U.S. patent application number 16/065402 was filed with the patent office on 2018-12-27 for formulations of phosphoramidate derivatives of nucleoside drugs.
The applicant listed for this patent is NuCana plc. Invention is credited to Hugh Griffith, Gordon Kennovin.
Application Number | 20180369266 16/065402 |
Document ID | / |
Family ID | 55311533 |
Filed Date | 2018-12-27 |
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United States Patent
Application |
20180369266 |
Kind Code |
A1 |
Kennovin; Gordon ; et
al. |
December 27, 2018 |
FORMULATIONS OF PHOSPHORAMIDATE DERIVATIVES OF NUCLEOSIDE DRUGS
Abstract
This invention relates to pharmaceutical formulations and
formulation strategies of protides (phosphoramidate derivatives of
nucleosides) and, in particular, protides useful in the treatment
of cancer, such as NUC-3373
(5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl (benzoxy-L-alaninyl)]
phosphate) and NUC-7738
(3'-deoxyadenosine-5'-O-[phenyl(benzyloxy-L-alaninyl)] phosphate).
In particular, the invention relates to formulations that comprise
a polar aprotic solvent, for example, dimethyl acetamide (DMA).
Inventors: |
Kennovin; Gordon;
(Edinburgh, GB) ; Griffith; Hugh; (Edinburgh,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NuCana plc |
Edinburgh |
|
GB |
|
|
Family ID: |
55311533 |
Appl. No.: |
16/065402 |
Filed: |
December 21, 2016 |
PCT Filed: |
December 21, 2016 |
PCT NO: |
PCT/GB2016/054025 |
371 Date: |
June 22, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 31/7072 20130101; A61K 47/18 20130101; A61K 47/22 20130101;
A61K 47/20 20130101; A61K 31/7076 20130101; A61P 35/02 20180101;
A61K 9/0019 20130101; A61K 9/08 20130101 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076; A61K 9/00 20060101 A61K009/00; A61K 31/7072 20060101
A61K031/7072; A61K 9/08 20060101 A61K009/08; A61K 47/18 20060101
A61K047/18; A61K 47/20 20060101 A61K047/20; A61K 47/22 20060101
A61K047/22; A61P 35/02 20060101 A61P035/02 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 2015 |
GB |
1522764.8 |
Claims
1. A pharmaceutical formulation comprising: a protide; a polar
aprotic solvent; and optionally one or more pharmaceutically
acceptable excipients; wherein the protide is not
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate (NUC-1031).
2. The formulation of claim 1, wherein the polar aprotic solvent is
selected from the group consisting of dimethyl acetamide (DMA),
dimethylsulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP).
3. The formulation of claim 1, wherein the polar aprotic solvent is
DMA.
4. The formulation of claim 1, wherein the formulation further
comprises an aqueous vehicle.
5. (canceled)
6. (canceled)
7. The formulation of claim 1, wherein the formulation further
comprises a solubilizer.
8. (canceled)
9. (canceled)
10. The formulation of claim 1, wherein the formulation comprises:
from 30% to 95% by volume DMA; from 5% to 50% by volume aqueous
vehicle; and from 100 mg to 400 mg per mL protide.
11. (canceled)
12. The formulation of claim 1, wherein the formulation comprises
from 0.1% to 10% by volume DMA; from 0.1% to 10% by volume
solubilizer or solubilizers; from 85% to 99% by volume aqueous
vehicle; and from 2.0 mg to 12.0 mg per mL protide.
13. (canceled)
14. The formulation of claim 1, wherein the protide is
5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl (benzoxy-L-alaninyl)]
phosphate (NUC-3373).
15. The formulation of claim 1, wherein the protide is
3'-deoxyadenosine-5'-O-[phenyl(benzyloxy-L-alaninyl)] phosphate
(NUC-7738).
16. The formulation of claim 1, wherein the protide is
2-chloro-2'-beta-fluoro-2'-deoxyadenosine-5'-[phenyl-(benzoxy-L-alaninyl)-
]-phosphate (CPF-448).
17. (canceled)
18. A method of treating cancer, the method comprising
administering to a subject in need thereof a pharmaceutical
formulation comprising: a protide; a polar aprotic solvent; and
optionally one or more pharmaceutically acceptable excipients;
wherein the protide is not
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate (NUC-1031).
19. (canceled)
20. (canceled)
21. The method of claim 18, wherein the polar aprotic solvent is
DMA.
22. The method of claim 18, wherein the protide is
5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl (benzoxy-L-alaninyl)]
phosphate (NUC-3373).
23. The method of claim 18, wherein the protide is
3'-deoxyadenosine-5'-O-[phenyl(benzyloxy-L-alaninyl)] phosphate
(NUC-7738).
24. The method of claim 18, wherein the protide is
2-chloro-2'-beta-fluoro-2'-deoxyadenosine-5'-[phenyl-(benzoxy-L-alaninyl)-
]-phosphate (CPF-448).
25. A kit, comprising: a first formulation comprising the polar
aprotic and the protide and optionally an aqueous vehicle; a second
formulation comprising the polar aprotic solvent and one or more
solubilizers; wherein the protide is not
gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate (NUC-1031).
26. (canceled)
27. The kit of claim 25, wherein the polar aprotic solvent is
DMA.
28. The kit of claim 25, wherein the protide is NUC-3373
5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl (benzoxy-L-alaninyl)]
phosphate (NUC-3373).
29. The kit of claim 25, wherein the protide is
3'-deoxyadenosine-5'-O-[phenyl(benzyloxy-L-alaninyl)] phosphate
(NUC-7738).
30. The kit of claim 25, wherein the protide is
2-chloro-2'-beta-fluoro-2'-deoxyadenosine-5'-[phenyl-(benzoxy-L-alaninyl)-
]-phosphate (CPF-448).
Description
[0001] This invention relates to pharmaceutical formulations and
formulation strategies of protides (phosphoramidate derivatives of
nucleosides) and, in particular, protides useful in the treatment
of cancer such as NUC-3373
(5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl (benzoxy-L-alaninyl)]
phosphate), NUC-7738
(3'-deoxyadenosine-5'-O-[phenyl(benzyloxy-L-alaninyl)] phosphate)
and CPF-448
(2-chloro-2'-beta-fluoro-2'-deoxyadenosine-5'-[phenyl-(benzoxy-L--
(alaninyl)]-phosphate). In particular, the invention relates to
formulations which comprise a polar aprotic solvent, for example
dimethyl acetamide (DMA).
BACKGROUND
[0002] Protides are masked phosphate derivatives of nucleosides.
They have been shown to be particularly potent therapeutic agents
in the fields of both antivirals and oncology. Protides, more
specifically, are prodrugs of monophosphorylated nucleosides. These
compounds appear to avoid many of the inherent and acquired
resistance mechanisms which limit the utility of the parent
nucleosides (see, for example, `Application of Pro Tide Technology
to Gemcitabine: A Successful Approach to Overcome the Key Cancer
Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical
Development`; Slusarczyk et al; J. Med. Chem.; 2014, 57,
1531-1542).
[0003] NUC-3373 (5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl
(benzoxy-L-alaninyl)] phosphate) is a protide adaptation of
5FU/FUDR, the current foundation treatment against colorectal
cancer. NUC-3373 and a range of related compounds have shown
activity in vitro against a range of cancer models, in many cases
and in particular for NUC-3373 that activity was outstanding and
far superior to the results obtained with 5-fluorouracil. The
addition of the protide phosphoramidate moiety to the
5-fluorouracil/FUDR molecule confers the specific advantages of
delivering the key activated form of the agent (FdUMP) into the
tumour cells. Non clinical studies have demonstrated that NUC-3373
overcomes the key cancer cell resistance mechanisms associated with
5-FU and its oral pro-drug capecitabine, generating high
intracellular levels of the active FdUMP metabolite, resulting in a
much greater inhibition of tumour cell growth. Furthermore, in
formal dog toxicology studies, NUC-3373 is significantly better
tolerated than 5-FU (see WO2012/117246; McGuigan et al.;
Phosphoramidate Pro Tides of the anticancer agent FUDR successfully
deliver the preformed bioactive monophosphate in cells and confer
advantage over the parent nucleoside; J. Med. Chem.; 2011, 54,
7247-7258; and Vande Voorde et al.; The cytostatic activity of
NUC-3073, a phosphoramidate prodrug of 5-fluoro-2'-deoxyuridine, is
independent of activation by thymidine kinase and insensitive to
degradation by phosphorolytic enzymes; Biochem. Pharmacol.; 2011,
82, 441-452).
[0004] Protide derivatives of purine nucleosides such as
clofarabine and deoxyadenosine and related compounds have also
shown excellent activity in vitro against a range of solid tumors,
leukaemias and lymphomas (see WO2006/100439 and WO2016/083830
(PCT/GB2015/053628)). Deoxyadenosine itself is not a particularly
potent anticancer agent.
[0005] Unfortunately, protides are often extremely lipophilic and
thus poorly water soluble, and the ionisable moieties, tend to have
calculated pKa values which lie outside the pH range suitable for
parenteral administration. Many are essentially insoluble in water,
regardless of salt content or pH within physiological ranges, and
this puts limitations on the development of clinically acceptable
methods for delivering the compounds at sufficiently high dosages
for effective treatment.
