U.S. patent application number 17/268022 was filed with the patent office on 2021-10-21 for stable ready-to-use carmustine pharmaceutical composition.
This patent application is currently assigned to EMCURE PHARMACEUTICALS LTD.. The applicant listed for this patent is EMCURE PHARMACEUTICALS LTD.. Invention is credited to Aasiya Aslam Burhan, Deepak Pragjibhai Gondaliya, Mukund Keshav Gurjar, Hiren Pravinbhai Patel, Sougata Pramanick.
Application Number | 20210322304 17/268022 |
Document ID | / |
Family ID | 1000005737401 |
Filed Date | 2021-10-21 |
United States Patent
Application |
20210322304 |
Kind Code |
A1 |
Pramanick; Sougata ; et
al. |
October 21, 2021 |
STABLE READY-TO-USE CARMUSTINE PHARMACEUTICAL COMPOSITION
Abstract
The present invention relates to a ready-to-use solution of
carmustine that does not require dissolution or dilution of the
carmustine prior to addition to saline and dextrose parenteral
solutions. In particular, the invention relates to a stable liquid
pharmaceutical composition containing carmustine in the form of
ready-to-use solution and method for preparing the same.
Inventors: |
Pramanick; Sougata;
(Bhosari, IN) ; Burhan; Aasiya Aslam; (Bhosari,
IN) ; Gurjar; Mukund Keshav; (Bhosari, IN) ;
Patel; Hiren Pravinbhai; (Bhosari, IN) ; Gondaliya;
Deepak Pragjibhai; (Bhosari, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EMCURE PHARMACEUTICALS LTD. |
Pune |
|
IN |
|
|
Assignee: |
EMCURE PHARMACEUTICALS LTD.
Pune
IN
|
Family ID: |
1000005737401 |
Appl. No.: |
17/268022 |
Filed: |
September 3, 2019 |
PCT Filed: |
September 3, 2019 |
PCT NO: |
PCT/IB2019/057404 |
371 Date: |
February 11, 2021 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0029 20130101;
A61K 31/175 20130101; A61K 47/26 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/175 20060101 A61K031/175; A61K 47/26 20060101
A61K047/26 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 5, 2018 |
IN |
201821033221 |
Claims
1. A liquid, ready-to-use parenteral pharmaceutical composition of
carmustine dissolved in polysorbate as the sole solvent, wherein
the pharmaceutical composition has a concentration of about 2 mg/mL
to about 500 mg/mL of carmustine and wherein the liquid
ready-to-use parenteral pharmaceutical composition is water
free.
2. The pharmaceutical composition according to claim 1, wherein the
polysorbate is selected from polysorbate 20, polysorbate 40,
polysorbate 60, polysorbate 80 and mixtures thereof.
3. The pharmaceutical composition according to claim 1, wherein the
polysorbate is super refined polysorbate 80 with a peroxide value
below 10 meq 02/kg.
4. The pharmaceutical composition according to claim 1, wherein the
pharmaceutical composition, after storage at 2-8.degree. C. for 3
months, contains at least 90% by weight of the initial amount of
carmustine.
5. The pharmaceutical composition according to claim 1, wherein the
pharmaceutical composition is admixed with 500 mL of 0.9% sodium
chloride injection or 5% dextrose injection to form an
administrable solution prior to administration to a patient.
6. The pharmaceutical composition according to claim 5, wherein the
administrable solution has a concentration of about 0.2 mg/mL of
carmustine.
7. A method for administering carmustine comprising: (a) adding the
liquid, ready-to-use parenteral pharmaceutical composition of claim
1 to 500 mL of 0.9% sodium chloride solution for injection or 5%
dextrose solution for injection to form an administrable solution,
wherein the pharmaceutical composition consists of carmustine
dissolved in polysorbate 80 as the sole solvent, wherein the
pharmaceutical composition has concentration of about 100 mg/mL of
carmustine and the pharmaceutical composition has been stored at 2
to 8.degree. C. in a sealed vial, and (b) parenterally
administering the administrable solution to a patient in need
thereof.
8. The pharmaceutical composition according to claim 3, wherein the
polysorbate is super refined polysorbate 80 with a peroxide value
about 0.5 meq 02/kg.
