9342 .ANG., 6.1301 .ANG., 5.9567
.ANG., 5.7936 .ANG., 4.4451 .ANG., 3.9171 .ANG. and 3.6158 .ANG.
respectively) .+-.0.2. In some embodiments, the co-crystal has an
XRPD pattern comprising peaks at diffraction angles 2-Theta of
6.338.degree., 14.437.degree., 14.860.degree., 15.281.degree.,
19.958.degree., 22.682.degree. and 24.600.degree..+-.0.1. In some
embodiments, the co-crystal has an XRPD pattern comprising peaks at
diffraction angles 2-Theta of 6.338.degree., 14.437.degree.,
14.860.degree., 15.281.degree., 19.958.degree., 22.682.degree. and
24.600.degree..+-.0.05. In some embodiments, the co-crystal has an
x-ray diffraction pattern comprising peaks as set forth in FIG. 11.
In some embodiments, the co-crystal has an x-ray diffraction
pattern substantially similar to the pattern as set forth in FIG.
11.
[0063] In some embodiments, the co-crystal of the present invention
comprises the platinum analogue of formula Pt-02 and the diacid of
formula CF-02 bonded at 1:1 ratio. In some embodiments, the
co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 7.338.degree., 9.401.degree., 10.057.degree.,
12.535.degree., 13.619.degree. and 23.361.degree. (round to
7.3.degree., 9.4.degree., 10.1.degree., 12.5.degree., 13.6.degree.
and 23.4.degree., respectively) (corresponding to d-spacing of
12.0363 .ANG., 9.3993 .ANG., 8.7877 .ANG., 7.0557 .ANG., 6.4967
.ANG. and 3.8048 .ANG. respectively) .+-.0.2. In some embodiments,
the co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 7.338.degree., 9.401.degree., 10.057.degree.,
12.535.degree., 13.619.degree. and 23.361.degree..+-.0.1. In some
embodiments, the co-crystal has an XRPD pattern comprising peaks at
diffraction angles 2-Theta of 7.338.degree., 9.401.degree.,
10.057.degree., 12.535.degree., 13.619.degree. and
23.361.degree..+-.0.05. In some embodiments, the co-crystal has an
x-ray diffraction pattern comprising peaks as set forth in FIG. 14.
In some embodiments, the co-crystal has an x-ray diffraction
pattern substantially similar to the pattern as set forth in FIG.
14.
[0064] In some embodiments, the co-crystal of the present invention
comprises the platinum analogue of formula Pt-02 and the diacid of
formula CF-01 bonded at 1:1 ratio. In some embodiments, the
co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 7.079.degree., 9.180.degree., and 10.060.degree.
(round to 7.1.degree., 9.2.degree., and 10.1.degree., respectively)
(corresponding to d-spacing of 12.4769 .ANG., 9.6252 .ANG. and
8.7856 .ANG. respectively) .+-.0.2. In some embodiments, the
co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 7.079.degree., 9.180.degree., and
10.060.degree..+-.0.1. In some embodiments, the co-crystal has an
XRPD pattern comprising peaks at diffraction angles 2-Theta of
7.079.degree., 9.180.degree., and 10.060.degree..+-.0.05. In some
embodiments, the co-crystal has an x-ray diffraction pattern
comprising peaks as set forth in FIG. 15. In some embodiments, the
co-crystal has an x-ray diffraction pattern substantially similar
to the pattern as set forth in FIG. 15.
[0065] In some embodiments, the co-crystal of the present invention
comprises the platinum analogue of formula Pt-02 and the diacid of
formula CF-08 bonded at 1:1 ratio. In some embodiments, the
co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 7.858.degree., 11.881.degree., 14.463.degree.,
15.757.degree., 16.999.degree., 17.376.degree. and 17.841.degree.
(round to 7.9.degree., 11.9.degree., 14.5.degree., 15.8.degree.,
17.0.degree., 17.4.degree. and 17.8.degree., respectively)
(corresponding to d-spacing of 11.2418 .ANG., 7.4427 .ANG., 6.1193
.ANG., 5.6194 .ANG., 5.2115 .ANG., 5.0993 .ANG. and 4.9676 .ANG.
respectively) .+-.0.2. In some embodiments, the co-crystal has an
XRPD pattern comprising peaks at diffraction angles 2-Theta of
7.858.degree., 11.881.degree., 14.463.degree., 15.757.degree.,
16.999.degree., 17.376.degree. and 17.841.degree..+-.0.1. In some
embodiments, the co-crystal has an XRPD pattern comprising peaks at
diffraction angles 2-Theta of 7.858.degree., 11.881.degree.,
14.463.degree., 15.757.degree., 16.999.degree., 17.376.degree. and
17.841.degree..+-.0.05. In some embodiments, the co-crystal has an
x-ray diffraction pattern comprising peaks as set forth in FIG. 17.
In some embodiments, the co-crystal has an x-ray diffraction
pattern substantially similar to the pattern as set forth in FIG.
17.
[0066] In some embodiments, the co-crystal of the present invention
comprises the platinum analogue of formula Pt-03 and the diacid of
formula CF-01 bonded at 1:1 ratio. In some embodiments, the
co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 7.181.degree., 9.499.degree., 13.740.degree. and
14.421.degree. (round to 7.2.degree., 9.5.degree., 13.7.degree. and
14.4.degree., respectively) (corresponding to d-spacing of 12.2995
.ANG., 9.3029 .ANG., 6.4398 .ANG. and 6.1371 .ANG. respectively)
.+-.0.2. In some embodiments, the co-crystal has an XRPD pattern
comprising peaks at diffraction angles 2-Theta of 7.181.degree.,
9.499.degree., 13.740.degree. and 14.421.degree..+-.0.1. In some
embodiments, the co-crystal has an XRPD pattern comprising peaks at
diffraction angles 2-Theta of 7.181.degree., 9.499.degree.,
13.740.degree. and 14.421.degree..+-.0.05. In some embodiments, the
co-crystal has an x-ray diffraction pattern comprising peaks as set
forth in FIG. 20. In some embodiments, the co-crystal has an x-ray
diffraction pattern substantially similar to the pattern as set
forth in FIG. 20.