[0006] It is an aim of certain embodiments of this invention to
provide a pharmaceutical formulation of protides that delivers an
effective dose.
[0007] It is an aim of certain embodiments of this invention to
provide a stable pharmaceutical formulation of protides. For
intravenous administration, suitable infusion formulations
typically should be stable for greater than 30 minutes and up to 48
hours. Typically, for intravenous administration the formulation
should be stable both to precipitation of the protide and to
degradation of the protide.
[0008] It is an aim of certain embodiments of this invention to
provide a pharmaceutical formulation of the protide which delivers
an effective dose intravenously.
[0009] It is an aim of certain embodiments of this invention to
provide a parenteral formulation of the protide which can be
administered in either a peripheral vein or via a Central Venous
Access Device (CVAD). Thus, it is an aim of certain embodiments of
this invention to provide a formulation which has an osmolarity and
pH that are acceptable for administration via a peripheral vein. It
may be that the osmolarity and pH are such that the level of pain
experienced by the patient is acceptable.
[0010] Certain embodiments of this invention satisfy some or all of
the above aims.
BRIEF SUMMARY OF THE DISCLOSURE
[0011] In accordance with a first aspect of the present invention
there is provided a pharmaceutical formulation comprising:
[0012] a protide;
[0013] a polar aprotic solvent; and
[0014] optionally one or more pharmaceutically acceptable
excipients;
wherein the protide is not
gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (NUC-1031).
[0015] The polar aprotic solvent may be selected from
dimethylacetamide (DMA) dimethylsulfoxide (DMSO) and
N-methylpyrrolidone (NMP). Preferably, the polar aprotic solvent is
DMA. In an alternative preferred embodiment, the polar aprotic
solvent is NMP. For certain protides, DMA offers the best
solubility profile of those tested. For others, NMP may offer the
best solubility profile.
[0016] A polar aprotic solvent is a solvent molecule of which
comprise at least one heteroatom (e.g. O, N or S) but which does
not have a hydrogen atom attached to the heteroatom or, where more
than one heteroatom, any of the heteroatoms in the molecule. The
polar aprotic solvent (e.g. DMA, DMSO or NMP) may be pharmaceutical
grade. The polar aprotic solvent (e.g. DMA) may be the
administration vehicle or it may be that the formulation is diluted
before use with an administration vehicle which provides desirable
characteristics. Thus, the formulation may be ready for infusion
and have the polar aprotic solvent (e.g. DMA) as a major component;
or it may be a formulation which has the polar aprotic solvent
(e.g. DMA) as a major component and is intended to be diluted
before administration to generate a formulation which is ready for
infusion and has the polar aprotic solvent (e.g. DMA) only as a
minor component; or it may be a formulation which is ready for
infusion, has the polar aprotic solvent (e.g. DMA) only as a minor
component and results from the dilution of a formulation in which
polar aprotic solvent (e.g. DMA) is a major component. Thus, the
polar aprotic solvent (e.g. DMA) may represent from 0.1% v/v to
100% v/v of the formulation.
[0017] Very few pharmaceutically acceptable solvents dissolve
sufficient quantities of protides to deliver a therapeutically
effective dose intravenously. Of those that do, many do not form
stable solutions and protides will tend to precipitate out. The
inventors have surprisingly found that solvents which do generate a
stable solution are generally polar aprotic solvents, for example
DMA, DMSO and NMP. Of those solvents that have been found to be
capable of dissolving protides, the inventors have found that
certain polar aprotic solvents, and in particular DMA either on its
own or in conjunction with other solubilizers, are particularly
able to hold certain protides in solution at a concentration
necessary to deliver the required dose when that solution is
diluted with an aqueous vehicle. For other protides, NMP was found
to be the most effective at holding the protide in solution when
that solution is diluted with an aqueous vehicle.
[0018] Thus, the use of polar aprotic solvents, and in particular
DMA, provides an advantage over other formulation solvents which,
surprisingly, makes it an excellent medium for delivering protides
to patients in a practical and therapeutically effective
manner.
[0019] The formulation of the invention may be for dilution by a
predetermined amount shortly before administration, i.e. up to 48
hours (e.g. up to 24, 12 or 2 hours) before administration.
[0020] The formulation may also comprise one or more
pharmaceutically acceptable solubilizers, e.g. a pharmaceutically
acceptable non-ionic solubilizers. Solubilizers may also be called
surfactants. Illustrative solubilizers include polyethoxylated
fatty acids and fatty acid esters and mixtures thereof. Suitable
solubilizers include polyethoxylated castor oil (e.g. that sold
under the trade name Kolliphor.RTM. ELP); or polyethoxylated
stearic acid (e.g. that sold under the trade names Solutol.RTM. or
Kolliphor.RTM. HS15); or polyethoxylated (e.g. polyoxyethylene
(20)) sorbitan monooleate, (e.g. that are sold under the trade
names Polysorbate 80 or Tween.RTM. 80). Tween.RTM. 80, a
polyethoxylated sorbitan monooleate, for example, has been shown to
be particularly effective in formulations of NUC-7738.
[0021] In certain preferred embodiments, the formulation comprises
more than one pharmaceutically acceptable solubilizer. Formulations
comprising more than one solubilizer have been found to be
particularly effective in formulations of NUC-3373.
[0022] The formulation may also comprise an aqueous vehicle. The
formulation of the invention may be ready to administer, in which
case it will typically comprise an aqueous vehicle.
[0023] The formulation may be for parenteral, e.g. for intravenous,
subcutaneous or intramuscular administration. Preferably, the
formulation is for intravenous administration. The administration
may be through a CVAD or it may be through a peripheral vein.
[0024] The total dose of protide in a formulation suitable for
administration will typically be from 250 mg to 5 g, from 250 mg to
3 g, from 500 mg to 2 g or from 1 g to 1.5 g.
[0025] While the formulations of the invention are preferably for
parenteral administration, certain embodiments of the invention may
also be administered orally.
[0026] In a second aspect of the invention is provided a
pharmaceutical formulation comprising: [0027] a protide; [0028] a
polar aprotic solvent (e.g. DMA); and [0029] optionally one or more
pharmaceutically acceptable excipients; wherein the formulation is
for medical use; wherein the protide is not
gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
[0030] In a third aspect of the invention is provided a
pharmaceutical formulation comprising: [0031] a protide; [0032] a
polar aprotic solvent (e.g. DMA); and [0033] optionally one or more
pharmaceutically acceptable excipients; wherein the formulation is
for use in treating cancer; wherein the protide is not
gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
[0034] The cancer may be a cancer selected from: pancreatic cancer,
breast cancer, ovarian cancer, bladder cancer, colorectal cancer,
lung cancer, bladder cancer, prostate cancer, cholangiocarcinoma,
renal cancer, cervical cancer, thymic cancer, a cancer of an
unknown primary origin, lymphoma or leukaemia.
Stock Solution Formulations
[0035] It may be that the polar aprotic solvent (e.g. DMA)
represents 30% or more by volume of the formulation. Thus, it may
be that the polar aprotic solvent (e.g. DMA) represents 50% or
more, e.g. 60% or more by volume of the formulation. The polar
aprotic solvent (e.g. DMA) may represent 95% or less by volume of
the formulation, e.g. 90% or less. The formulation may also
comprise an aqueous vehicle (e.g. saline). The aqueous vehicle may
be present in 50% or less by volume of the formulation, e.g. 30% or
less by volume of the formulation. Typically the aqueous vehicle
(e.g. saline) will represent 5% or more, e.g. 10% or more, by
volume of the formulation.
[0036] It may be that the concentration of the protide in the
formulation solvent(s) is 1 g or less per mL. It may be that the
concentration of the protide in the formulation solvent(s) is 500
mg or less per mL. It may be that the concentration 100 mg or more
per mL.
[0037] Preferably, the concentration is from 200 mg to 300 mg, e.g.
from 225 mg to 275 mg, e.g. about 250 mg, per mL.
[0038] Certain preferred formulations comprise: [0039] from 30% to
95% by volume DMA; [0040] from 5% to 50% by volume aqueous vehicle;
and [0041] from 100 mg to 400 mg (e.g. from 100 mg to 300 mg) per
mL protide.
[0042] More preferred formulations comprise: [0043] from 70% to 90%
by volume DMA; [0044] from 10% to 30% by volume aqueous vehicle
(e.g. saline); and [0045] from 200 mg to 300 mg per mL protide.
[0046] The formulations described in the previous four paragraphs,
in which the polar aprotic solvent (e.g. DMA) is present as a major
component may be for administering (e.g. by infusion or injection)
the formulation without it being diluted prior to said
administration. They may, for example, be for administration
through a Central Venous Administration Device (CVAD). When
administered via a CVAD, the formulation is typically not
diluted.
[0047] Alternatively, these formulations may be stock solutions
which are diluted prior to use to form a formulation suitable for
administration, e.g. through a peripheral vein.
Surfactant Solution Formulations
[0048] It may be that the polar aprotic solvent (e.g. DMA)
represents 10% or more, e.g. 20% or more by volume of the
formulation. Thus, it may be that the polar aprotic solvent (e.g.
