U.S. patent application number 16/225485 was filed with the patent office on 2019-04-25 for ready-to-administer solution of fentanyl citrate.
This patent application is currently assigned to SUN PHARMACEUTICAL INDUSTRIES LTD.. The applicant listed for this patent is SUN PHARMACEUTICAL INDUSTRIES LTD.. Invention is credited to Subhas Balaram BHOWMICK, Kandarp Maheshkumar DAVE, Prashant KANE, Samarth KUMAR, Milan Natvarbhai THAKKAR.
Application Number | 20190117560 16/225485 |
Document ID | / |
Family ID | 57546663 |
Filed Date | 2019-04-25 |
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United States Patent
Application |
20190117560 |
Kind Code |
A1 |
KUMAR; Samarth ; et
al. |
April 25, 2019 |
READY-TO-ADMINISTER SOLUTION OF FENTANYL CITRATE
Abstract
A method of treating a patient in need of therapy with fentanyl
or a salt thereof, the method comprising providing a
ready-to-administer solution consisting essentially of fentanyl or
a salt thereof as the sole active ingredient, a sugar or sugar
alcohol and water for injection, the solution having a pH in the
range of 3.5 to 7.5, and parenterally administering the solution to
the patient.
Inventors: |
KUMAR; Samarth; (Vadodara,
IN) ; KANE; Prashant; (Vadodara, IN) ;
BHOWMICK; Subhas Balaram; (Vadodara, IN) ; THAKKAR;
Milan Natvarbhai; (Vadodara, IN) ; DAVE; Kandarp
Maheshkumar; (Vadodara, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUN PHARMACEUTICAL INDUSTRIES LTD. |
Maharashtra |
|
IN |
|
|
Assignee: |
SUN PHARMACEUTICAL INDUSTRIES
LTD.
|
Family ID: |
57546663 |
Appl. No.: |
16/225485 |
Filed: |
December 19, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15185452 |
Jun 17, 2016 |
10206872 |
|
|
16225485 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 23/00 20180101;
A61P 43/00 20180101; A61K 47/26 20130101; A61P 25/04 20180101; A61K
31/4468 20130101; A61K 9/0019 20130101; A61K 9/08 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/08 20060101 A61K009/08; A61K 31/4468 20060101
A61K031/4468; A61K 47/26 20060101 A61K047/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 19, 2015 |
IN |
2346/MUM/2015 |
Claims
1. A method of treating a patient in need of therapy with fentanyl
or a salt thereof, said method comprising: a. providing a
ready-to-administer solution consisting essentially of fentanyl or
a salt thereof as the sole active ingredient, a sugar or sugar
alcohol, and water for injection, said solution having a pH in the
range of 3.5 to 7.5, and b. parenterally administering said
solution to the patient.
2. The method as claimed in claim 1, wherein the sugar is selected
from the group consisting of dextrose, glucose, fructose or
mixtures thereof.
3. The method as claimed in claim 1, wherein the sugar alcohol is
selected from the group consisting of mannitol or sorbitol or
mixtures thereof.
4. The method as claimed in claim 1, wherein the solution is
present in one or more containers, and fentanyl or a salt thereof
is present in amount ranging from 0.001 mg/ml to 0.1 mg/ml.
5. The method as claimed in claim 4, wherein fentanyl or a salt
thereof is present in an amount ranging from 0.005 mg/ml to 0.075
mg/ml and the volume of the solution in containers is from 50 ml to
500 ml.
6. The method as claimed in claim 5, wherein the patient in need of
therapy with fentanyl or a salt thereof is a patient undergoing
surgical procedure.
7. The method as claimed in claim 4, wherein the container
comprises a polymer of a cyclic olefin.
8. The method as claimed in claim 4, wherein the solution has been
sterilized by autoclaving.
9. The method as claimed in claim 1, wherein the method does not
include the administration of sodium other than sodium hydroxide
and/or a buffer component present in an amount sufficient to adjust
a pH of the solution.
10. The method as claimed in claim 1, wherein the solution is
present in a plurality of containers comprising larger and smaller
containers, wherein a concentration of fentanyl or a salt thereof
is greater in the smaller containers than in the larger containers,
and wherein said administration occurs simultaneously or
sequentially from the plurality of containers.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. application Ser. No.