[0067] In some embodiments, the co-crystal of the present invention
comprises the platinum analogue of formula Pt-05 and the diacid of
formula CF-01 bonded at 1:1 ratio. In some embodiments, the
co-crystal has an XRPD pattern comprising peaks at diffraction
angles 2-Theta of 6.697.degree., 7.381.degree., 8.239.degree.,
12.320.degree. and 16.478.degree. (round to 6.7.degree.,
7.4.degree., 8.2.degree., 12.3.degree. and 16.5.degree.,
respectively) (corresponding to d-spacing of 13.1874 .ANG., 11.9662
.ANG., 10.7224 .ANG., 7.1785 .ANG. and 5.3751 .ANG. respectively)
.+-.0.2. In some embodiments, the co-crystal has an XRPD pattern
comprising peaks at diffraction angles 2-Theta of 6.697.degree.,
7.381.degree., 8.239.degree., 12.320.degree. and
16.478.degree..+-.0.1. In some embodiments, the co-crystal has an
XRPD pattern comprising peaks at diffraction angles 2-Theta of
6.697.degree., 7.381.degree., 8.239.degree., 12.320.degree. and
16.478.degree..+-.0.05. In some embodiments, the co-crystal has an
x-ray diffraction pattern comprising peaks as set forth in FIG. 21.
In some embodiments, the co-crystal has an x-ray diffraction
pattern substantially similar to the pattern as set forth in FIG.
21.
[0068] In some embodiments, the co-crystal of the present invention
comprises: (i) a diacid as a co-former; and (ii) a platinum
analogue as a co-former and the active pharmaceutical ingredient
(API). In some embodiments, the diacid and the platinum analogue
are bonded in 1:1 ratio.
[0069] As described here, the solid state of the co-crystal of the
current invention is any crystalline polymorphic forms or a mixture
thereof. The co-crystal may also be made into an amorphous form,
which may be combined with any crystalline forms. In other
embodiments, the solid state of the co-crystal is an amorphous
form. Different forms of the co-crystal of the current invention
may be obtained through different crystallization process and the
co-crystals may be made into amorphous forms with known
technology.
[0070] The compound of the co-crystals of the current invention
(e.g. co-crystals of formula I) may demonstrate a sufficient level
of bioavailablity to be therapeutically effective in pharmaceutical
use and maintains that level in a subject for a prolonged period of
time.
[0071] The co-crystals of the current invention may be produced by
a process comprising: (i) providing and mixing a platinum analogue,
a diacid and an appropriate solvent, (ii) slurrying or stirring the
mixture from step i) for a sufficient period of time; and (iii)
isolating the co-crystal formed thereby. In some embodiments, the
reaction of the platinum analogue and the diacid may be carried out
30.degree. C. In some embodiments, the mixture after the reaction
may be cooled to 0-5.degree. C. and stirred.
[0072] The specific conditions of the process may be adjusted to
ensure optimized purity, quantity, and/or physiochemical
properties. In some embodiments, the proper ratio is in the molar
range of 1:0.1-1:20, 1:0.2-1:20, 1:0.3-1:20, 1:0.4-1:20,
1:0.5-1:20, 1:0.6-1:20, 1:0.7-1:20; 1:0.8-1:20, 1:0.9-1:20,
1:1-1:1.20, 1:2-1:20, 1:3-1:20, 1:4-1:20, 1:5-1:20, 1:6-1:18,
1:7-1:15, 1:8-1:13, 1:9-1:12, or 1:10-1:11. In some embodiments,
the proper ratio is about 1:1 (molar). In some embodiments, the
period of time for slurrying or stirring the mixtures may be in the
range of 0.1-24 hours, 0.2-12 hours, 0.25-6 hours, 0.3-2 hours,
0.4-1 hour, or 0.5-1 hour. In some embodiments, the period of time
for slurrying or stirring the mixtures may be about 0.5 hour. In
some embodiments, the co-crystal compound may be obtained by
drying, filtering, centrifugation, pipetting, or a combination
thereof. In some embodiments, the co-crystal compound may be
obtained by centrifugation.
[0073] In some embodiments, the reaction of the platinum analogue
and the diacid may be carried out 30.degree. C. In some
embodiments, the mixture after the reaction may be cooled to
0-5.degree. C. and stirred.
[0074] The current invention relates to the pharmaceutical use of
compounds of the co-crystals of the present invention, and methods
of treating or preventing a disease in a subject in need thereof.
In some embodiments, the method comprises administering to the
subject a pharmaceutical composition comprising a therapeutically
effective amount of a compound of one or more of the co-crystals of
the present invention.
[0075] In some embodiments, the compound of the co-crystal of the
current invention demonstrates advantageous therapeutic properties.
For example, in some embodiments, the compound of the co-crystals
of the present invention may be more effective in killing cancerous
or virus-infected cells compared to carboplatin or other known
drugs. In other embodiments, the compound of the co-crystals of the
present invention may be less effective in killing cancerous or
virus-infected cells compare to carboplatin or other known drugs or
have substantially similar effects, but are less toxic to healthy
and normal cells, resulting in a net health benefit. For instance,
comparing to know platin analogues in the treatment of cancer cells
or virus-infected cells, a compound of the MD39551 (as shown in
Table 7) co-crystal may be less toxic and more stable than
cisplatin and carboplatin. In addition, a compound of the MD39433
or MD39703 (as shown in Table 7) co-crystals may be less toxic and
more stable than oxaliplatin and carboplatin. In some embodiments,
the compounds of MD39551, MD39433 or MD39703 may provide reduced
side effects. In some embodiments, the compounds of MD39551,
MD39433 or MD39703 may demonstrate more versatility in
pharmaceutical uses, e.g. when compared to carboplatin.
[0076] In some embodiments, the compound of the carboplatin-based
co-crystal of the current invention demonstrates advantageous
physiochemical properties. For example, in some embodiments,
compounds of MD39551, MD39433 or MD39703 may have increased
solubility, stability, and bioavailability. For example, in
comparison with carboplatin, the compounds of MD39551, MD39433 or
MD39703 may be more stable and could be stable in solid form of
various doses. Meanwhile, water solubility of compounds of MD39551,
MD39433 or MD39703 may be higher than carboplatin, providing
significantly more possibility of formulations and
administration.
[0077] In some embodiments, the pharmaceutical composition may
consist of the compounds of the co-crystals of the present
invention. In some embodiments, the pharmaceutical composition may
comprise the compounds of the co-crystals of the present invention
and at least one additional therapeutic agent or adjuvant therapy
agent. The additional therapeutic agent or adjuvant therapy agent
may be selected from but is not limited to: folic acid, coenzyme
Q10, curcumin, glutathione (GSH), aloe vera, oryzanol,
5-fluorouracil, bortezomib, or a combination thereof. Depending on
the particular disease to be treated, the additional therapeutic
agent or adjuvant therapy agent may include drugs already known. In
some embodiments, the additional therapeutic agent or adjuvant
therapy agent may include drugs that have already been clinically
accepted to treat or prevent the disease.
[0078] In some embodiments, the pharmaceutical composition may
comprise the compounds of the co-crystals of the present invention
and a pharmaceutically acceptable carrier or excipient.
"Pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" is intended to include any and all solvents,
dispersion media, coatings, antibacterial and antifungal agents,
isotonic and absorption delaying agents, and inert ingredients. The
use of such pharmaceutically acceptable carriers or
pharmaceutically acceptable excipients for active pharmaceutical
ingredients is well known in the art. Except insofar as any
conventional pharmaceutically acceptable carrier or
pharmaceutically acceptable excipient is incompatible with the
active pharmaceutical ingredient, its use in the therapeutic
compositions of the invention is contemplated. Additional active
pharmaceutical ingredients, such as other drugs, can also be
incorporated into the described compositions and methods.
[0079] In yet another aspect, the amount of the compound of the
co-crystals of the present invention in the pharmaceutical
composition administered to a subject may be about 0.005 to 20
mg/kg body weight, about 0.005 to 10 mg/kg body weight, about 0.005
to 5 mg/kg body weight, about 0.005 to 2.5 mg/kg body weight, 0.01
to 20 mg/kg body weight, about 0.01 to 10 mg/kg body weight, about
0.01 to 5 mg/kg body weight, about 0.01 to 2.5 mg/kg body weight,
0.1 to 20 mg/kg body weight, about 0.1 to 10 mg/kg body weight,
about 0.1 to 5 mg/kg body weight, or about 0.1 to 2.5 mg/kg body
weight. The specific amount of the compound depends on the
particular disease to be treated and the subject's specific
conditions.
[0080] In yet another aspect, the administration of the
pharmaceutical composition comprising the compounds of the
co-crystals of the present invention may last at least 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42, 49, 56, 63, 70,
77, 84, 91 or 98 days. In some embodiments, the administering of
the pharmaceutical composition may last at least one week. In some
embodiments, the administering of the pharmaceutical composition
may last at least two weeks. The specific period of administration
depends on the particular disease to be treated and the subject's
specific conditions.
[0081] The present invention in various aspects and embodiments
involves uses of the co-crystals of the present invention for the
prevention or treatment of various diseases and methods of treating
or preventing the diseases by administering a pharmaceutical
composition comprising the compounds of the co-crystals of the
present invention. The diseases to be treated or prevented include
but are not limited to cancers and viral infections. For example,
the co-crystals may be MD39551, MD39433 or MD39703.
[0082] In some embodiments, the disease is a cancer. In some
embodiments, the cancer is selected from: bladder cancer, non-small
cell lung cancer, cervical cancer, anal cancer, pancreatic cancer,
squamous cell carcinoma including head and neck cancer, renal cell
carcinoma, basal-cell skin cancer (BCC), squamous-cell skin cancer
(SCC), melanoma, ovarian cancer, small cell lung cancer,
endometrial cancer, glioblastoma, astroycytoma, oligodendroglioma,
ependymoma, neurofibrosarcoma, meningioma, gastrointestinal stromal
tumor, breast cancer, lung cancer, colorectal cancer, thyroid
cancer, bone sarcoma, stomach cancer, oral cavity cancer,
oropharyngeal cancer, gastric cancer, renal adenocarcinoma, liver
cancer, prostate cancer, esophageal cancer, testicular cancer,
gynecological cancer, colorectal cancer, brain cancer, leukemia,
leucocythemia, chronic lymphocytic leukemia (CLL), small
lymphocytic leukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse
large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle
cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic
leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's
macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, and
myelofibrosis.
[0083] In some embodiments, the pharmaceutical composition
comprising the compound of the co-crystals of the present invention
may be used to prevent or treat prostate cancer, colorectal cancer,
or renal adenocarcinoma. In some embodiments, the therapeutically
effective amount of the co-crystals of the present invention to
prevent or treat cancer may about 0.01 to about 10 mg/kg body
weight. In another embodiment, the therapeutically effective amount
of the compound of the co-crystals of the present invention to
prevent or treat cancer is about 0.01 to about 5 mg/kg body
weight.
[0084] In some embodiments, the disease is a viral infection. In
some embodiments, the virus is a DNA virus or an RNA virus. For
example, in some embodiments the virus may be a DNA virus such as
but not limited to adenovirus, herpes simplex virus, human
pepillomavrus, VITAMIN K virus, smallpox virus, hepatitis B virus
(HBV), and parvovirus B19. In other embodiments, the virus may be
an RNA virus such as but not limited to human astrovirus, norwalk
virus, hepatitis A virus (HAV), severe acute respiratory syndrome
virus, hepatitis C virus (HCV), yellow fever virus, dengue virus,
West Nile virus, TBE virus, rubella virus, hepatitis E virus (HEV),
human immunodeficiency virus (HIV), influenza virus, Lassa virus
(LASV), Crimean-Congo hemorrhagic fever virus, Hantaan virus, Ebola
virus, Marburg virus, Measles virus, mumps virus, parainfluenza
virus, respiratory syncytial virus, rabies virus, and hepatitis D
virus (HDV), rotavirus, orbivirus, coltivirus, Banna virus.
[0085] In some embodiments, the pharmaceutical composition may be
used to prevent or treat viral infections caused by HBV, HCV, HIV
or Hantaan virus. In some embodiments, the therapeutically
effective amount of the compound of the co-crystals of the present
invention to prevent or treat viral infection is about 0.01 to
about 10 mg/kg body weight. In another embodiment, the
therapeutically effective amount of the compound of the co-crystals
of the present invention to prevent or treat cancer is about 0.01
to about 5 mg/kg body weight.
[0086] In some embodiments, the present invention provides a method
of treating, preventing, reducing or alleviating the symptoms of,
and/or slowing or halting the progress of prostate cancer,
colorectal cancer, renal adenocarcinoma or leucocythemia in a
subject in need thereof, the method comprising administrating to
the subject an effective amount of a pharmaceutical composition
comprising the compound of the co-crystals of the present
invention. In some embodiments, the pharmaceutical composition
consists of the compound of the co-crystals of the present
invention. In some embodiments, the pharmaceutical composition
further comprises at least one additional therapeutic agent or
adjuvant therapy agent. In a specific embodiment, the additional
therapeutic agent or adjuvant therapy agent may be selected from:
folic acid, coenzyme Q10, curcumin, glutathione (GSH), aloe vera,
oryzanol, 5-fluorouracil, and bortezomib. In some embodiments, the
pharmaceutical composition comprises the compound of the
co-crystals of the present invention and a pharmaceutically
acceptable carrier or excipient.
[0087] In some embodiments, the present invention provides a method
of treating, preventing, reducing or alleviating the symptoms of,
and/or slowing or halting the progress of prostate cancer, the
method comprising administrating to the subject an effective amount
of a pharmaceutical composition comprising the compound of
co-crystal MD39551.