DMA) represents 80% or less, e.g. 70% or less by volume of the
formulation. The polar aprotic solvent (e.g. DMA) may represent 55%
or less by volume of the formulation. The formulation may also
comprise one or more solubilizers (e.g. one or more polyethoxylated
fatty acids). The one or more solubilizers may represent 70% or
less by volume of the formulation, e.g. 60% or less by volume of
the formulation. Typically the one or more solubilizers will
represent 20% or more, e.g. 35%, by volume of the formulation. The
formulation may also comprise an aqueous vehicle, e.g. in an amount
from 1% to 15% by volume or from 5% to 12% by volume.
[0049] It may be that the concentration of the protide in the
formulation solvent(s) is 200 mg or less per mL, e.g. 150 mg or
less or 130 mg or less. It may be that the concentration is 40 mg
or more per mL, e.g. 60 mg or more. Preferably, the concentration
is from 70 mg to 120 mg per mL, e.g. about 100 mg per mL.
[0050] Certain preferred formulations comprise: [0051] from 20% to
70% by volume DMA; [0052] from 20% to 70% by volume solubilizer or
solubilizers; and [0053] from 50 mg to 150 mg per mL protide. The
formulation may also comprise an aqueous vehicle, e.g. in an amount
from 1% to 15% by volume.
[0054] Certain particularly preferred formulations comprise: [0055]
from 30% to 60% by volume DMA; [0056] from 10% to 35% by volume a
first solubilizer; [0057] from 10% to 35% by volume a second
solubilizer; [0058] from 2% to 15% an aqueous vehicle; and [0059]
from 50 mg to 150 mg per mL protide. The first solubilizer may be a
polyethoxylated castor oils (e.g. that sold under the trade name
Kolliphor.RTM. ELP).The second solubilizer may be a polyethoxylated
sorbitan monooleate (e.g. that sold under the trade name Tween.RTM.
80).
[0060] The formulation may comprise:
[0061] from 35% to 50% by volume DMA;
[0062] from 15% to 30% by volume the first solubilizer;
[0063] from 15% to 30% by volume the second solubilizer;
[0064] from 5% to 12% an aqueous vehicle; and
[0065] from 50 mg to 150 mg per mL protide.
[0066] The surfactant solutions formulations described in the
previous five paragraphs, in which the polar aprotic solvent (e.g.
DMA) is present as a major component are typically diluted with an
aqueous vehicle prior to administration. They are typically
prepared from the stock solutions mentioned above before being
further diluted ready for administration. Once diluted, they may be
administered through a peripheral vein.
[0067] These formulations may be formed by diluting a stock
solution formulation that does not contain any solubilizers with a
solution which does contain solubilizers. Protides can degrade in
the presence of certain solubilizers.
Infusion Solution Formulations
[0068] It may be that the polar aprotic solvent (e.g. DMA)
represents 0.1% or more, e.g. 0.5% or more or 1% or more by volume
of the formulation. Thus, it may be that DMA represents 12% or
less, e.g. 10% or less or 8% or less by volume of the formulation.
The formulation may also comprise an aqueous vehicle (e.g. saline
or WFI). The aqueous vehicle may be present in 99.5% or less by
volume of the formulation, e.g. 99% or 98% or less by volume of the
formulation. Typically the aqueous vehicle will represent 80% or
more, e.g. 95% or more, by volume of the formulation. The
formulation may also comprise one or more solubilizers (e.g. one or
more polyethoxylated fatty acids). The one or more solubilizers may
present in 12% or less by volume of the formulation, e.g. 10% or
less or 8% or less by volume of the formulation. Typically the one
or more solubilizers will be present in 0.1% or more, e.g. 0.5% or
more or 1% or more, by volume of the formulation.
[0069] It may be that the concentration of the protide in the
formulation solvent(s) is 15.0 mg or less per mL or 12.0 mg or less
per mL, e.g. 10.0 mg or less or 8 mg or less per mL. It may be that
the concentration is 1.0 mg or more per mL, e.g. 2.0 mg or more.
Preferably, the concentration is from 2.5 mg to 12 mg per mL, e.g.
from 3 mg to 11 mg per mL.
[0070] Certain preferred formulations comprise:
[0071] from 0.1% to 10% by volume DMA;
[0072] from 0.1% to 10% by volume solubilizer or solubilizers;
[0073] from 85% to 99% by volume aqueous vehicle; and
[0074] from 2.0 mg to 12.0 mg per mL protide.
[0075] Certain particularly preferred formulations comprise:
[0076] from 1% to 8% by volume DMA;
[0077] from 0.5% to 4% by volume a first solubilizer;
[0078] from 0.5% to 4% by volume a second solubilizer;
[0079] from 85% to 99% by volume aqueous vehicle; and
[0080] from 2.0 mg to 12.0 mg per mL protide. The first solubilizer
may be a polyethoxylated castor oil (e.g. that sold under the trade
name Kolliphor.RTM. ELP). The second solubilizer may be a
polyethoxylated sorbitan monooleate (e.g. that sold under the trade
name Tween.RTM. 80).
[0081] The infusion solution formulations described in the previous
four paragraphs, in which the polar aprotic solvent (e.g. DMA) is
present as a minor component, will typically have been prepared by
diluting a concentrated solution of the protide with the aqueous
vehicle up to 48 hours prior to administration. Said concentrated
solution may be either a solution of the protide in a polar aprotic
solvent (see under the heading `stock solution formulation` above)
a solution of the protide in mixture of a polar aprotic solvent and
a solubilizer (see under the heading `surfactant solution
formulation` above). These formulations in which the polar aprotic
solvent (e.g. DMA) is present as a minor component may be
administered through a peripheral vein. The low concentrations of
the polar aprotic solvent (e.g. DMA) in said formulations mean that
they tend not to cause pain upon peripheral administration.
Methods of Treatment and Kits
[0082] In a fourth aspect of the invention is provided a method of
treating cancer, the method comprising administering to a subject
in need thereof a pharmaceutical formulation comprising: [0083] a
protide; [0084] a polar aprotic solvent (e.g. DMA); and [0085]
optionally one or more pharmaceutically acceptable excipients;
wherein the protide is not
gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
[0086] The method may comprise the steps of;
[0087] diluting a solution comprising the protide, a polar aprotic
solvent (e.g. DMA) and optionally one or more pharmaceutically
acceptable excipients with an aqueous vehicle to provide a
formulation for infusion or injection; and
[0088] administering the formulation for infusion or injection to
the subject by infusion or injection.
[0089] The method may comprise the steps of;
[0090] diluting a first solution comprising the protide and a polar
aprotic solvent (e.g. DMA) and optionally an aqueous vehicle with a
second solution comprising a polar aprotic solvent (e.g. DMA) and
one or more solubilizers to form a third solution (`surfactant
solution formulation`);
[0091] diluting the third solution with an aqueous vehicle to
provide a fourth solution (infusion solution formulation`); and
[0092] administering the fourth solution to the subject by infusion
or injection.
[0093] The second solution may comprise more than one solubilizer.
Typically, the second formulation will not comprise a
pharmaceutically active substance.
[0094] The or each dilution may be by a predetermined amount. The
second solution may be called a `diluent solution`.
[0095] The first solution may be a formulation of the first aspect
(see under the heading `stock solution formulation` above).
Likewise, the third solution may be a formulation of the first
aspect (see under the heading `surfactant solution formulation`
above). Likewise, the fourth solution may be a formulation of the
first aspect (see under the heading `infusion solution formulation`
above).
[0096] The fourth solution may be administered via a CVAD.
Preferably, however, the fourth formulation is administered via a
peripheral vein.
[0097] The first solution may comprise:
[0098] from 30% to 95% by volume DMA;
[0099] from 5% to 50% by volume aqueous vehicle; and
[0100] from 100 mg to 400 mg (e.g. from 100 mg to 300 mg) per mL
protide; and
[0101] The second solution may comprise:
[0102] from 10% to 50% by volume DMA;
[0103] from 20% to 60% by volume a first solubilizer;
[0104] from 20% to 60% by volume a second solubilizer.
[0105] It may be that the administration step is carried out up to
48 hours (e.g. up to 12 or 2 hours) after the dilution step, e.g.
the second dilution step to form the fourth solution.
[0106] In a fifth aspect of the invention is provided a kit, the
kit comprising:
[0107] a first formulation comprising the polar aprotic (e.g. DMA)
and the protide and optionally an aqueous vehicle;
[0108] a second formulation comprising the polar aprotic solvent
and one or more solubilizers;
[0109] wherein the protide is not
gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
[0110] Thus, the kit may comprise: [0111] a first formulation
comprising: [0112] from 30% to 95% by volume DMA; [0113] from 5% to
50% by volume aqueous vehicle; and [0114] from 100 mg to 400 mg
(e.g. from 100 mg to 300 mg) per mL a protide; and [0115] a second
formulation comprising: [0116] from 10% to 50% by volume DMA;
[0117] from 20% to 60% by volume a first solubilizer; [0118] from
20% to 60% by volume a second solubilizer.
[0119] Typically the second formulation will not comprise any
active. The kit of the fifth aspect is useful for the preparation
of formulations suitable for peripheral administration. The first
formulation is diluted with the second formulation up to 48 h, e.g.
up to 24 h before administration to form a third formulation. The
third formulation is further diluted with an aqueous vehicle before
administration to the desired concentration to form the formulation
which is used administered by infusion or injection to the patient.
In order to achieve formulations for peripheral administration
which are stable with respect to precipitation of the protide, it
is typically desirable to include solubilizers. However, protides
can be prone to degradation in the presence of such solubilizers.