9. The pharmaceutical composition according to claim 3, wherein the
polysorbate is super refined polysorbate 80 with a peroxide value
about 0.2 meq 02/kg.
10. A liquid, ready-to-use parenteral pharmaceutical composition of
carmustine dissolved in polysorbate as the sole solvent, wherein
the pharmaceutical composition has a concentration of about 2 mg/mL
to about 500 mg/mL of carmustine; the polysorbate is super refined
polysorbate with a peroxide value below 10 meq 02/kg, the liquid
ready-to-use parenteral pharmaceutical composition is water free,
free of visible particles and is stored in a container that is free
of polyvinyl chloride and free of di-2-ethylhexylphthalate.
11. The pharmaceutical composition according to claim 10, wherein
the polysorbate is selected from polysorbate 20, polysorbate 40,
polysorbate 60, polysorbate 80 and mixtures thereof.
12. The pharmaceutical composition according to claim 10, wherein
the polysorbate is super refined polysorbate with a peroxide value
about 0.5 meq 02/kg.
13. The pharmaceutical composition according to claim 12, wherein
the polysorbate is super refined polysorbate with a peroxide value
about 0.2 meq 02/kg.
14. The pharmaceutical composition according to claim 10, wherein
the pharmaceutical composition, after storage at 2-8.degree. C. for
3 months, contains at least 90% by weight of the initial amount of
carmustine.
15. The pharmaceutical composition according to claim 10 wherein
the composition is stored in a vial with a head space within the
vial comprising not more than 6% oxygen.
16. The pharmaceutical composition according to claim 10, wherein
the pharmaceutical composition is admixed with 500 mL of 0.9%
sodium chloride injection or 5% dextrose injection to form an
administrable solution prior to administration to a patient.
17. A method for administering carmustine comprising: (a) adding
the liquid, ready-to-use parenteral pharmaceutical composition of
claim 10 to 500 mL of 0.9% sodium chloride solution for injection
or 5% dextrose solution for injection to form an administrable
solution, wherein the pharmaceutical composition has concentration
of about 100 mg/mL of carmustine and the pharmaceutical composition
has been stored at 2 to 8.degree. C. in a sealed vial, and (b)
parenterally administering the administrable solution to a patient
in need thereof.
18. A liquid, ready-to-use parenteral pharmaceutical composition of
carmustine dissolved in super refined polysorbate 80 with a
peroxide value below 10 meq 02/kg as the sole solvent, wherein the
pharmaceutical composition has a concentration of about 100 mg/mL,
the liquid ready-to-use parenteral pharmaceutical composition is
water free, free of visible particles and is stored in a container
with a head space containing no more than 6% oxygen and wherein the
container is free of polyvinyl chloride and free of
di-2-ethylhexylphthalate.
19. The pharmaceutical composition as defined in claim 18 wherein
the polysorbate 80 has a peroxide value about 0.2 meq 02/kg to
about 0.5 meq 02/kg.
Description
[0001] The present application claims the benefit of Indian Patent
Application No. 201821033221 Sep. 5, 2018, which is hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a ready-to-use solution of
carmustine that does not require dissolution or dilution of the
carmustine prior to addition to saline and dextrose parenteral
solutions. In particular, the invention relates to a stable liquid
pharmaceutical composition containing carmustine in the form of
ready-to-use solution and method for preparing the same.
BACKGROUND OF THE INVENTION
[0003] Carmustine (bischloroethyl nitrosurea also known as BCNU) is
a nitrosurea drug for the treatment of brain cancers owing to its
ability to cross the blood-brain barrier and excellent activity
against brain tumours.
[0004] Carmustine chemically known as
1,3-bis(2-chloroethyl)-1-nitrosourea (shown below) alkylates DNA,
RNA and interferes with its synthesis and functions. It also binds
and modifies (carbamoylates) glutathione reductase, which
consequently leads to cell death.
##STR00001##
[0005] Carmustine is highly soluble in alcohol and lipids.
Carmustine, however, is poorly soluble in water and is unstable in
many formulations. For instance, carmustine gets readily hydrolyzed
in water at pH>6. The solubility and stability issues of
carmustine have been discussed previously. See, for example, Levin
et al., Selective Cancer Therapeutics, 1989, 5(1), 33-35.