[0088] In some embodiments, the present invention provides a method
of treating, preventing, reducing or alleviating the symptoms of,
and/or slowing or halting the progress of colorectal cancer, the
method comprising administrating to the subject an effective amount
of a pharmaceutical composition comprising the compound of
co-crystal MD39433 or MD39703.
[0089] In some embodiments, the present invention provides a method
of treating, preventing, reducing or alleviating the symptoms of,
and/or slowing or halting the progress of viral infections caused
by HBV, HCV, HIV or Hantaan virus in a subject in need thereof, the
method comprising administrating to the subject an effective amount
of a pharmaceutical composition comprising the compound of the
co-crystals of the present invention. In some embodiments, the
pharmaceutical composition consists of the compound of the
co-crystals of the present invention. In some embodiments, the
pharmaceutical composition further comprises at least one
additional therapeutic agent or adjuvant therapy agent. In a
specific embodiment, the additional therapeutic agent or adjuvant
therapy agent may be selected from: folic acid, coenzyme Q10,
curcumin, glutathione (GSH), aloe vera, oryzanol, 5-fluorouracil,
and bortezomib. In some embodiments, the pharmaceutical composition
comprises the compound of the co-crystals of the present invention
and a pharmaceutically acceptable carrier or excipient.
[0090] In some embodiments, the administration of the
pharmaceutical composition according to the present invention can
be via any common route as long as the target issue is available
via the route. Suitable routes may include oral, buccal, by
inhalation spray, sublingual, rectal, transdermal, vaginal,
transmucosal, topical, nasal or intestinal administration;
parenteral delivery, including intramuscular, subcutaneous,
intramedullary injections, as well as intrathecal, direct
intraventricular, orthotopic, intrademal, intraperitoneal,
intravenous, intra-articular, intra-sternal, intra-synovial,
intra-hepatic, intralesional, intracranial, intraperitoneal,
intranasal, or intraocular injections or other modes of delivery.
The preferred delivery route depends on the particular disease to
be treated and the subject's specific conditions.
[0091] In some embodiments, for prevention or treatment of prostate
cancer, colorectal cancer, renal adenocarcinoma or leucocythemia,
the pharmaceutical composition comprising the compound of the
co-crystals of the present invention is administered with infusion,
injections or via the oral route. In some embodiments, for
prevention or treatment of prostate cancer, colorectal cancer,
renal adenocarcinoma or leucocythemia, the pharmaceutical
composition comprising the compound of the co-crystals of the
present invention is administered for at least one, two or three
weeks.
[0092] In some embodiments, for prevention or treatment of viral
infections caused by HBV, HCV, HIV or Hantaan virus, the
pharmaceutical composition comprising the compound of the
co-crystals of the present invention is administered with infusion,
injections or via the oral route. In some embodiments, for
prevention or treatment of viral infections caused by HBV, HCV, HIV
or Hantaan virus, the pharmaceutical composition comprising the
compound of the co-crystals of the present invention is
administered for at least one, two or three weeks.
EXAMPLES
[0093] The effects of the co-crystal of the present invention on
certain diseases are shown in the following example. In addition,
the process of making the co-crystals of the present invention and
the physiochemical properties of these crystals are also described.
These examples do not in any way limit the scope of the
invention.
[0094] A number of co-crystals are produced by mixing a platinum
analogue with a diacid. The resulting co-crystals meet partly or
completely the targeted objectives, such as increased solubility,
stability and bioavailability and more versatile in pharmaceutical
use compared to carboplatin or other platin compounds.
[0095] In comparison with carboplatin, the co-crystal of the
current inventions is more stable and can be stable in solid forms.
In comparison to the reported platin analogues for the treatment of
cancer cells, some of the co-crystals of the current inventions are
less toxic and much stable than cisplatin and carboplatin.
[0096] The inventors have determined that the formation of
crystalline polymorphic forms was confirmed with various methods
such as but not limited to XRPD, HPLC, .sup.1H-NMR; DSC and SEM.
Amorphous forms of the co-crystal and other forms may be existent
using different crystallization process.
[0097] The Effects of MD-39551 on Prostate Cancer Cells
[0098] The co-crystal MD-39551, which comprises the platinum
analogue of formula Pt-01 and the diacid of formula CF-08 bonded at
1:1 ratio, was tested in the treatment of prostate cancers and
compared to docetaxel and cisplatin, widely accepted drugs for
prostate cancer patients.
[0099] PC-3 cells are a cell line derived from advanced prostate
cancer patient with bone metastasis and are characteristic of
prostate cancer such as prostate small cell carcinoma. PC-3 cells
were treated with drugs (MD-39551, docetaxel, or cisplatin) at
step-wise concentrations, and the cell viability was evaluated with
the CellTiter 96 AQueous One Solution Cell Proliferation Assay from
Promega Corp. (Madison, Wis., USA). The index of cell growth
repression ratio was obtained by comparing the OD490 data of
treatment group to the negative control. The drug response rate
IC.sub.50 was calculated with the SPSS 16.0 system. The results are
shown in FIG. 1.
[0100] The IC.sub.50 of MD-39551 was 47.186 .mu.M, while IC.sub.50
of docetaxel and cisplatin were 49.924 .mu.M and 2.489 .mu.M
respectively (FIG. 1).
[0101] LNCaP cells are a cell line derived from advanced prostate
cancer patient with lymph node metastasis. LNCaP cells were treated
with drugs (MD-39551, docetaxel, or cisplatin) at step-wise
concentrations, and the cell viability was evaluated with the
CellTiter 96 AQueous One Solution Cell Proliferation Assay from
Promega Corp. (Madison, Wis., USA). The index of cell growth
repression ratio was obtained by comparing the OD490 data of
treatment group to the negative control. The drug response rate
IC.sub.50 was calculated with the SPSS 16.0 system. The results are
shown in FIG. 2.
[0102] For LNCaP cells, the IC.sub.50 of MD-39551 was 33.232 .mu.M;
the IC.sub.50s of docetaxel and cisplatin were 4.034 .mu.M and
2.245 .mu.M respectively (FIG. 2).
[0103] HL-7002 cells are an immortalized human fetal hepatic cell
line. HL-7002 cells were treated with drugs (MD-39551, docetaxel,
or cisplatin) at step-wise concentrations, and the cell viability
was evaluated with the CellTiter 96 AQueous One Solution Cell
Proliferation Assay from Promega Corp. (Madison, Wis., USA). The
index of cell growth repression ratio was obtained by comparing the
OD490 data of treatment group to the negative control. The drug
response rate IC.sub.50 was calculated with the SPSS 16.0 system.
The results are shown in FIG. 3.