Thus, a two stage dilution method is, in certain embodiments of the
invention, the preferable means by which formulations for
peripheral administration are achieved.
[0120] The method may comprise:
[0121] flushing a CVAD with a first portion of a first solution,
the first solution comprising a polar aprotic solvent (e.g. DMA)
and an aqueous vehicle;
[0122] administering a second formulation to the patient via the
CVAD, the second formulation comprising the polar aprotic solvent,
the aqueous vehicle and the protide; and
[0123] optionally flushing the CVAD with a second portion of the
first formulation.
[0124] Preferably, the relative amounts of the polar aprotic
solvent and the aqueous vehicle in the first formulation are the
same as the relative amounts in the second formulation.
[0125] Thus, the method of treatment may comprise:
[0126] flushing a CVAD with a first portion of a first solution,
the first solution comprising: [0127] from 30% to 95% by volume
DMA; [0128] from 5% to 50% by volume aqueous vehicle; and
[0129] administering a second formulation to the patient via the
CVAD, the second formulation comprising: [0130] from 30% to 95% by
volume DMA; [0131] from 5% to 50% by volume aqueous vehicle; and
[0132] from 100 mg to 400 mg (e.g. from 100 mg to 300 mg) per mL
protide; and optionally flushing the administration device with a
second portion of the first formulation. Typically, the first
formulation will not comprise an active.
[0133] In a sixth aspect of the invention is provided a kit, the
kit comprising:
[0134] a first solution comprising a polar aprotic solvent (e.g.
DMA) and an aqueous vehicle; and
[0135] a second formulation comprising the polar aprotic solvent,
the aqueous vehicle and the protide;
[0136] wherein the protide is not
gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
[0137] Thus, the kit may comprise: [0138] a first formulation
comprising: [0139] from 30% to 95% by volume DMA; [0140] from 5% to
50% by volume aqueous vehicle; and [0141] a second formulation
comprising: [0142] from 30% to 95% by volume DMA; [0143] from 5% to
50% by volume aqueous vehicle; and [0144] from 100 mg to 400 mg
(e.g. from 100 mg to 300 mg) per mL protide.
[0145] The first formulation will typically not comprise a
pharmaceutically active substance. Thus, it will typically not
comprise the protide. The first formulation may be provided in two
separate vessels or in a single vessel.
[0146] The kit of the sixth aspect of the invention is useful for
the intravenous administration of a protide via a CVAD. The CVAD is
flushed with the first formulation prior to administration of the
second formulation. This mitigates the risk of precipitation of the
protide in or at the entrance to the intravenous administration
apparatus, i.e. the CVAD, by avoiding the direct contact of the
active formulation with aqueous media (e.g. a saline flushing
solution). The CVAD may also be flushed with the first formulation
after administration of the second formulation. This further
prevents precipitation.
Methods of Preparing Formulations
[0147] In a fifth aspect of the invention is provided a method of
preparing a pharmaceutical formulation of a protide for infusion or
injection, the method comprising: [0148] diluting a solution
comprising the protide, a polar aprotic solvent (e.g. DMA) and
optionally one or more pharmaceutically acceptable excipients with
an aqueous vehicle to provide the formulation for infusion or
injection; [0149] wherein the protide is not
gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
[0150] The dilution may be by a predetermined amount.
[0151] The starting solution may be a formulation of the first
aspect (see under the heading `stock solution formulations` and
`surfactant solution formulations`). Likewise, the formulation for
infusion or injection may be a formulation of the first aspect (see
under the heading `infusion solution formulation` above). It may be
that the administration step is carried out up to 48 hours (e.g. up
to 12 or 2 hours) after the dilution step.
[0152] The aqueous vehicle may be selected from saline (e.g. 0.9%
saline or 0.45% saline), glucose solution and water for infusion
(WFI). The aqueous vehicle may be WFI. Alternatively, the aqueous
vehicle may be 0.9% saline.
[0153] The osmolarity of the infusion solution is critically
dependent on the dose required together with the volume and type of
aqueous medium used, (i.e. the amount of surfactant solution used
in the saline, and the % saline (0.45 or 0.9%)). Where the
formulation is for administration via a peripheral vein, it may be
that the aqueous vehicle is selected such that, at the desired dose
and volume, the osmolarity of the infusion solution is between 200
mosm/L and 600 mosm/L. Preferably, where the formulation is for
administration via a peripheral vein, the aqueous vehicle is
selected such that the infusion solution is substantially isotonic
with blood (e.g. the osmolarity of the infusion solution is from
250 mosm/L to 400 mosm/L).
[0154] The aqueous vehicle may comprise one or more
pharmaceutically acceptable solubilizers (also known as a
surfactants), e.g. a pharmaceutically acceptable non-ionic
solubilizer. An exemplary solubilizer is polyoxyethylene (20)
sorbitan monooleate (marketed as Tween.RTM. 80).
Protides
[0155] The formulations and formulation methods described in this
specification are suitable for the administration of any protide.
NUC-1031 (gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate or, to
give it its full chemical name:
2'-deoxy-2',2'-difluoro-D-cytidine-5'-O-[phenyl
(benzoxy-L-alaninyl)] phosphate) is however explicitly excluded
from the scope of this application.
[0156] The term `protide` is readily understood in the art to mean
an aryloxy .alpha.-amino acid ester phosphoramidate derivative of a
nucleoside or nucleoside analogue. Thus, the protide may be a
compound having a structure according to formula (I):
##STR00001##
wherein
[0157] R.sup.1 is aryl;
[0158] R.sup.2 is C.sub.1-C.sub.24-alkyl, C.sub.3-C.sub.24-alkenyl,
C.sub.3-C.sub.24-alkynyl,
C.sub.0-C.sub.4-alkylene-C.sub.3-C.sub.6-cycloalkyl or
C.sub.0-C.sub.4-alkylene-aryl;
[0159] R.sup.3 and R.sup.4 are each independently selected from H,
C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.3-alkylene-R.sup.6; or
wherein R.sup.3 and R.sup.4 together with the atom to which they
are attached form a 3- to 6-membered cycloalkyl or heterocycloalkyl
group;
[0160] R.sup.5 is a nucleoside or nucleoside analogue;
[0161] R.sup.6 is independently selected from aryl (e.g. phenyl),
imidazole, indole, SR.sup.a, OR.sup.a, CO.sub.2R.sup.a,
CO.sub.2NR.sup.aR.sup.a, NR.sup.aR.sup.b and
NH(.dbd.NH)NH.sub.2;
[0162] wherein any aryl group is either phenyl or naphthyl and
wherein any phenyl or naphthyl group is optionally substituted with
from 1 to 4 substituents selected from: halo, nitro, cyano,
NR.sup.aR.sup.a, NR.sup.aS(O).sub.2R.sup.a, NR.sup.aC(O)R.sup.a,
NR.sup.aCONR.sup.aR.sup.a, NR.sup.aCO.sub.2R.sup.a, OR.sup.a;
SR.sup.a, SOR.sup.a, SO.sub.3R.sup.a, SO.sub.2R.sup.a,
SO.sub.2NR.sup.aR.sup.a, CO.sub.2R.sup.aC(O)R.sup.a,
CONR.sup.aR.sup.a, CR.sup.aR.sup.aNR.sup.aR.sup.a,
C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl,
C.sub.2-C.sub.4-alkynyl and C.sub.1-C.sub.4-haloalkyl;
[0163] wherein R.sup.a is independently at each occurrence selected
from: H and C.sub.1-C.sub.4-alkyl; and R.sup.b is independently at
each occurrence selected from: H, and C.sub.1-C.sub.4-alkyl and
C(O)-C.sub.1-C.sub.4-alkyl.
[0164] The nucleoside or nucleoside analogue may have the
structure:
##STR00002##
wherein:
[0165] Q is independently selected from O, NR.sup.a and
CH.sub.2;
[0166] R.sup.7 is independently selected from: OR.sup.a, SR.sup.a,
NR.sup.aR.sup.b; halo (e.g. F), cyano, C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.4-alkenyl and C.sub.2-C.sub.4-alkynyl;
[0167] R.sup.8 and R.sup.9 together with the nitrogen to which they
are attached form a substituted pyrimidine or a substituted purine;
wherein the purine or pyrimidine is substituted with from 1 to 5
groups selected from: OR.sup.a, SR.sup.a, NR.sup.aR.sup.b; halo,
cyano, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl and
C.sub.2-C.sub.4-alkynyl.
[0168] n is typically an integer from 0 to 4.
[0169] As will be readily appreciated by the skilled person, where
a pyrimidine or purine is substituted with an OH group attached to
a carbon atom neighbouring one of the nitrogen atoms in the
pyrimidine or purine core, the pyrimidine or purine will typically
exist primarily in the tautomeric form, i.e. one in which there is
no double bond between the nitrogen and the neighbouring carbons
but in which there is a double bond between the neighbouring carbon
and the oxygen of the OH group. Said nitrogen may itself be
substituted, e.g. with a C.sub.1-C.sub.4-alkyl group.
[0170] It may be that R.sup.8 and R.sup.9 together with the
nitrogen to which they are attached form a substituted pyrimidine.
It may be that R.sup.8 and R.sup.9 together with the nitrogen to
which they are attached form a substituted purine.