[0006] Though the drug has poor oral bioavailability, following IV
infusion, it is rapidly taken up by the tissues, and due to its
high lipid solubility, it can cross the blood brain barrier.
However, it is rapidly degraded, with no unmetabolized drug
detectable after 15 minutes.
[0007] Carmustine is commercially available as a lyophilized 100 mg
powder for injection under the trade name BiCNU.RTM. in single dose
vials. See the March 2017 prescribing information for BiCNU.RTM.,
which is hereby incorporated by reference. Ethanol (dehydrated
alcohol) (3 mL) is co-packaged with the drug product as a sterile
diluent for reconstitution. To prepare the drug for administration,
three preparation steps need to be performed. First, the
lyophilized carmustine is reconstituted with the co-packed sterile
dehydrated alcohol (3 mL) diluent. Second, the solution is further
diluted with 27 mL of sterile water to form the reconstituted
solution. Third, the reconstituted solution is further diluted with
5% Dextrose Injection, USP or Sodium Chloride Injection, USP (0.9%
sodium chloride). This complicated preparation of carmustine
solutions is time-consuming and can lead to errors in preparation
and dosing.
[0008] The lyophilized formulation has several disadvantages
including:
a) Extra handling, for example, due to the two step reconstitution;
b) In some cases, complete dissolution of the lyophilized powder
may require prolonged shaking because of solubilisation problems;
c) Improper reconstitution of a lyophilized powder sometimes
results in the formation of air-borne droplets ("blow-back"),
which, in the case of a potent antitumor agent such as carmustine
may be a health hazard to the personnel preparing the solution for
injection; d) Risk of improper dosing of a patient due to dilution
with the wrong quantity of diluents; and and e) The manufacturing
of a lyophilized formulation is quite costly, since it not only
requires capital investment for installation of a lyophilizer, but
also its maintenance.
[0009] International patent application no. WO 2008/119260
discloses a pharmaceutical composition comprising a
pharmaceutically effective amount of carmustine, Tween surfactant
and a co-solvent selected from glycerol, polyethylene glycol, and a
mixture thereof. The pharmaceutical composition may be in liquid
form. Comparative example 2 of WO 2008/119260, which included
carmustine, Tween 80, and 6 mL water for injection, was found to be
less stable and failed to form a clear solution (turbidity) before
freezing and freeze drying in 10 mL water for injection.
[0010] Indian patent application no. 1909/MUM/2015 discloses a
ready-to-use injectable formulation which is free of
surfactants.
[0011] There is an ongoing need for improved and simplified
formulation of carmustine whose preparation and administration does
not require either lyophilization or reconstitution. In particular,
there is need for a stable, liquid, ready-to-use parenteral
formulation of carmustine, which can be administered to a person in
need thereof, without the hassles of reconstitution.
SUMMARY OF THE INVENTION
[0012] The present inventors while working on liquid, ready-to-use
formulations of carmustine, surprisingly found that stable and
clear solution of carmustine can be formulated with a suitable
surfactant as the sole solvent. The present invention also provides
a simple and cost-effective method of preparing a liquid,
ready-to-use parenteral formulation of carmustine.
[0013] One embodiment of the invention is a liquid, ready-to-use
parenteral pharmaceutical composition of carmustine.
[0014] Another embodiment is a liquid, ready-to-use parenteral
pharmaceutical composition of carmustine dissolved in a suitable
surfactant as the sole solvent.
[0015] The liquid, ready-to-use parenteral pharmaceutical
composition of carmustine may have a concentration from about 2
mg/mL to about 500 mg/mL, preferably 100 mg/mL, 200 mg/mL or 300
mg/mL of carmustine.
[0016] The liquid, ready-to-use parenteral pharmaceutical
composition of carmustine may be further admixed with 500 mL of
0.9% sodium chloride injection or 5% dextrose injection prior to
actual clinical use.
[0017] One preferred embodiment is a liquid, ready-to-use
parenteral pharmaceutical composition of 100 mg of carmustine
dissolved in 1 mL of polysorbate (e.g., polysorbate 80) as the sole
solvent. The pharmaceutical composition may be in a sealed vial.