[0104] For HL-7002 cells, while no MD-39551 toxicity was detected,
docetaxel and cisplatin showed significant toxicity. The IC.sub.50
of docetaxel and cisplatin were 0.095 .mu.M and 2.008 .mu.M
respectively (FIG. 3).
[0105] HEK293 cells are an immortalized human fetal kidney cell
line. HEK293 cells were treated with drugs (MD-39551, docetaxel, or
cisplatin) at step-wise concentrations, and the cell viability was
evaluated with the CellTiter 96 AQueous One Solution Cell
Proliferation Assay from Promega Corp. (Madison, Wis., USA). The
index of cell growth repression ratio was obtained by comparing the
OD490 data of treatment group to the negative control. The drug
response rate IC.sub.50 was calculated with the SPSS 16.0 system.
The results are shown in FIG. 4.
[0106] For HEK293 cells, while no MD-39551 toxicity was detected,
docetaxel and cisplatin showed significant toxicity. The IC.sub.50
of docetaxel and cisplatin were 1.741 .mu.M and 6.899 .mu.M,
respectively (FIG. 4.).
[0107] Methods and Strategies:
[0108] Cell culture: Prostate cancer cell lines LNCaP and PC-3 were
purchased from ATCC (Manassas, Va.). The fetal hepatocytes HL-7002
and human embryonic kidney cells HEK393 were purchased from ATCC.
The cells were cultured in RPMI+5% Fetal Bovine Serum (FBS).
[0109] Drug treatment and cell viability (MTS) assay: The cells
(105/100 mL/well) were cultured in a 96 well plate, and treated
with drugs (e.g. MD-39551) at step-wise concentrations from 0.01 to
300 .mu.M. The cells treated with the solvents were used as the
negative control, and cisplatin and docetaxel were used as the
positive controls. The cells were monitored daily, and the cell
viability was evaluated with the Promega CellTiter 96 AQueous One
Solution Cell Proliferation Assay (Promega, Madison, Wis., USA)
according to the manufacture manuals. The cell viability was
monitored at OD490 reading in a bio-spectrometer (Perkin Elmer,
Walthan, Mass., USA).
[0110] Data analysis: The OD490 reading data were collected hourly
from 1 h to 4 h after the addition of lysis buffer. The index of
cell growth repression ratio was obtained by comparing the OD490
data of treatment to the negative control. The drug response rate
IC.sub.50 was calculated with the SPSS 16.0.
[0111] Summary of Effects:
[0112] For PC-3, a cell line derived from advanced prostate cancer
patient with bone metastasis, MD-39551 showed similar cellular
toxicity to docetaxel, but weaker than for Cisplatin. For LNCaP, a
cell line derived from advanced prostate cancer patient with lymph
node metastasis, the cellular toxicity of MD-39551 was weaker than
docetaxel and cisplatin. For HL-7002 and HEK293 cells, which
respectively represent normal human hepatic cells and kidney cells,
while MC-39551 showed no toxicity, both docetaxel and cisplatin
demonstrated high toxicity.
[0113] The Effects of MD-39703 and MD-39433 on Colorectal Cancer
Cells
[0114] The co-crystals MD-39703 and MD-39433 was tested in the
treatment of colorectal cancers in comparison to oxaliplatin and
fluorouracil (5-FU), widely used drugs in treating colorectal
cancer patients. MD-39703 comprises the platinum analogue of
formula Pt-02 and the diacid of formula CF-08 bonded at 1:1 ratio;
MD-39433 comprises the platinum analogue of formula Pt-02 and the
diacid of formula CF-01 bonded at 1:1 ratio.
[0115] HCT-116 cells are a colorectal cancer cell line. HCT-116
cells were treated with drugs (MD-39703, MD-39433, oxaliplatin, or
5-FU) at step-wise concentrations, and the cell viability was
evaluated with the CellTiter 96 AQueous One Solution Cell
Proliferation Assay from Promega Corp. (Madison, Wis., USA). The
index of cell growth repression ratio was obtained by comparing the
OD490 data of treatment group to the negative control. The drug
response rate IC.sub.50 was calculated with the SPSS 16.0 system.
The results are shown in FIG. 5.
[0116] For the reduction of HCT-116 cell number, the IC.sub.50 of
MD-39703 was 26.019 .mu.M and IC.sub.50 of MD-39433 was 25.293;
IC.sub.50s of oxaliplatin and 5-FU were be 8.151 .mu.M and 4.214
.mu.M respectively (FIG. 5).
[0117] HT29 cells are a colorectal cancer cell line. HT29 cells
were treated with drugs (MD-39703, MD-39433, oxaliplatin, or 5-FU)
at step-wise concentrations, and the cell viability was evaluated
with the CellTiter 96 AQueous One Solution Cell Proliferation Assay
from Promega Corp. (Madison, Wis., USA). The index of cell growth
repression ratio was obtained by comparing the OD490 data of
treatment group to the negative control. The drug response rate
IC.sub.50 was calculated with the SPSS 16.0 system. The results are
shown in FIG. 6.
[0118] For HT29 cells, the IC.sub.50 of MD-39703 was 24.865 .mu.M
and IC.sub.50 of MD-39433 was 24.941; IC.sub.50, of oxaliplatin and
5-FU were determined to be 29.993 .mu.M and 7.556 respectively
(FIG. 6).
[0119] HL-7002 hepatocyte cell line cells were treated with drugs
(MD-39703, MD-39433, oxaliplatin, or 5-F U) at step-wise
concentrations, and the cell viability was evaluated with the
CellTiter 96 AQueous One Solution Cell Proliferation Assay from
Promega Corp. (Madison, Wis., USA). The index of cell growth
repression ratio was obtained by comparing the OD490 data of
treatment group to the negative control. The drug response rate
IC.sub.50 was calculated with the SPSS 16.0 system. The results are
shown in FIG. 7.
[0120] For HL-7002 cells, no toxicity was detected for MD-39703 and
MD-39433. IC.sub.50s of oxaliplatin and 5-FU were 2.44 .mu.M and
4.418 .mu.M, respectively (FIG. 7).
[0121] HEK293 kidney cell line cells were treated with drugs
(MD-39703, MD-39433, oxaliplatin, or 5-FU) at step-wise
concentrations, and the cell viability was evaluated with the
CellTiter 96 AQueous One Solution Cell Proliferation Assay from
Promega Corp. (Madison, Wis., USA). The index of cell growth
repression ratio was obtained by comparing the OD490 data of
treatment group to the negative control. The drug response rate
IC.sub.50 was calculated with the SPSS 16.0 system. The results are
shown in FIG. 8.
[0122] For HEK293, no toxicity was detected for MD-39703 and
MD-39433. IC.sub.50s of oxaliplatin and 5-FU were 10.131 .mu.M and
3.744 .mu.M respectively (FIG. 8).