15/185,452 filed Jun. 17, 2016, which claims the benefit of
priority from Indian Patent Application No. 2346/MUM/2015, filed
Jun. 19, 2015, the disclosure of which are incorporated by
reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present disclosure relates to a method of treating a
patient in need of therapy with fentanyl or a salt thereof by
providing a ready-to-administer solution of fentanyl or a salt
thereof.
BACKGROUND OF THE INVENTION
[0003] Fentanyl, or its pharmaceutically acceptable salt, is an
opioid receptor agonist. A preferred pharmaceutically acceptable
salt of fentanyl is fentanyl citrate. The chemical name of fentanyl
citrate is N-(1-phenylethyl)-4-piperidyl)-propionanilide citrate
(1:1), which has the following structural formula:
##STR00001##
[0004] The approved products of fentanyl include tablets, lozenges
(oral), transdermal patches and injectable solutions. Most of the
injectable products of fentanyl currently available in the market
contain sodium chloride, and these products, when intended for
intravenous infusion, require dilution before administration using
a suitable diluent, such as normal saline. For patients in need of
therapy with fentanyl or a salt thereof, who also suffer from one
or more conditions that are aggravated by increased plasma
concentration of sodium ions, such as hypertension, hypernatremia,
heart ailments such as congenital heart diseases, renal
insufficiency, critical illness, and the like, it is important to
avoid administration of sodium ions either as a constituent of the
formulation or as a diluent. Because the currently available
options involve the possibility of the use of preparations
containing sodium ions, there always remains a chance that sodium
ions may be accidentally administered to these patients. If proper
care or attention is not taken and such patients are accidentally
administered a preparation containing sodium ions, the patient's
condition may be aggravated and become life threatening. There have
been several reports of the accidental administration of
sodium-containing preparations to patients who suffer from one or
more conditions that get aggravated by an increased plasma
concentration of sodium ions. Thus, there remains a need for a
method of treating patients in need of therapy with fentanyl or a
salt thereof, which method advantageously prevents or avoids the
accidental infusion of preparations containing sodium to the
patients who are in need of therapy with fentanyl or a salt thereof
and who are also suffering from a condition which is aggravated by
an increased plasma concentration of sodium ions.
SUMMARY OF THE INVENTION
[0005] The present disclosure provides a method of treating a
patient in need of therapy with fentanyl or a salt thereof, said
method comprising: [0006] a. providing a ready-to-administer
solution consisting essentially of fentanyl or a salt thereof as
the sole active ingredient, sugar or sugar alcohol and water for
injection, said solution having a pH in the range of 3.5 to 7.5;
and [0007] b. parenterally administering the said solution to the
patient.
[0008] The present disclosure also provides a sterile,
ready-to-administer solution consisting essentially of fentanyl or
a salt thereof as the sole active ingredient, a sugar or sugar
alcohol and water for injection, said solution having a pH in the
range of 3.5 to 7.5.
[0009] In another aspect, the present disclosure provides a
sterile, ready-to-administer solution consisting essentially of
fentanyl or a salt thereof as the sole active ingredient, a sugar
or sugar alcohol and water for injection, said solution having a pH
in the range of 3.5 to 7.5 for use in the treating a patient in
need of therapy with fentanyl or a salt thereof, by parenterally
administering the solution to the patient.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The solution according to the present disclosure is suitable
for direct parenteral administration, i.e., it is
"ready-to-administer" meaning that the solution is prepared, filled
into infusion container during manufacture, the solution is sterile
and the parenteral administration does not require any steps or
handling or manipulation before administration and can be directly
administered parenterally to the patient. The solution of the
present disclosure is premixed or ready to be administered and can
be directly administered without the need for any intervening steps
of reconstitution and/or dilution or mixing.
[0011] The term "consisting essentially of" denotes the nature of
the solution used in the method of the present disclosure and is
intended to mean a ready-to-administer solution that does not
include a sodium ion containing excipient other than sodium
hydroxide and/or a buffer component for example, sodium hydrogen
phosphate which may be used, if required, in amounts sufficient to
adjust the pH. The term "consisting essentially of" is intended to
mean a ready-to-administer solution that does not include
mucoadhesive components such as pectins or alginates or chitosan
and the like; or surfactants or emulsifiers such as tweens,
polysorbates, poloxamers and the like. The term "consisting
essentially of" is further intended to mean a ready-to-administer
solution that does not include a water miscible organic solvent
such as ethanol, propylene glycol and the like. Accordingly, in an
embodiment, the present disclosure pertains to a method that does
not include the administration of sodium, other than sodium
hydroxide and/or a buffer component for example, sodium hydrogen
phosphate which may be used, if required, in amounts sufficient to
adjust the pH.