The polysorbate may be polysorbate 20, polysorbate 40, polysorbate
60, polysorbate 80 or any combination of any of the foregoing. In a
preferred embodiment, the polysorbate is polysorbate 80, such as
super refined polysorbate 80 (and more preferably polysorbate 80
with a peroxide value below 10 meq O.sub.2/kg). In one embodiment,
the peroxide value is about 0.5 meq O.sub.2/kg. In yet another
embodiment the peroxide value is about 0.2 meq O.sub.2/kg.
[0018] Preferably, the pharmaceutical composition, after storage at
2-8.degree. C. for 3 months, contains at least 90% by weight of the
initial amount of carmustine. In one embodiment, the pharmaceutical
composition is admixed with 500 mL of 0.9% sodium chloride
injection or 5% dextrose injection to form an administrable
solution prior to administration to a patient.
[0019] Yet another embodiment is a process for the preparation of a
liquid, ready-to-use parenteral formulation of carmustine
comprising: [0020] a) dissolving carmustine in a sufficient
quantity of a suitable surfactant, for example, to achieve a
concentration of 100 mg/ml; [0021] b) aseptic filtration (e.g.,
with a sterile 0.22 micron filter) of solution obtained in step (a)
to obtain a sterile product, and [0022] c) filling the solution
obtained in step (b) into a suitable container/closure system.
[0023] d) optionally, inert gas purging (nitrogen) can be carried
out during any of the steps.
[0024] Another embodiment is a method of preparing an administrable
solution of carmustine comprising diluting the ready-to-use
parenteral formulation of carmustine with an aqueous 0.9% sodium
chloride solution (preferably Sodium Chloride Injection, USP) or an
aqueous 5% dextrose solution (preferably 5% Dextrose Injection,
USP) to obtain the administrable solution.
[0025] In one embodiment, the ready-to-use parenteral formulation
of carmustine is diluted with 500 mL of an aqueous 0.9% sodium
chloride solution (preferably Sodium Chloride Injection, USP) or
500 mL of an aqueous 5% dextrose solution (preferably 5% Dextrose
Injection, USP).
[0026] In one preferred embodiment, the administrable solution has
a pH in the range of 4 to 7 and an osmolality in the range of
330-390 mOsmol/L.
[0027] Yet another embodiment is a method of administering
carmustine comprising intravenously administering an administrable
carmustine solution as described herein to a patient in need
thereof. The administrable carmustine solution may be prepared as
described herein.
[0028] Yet another embodiment is a method for administering
carmustine comprising:
(a) adding a liquid, ready-to-use parenteral pharmaceutical
composition of carmustine to 500 mL of 0.9% sodium chloride
solution for injection or 5% dextrose solution for injection to
form an administrable solution, wherein the pharmaceutical
composition comprises, consists essentially of, or consists of 100
mg of carmustine dissolved in 1 mL of polysorbate 80 as the sole
solvent, and (b) parenterally administering the administrable
solution to a patient in need thereof.
[0029] In one embodiment, the ready-to-use pharmaceutical
composition is stored at 2 to 8.degree. C. in a sealed vial (such
as, for example, 3, 6, 9, or 12 months) prior to being added to
0.9% sodium chloride solution for injection or 5% dextrose solution
for injection.
[0030] Yet another embodiment is a method of treating cancer in a
patient in need thereof by intravenously administering an
administrable carmustine solution as described herein to the
patient. The administrable carmustine solution may be prepared as
described herein. The patient may be suffering from brain tumors
glioblastoma, brainstem glioma, medulloblastoma, astrocytoma,
ependymoma, metastatic brain tumors, multiple myeloma, relapsed or
refractory Hodgkin's lymphoma, or relapsed or refractory
Non-Hodgkin's lymphomas.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The present invention relates to a stable, liquid
pharmaceutical composition containing carmustine in the form of a
ready-to-use solution and method for preparing the same.
[0032] As used herein, a "ready-to-use" or "RTU" composition is a
sterile, liquid, injectable composition that is stable and has not
been reconstituted from a lyophilizate.
[0033] Pharmaceutical Composition
[0034] One embodiment is a liquid, ready-to-use parenteral
composition of carmustine dissolved in a suitable surfactant as the
sole solvent.