[0123] Methods and Strategies:
[0124] Cell culture: Colorectal cancer cell lines HCT-116 and HT29
were purchased from ATCC (Manassas, Va.). The fetal hepatocytes
HL-7002 and human embryonic kidney cells HEK393 were purchased from
ATCC. The cells were cultured in RPMI+5% Fetal Bovine Serum
(FBS).
[0125] Drug treatment and cell viability (MTS) assay: The cells
(105/100 mL/well) were cultured in a 96 well plate, and treated
with drugs (e.g. MD-39703, MD-39433, oxaliplatin, or 5-FU) at
step-wise concentrations from 0.01 to 300 .mu.M. The cells treated
with the solvents were used as the negative control, and cisplatin
and docetaxel were used as the positive controls. The cells were
monitored daily, and the cell viability was evaluated with the
Promega CellTiter 96 AQueous One Solution Cell Proliferation Assay
(Promega, Madison, Wis., USA) according to the manufacture manuals.
The cell viability was monitored at OD490 reading in a
bio-spectrometer (Perkin Elmer, Walthan, Mass., USA).
[0126] Data analysis: The OD490 reading data were collected hourly
from 1 h to 4 h after the addition of lysis buffer. The index of
cell growth repression ratio was obtained by comparing the OD490
data of treatment to the negative control. The drug response rate
IC.sub.50 was calculated with the SPSS 16.0.
[0127] Summary of Effects:
[0128] For colorectal cancer cell line HCT-116, MD-39703 and
MD-39433 showed weaker but comparable toxicity than for oxaliplatin
and 5-FU. For colorectal cancer cell line HT29, MD-39703 and
MD-39433 showed a weaker but comparable toxicity than for
oxaliplatin, and stronger toxcity than for 5-FU. For HL-7002, an
immortalized human fetal hepatic cell line, MD-39703 and MD-39433
showed no toxicity. For HEK293, an immortalized human fetal kidney
cell line, MD-39703 and MD-39433 showed no toxicity.
[0129] Process to Produce the Co-Crystals and their
Charaterizations
[0130] Each of the co-crystals of the current invention was formed
from a platinum analogues and a diacid as co-crystal formers. The
co-crystals were obtained by slurrying or grinding platinum
analogues and diacids in no solvent or some solvent or mixture of
solvents, or by treating the solution with one or more of several
methods, e.g., stepwise heating and cooling the solution,
evaporation of the co-crystal formers solution, freeze drying of
the co-crystal formers solution, cooling and evaporation of the
co-crystal formers solution.
[0131] Some crystalline polymorphic forms of the co-crystals of the
present invention were first produced. Amorphous forms of the
co-crystal and other forms may be existent using different methods
such as but not limited to crystallization processes. Polymorphic
forms of the co-crystal of platinum analogues were confirmed by
X-Ray powder diffraction (XRPD), thermal gravimetric analysis (TGA)
and differential scanning calorimetry (DSC), scanning electron
microscopy (SEM), and other methods. Analysis of the co-crystals
showed that each co-crystal contains one platinum analogue and the
corresponding diacid in a 1:1 mol ratio. Different ratios of the
platinum analogues and the acids may exist using different
processes.
[0132] Some representative co-crystals with platinum analogues and
diacids as co-crystal formers are listed in Table 7.
TABLE-US-00007 TABLE 7 Co-crystal Formula number Characterizations
##STR00060## MD36042 HPLC, MS, .sup.1H-NMR XRPD (FIG. 9); SEM (FIG.
10); ##STR00061## MD39551 HPLC, MS, .sup.1H-NMR XRPD (FIG. 11); DSC
(FIG. 12); SEM (FIG. 13) ##STR00062## MD39433 HPLC, MS, .sup.1H-NMR
XRPD (FIG. 15); SEM (FIG. 16) ##STR00063## MD39442 HPLC, MS,
.sup.1H-NMR XRPD (FIG. 14) ##STR00064## MD39703 HPLC, MS,
.sup.1H-NMR XRPD (FIG. 17); DSC (FIG. 18); SEM (FIG. 19)
##STR00065## HP309 HPLC, MS, .sup.1H-NMR XRPD (FIG. 20)
##STR00066## MD3176 HPLC, MS, .sup.1H-NMR XRPD (FIG. 21)
Experiment 1
[0133] Mixtures of 550 mg of carboplatin (Pt-01), 300 mg of
cis-endo-5-Norbornene-2,3-dicarboxylic acid (CF-08) and 3.0 mL of
distilled water were stirred around 30.degree. C. for 5 hours. Then
more distilled water was added to dissolve the mixtures. The
obtained solution was filtered through a 0.45 um filter and the
solution was dried by stepwise cooling. After cooling dry, the
resulted crude crystal was treated with ethanol and heptane and 448
mg of pure crystal (MD-39551) was obtained. Its characterization by
XRPD, DSC/TGA and .sup.1H-NMR confirmed the structure the same as
indicated in the Table 6.
Experiment 2
[0134] Mixtures of 400 mg of lobaplatin (Pt-05 in Table 1), 400 mg
of 1,1-cyclobutane dicarboxylate (CF-01 in Table 6) and 3.0 mL of
distilled water were stirred around 30.degree. C. for 5 hours. Then
the reaction was cooled to 0-5.degree. C. and stirred over 5 hours.
The resulted crude crystal was obtained by filtering and was washed
by cooling distilled water, ethanol and heptane. After dried in
vacuum, and 417 mg of pure crystal was obtained. It was analyzed by
HPLC, MS and .sup.1H-NMR. The characterization indicated 1:1 ratio
of lobaplatin to 1,1-cyclobutane dicarboxylate in this co-crystal
(MD-3176) structure. Its characterization by XRPD, DSC/TGA and
.sup.1H-NMR confirmed the structure the same as indicated in the
Table 6.
Experiment 3
[0135] Mixtures of 400 mg of lobaplatin (Pt-05 in Table 1), 520 mg
of CF-10A (CF-10A in Table 6) and 3.0 mL of distilled water were
stirred around 30.degree. C. for 5 hours. Then the reaction was
cooled to 0-5.degree. C. and stirred over 5 hours. The resulted
crude crystal was obtained by filtering and was washed by cooling
distilled water, ethanol and heptane. After dried in vacuum, and
406 mg of pure crystal was obtained. It was analyzed by HPLC, MS
and .sup.1H-NMR. The characterization indicated 1:1 ratio of
lobaplatin to 1,1-cyclobutane dicarboxylate in this co-crystal
structure.