[0012] The ready-to-administer solution according to the present
disclosure does not include pectin or chitosan. In one or more
embodiments, the ready-to-administer solution according to the
present disclosure does not include surfactants like tweens,
polysorbates, poloxamers. In one or more embodiments, the
ready-to-administer solution according to the present disclosure
does not include organic solvents such as ethanol, propylene
glycol.
[0013] Impurity A as used herein is a degradation impurity and is
N-phenyl-N-[cis,
trans-1-oxido-1-(2-phenylethyl)piperidin-4-yl]propanamide. The
chemical structure of impurity A is given below:
##STR00002##
[0014] Impurity B as used herein is
N-phenyl-N-(piperidin-4-yl)propanamide and is structurally
represented by the following structure:
##STR00003##
[0015] Impurity C as used herein is
N-Phenyl-n-[1-(2-phenylethyl)-4-piperidinyl] acetanilide, a
potential synthetic impurity and is structurally represented by the
following structure:
##STR00004##
[0016] Impurity D as used herein is
N-Phenyl-1-(2-phenylethyl)-4-piperidinamine and is structurally
represented by the following structure:
##STR00005##
[0017] The present disclosure provides a method of treating a
patient in need of therapy with fentanyl or a salt thereof, said
method comprising (a) providing a ready-to-administer solution
consisting essentially of fentanyl or a salt thereof as the sole
active ingredient, a sugar or sugar alcohol and water for
injection, said solution having a pH in the range of 3.5 to 7.5;
and (b) parenterally administering the solution to the patient.
[0018] The method of the present disclosure presents an advantage
in that it prevents or avoids accidental infusion of preparations
containing sodium to patients who are in need of therapy with
fentanyl or a salt thereof but who are also suffering from a
condition which is aggravated by increased plasma concentration of
sodium ions. Accidental infusion of a preparation containing sodium
can occur in several instances, including as a result of accident
or error by a medical practitioner or hospital care individuals, to
patients who are contraindicated for sodium ion intake.
Contraindications may exist in patients suffering from, e.g.,
hypertension or hypernatremia, patients in medical surgical
hospitals suffering from hypernatremia, or patients suffering from
congenital heart disease, renal insufficiency, critical illness and
the like. Such accidental administration can happen as a result of
either ignorance or unawareness. The injectable infusion products
of fentanyl currently available in the market contain sodium
chloride, and these products when intended for intravenous
infusion, require dilution before administration, as they are not
ready-to-administer. Therefore, there always remains a chance of
accidental administration of preparations containing large
quantities of sodium ions, such as is present in a normal saline
diluent, to patients such as those discussed above. Particularly,
in case when large volume of solution is required in indications
such as general anaesthesia, post-operative pain control etc.,
there are chances of administering huge amounts of sodium chloride
if the product itself contains sodium chloride or requires a
diluent containing sodium chloride. This accidental administration
can lead to the aggravation of the patient's condition, which can
have life threatening consequences. The ready-to-administer
solution of the present disclosure, which is devoid of sodium other
than sodium hydroxide and/or a buffer component, for example,
sodium hydrogen phosphate which may be used, if required, in
amounts sufficient to adjust the pH, and which does not require the
use of any diluent before administration, will avoid such errors or
accidents, which may be otherwise a huge concern, especially for
administration during critical care or during critical conditions,
such as a patient undergoing surgery or the like. The method of the
present invention avoids such administration. The present
disclosure provides a method of treating patients in need of
therapy with fentanyl or a salt thereof, which method also prevents
or avoids the accidental infusion of preparations containing sodium
to the patients. The method of treatment according to the present
disclosure is suitable for treatment of patients in need of therapy
with fentanyl or a salt thereof, for instance patients suffering
from pain, patients undergoing a surgical procedure, as an adjunct
to general anesthesia, as an adjunct to regional anesthesia, as a
general anesthesia, or as premedication. For patient undergoing
surgical procedure, the ready-to-administer solution may be given
before, during and after surgical procedure.