[0035] The concentration of carmustine in the liquid, ready-to-use
parenteral composition may vary from about 2 mg/mL to about 500
mg/mL, preferably 100 mg/mL, 200 mg/mL or 300 mg/mL.
[0036] Suitable surfactants include, but are not limited to, sodium
salts of fatty alcohol sulphates, partial fatty acid esters of
polyhydroxyethylene sorbitan such as polyoxyethylene sorbitan
monolaurate (e.g., polyoxyethylene (20) sorbitan monolaurate, which
is referred to as polysorbate 20 or Tween.RTM. 20), polyoxyethylene
sorbitan monopalmitate (e.g., polyoxyethylene (20) sorbitan
monopalmitate, which is referred to as polysorbate 40 or Tween.RTM.
40), polyoxyethylene sorbitan monostearate (e.g., polyoxyethylene
(20) sorbitan monosterate, which is referred to as polysorbate 60
or Tween.RTM. 60), and polyoxyethylene sorbitan monooleate (e.g.,
polyoxyethylene (20) sorbitan monooleate, which is referred to as
polysorbate 80 or Tween.RTM. 80), polyoxyethylene sorbitan
tristearate (e.g., polyoxyethylene (20) sorbitan tristearate, which
is referred to as polysorbate 65 or Tween.RTM. 65), and
polyoxyethylene sorbitan trioleate (e.g., polyoxyethylene (20)
sorbitan trioleate, which is referred to as polysorbate 85 or
Tween.RTM. 85), polyoxyethylene glycol esters, polyoxyethylene
castor oil derivatives, Cremophor.RTM. EL (PEG-35 castor oil),
Cremophor.RTM. RH40 (PEG-40 hydrogenated castor oil),
polyoxyethylene 15 hydroxystearate, polyoxyethylene alkyl ethers
(sold under the tradename Brij.RTM.); polyoxyethylene stearates
(Myrj.RTM.), sorbitan derivatives, fatty acid esters of sorbitan,
poloxamers (e.g., poloxamer 188, poloxamer 407, poloxamer 338, and
poloxamer 184), poloxamine (e.g., poloxamine 304, poloxamine 904,
and poloxamine 908), lecithin, an ethoxylated vegetable oil,
vitamin E tocopherol propylene glycol succinate (vitamin E-TPGS),
polyoxyethylene-polyoxypropylene block copolymers, incrocas 35,
TPGS (D-.alpha.-tocopherol polyethylene glycol 1000 succinate),
tyloxapol, sodium oleate, sodium deoxycholate and mixtures
thereof.
[0037] In one preferred embodiment, the surfactant is selected from
various grades of polysorbate, such as polysorbate 20, polysorbate
40, polysorbate 60, polysorbate 80 and mixtures thereof. More
preferably, the surfactant is polysorbate (e.g., super refined
polysorbate 80) with a peroxide value below 10 meq O.sub.2/kg. In
one embodiment, the peroxide value is about 0.5 meq O.sub.2/kg. In
yet another embodiment the peroxide value is about 0.2 meq
O.sub.2/kg.
[0038] According to one preferred embodiment, 100 mg of carmustine
is dissolved in a sufficient quantity of surfactant (up to 1 mL to
make up the final volume). In one embodiment, the fill volumes of
RTU liquid may be 1 mL or 3 mL.
[0039] The pharmaceutical composition may optionally include other
optional pharmaceutical excipients such as antioxidants. Suitable
antioxidants include, but are not limited to, acetone sodium
bisulfite, argon, ascorbyl palmitate, ascorbic acid, sodium
bisulfite, butylated hydroxy anisole (BHA), butylated hydroxy
toluene (BHT), citric acid, cystein/cysteinate HCl, acetylcystein,
dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid,
gentisic acid, ethanolamine, glutamate monosodium, glutathione,
formaldehyde sulfoxylate sodium, metabisulfite sodium,
metabisulfite potassium, methionine, monothioglycerol
(thioglycerol), sulfite sodium, tocopherols alpha, alpha tocopherol
hydrogen succinate, thioglycolate sodium, sodium formaldehyde
sulfoxylate, thiourea, and any combination of any of the
foregoing.
[0040] The concentration of antioxidant may range between 0.001
mg/mL to 5 mg/mL.