Experiment 4
[0136] Mixtures of 400 mg of lobaplatin (Pt-05 in Table 1), 532 mg
of CF-10B (CF-10B in Table 6) and 3.0 mL of distilled water were
stirred around 30.degree. C. for 5 hours. Then the reaction was
cooled to 0-5.degree. C. and stirred over 5 hours. The resulted
crude crystal was obtained by filtering and was washed by cooling
distilled water, ethanol and heptane. After dried in vacuum, and
375 mg of pure crystal was obtained. It was analyzed by HPLC, MS
and .sup.1H-NMR. The characterization indicated 1:1 ratio of
lobaplatin to 1,1-cyclobutane dicarboxylate in this co-crystal
structure.
Experiment 5
[0137] Mixtures of 400 mg of lobaplatin (Pt-05 in Table 1), 540 mg
of CF-10C (CF-10C in Table 6) and 3.0 mL of distilled water were
stirred around 30.degree. C. for 5 hours. Then the reaction was
cooled to 0-5.degree. C. and stirred over 5 hours. The resulted
crude crystal was obtained by filtering and was washed by cooling
distilled water, ethanol and heptane. After dried in vacuum, and
427 mg of pure crystal was obtained. It was analyzed by HPLC, MS
and .sup.1H-NMR. The characterization indicated 1:1 ratio of
lobaplatin to 1,1-cyclobutane dicarboxylate in this co-crystal
structure.
Experiment 6
[0138] Mixtures of 400 mg of lobaplatin (Pt-05 in Table 1), 540 mg
of CF-10D (CF-10D in Table 6) and 3.0 mL of distilled water were
stirred around 30.degree. C. for 5 hours. Then the reaction was
cooled to 0-5.degree. C. and stirred over 5 hours. The resulted
crude crystal was obtained by filtering and was washed by cooling
distilled water, ethanol and heptane. After dried in vacuum, and
465 mg of pure crystal was obtained. It was analyzed by HPLC, MS
and .sup.1H-NMR. The characterization indicated 1:1 ratio of
lobaplatin to 1,1-cyclobutane dicarboxylate in this co-crystal
structure.
Experiment 7
[0139] Mixtures of 400 mg of lobaplatin (Pt-05 in Table 1), 550 mg
of Lactic acid and 20.0 mL of distilled water were stirred around
30.degree. C. for 5 hours. Then the obtained solution was filtered
through 0.45 um filter and the solution was dried by stepwise
cooling. After cooling dry, the resulted crude crystal was treated
with ethanol and heptane and 355 mg of pure crystal was obtained.
It was analyzed by HPLC, MS and .sup.1H-NMR. The characterization
indicated 1:1 ratio of lobaplatin to Lactic acid in this co-crystal
structure.
Experiment 8
[0140] General procedure for the preparation of co-crystals based
on 1,1-cyclobutane dicarboxylate (CF-01 in Table 6) as a co-crystal
former with one platinum analogue from Pt-02, Pt-03, Pt-04, Pt-05,
Pt-06, Pt-07, Pt-08, Pt-09, Pt-10, Pt-11, Pt-12, Pt-13, Pt-14,
Pt-15, Pt-16, Pt-17, Pt-18, Pt-19, Pt-20, Pt-21, Pt-22, Pt-23,
Pt-24, Pt-25, Pt-26, Pt-27, Pt-28, Pt-29, Pt-30, Pt-31, Pt-32, and
Pt-33,
[0141] Mixtures of 1.0 mmol of any one platin analogues, 400 mg of
1,1-cyclobutane dicarboxylate (CF-01 in Table 6) and 3.0 mL of
distilled water are stirred around 30.degree. C. for 5 hours. Then
the reaction is cooled to 0-5.degree. C. and stirred over 5 hours.
The resulted crude crystal is obtained by filtering and washed by
cooling distilled water, ethanol and heptane. After dried in
vacuum, and the desired pure crystal is obtained. Some products are
analyzed by XRPD, DSC, HPLC, MS and .sup.1H-NMR. The
characterization indicate 1:1 ratio of selected platin analogues to
1,1-cyclobutane dicarboxylate in this co-crystal structure.
Experiment 9
[0142] Mixtures of 859 mg of Pt-36 (Pt-31 in Table 5), 1.36 g of
1,1-cyclobutane dicarboxylate (CF-01 in Table 6) and 10.0 mL of
distilled water were stirred around 20.degree. C. for 10 hours.
Then the reaction was cooled to 0-5.degree. C. and stirred over 5
hours. The resulted crude crystal was obtained by filtering and was
washed by cooling distilled water, ethanol and heptane. After dried
in vacuum, and 1.15 g of pure crystal was obtained. It was analyzed
by HPLC, MS and .sup.1H-NMR. The characterization indicated 1:1
ratio of Pt-31 (Pt-31 in Table 5) to 1,1-cyclobutane dicarboxylate
in this co-crystal structure.
Experiment 10
[0143] Mixtures of 400 mg of nedaplatin (Pt-03 in Table 1), 520 mg
of phenylmalonic acid (CF-10A in Table 6) and 3.0 mL of distilled
water were stirred around 30.degree. C. for 5 hours. Then the
reaction was cooled to 0-5.degree. C. and stirred over 5 hours. The
resulted crude crystal was obtained by filtering and was washed by
cooling distilled water, ethanol and heptane. After dried in
vacuum, and 470 mg of pure crystal was obtained. It was analyzed by
HPLC, MS and .sup.1H-NMR. The characterization indicated 1:1 ratio
of nedaplatin to phenylmalonic acid in this co-crystal
structure.
Experiment 11
[0144] Mixtures of 410 mg of Pt-06 (Pt-06 in Table 1), 600 mg of
1,1-cyclobutane dicarboxylate (CF-01 in Table 6) and 5.0 mL of
toluene was stirred around 30.degree. C. for 5 hours. Then the
reaction was cooled to 0-5.degree. C. and stirred over 5 hours. The
resulted crude crystal was obtained by filtering and was washed by
pre-cooled toluene, ethanol and heptane. After dried in vacuum, and
220 mg of pure crystal was obtained. It was analyzed by HPLC, MS
and .sup.1H-NMR. The characterization indicated 1:1 ratio of Pt-06
to 1,1-cyclobutane dicarboxylate in this co-crystal structure.
Experiment 12
[0145] Mixtures of 466 mg of Pt-28 (Pt-21 in Table 5), 520 mg of
tartaric acid and 5.0 mL of distilled water was stirred around
30.degree. C. for 5 hours. Then the reaction was cooled to
0-5.degree. C. and stirred over 5 hours. The resulted crude crystal
was obtained by filtering and was washed by pre-cooled distilled
water, ethanol and heptane. After dried in vacuum, and 420 mg of
pure crystal was obtained. It was analyzed by HPLC, MS and
.sup.1H-NMR. The characterization indicated 1:1 ratio of Pt-21 to
tartaric acid in this co-crystal structure.