[0019] The ready-to-administer solution of the present invention is
suitable for direct parenteral administration. The parenteral
administration routes suitably include, but are not limited to,
intravenous infusion or injection, intramuscular, intra-arterial,
subcutaneous and the like.
[0020] In one embodiment the ready-to-administer solution does not
contain or is free of sodium or sodium ions, other than sodium
hydroxide and/or a buffer component, for example, sodium hydrogen
phosphate which may be used, if required, in amounts sufficient to
adjust the pH.
[0021] In one embodiment the solution does not contain pectin. In
one embodiment the solution does not contain chitosan. In one
embodiment the solution does not contain poloxamer and other
surface active agents like tween or polysorbate. In one embodiment
the solution does not contain benzalkonium chloride. In one
embodiment the solution does not contain ethanol and propylene
glycol.
[0022] In one embodiment the solution does not contain an
additional diluent. In one embodiment the method does not require a
dilution step.
[0023] Fentanyl or a salt thereof as used herein includes
pharmaceutically acceptable salts of fentanyl. Examples of suitable
pharmaceutically acceptable salts of fentanyl for use in accordance
with the present disclosure include for example, but not limited to
citrate, hydrochloride, chloride, sulphate, tartrate, or other
similar salt forms. In certain embodiments, the fentanyl may be
employed as the free base in the ready-to-administer solution of
the present disclosure. In preferred embodiments, the
pharmaceutically acceptable salt of fentanyl is fentanyl
citrate.
[0024] The method of treating a patient in need of therapy with
fentanyl or a salt thereof according to the present disclosure
comprises ready-to-administer solution of fentanyl or a salt
thereof, said solution containing fentanyl or a salt thereof as the
sole active ingredient in an amount ranging from about 0.001 mg/ml
to about 0.1 mg/ml, such as about 0.005, 0.01, 0.015, 0.02, 0.025,
0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075,
0.08, 0.085, 0.09 or 0.095 mg/ml, preferably from about 0.005 mg/ml
to 0.075 mg/ml, more preferably from about 0.01 mg/ml to about 0.05
mg/ml. Suitably, the amount of fentanyl or its salt used in the
present disclosure is expressed as amounts equivalent to fentanyl
base. In one embodiment, the ready-to-administer solution contains
from about 0.001 mg/ml to about 0.1 mg/ml of fentanyl citrate. In
one preferred embodiment, the ready-to-administer solution contains
0.01 mg/ml of fentanyl citrate. In another preferred embodiment,
the ready-to-administer solution contains 0.05 mg/ml of fentanyl
citrate.
[0025] According to one embodiment, the ready-to-administer
solution may be provided in volumes ranging from small volumes to
large volumes, such as from about 1 ml to 1000 ml, such as about
10, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650,
700, 750, 800, 850 or 900 ml. When the solution is provided in
small volumes, it may be filled into containers such as vials,
syringes, ampoules, auto-injectors, prefilled syringes and similar
packaging systems. Typically, in some embodiments, the volumes
range from 1 ml to 50 ml, such as about 5, 10, 15, 20, 25, 30, 35,
40 or 45 ml, preferably 2 ml to 30 ml. However, it is possible to
present the ready-to-administer solution of the present invention
in different volumes by adjusting the concentration of fentanyl or
a salt thereof.
[0026] Alternatively, when the solution is provided in large
volumes, it may be it filled into containers such as infusion bags,
bottles, pouches, large volume prefilled syringes, and such similar
packaging systems. Typically, in some embodiments, the volumes
range from 50 ml to 1000 ml, preferably, 50 ml to 500 ml, such as
60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400 or 450 ml.
Preferred embodiments include volumes of the solution filled into
containers in the range of 100 ml to 300 ml. In one preferred
embodiment, the volume is 100 ml. In another preferred embodiment,
the volume is 250 ml. However, it is possible to present the
ready-to-administer solution of the present disclosure in different
volumes by adjusting the concentration of fentanyl or a salt
thereof. For example, in one specific embodiment, the amount of
fentanyl or a salt thereof ranges from 0.005 mg/ml to 0.075 mg/ml
and is present in large volumes ranging from 50.0 ml to 500 ml.