[0171] The protide may be a compound having a structure according
to formula (II):
##STR00003##
wherein
[0172] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described above
for compounds of formula (I). NUC-1031 is excluded from the scope
of this application and thus, for the absence of doubt, where the
protide is a compound of formula (II), it cannot be the case that
R.sup.1 is unsubstituted phenyl, R.sup.2 is unsubstituted benzyl,
R.sup.3 is Me and R.sup.4 is H.
[0173] The protide may be a compound having a structure according
to formula (III):
##STR00004##
wherein
[0174] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described above
for compounds of formula (I).
[0175] The protide may be a compound having a structure according
to formula (IV):
##STR00005##
wherein
[0176] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described above
for compounds of formula (I); and wherein Y is independently
selected from H, F, Cl and OMe. In certain preferred embodiments, Y
is H. In other preferred embodiments, Y is F.
[0177] The Protide may be a compound having a structure according
to formula (V):
##STR00006##
wherein
[0178] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described above
for compounds of formula (I). Protides of formula (V) are
derivatives of clofarabine.
[0179] The protide may be a compound having a structure according
to formula (VI):
##STR00007##
wherein
[0180] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described above
for compounds of formula (I). ProTides of formula (VI) are
derivatives of fludarabine.
[0181] The protide may be a compound having a structure according
to formula (VII):
##STR00008##
wherein
[0182] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as described above
for compounds of formula (I). Protides of formula (VII) are
derivatives of cladribine.
[0183] The following statements apply to protides of any of
formulae (I) to (V). These statements are independent and
interchangeable. In other words, any of the features described in
any one of the following statements may (where chemically
allowable) be combined with the features described in one or more
other statements below. In particular, where a compound is
exemplified or illustrated in this specification, any two or more
of the statements below which describe a feature of that compound,
expressed at any level of generality, may be combined so as to
represent subject matter which is contemplated as forming part of
the disclosure of this invention in this specification.
[0184] It may be that R.sup.1 is substituted or unsubstituted
phenyl. It may be that R.sup.1 is substituted or unsubstituted
naphthyl (e.g. 1-naphthyl). Preferably, R.sup.1 is unsubstituted
phenyl or unsubstituted naphthyl (e.g. 1-naphthyl). Thus, R.sup.1
may be unsubstituted phenyl. Alternatively, R.sup.1 may be or
unsubstituted naphthyl (e.g. 1-naphthyl).
[0185] R.sup.2 is preferably selected such that it comprises five
or more carbon atoms. R.sup.2 may therefore be selected such that
it includes six or more carbon atoms. R.sup.2 is preferably
selected such that it comprises only carbon and hydrogen atoms.
R.sup.2 may be selected from C.sub.5-C.sub.7-cycloalkyl,
C.sub.5-C.sub.8-alkyl and benzyl, optionally wherein said groups
are unsubstituted. R.sup.2 may be benzyl.
[0186] It may be that R.sup.4 is H. It may be that R.sup.3 is
selected from C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.3-alkylene-R.sup.6. It may be that R.sup.3 is
C.sub.1-C.sub.4-alkyl. It may be that R.sup.3 is methyl.
[0187] Q is preferably O.
[0188] n may be an integer from 1 to 3. n may be 1. n may be 2. n
may be 3.
[0189] The protide is preferably a compound useful in the treatment
of cancer.
[0190] Exemplary protides of formula (II) include the compounds
described in WO 2005/012327, incorporated herein by reference.
Exemplary protides of formula (II) include:
##STR00009##
[0191] Exemplary protides of formula (III) include the compounds
described in WO 2012/117246, incorporated herein by reference.
Exemplary protides of formula (III) include:
##STR00010## ##STR00011## [0192] Exemplary protides of formula (IV)
include the compounds described in WO2016/083830
(PCT/GB2015/053628),incorporated herein by reference. Exemplary
protides of formula (IV) include:
##STR00012##
[0192] Exemplary protides of formulae (V), (VI) and (VII) include
the compounds described in WO2006/100439. Exemplary protides of
formula (V) include:
##STR00013##
Exemplary protides of formula (VI) include:
##STR00014##
[0193] Exemplary protides of formula (VII) include:
##STR00015##
[0194] It may be that the protide is NUC-3373. It may be that the
protide is NUC-3373 and the polar aprotic solvent is DMA. It may be
that the protide is NUC-7738. It may be that the protide is
NUC-7738 and the polar aprotic solvent is DMA. It may be that the
protide is NUC-7738 and the polar aprotic solvent is NMP. It may be
that the protide is CPF-448. It may be that the protide is CPF-448
and the polar aprotic solvent is DMA. It may be that the protide is
CPF-448 and the polar aprotic solvent is NMP.
[0195] Protides typically comprise a chiral centre at the
phosphorous atom. The protide may be present as a mixture of
phosphate diastereoisomers, as the (S)-epimer at the phosphorus
atom in substantially diastereomerically pure form or as the
(R)-epimer at the phosphorus atom in substantially
diastereomerically pure form. `Substantially diastereomerically
pure` is defined for the purposes of this invention as a
diastereomeric purity of greater than about 90%. If present as a
substantially diastereoisomerically pure form, the protide may have
a diastereoisomeric purity of greater than 95%, 98%, 99%, or even
99.5%. Alternatively, the protide may be present as a mixture of
phosphate diastereoisomers.
[0196] The (R)- and/or (S)-epimers of the protides can be obtained
in substantially diastereomerically pure form by chromatography,
e.g. HPLC optionally using a chiral column. Alternatively, the (R)-
and/or (S)-epimers of the protides can be obtained in substantially
diastereomerically pure form by crystallisation from an appropriate
solvent or solvent system In a further alternative, the (R)- and/or
(S)-epimers of the protides can be synthesised as an
diastereomerically pure form using a diastereoselective synthesis.
It may be that any combination of these techniques could be used to
provide a diastereomerically pure form, e.g. a diastereoselective
synthesis followed by crystallisation or chromatography.
DETAILED DESCRIPTION
[0197] The term `saline` is intended to refer to an aqueous
solution of sodium chloride. Saline solutions of the present
invention will typically be sterile and will typically be at a
concentration suitable for use in parenteral administration.
Suitable concentrations are up to 2 w/v % or up to 1 w/v %. To
optimise osmolarity different concentrations of saline can be used
in the formulations of the invention, e.g. 0.9% or 0.45%.
[0198] The formulations of the present invention can be used in the
treatment of the human body. They may be used in the treatment of
the animal body. In particular, the compounds of the present
invention can be used to treat commercial animals such as
livestock. Alternatively, the compounds of the present invention
can be used to treat companion animals such as cats, dogs, etc.
[0199] The compounds in the formulations of the invention may be
obtained, stored and/or administered in the form of a
pharmaceutically acceptable salt. Suitable pharmaceutically
acceptable salts include, but are not limited to, salts of
pharmaceutically acceptable inorganic acids such as hydrochloric,
sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and
hydrobromic acids, or salts of pharmaceutically acceptable organic
acids such as acetic, propionic, butyric, tartaric, maleic,
hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic,
benzoic, succinic, oxalic, phenylacetic, methanesulphonic,
toluenesulphonic, benzenesulphonic, salicylic, sulphanilic,
aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric,
pantothenic, tannic, ascorbic and valeric acids. Suitable base
salts are formed from bases which form non-toxic salts. Examples
include the aluminium, arginine, benzathine, calcium, choline,
diethylamine, diolamine, glycine, lysine, magnesium, meglumine,
olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts
of acids and bases may also be formed, for example, hemisulfate,
hemioxalate and hemicalcium salts. Preferably, the compound of the
invention are not in the form of a salt, i.e. they are in the form
of the free base/free acid.
[0200] For the above-mentioned formulations of the invention the
dosage administered will, of course, vary with the compound
employed, the precise mode of administration, the treatment desired
and the disorder indicated. Dosage levels, dose frequency, and
treatment durations of compounds of the invention are expected to
differ depending on the formulation and clinical indication, age,
and co-morbid medical conditions of the patient. The size of the
dose for therapeutic purposes of compounds of the invention will
naturally vary according to the nature and severity of the
conditions, the age and sex of the animal or patient and the route
of administration, according to well known principles of
medicine.
[0201] A pharmaceutical formulation typically takes the form of a
composition in which active compounds, or pharmaceutically
acceptable salts thereof, are in association with a
pharmaceutically acceptable adjuvant, diluent or carrier. One such
pharmaceutically acceptable adjuvant, diluent or carrier in the
formulations of the invention is the polar aprotic solvent.
Conventional procedures for the selection and preparation of
suitable pharmaceutical formulations are described in, for example,
"Pharmaceuticals--The Science of Dosage Form Designs", M. E.
Aulton, Churchill Livingstone, 1988.
[0202] The formulations may be suitable for topical application
(e.g. to the skin or bladder), for oral administration or for
parenteral (e.g. intravenous administration).
[0203] Any solvents used in pharmaceutical formulations of the
invention should be pharmaceutical grade, by which it is meant that
they have an impurity profile which renders them suitable for
administration (e.g. intravenous administration) to humans.