Experiment 13
[0146] Mixtures of 580 mg of Pt-32 (Pt-32 in Table 5), 720 mg of
phenylmalonic acid (CF-10A in Table 5) and 7.0 mL of distilled
water was stirred around 30.degree. C. for 5 hours. Then the
reaction was cooled to 0-5.degree. C. and stirred over 5 hours. The
resulted crude crystal was obtained by filtering and was washed by
pre-cooled distilled water, ethanol and heptane. After dried in
vacuum, and 437 mg of pure crystal was obtained. It was analyzed by
HPLC, MS and .sup.1H-NMR. The characterization indicated 1:1 ratio
of Pt-32 to phenylmalonic acid in this co-crystal structure.
Experiment 14
[0147] Mixtures of 526 mg of Pt-33 (Pt-28 in Table 5), 520 mg of
critic acid and 5.0 mL of distilled water was stirred around
30.degree. C. for 5 hours. Then the reaction was cooled to
0-5.degree. C. and stirred over 10 hours. The resulted crude
crystal was obtained by filtering and was washed by pre-cooled
distilled water, ethanol and heptane. The crude solid was purified
by re-crystallization in water. After dried in vacuum, and 320 mg
of pure crystal was obtained. It was analyzed by HPLC, MS and
.sup.1H-NMR. The characterization indicated 1:1 ratio of Pt-28 to
critic acid in this co-crystal structure.
Experiment 15
[0148] Mixtures of 465 mg of Pt-21 (Pt-21 in Table 5), 522 mg of
1,2-cis-cyclobutane dicarboxylate (CF-04 in Table 6) and 5.0 mL of
distilled water was stirred around 20.degree. C. for 7 hours. Then
the reaction was cooled to 0-5.degree. C. and stirred over 10
hours. The resulted crude crystal was obtained by filtering and was
washed by pre-cooled distilled water, ethanol and heptane. The
crude solid was purified by re-crystallization in water. After
dried in vacuum, and 458 mg of pure crystal was obtained. It was
analyzed by HPLC, MS and .sup.1H-NMR. The characterization
indicated 1:1 ratio of Pt-21 to 1,2-cis-cyclobutane dicarboxylate
in this co-crystal structure.
[0149] Analytical Methods
[0150] X-Ray Powder Diffraction (XRPD):
[0151] Polarized light microscopic picture was captured at room
temperature (RT). X-ray intensity data were collected at 296(2) K
using a Bruker APEX 11 CCD diffractometer (Mo K.alpha. radiation,
.lamda.=0.71073 .ANG.). XRPD pattern was collected by Panalytical
Empyrean system at RT. Direct methods structure solution,
difference Fourier calculations and full-matrix least-squares
refinement against F2 were performed with SHELXTL and OLEX2, See
Sheldrick G M. Acta Crystallogr A, 64: 112-122, 2008; and O. V.
Dolomanov, et al. J. Appl. Cryst. 42, 339-341, 2009; and
Brandenburg, K. DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany.
Molecular graphics were created according to Brandenburg, K.
DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany.
[0152] Analytical Instrument: Panalytical Empyrean. The X-ray
powder diffraction was conducted by mounting a sample of the
crystalline material on a Si single crystal low-background holder
and spreading out the sample into a thin layer with the aid of a
microscope slide. The 2.theta. position was calibrated against
Panalytical 640 Si powder standard. The sample was irradiated with
X-rays generated by a copper long-fine focus tube operated at 45 kV
and 40 mA with a wavelength of K.alpha.1=1.540589 angstroms and
K.alpha.2=1.544426 angstroms (K.alpha.2/K.alpha.1 intensity ratio
is 0.50). The collimated X-ray source was passed through a
programmed divergence slit set at 10 mm and the reflected radiation
directed through a 5.5 mm anti-scatter slit. The sample was exposed
for 16.3 seconds per 0.013.degree. 2-theta increment (continuous
scan mode) over the range 3 degrees to 40 degrees 2-theta in
theta-theta mode. The running time was 3 minutes and 57 seconds.
The instrument was equipped with a RTMS detector (X'Celerator).
Control and data capture was by means of a Dell Optiplex 780 XP
operating with data collector software.
[0153] Persons skilled in the art of X-ray powder diffraction will
realize that the relative intensity of peaks can be affected by,
for example, grains above 30 microns in size and non-unitary aspect
ratios that may affect analysis of samples. The skilled person will
also realize that the position of reflections can be affected by
the precise height at which the sample sits in the diffractometer
and the zero calibration of the diffractometer. The surface
planarity of the sample may also have a limited effect. Hence the
diffraction pattern data presented are not intended to be limited
to the absolute values.
Differential Scanning Calorimetry (DSC)
[0154] DSC was used as a thermoanalytical method to measure the
difference in the amount of heat required to increase the
temperature of a sample and reference was measured as a function of
temperature. The general process of DSC is known and the specific
instruments and conditions in the following Examples were as
follows:
[0155] Analytical Instrument: TA Instruments Q2000 DSC;
[0156] Heating rate: 10.degree. C. per minute; and Purge gas:
nitrogen.
Thermal Gravimetric Analysis (TGA)
[0157] TGA was used to measure changes in physical and chemical
properties of samples as a function of increasing temperature (with
constant heating rate), or as a function of time (with constant
temperature and/or constant mass loss). The general process of TGA
is known and the specific instruments and conditions in the
following Examples were as follows:
[0158] Analytical Instrument: TA Instruments Q5000 TGA;
[0159] Heating rate: 10.degree. C. per minute; and
[0160] Purge gas: nitrogen.
[0161] Sample Pharmaceutical Composition and its Administration
[0162] Aqueous or solid pharmaceutical composition of the present
invention comprises an effective amount of the co-crystal of the
current invention, e.g. MD39551, with or without an appropriate
amount of at least one additional therapeutic agent or adjuvant
therapy agent. The co-crystal, as well as the therapeutic agent or
adjuvant therapy agent, may be dissolved or dispersed in a
pharmaceutical acceptable carrier or aqueous media.
[0163] Depending on the particular cancer to be treated,
administration of pharmaceutical composition according to the
present invention can via any common route as long as the target
issue is available via the route. For example, the pharmaceutical
composition may be administered by infusion, injection, or via the
oral route.
[0164] A Number of Pharmaceutical Compositions were Produced:
[0165] Pharmaceutical composition sample A: 70 g of MD-39551 was
dissolved in pre-treated normal saline or 5% of aqueous glucose (in
water) and the final volume of the solution was adjusted to 5.0 L.
Then the solution was filtered through 0.22 um filter and dispersed
into ample bottles with 50.0 mL in each.
* * * * *