[0027] According to the present disclosure, the ready-to-administer
solution used in the method of the present disclosure is contained
in a container suitable for parenteral administration. The
container used according to the present disclosure may be an
infusion bag, infusion bottle, a flexible pouch, a prefilled
syringe, and the like. In some embodiments, the container may be a
syringe, a vial or an ampoule. The container may be of variable
size or volume.
[0028] The containers used to hold the solution may be made up of
glass or polymeric materials. It is possible to use a glass which
has been coated with a barrier/polymer. In one preferred
embodiment, the container is made up of a material which comprises
a polymer of a cyclic olefin.
[0029] The polymer of a cyclic olefin may be a cyclooolefin
homopolymer (COP) or a cycloolefin copolymer (COC) or a mixture
thereof. Cycloolefin homopolymers (cycloolefin polymers, or COP)
are homopolymers comprising single type of cycloolefin monomers.
Cycloolefins (cyclic olefins) are mono or polyunsaturated, mono or
polycyclic ring systems such as cycloalkenes (like cyclopropene,
cyclopentene, cyclobutene, cyclohexene), bicycloalkenes (like
norbornene, dicyclopentadiene), tricycloalkenes, tetracycloalkenes
(tetracyclododecene)and the like. The ring system can be
monosubstituted or polysubstituted. Cycloolefin copolymers (COC)
comprise cycloolefins and co-monomers, wherein cycloolefins are
copolymerized with one or more comonomers. Suitable co-monomers are
unsubstituted or substituted olefins, of 2 to 20 carbon atoms,
preferably 2 to 6 carbon atoms, such as ethylene, propylene,
butene, hexene. Any of these olefins may be used individually, or
two or more types of olefins may be used in combination. In one or
more embodiments of the present disclosure, the container may
comprise one or more layers, wherein at least a portion of the
inside wall of the container, i.e. the inner layer, comprises a
polymer of cycloolefin. The container additionally may have layers
on the outer side which may be another layer of polymer of
cycloolefin or a layer of another polymer, such as for example, a
polyethylene polymer, low density polyethylene, linear low density
polyethylene. In one embodiment, the container may comprise a first
portion including a first polymer that forms the inner surface of
the container and a second portion including a second polymer that
forms the outer surface of the container. The first polymer and the
second polymer layer may be directly bondable to each other as such
or through a third polymer that is bondable to the first and second
polymer and fixedly secures the first and second portions to each
other. In some embodiments, the first and second polymer or the
first, second, and third polymers layers are co-extruded or
moulded. In some embodiments, the first and second portions may be
non-bondable and one of these may be flexible, while the other may
be rigid. The polymer that forms the inner surface/layer of the
container that remains in contact with the solution of fentanyl or
a salt thereof is preferably cycloolefin-based. In one preferred
embodiment, the container is an infusion bag wherein at least a
portion of the inside wall of the container is made up of polymer
of a cyclic olefin selected from cycloolefin homopolymer or
cycloolefin copolymer.
[0030] According to one preferred embodiment of the present
disclosure, the container may be over wrapped with a secondary
packaging. The secondary packaging may comprise a second container,
such as a pouch or overwrap or carton. The secondary packaging may
comprise a suitable pouch, such as an aluminum pouch covering the
infusion container. The overwrap pouch may have a layer of oxygen
absorbing material or alternatively the secondary packaging may
comprise an oxygen scavenger that may be placed in between the
infusion container and overwrap/pouch. In one preferred embodiment,
the secondary packaging comprises both an aluminum pouch and an
oxygen scavenger.
[0031] Preferably, the concentration of the fentanyl or a salt
thereof and the volume of solution in the infusion containers is
such that it allows direct infusion of the solution so as to
deliver the required dose to the patient, without any intervening
steps of dilution or reconstitution. The presentation of a
ready-to-administer solution provides advantages over the existing
products of fentanyl in which the solution may require further
dilution before administration. The present disclosure, in one
embodiment, provides a kit with containers having different volumes
of solution of fentanyl or a salt thereof so that low, moderate and
high doses of fentanyl may be injected without the step of
dilution. In one embodiment, the present disclosure provides a kit
with plurality of containers having one set of large volume
containers and further sets of small volume top-up containers
filled with solution of fentanyl or a salt thereof at same or
different concentrations, such that one or more container(s) from
the first set and if required one or more top-up container(s) from
the second or further third set, directly administers the desired
dose of fentanyl calculated based on body weight and approved
indication. According to one embodiment of the present invention,
the ready-to-administer solution is present in a plurality of
containers comprising larger and smaller containers, wherein a
concentration of fentanyl or a salt thereof is greater in the
smaller containers than in the larger containers, and wherein the
desired dose is administered simultaneously or sequentially from
the plurality of containers. The following table provides an
example of dosages that may be used for certain indications.