[0204] For oral administration the formulations of the invention
may comprise the active compound admixed with an adjuvant or a
carrier, for example, lactose, saccharose, sorbitol, mannitol; a
starch, for example, potato starch, corn starch or amylopectin; a
cellulose derivative; a binder, for example, gelatine or
polyvinylpyrrolidone; and/or a lubricant, for example, magnesium
stearate, calcium stearate, polyethylene glycol, a wax, paraffin,
and the like, and then compressed into tablets. If coated tablets
are required, the cores, prepared as described above, may be coated
with a concentrated sugar solution which may contain, for example,
gum arabic, gelatine, talcum and titanium dioxide. Alternatively,
the tablet may be coated with a suitable polymer dissolved in a
readily volatile organic solvent.
[0205] For the preparation of soft gelatine capsules, the active
compounds may be admixed with, for example, a vegetable oil or
polyethylene glycol. Hard gelatine capsules may contain granules of
the compound using either the above-mentioned excipients for
tablets. Also liquid or semisolid formulations of the active
compounds may be filled into hard gelatine capsules.
[0206] Liquid preparations for oral application may be in the form
of syrups or suspensions, for example, solutions containing the
compound of the invention, the balance being sugar and a mixture of
ethanol, water, glycerol and propylene glycol. Optionally such
liquid preparations may contain colouring agents, flavouring
agents, sweetening agents (such as saccharine), preservative agents
and/or carboxymethylcellulose as a thickening agent or other
excipients known to those skilled in art.
[0207] Preferably, however the formulations of the invention are
for parenteral (e.g. intravenous) administration or for dilution to
form a formulation for parenteral (e.g. intravenous)
administration. For parenteral (e.g. intravenous) administration
the active compounds may be administered as a sterile aqueous or
oily solution. Preferably, the active compounds are administered as
a sterile aqueous solution.
[0208] The pharmaceutical composition of the invention will
preferably comprise from 0.05 to 99% w (per cent by weight)
protide, more preferably from 0.05 to 80% w protide, still more
preferably from 0.10 to 70% w protide, and even more preferably
from 0.10 to 50% w protide, all percentages by weight being based
on total composition.
[0209] Cyclodextrins have been shown to find wide application in
drug delivery (Rasheed et al, Sci. Pharm., 2008, 76, 567-598).
Cyclodextrins are a family of cyclic oligosaccharides. They act as
a `molecular cage` which encapsulates drug molecules and alters
properties of those drug molecules such as solubility.
Cyclodextrins comprise (.alpha.-1,4)-linked .alpha.-D-glucopyranose
units. Cyclodextrins may contains 6, 7 or 8 glucopyranose units
(designated .alpha.-, .beta.- and .gamma.-cyclodextrins
respectively). Cyclodextrins used in pharmaceutical formulations
are often .beta.-cyclodextrins. The pendant hydroxyl groups can be
alkylated with a C.sub.1-C.sub.6 substituted or unsubstituted alkyl
group. Examples of cyclodextrins are .alpha.-cyclodextrin,
.beta.-cyclodextrin, .gamma.-cyclodextrin,
2-hydroxypropyl-.beta.-cyclodextrin (HP-.beta.-CD), sulfobutylether
.beta.-cyclodextrin sodium salt, partially methylated
.beta.-cyclodextrin. The formulations of the invention may also
comprise at least one cyclodextrin.
[0210] The term C.sub.m-C.sub.n refers to a group with m to n
carbon atoms.
[0211] The term "alkyl" refers to a linear or branched hydrocarbon
group. An alkyl group is monovalent. For example,
C.sub.1-C.sub.6-alkyl may refer to methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
The alkyl groups are preferably unsubstituted.
[0212] The term "alkylene" refers to a linear hydrocarbon chain. An
alkylene group is divalent. For example, C.sub.1-alkylene may refer
to a CH.sub.2 group. C.sub.2-alkylene may refer to
--CH.sub.2CH.sub.2-- group. The alkylene groups are preferably
unsubstituted.
[0213] The term "haloalkyl" refers to a hydrocarbon chain
substituted with at least one halogen atom independently chosen at
each occurrence from: fluorine, chlorine, bromine and iodine. The
halogen atom may be present at any position on the hydrocarbon
chain. For example, C.sub.1-C.sub.4-haloalkyl may refer to
chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g.
1-chloromethyl and 2-chloroethyl, trichloroethyl e.g.
1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.
1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g.
1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl,
trichloropropyl, fluoropropyl, trifluoropropyl. A halo alkyl group
may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted
with at least one fluorine atom.
[0214] The term "alkenyl" refers to a branched or linear
hydrocarbon chain containing at least one carbon-carbon double
bond. The double bond(s) may be present as the E or Z isomer. The
double bond may be at any possible position of the hydrocarbon
chain. For example, "C.sub.2-C.sub.4-alkenyl" may refer to ethenyl,
allyl and butenyl. The alkenyl groups are preferably
unsubstituted.
[0215] The term "alkynyl" refers to a branched or linear
hydrocarbon chain containing at least one carbon-carbon triple
bond. The triple bond may be at any possible position of the
hydrocarbon chain. For example, "C.sub.2-C.sub.6-alkynyl" may refer
to ethynyl, propynyl, butynyl. The alkynyl groups are preferably
unsubstituted.
[0216] The term "cycloalkyl" refers to a saturated hydrocarbon ring
system containing 3, 4, 5 or 6 carbon atoms. For example, "3- to
6-membered cycloalkyl" may refer to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl. The cycloalkyl groups are preferably
unsubstituted.
[0217] The term "heterocycloalkyl" may refer to a saturated
monocyclic group comprising 1 or 2 heteroatoms independently
selected from O, S and N in the ring system (in other words 1 or 2
of the atoms forming the ring system are selected from O, S and N).
Examples of heterocycloalkyl groups include; piperidine,
piperazine, morpholine, thiomorpholine, pyrrolidine,
tetrahydrofuran, tetrahydrothiophene, tetrahydropyran,
dihydropyran, dioxane, azepine. The heterocycloalkyl groups are
preferably unsubstituted or substituted.
[0218] The present invention also includes formulations of all
pharmaceutically acceptable isotopically-labelled forms of compound
wherein one or more atoms are replaced by atoms having the same
atomic number, but an atomic mass or mass number different from the
atomic mass or mass number of the predominant isotope usually found
in nature.
[0219] Examples of isotopes suitable for inclusion in the compounds
of the invention include isotopes of hydrogen, such as .sup.2H and
.sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine,
such as .sup.36Cl, fluorine, such as .sup.18F, iodine, such as
.sup.123I and .sup.125I, nitrogen, such as .sup.13N and .sup.15N,
oxygen, such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such
as .sup.32P, and sulphur, such as .sup.35S.
[0220] Certain isotopically-labelled compounds, for example, those
incorporating a radioactive isotope, are useful in drug and/or
substrate tissue distribution studies. The radioactive isotopes
tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, and .sup.18F
are particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0221] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0222] Isotopically-labelled compounds can generally be prepared by
conventional techniques known to those skilled in the art or by
processes analogous to those described using an appropriate
isotopically-labelled reagent in place of the non-labelled reagent
previously employed.
[0223] The method of treatment or the formulation for use in the
treatment of cancer, lymphoma or leukemia may involve, in addition
to the formulations of the invention, conventional surgery or
radiotherapy or chemotherapy. Such chemotherapy may include the
administration of one or more other active agents.
[0224] Where a further active agent is administered as part of a
method of treatment of the invention, such combination treatment
may be achieved by way of the simultaneous, sequential or separate
dosing of the individual components of the treatment. Such
combination products employ the compounds of this invention within
a therapeutically effective dosage range described hereinbefore and
the one or more other pharmaceutically-active agent(s) within its
approved dosage range.
[0225] Thus, the pharmaceutical formulations of the invention may
comprise another active agent.