[0041] In one embodiment, the pharmaceutical composition, after
storage at 2-8.degree. C. for 3, 6, 9, or 12 months, contains at
least 90, 92, 94, 95, 96, 97, or 98% by weight of the initial
amount of carmustine. In another embodiment, the pharmaceutical
composition, after storage at 2-8.degree. C. for 3, 6, 9, or 12
months, contains at least 90% by weight of the initial amount of
carmustine.
[0042] Process of Preparation for the RTU Composition
[0043] The liquid, ready-to-use parenteral composition of
carmustine may be prepared by: [0044] a) dissolving carmustine in a
sufficient quantity of a suitable surfactant (e.g., to achieve 100
mg/mL concentration), [0045] b) aseptic filtration (e.g., with a
sterile 0.22 micron filter) of the carmustine solution obtained in
step (a) to obtain a sterile product, and [0046] c) filling the
solution obtained in step (b) into a suitable container/closure
system
[0047] Optionally, purging inert gas (nitrogen) during any of the
aforementioned steps.
[0048] The liquid, ready-to-use parenteral formulation of
carmustine may be a clear, pale yellow and free from visible
particles.
[0049] In one embodiment, the stable liquid, ready-to-use
parenteral formulation of carmustine of present invention has a
concentration of about 100 mg/mL of carmustine.
[0050] This liquid, ready-to-use parenteral formulation of
carmustine can be filled in a suitable container/closure system,
e.g., ampoules, vials, and prefilled syringe system. The
ready-to-use solution may be stored in an amber type-I glass vial
or polypropylene container (such as a polypropylene container which
is polyvinyl chloride (PVC) free and di-2-ethylhexy phthalate
(DEHP) free). These solutions are preferably not stored in a
polyvinyl chloride container. In one embodiment, the head space of
each vial contains no more than 6.0% by volume oxygen.
[0051] The liquid, ready-to-use parenteral formulation of
carmustine may have a pH in the range of 4-7.
[0052] Prior to administration, the liquid, ready-to-use parenteral
composition of carmustine may be further admixed with 0.9% sodium
chloride injection (e.g., Sodium Chloride Injection, USP) or 5%
dextrose injection (e.g., 5% Dextrose Injection, USP) to form an
administrable solution. For instance, in one embodiment, the
ready-to-use composition is further admixed with 500 mL of 0.9%
sodium chloride injection or 5% dextrose injection.
[0053] The U.S. Pharmacopeia, USP 42-NF 37 (2019) is hereby
incorporated by reference, including the entries for Sodium
Chloride Injection, USP and 5% Dextrose Injection, USP.
[0054] The administrable solution may be a faint yellow colour with
a pH in the range of 4 to 7 and osmolality in the range of 330-390
mOsmol/L.
[0055] The administrable solution may be stored in a glass or
polypropylene container (such as a polypropylene container which is
polyvinyl chloride (PVC) free and di-2-ethylhexy phthalate (DEHP)
free). These solutions are preferably not stored in a polyvinyl
chloride container.
[0056] The administrable carmustine solution can have a
concentration of about 0.2 mg/mL of carmustine
[0057] As used herein, a "stable" composition means no aggregation
observed when stored at conventional storage conditions like
2.degree. C. to 8.degree. C. (long term) for appropriate time and
wherein the assay of carmustine is not less than 90% (based on 100%
initial carmustine).
[0058] The carmustine content may be determined by methods known in
the art, such as high performance liquid chromatography (HPLC
method), and spectrophotometry (UV spectrophotometry). HPLC was
used for performing the carmustine assay studies described
herein.
[0059] Based on the results of table 2, it was concluded that the
liquid, ready-to-use parenteral formulation of carmustine of the
present invention, was stable for up to 3 months when stored at
2.degree. C.-8.degree. C.
[0060] Administration
[0061] The carmustine administrable solution may be administered by
slow intravenous infusion over at least two hours. In one
embodiment, the injected area is monitored during the
administration. In another embodiment, the rate of administration
of the intravenous infusion is no more than 1.66
mg/m.sup.2/min.
[0062] The carmustine administrable solution may be administered to
a patient to treat brain tumors glioblastoma, brainstem glioma,
medulloblastoma, astrocytoma, ependymoma, metastatic brain tumors,
multiple myeloma, relapsed or refractory Hodgkin's lymphoma, or
relapsed or refractory Non-Hodgkin's lymphomas.