[0226] The one or more other active agents may be one or more of
the following categories of anti-tumor agents:
(i) antiproliferative/antineoplastic drugs and combinations
thereof, such as alkylating agents (for example cyclophosphamide,
nitrogen mustard, bendamustin, melphalan, chlorambucil, busulphan,
temozolamide and nitrosoureas); antimetabolites (for example
gemcitabine and antifolates such as fluoropyrimidines like
5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed,
cytosine arabinoside, and hydroxyurea); antibiotics (for example
anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,
epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);
antimitotic agents (for example vinca alkaloids like vincristine,
vinblastine, vindesine and vinorelbine and taxoids like taxol and
taxotere and polokinase inhibitors); proteasome inhibitors, for
example carfilzomib and bortezomib; interferon therapy; and
topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan, mitoxantrone and
camptothecin); (ii) cytostatic agents such as antiestrogens (for
example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene
and iodoxyfene), antiandrogens (for example bicalutamide,
flutamide, nilutamide and cyproterone acetate), LHRH antagonists or
LHRH agonists (for example goserelin, leuprorelin and buserelin),
progestogens (for example megestrol acetate), aromatase inhibitors
(for example as anastrozole, letrozole, vorazole and exemestane)
and inhibitors of 5.alpha.-reductase such as finasteride; (iii)
anti-invasion agents, for example dasatinib and bosutinib
(SKI-606), and metalloproteinase inhibitors, inhibitors of
urokinase plasminogen activator receptor function or antibodies to
Heparanase; (iv) inhibitors of growth factor function: for example
such inhibitors include growth factor antibodies and growth factor
receptor antibodies, for example the anti-erbB2 antibody
trastuzumab [Herceptin.TM.], the anti-EGFR antibody panitumumab,
the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for
example inhibitors of the epidermal growth factor family (for
example EGFR family tyrosine kinase inhibitors such as gefitinib,
erlotinib and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazol-
in-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as
lapatinib); inhibitors of the hepatocyte growth factor family;
inhibitors of the insulin growth factor family; modulators of
protein regulators of cell apoptosis (for example Bcl-2
inhibitors); inhibitors of the platelet-derived growth factor
family such as imatinib and/or nilotinib (AMN107); inhibitors of
serine/threonine kinases (for example Ras/Raf signalling inhibitors
such as farnesyl transferase inhibitors, for example sorafenib,
tipifarnib and lonafarnib), inhibitors of cell signalling through
MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors,
PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase
inhibitors, IGF receptor, kinase inhibitors; aurora kinase
inhibitors and cyclin dependent kinase inhibitors such as CDK2
and/or CDK4 inhibitors; (v) antiangiogenic agents such as those
which inhibit the effects of vascular endothelial growth factor,
[for example the anti-vascular endothelial cell growth factor
antibody bevacizumab (Avastin.TM.); thalidomide; lenalidomide; and
for example, a VEGF receptor tyrosine kinase inhibitor such as
vandetanib, vatalanib, sunitinib, axitinib and pazopanib; (vi) gene
therapy approaches, including for example approaches to replace
aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;
(vii) immunotherapy approaches, including for example antibody
therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan
(Zevalin.RTM.) and ofatumumab; interferons such as interferon
.alpha.; interleukins such as IL-2 (aldesleukin); interleukin
inhibitors for example IRAK4 inhibitors; cancer vaccines including
prophylactic and treatment vaccines such as HPV vaccines, for
example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge);
and toll-like receptor modulators for example TLR-7 or TLR-9
agonists; (viii) cytotoxic agents for example fludarabine
(fludara), cladribine, pentostatin (Nipent.TM.); (ix) steroids such
as corticosteroids, including glucocorticoids and
mineralocorticoids, for example aclometasone, aclometasone
dipropionate, aldosterone, amcinonide, beclomethasone,
beclomethasone dipropionate, betamethasone, betamethasone
dipropionate, betamethasone sodium phosphate, betamethasone
valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol
propionate, cloprednol, cortisone, cortisone acetate, cortivazol,
deoxycortone, desonide, desoximetasone, dexamethasone,
dexamethasone sodium phosphate, dexamethasone isonicotinate,
difluorocortolone, fluclorolone, flumethasone, flunisolide,
fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin
butyl, fluorocortisone, fluorocortolone, fluocortolone caproate,
fluocortolone pivalate, fluorometholone, fluprednidene,
fluprednidene acetate, flurandrenolone, fluticasone, fluticasone
propionate, halcinonide, hydrocortisone, hydrocortisone acetate,
hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone
buteprate, hydrocortisone valerate, icomethasone, icomethasone
enbutate, meprednisone, methylprednisolone, mometasone
paramethasone, mometasone furoate monohydrate, prednicarbate,
prednisolone, prednisone, tixocortol, tixocortol pivalate,
triamcinolone, triamcinolone acetonide, triamcinolone alcohol and
their respective pharmaceutically acceptable derivatives. A
combination of steroids may be used, for example a combination of
two or more steroids mentioned in this paragraph; (x) targeted
therapies, for example Pl3Kd inhibitors, for example idelalisib and
perifosine; or compounds that inhibit PD-1, PD-L1 and CAR T.
[0227] The one or more other active agents may also be
antibiotic.
[0228] Throughout the description and claims of this specification,
the words "comprise" and "contain" and variations of them mean
"including but not limited to", and they are not intended to (and
do not) exclude other moieties, additives, components, integers or
steps. Throughout the description and claims of this specification,
the singular encompasses the plural unless the context otherwise
requires. In particular, where the indefinite article is used, the
specification is to be understood as contemplating plurality as
well as singularity, unless the context requires otherwise.
[0229] Features, integers, characteristics, compounds, chemical
moieties or groups described in conjunction with a particular
aspect, embodiment or example of the invention are to be understood
to be applicable to any other aspect, embodiment or example
described herein unless incompatible therewith. All of the features
disclosed in this specification (including any accompanying claims,
abstract and drawings), and/or all of the steps of any method or
process so disclosed, may be combined in any combination, except
combinations where at least some of such features and/or steps are
mutually exclusive. The invention is not restricted to the details
of any foregoing embodiments. The invention extends to any novel
one, or any novel combination, of the features disclosed in this
specification (including any accompanying claims, abstract and
drawings), or to any novel one, or any novel combination, of the
steps of any method or process so disclosed.
[0230] The reader's attention is directed to all papers and
documents which are filed concurrently with or previous to this
specification in connection with this application and which are
open to public inspection with this specification, and the contents
of all such papers and documents are incorporated herein by
reference.
[0231] The following abbreviations are used in this specification:
[0232] DMA--dimethylacetamide [0233] DMF--N,N-dimethylformamide
[0234] DMSO--dimethylsulfoxide [0235] IPA--isopropyl alcohol [0236]
NMP--N-methylpyrrolidone [0237] PEG--polyethylene glycol
EXAMPLES
Example 1--Solubility of NUC-3373
[0238] The solubility of NUC-3373 (mixture of diastereoisomers) in
a range of solvents is shown in Table 1.
TABLE-US-00001 TABLE 1 Solubility of NUC-3373 in a range of
pharmaceutically relevant solvents NUC-3373 Solvent (mg/mL) Ethanol
778 Propylene glycol 449 PEG 400 422 NMP 705 DMSO 948 DMA 950 Water
<2.0
As can readily be seen, the solubility of NUC-3373 in water is
extremely low. Of the solvents tested, the polar aprotic solvents
and particularly DMSO and DMA offered the best solubilities.
Example 2--Development of an Aqueous Formulation of NUC-3373
[0239] The successful development of the Diluent Solution to enable
preparation of the NUC-1031 aqueous formulation prompted its
development for an aqueous formulation of NUC-3373. An aqueous
NUC-3373 formulation was developed by adding 6.7 ml of a 250 mg/ml
solution of NUC-3373 in 80% DMA:20% 0.9% saline to 10 ml diluent
solution to generate a 100 mg/ml NUC-3373 surfactant solution (see
Table 4), prior to subsequent dilution into an infusion bag. The
clinical dose for NUC-3373 has yet to be established, but the
estimated maximum dose may be up to 3,000 mg, which set the upper
limit for the formulation development studies. Table 2 shows the
volume of 100 mg/ml NUC-3373 surfactant solution that is required
to be added to a 250 ml infusion bag for a variety of doses, and
the resulting composition of the aqueous infusion solution.
TABLE-US-00002 TABLE 2 Composition of saline infusion solution
across a variety of doses of NUC- 3373. NUC-3373 Dose (mg) 1,000 mg
2,000 mg 3,000 mg NUC-3373 3.85 mg/ml 7.41 mg/ml 10.72 mg/ml
Concentration Surfactant solution 10.0 ml 19.9 ml 29.9 ml volume
Composition DMA 4.4 ml 2% 8.8 ml 3% 13.2 ml 5% KELP 2.4 ml 1% 4.8
ml 2% 7.2 ml 3% Tw80 2.4 ml 1% 4.8 ml 2% 7.2 ml 3% Saline 250.8 ml
96% 251.6 ml 93% 252.4 ml 90% Infusion volume 260.0 ml 269.9 ml
279.9 ml
The stability of the 100 mg/ml NUC-3373 surfactant solution under
two storage conditions (5.degree. C. and 20.degree. C.) has been
shown to be stable for 48 hours at both conditions (see Table
3).
TABLE-US-00003 TABLE 3 Stability of 100 mg/ml NUC-3373 surfactant
solution. 0 hours 8 hours 24 hours 48 hours 5.degree. C. 20.degree.
C. 5.degree. C. 20.degree. C. 5.degree. C. 20.degree. C. 5.degree.
C. 20.degree. C. Assay content 105.5 104.8 102.5 100.7 103.7 99.1
102.4 99.4 (mg/ml) Purity (% area) 96.1 96.2 96.2 96.1 96.1 96.1
96.1 96.2 pH 7.8 7.8 7.9 7.8 7.9 7.8 7.9 7.9 Appearance Clear and
Clear and Clear and Clear and yellowish yellowish yellowish
yellowish
The stability of the aqueous infusion solution was also evaluated
using three different doses of NUC-3373 (1,000 mg, 2,000 mg and
3,000 mg) diluted in 250 ml 0.9% saline bags at two storage
conditions (5.degree. C. and 20.degree. C.). The results shown in
Tables 4, 5 and 6, demonstrate that the aqueous infusion solutions
at all dose strengths are stable for up to 48 hours under both
storage conditions.
TABLE-US-00004 TABLE 4 Stability of 1,000 mg NUC-3373 in 250 ml
0.9% saline infusion bag. 0 hours 8 hours 24 hours 48 hours
5.degree. C. 20.degree. C. 5.degree. C. 20.degree. C. 5.degree. C.
20.degree. C. 5.degree. C. 20.degree. C. Assay 3.7 3.9 3.6 3.7 3.6
3.7 3.6 3.8 content NUC-3373 (mg/ml) Total 960.9 1012.8 934.9 960.9
934.9 960.9 934.9 986.9 NUC-3373 (mg) Purity (% 96.2 96.1 96.1 96.1
96.1 96.1 96.2 96.1 area) pH 5.5 5.6 5.6 5.5 5.6 5.8 5.5 5.5
Osmolarity 457 462 450 459 456 462 451 455 (mosm/L H20) Appearance
Clear and Clear and Clear and Clear and colourless colourless
colourless colourless
TABLE-US-00005 TABLE 5 Stability of 2,000 mg NUC-3373 in 250 ml
0.9% saline infusion bag. 0 hours 8 hours 24 hours 48 hours
5.degree. C. 20.degree. C. 5.degree. C. 20.degree. C. 5.degree. C.
20.degree. C. 5.degree. C. 20.degree. C. Assay 7.2 7.4 7.0 7.5 6.9
7.2 7.0 7.1 content NUC-3373 (mg/ml) Total 1946 2000 1892 2027 1865
1946 1892 1919 NUC-3373 (mg) Purity (% 96.1 96.1 96.2 96.1 96.1
96.1 96.1 96.1 area) pH 5.5 5.5 5.5 5.5 5.5 5.5 5.4 5.4 Osmolarity
639 646 637 633 638 639 635 632 (mosm/L H20) Appearance Clear and
Clear and Clear and Clear and colourless colourless colourless
colourless
TABLE-US-00006 TABLE 6 Stability of 3,000 mg NUC-3373 in 250 ml
0.9% saline infusion bag. 0 hours 8 hours 24 hours 48 hours
5.degree. C. 20.degree. C. 5.degree. C. 20.degree. C. 5.degree. C.
20.degree. C. 5.degree. C. 20.degree. C. Assay content 10.2 10.4
10.4 10.5 10.1 10.4 10.0 10.1 NUC-3373 (mg/ml) Total 2857 2913 2913
2941 2829 2913 2801 2829 NUC-3373 (mg) Purity (% area) 96.1 96.1
96.2 96.1 96.1 96.1 96.2 96.1 pH 5.5 5.5 5.5 5.5 5.5 5.5 5.6 5.4
Osmolarity 831 818 823 812 825 817 821 812 (mosm/L H20) Appearance
Clear and Clear and Clear and Clear and colourless colourless
colourless colourless
The pH and osmolarity of the 1,000 mg and 2,000 mg dose solutions
in a 250 ml 0.9% saline bag are suitable for intravenous
administration via either a CVAD or peripheral vein.
Aqueous Infusion Solutions
[0240] The stability studies described above used 250 ml 0.9%
saline bags as the base infusion solution, however similar
stability results have been demonstrated if alternative aqueous
infusion solutions were used (e.g. Water for Injection(WFI), 0.45%
saline) or the volume of the infusion bag was increased (e.g. 500
ml). Lower saline concentrations or increased volume of infusion do
not affect the stability over 48 hours, and do not significantly
alter the pH, and serve to reduce the osmolarity of the infusion
solution. For example, using 0.45% saline or WFI reduces the
osmolarity of the high dose NUC-3373 (10 mg/ml ) from 812 mosm/l to
715 and 557 mosm/l H.sub.2O respectively, whereas increasing the
volume of the 0.9% saline infusion bag from 250 ml to 500 ml at the
high dose (3,000 mg) NUC-3373 infusion solution reduces the
osmolarity from 812 mosm/l to 524 mosm/l. These alternative
infusion solutions may make the high dose NUC-3373 aqueous based
formulation suitable for peripheral vein infusion as well as CVAD
infusion.
Example 3--Illustrative Description of a Formulation
Methodology
[0241] A formulation methodology (see WO2015/198059
(PCT/GB2015/051858)) has been developed for the intravenous
administration of protides. This methodology has been shown in
clinical trials to be effective for NUC-1031 which has broadly the
same solubility profile as NUC-3373 and NUC-7738. That methodology
is as follows: A 250 mg/mL solution of the protide (the S-epimer,
the R epimer or a mixture thereof) is formed in an 80:20 (by
volume) mixture of DMA and 0.9% saline. This stock solution
formulation is typically sufficiently stable for long term storage
and transport of protides. This stock solution formulation can be
administered to patients intravenously via a CVAD (e.g. a Hickman
line, PICC line). The intravenous administration apparatus will
typically be flushed with an 80:20 (by volume) mixture of DMA and
0.9% saline both before and after administration of the formulation
comprising the protide. This helps mitigate the risk of any
potential precipitation of protide in the intravenous
administration apparatus on contact with the saline flush.
Alternatively, where intravenous administration using a saline bag
infusion is the preferred method of administration, the stock
solution formulation is diluted to 100 mg/mL with a diluent
solution which is 20%:40%:40% mixture of DMA:Tween.RTM.
80:Kolliphor.RTM. ELP (e.g. 6.7 mL of 250 mg/ml protide in 80:20
DMA:0.9% saline is added to 10 mL of the
DMA:Tween.RTM.80:Kolliphor.RTM. ELP diluent solution). The
resultant (surfactant solution) formulation is typically stable for
up to 5 days. The infusion solution formulation is then prepared by
diluting this surfactant solution formulation to the desired
concentration with 0.9% saline. For NUC-1031, solutions of either
the S-isomer alone or a mixture of the R and S epimers at 4, 8 and
10 mg/mL have been shown to be stable (both to precipitation of
NUC-1031 and to degradation of NUC-1031) for 48 hours after
dilution of this formulation in both 0.45% and 0.9% saline at a
range of pHs (4.5, 6.0 and 7.0), providing the mixtures were not
stirred. The osmolarity of all of the NUC-1031 solutions has also
been shown to be acceptable for peripheral administration. In a
clinical trial of NUC-3373, this administration methodology has
allowed NUC-3373 to be successfully administered via a CVAD. Early
results are that the infusion solutions of NUC-3373 prepared as
described in this example have some efficacy in treating
cancer.
Example 4--Solubility of NUC-7738
[0242] The solubility of NUC-7738 in a range of solvents is shown
in Table 7.
TABLE-US-00007 TABLE 7 Solubility of NUC-7738 (mixture of
diastereoisomers) in a range of solvents NUC-7738 Solvent (mg/mL)
Ethanol >667 Propylene >667 Glycol DMSO >667 NMP >667
DMA >667 Heptane <12 .sub.tbutylmethylether <11
isopropylacetate <9 Water <5.2 5% Tween in <11.8 water
As can readily be seen, the solubility of NUC-7738 in water is
extremely low, even when the water incorporates a solubiliser.
NUC-7738 is, however, soluble in polar solvents, including NMP,
DMSO and DMA.
Example 5--Development of an Aqueous Formulation of NUC-7738
[0243] 50 .mu.L of a 100 mg/mL concentrate of NUC-7738 (mixture of
diastereoisomers) in a range of solvents (DMA, DMSO, NMP, ethanol,
benzyl alcohol) was mixed with 50 .mu.L of Tween.RTM. 80 and added
to 1.150 mL saline and the resultant solutions were checked by eye
for precipitation of NUC-7738. Similarly a 50 .mu.L concentrate of
NUC-7738 (mixture of diastereoisomers) in Tween.RTM. 80 was mixed
with 50 .mu.L water for injection and then added to 1.150 mL
saline. The results are shown in table 8.
TABLE-US-00008 TABLE 8 Solvents DMA DMSO NMP EtOH BnOH TW80 WFI
Saline Appearance 50 50 1150 Clear and limpid solution 50 50 1150
Clear and limpid solution 50 50 1150 Clear and limpid solution 50
50 1150 White precipitate, milky solution 50 50 1150 White
precipitate, milky solution 50 50 1150 White precipitate, milky
solution
Table 8 shows that DMSO, DMA and NMP are much more effective at
retaining NUC-7738 in aqueous solution than other solvents, for
example, ethanol in which NUC-7738 has good solubility in
non-aqueous conditions. Even a solubiliser is not effective, in the
absence of a polar aprotic solvent, at retaining NUC-7738 in
solution in aqueous conditions. The solutions prepared above were
assayed for NUC-7738 content and purity on being formed and also
after 48 h. Both the assay content and the purity were
substantially unchanged after 48 h, indicating that the solutions
were chemically and physically stable over this period. In a
further experiment, the minimum concentration of NUC-7738 in
solvents that could be diluted with saline without precipitation
was determined. Solutions of NUC-7738 (mixture of diastereoisomers)
at various concentrations in NMP, DMSO and DMA were prepared and
100 .mu.L of the solutions were added to 2.40 mL saline. The
resultant aqueous solutions were observed for precipitation of
NUC-7738. The results are provided in Table 9.
TABLE-US-00009 TABLE 9 Concentrate solutions NUC-7738 NMP NMP NMP
DMSO DMSO DMSO DMA 100 mg/ml 50 mg/ml 25 mg/ml 100 mg/ml 50 mg/ml
25 mg/ml 25 mg/ml Saline Appearance 100 2400 White insoluble
precipitate from the first drop 100 2400 White insoluble
precipitate from the first drop 100 2400 Clear and limpid solution
100 2400 White insoluble precipitate from the first drop 100 2400
White insoluble precipitate from the first drop 100 2400 White
precipitate after addition of 100 .mu.L 100 2400 White insoluble
precipitate from the first drop
[0244] As can be seen, the best solvent for retaining NUC-7738 in
aqueous solution appeared to be NMP which provided a clear and
limpid solution when a 25 mg/mL solution was diluted with
saline.
* * * * *