[0063] In one embodiment, the carmustine administrable solution is
administered to a patient as a single agent or in a combination
therapy (such as with other chemotherapeutic agents) to treat (i)
brain tumors glioblastoma, brainstem glioma, medulloblastoma,
astrocytoma, ependymoma, or metastatic brain tumors, (ii) multiple
myeloma in combination with prednisone, (iii) relapsed or
refractory Hodgkin's lymphoma in combination with other approved
drugs (such as chemotherapeutic agents), or (iv) relapsed or
refractory Non-Hodgkin's lymphomas in combination with other
approved drugs (such as chemotherapeutic agents).
[0064] The carmustine administrable solution may be administered as
a single agent in previously untreated patients at a dose of 150 to
200 mg/m.sup.2 carmustine intravenously every 6 weeks. The
carmustine administrable solution may be administered as a single
dose or divided into daily injections such as 75 to 100 mg/m.sup.2
on two successive days. The dose may be lowered when the carmustine
administrable solution is used with other myelosuppressive drugs or
in patients in whom bone marrow reserve is depleted. The carmustine
administrable solution may be administered for the duration
according to the established regimen. In one embodiment, the
patient is premedicated before each dose with antiemetics.
[0065] The dosing (after the initial dose) may be adjusted
according to the hematologic response of the patient to the
preceding dose. In one embodiment, the patient is dosed as
follows:
TABLE-US-00001 Nadir After Prior Dose Percentage of Prior
Leukocytes/mm.sup.3 Platelets/mm.sup.3 Dose to be Given >4000
>100,000 100% 3000-3999 75,000-99,999 100% 2000-2999
25,000-74,999 70% <2000 <25,000 50%
[0066] The hematologic toxicity can be delayed and cumulative. In
one embodiment, the patient's blood counts are monitored weekly. In
another embodiment, a repeat course of the carmustine administrable
solution is not administered until circulating blood elements have
returned to acceptable levels (platelets above 100 Gi/L, leukocytes
above 4 Gi/L and absolute neutrophil count above 1 Gi/L). In yet
another embodiment, the interval between courses is 6 weeks.
[0067] In yet another embodiment, renal function is evaluated prior
to administration and/or periodically during treatment. In one
embodiment, carmustine treatment is discontinued if the creatinine
clearance is less than 10 mL/min. In another embodiment, carmustine
is not administered to patients with compromised renal function. In
yet another embodiment, transaminases and bilirubin are monitored
periodically during treatment.
[0068] The following examples further illustrate the invention but
should not be construed as in any way limiting its scope. In
particular, the processing conditions are merely exemplary and can
be varied by one of ordinary skill in the art.
[0069] All patents and other references cited herein are hereby
incorporated by reference in their entireties
EXAMPLES
Example 1
TABLE-US-00002 [0070] TABLE 1 Composition of liquid, ready-to-use
parenteral formulations of carmustine Composition Formulation 1
Carmustine 100 mg Polysorbate 80 NF q.s to 1 mL
[0071] (a) 100 mg of carmustine was dissolved in sufficient
quantity (q.s. to 1 mL) of polysorbate 80 NF surfactant, under
inert (nitrogen) gas purging. [0072] (b) The solution obtained in
step (a) was aseptically filtered (sterile 0.22 micron filter)
under inert (nitrogen) gas purging to obtain a sterile product.
[0073] (c) The solution obtained in step (b) was filled into a
sterile amber coloured type-I glass vial.
[0074] The stability of the formulation was tested after 3 months
of storage at 2-8.degree. C. The results are provided in Table 2
below.
TABLE-US-00003 TABLE 2 Evaluation of liquid ready-to-use parenteral
formulations of carmustine Stability data 3 months Test Initial
(2.degree. C.-8.degree. C.) Description Clear pale yellow Clear
pale yellow color solution color solution Assay 101.50% 97.21%
Related substances Impurity A* 0.20% 1.80% Any unspecified impurity
BLD** BLD** Total impurities 0.20% 1.80% *Impurity A refers to
1,3-bis(2-chloroethyl)urea **BLD: below limit of detection
* * * * *