TABLE-US-00001 Total Dose For Volume administered Dose in 70 kg
person 50 mcg/ml 10 mcg/ml Indication Dose mcg/kg Dose in mcg
solution solution Adjunct to Low Dose 2.0 140 mcg 2.8 mL 14 ml
general Moderate 2 to 20 140 to 1400 mcg 2.8 to 28 ml 14 to 140 ml
anaesthesia dose High dose 20 to 50 1400 to 3500 mcg 28 to 70 ml
140 to 350 ml General Dose 50 to 100 3500 to 7000 to 70 to 140 ml
350 to 700 ml Anaesthesia to 150 10500 mcg to 210 ml to 1050 ml
[0032] Further, the infusion rate may vary from 0.7 mcg/kg/hour to
10 mcg/kg/hour, such as 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5,
4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0 or 9.5
mcg/kg/hour. For a patient of 70 kg weight the amount of drug
required in 24 hours, i.e., one day, may respectively vary from
1176 mcg to 16800 mcg.
[0033] In one embodiment, 117.6 ml to 1680 ml of a 10 mcg/ml
solution according to the present disclosure will cater to the dose
required. In another embodiment, 23.52 ml to 336 ml of a 50 mcg/ml
solution according to the present disclosure will cater to the dose
required. Infusion bags filled with different volumes of the
solution having same or different concentrations can be combined to
administer the desired dose with acceptable variation. For
instance, to administer drug at 5 mcg/kg/hour, 8400 mcg drug would
be required in 24 hours. This can be suitably administered using a
100 ml bag of 50 mcg/ml drug solution (=5000 mcg)+250 ml of 10
mcg/ml drug solution (=2500 mcg)+100 ml of a 10 mcg/ml drug
solution (=1000 mcg).
[0034] According to another aspect, the present disclosure also
provides a sterile, ready-to-administer solution consisting
essentially of fentanyl or a salt thereof as the sole active
ingredient, a sugar or sugar alcohol and water for injection, said
solution having a pH in the range of 3.5 to 7.5.
[0035] According to yet another aspect, the present disclosure
provides a sterile, ready-to-administer solution consisting
essentially of fentanyl or a salt thereof as the sole active
ingredient, a sugar or sugar alcohol and water for injection, said
solution having a pH in the range of 3.5 to 7.5 for use as a
medicament.
[0036] In one embodiment, the present disclosure provides a
sterile, ready-to-administer solution consisting essentially of
fentanyl or a salt thereof as the sole active ingredient, a sugar
or sugar alcohol and water for injection, said solution having a pH
in the range of 3.5 to 7.5 for use in the treating a patient in
need of therapy with fentanyl or a salt thereof, by parenterally
administering the solution to the patient.
[0037] In one embodiment, the present disclosure provides a
sterile, ready-to-administer solution of fentanyl or a salt thereof
for use as an analgesic.
[0038] The ready-to-administer solution of fentanyl or a salt
thereof according to the method of the present disclosure includes
a sugar or sugar alcohol. The sugar that is used in the solution
according to the method of the present disclosure is selected from
dextrose, glucose, fructose, sucrose, lactose, trehalose, and the
like and mixtures thereof. The sugar alcohol used in the solution
according to the method of the present disclosure is selected from
mannitol, sorbitol, inositol, xylitol and the like and mixtures
thereof. Preferably, in one embodiment the ready-to-administer
solution of fentanyl or a salt thereof includes a sugar such as
dextrose or glucose. Dextrose or glucose may be present in the
solution in an amount ranging from about 40 mg/ml to about 80
mg/ml, such as about 45, 50, 55, 60, 65, 70 or 75 mg/ml, preferably
in an amount ranging from about 50 mg/ml to about 75 mg/ml. In one
preferred embodiment, dextrose is present in the solution in an
amount of 50 mg/ml. In another embodiment, the ready-to-administer
solution of fentanyl or a salt thereof includes a sugar alcohol
such as mannitol or sorbitol. In one embodiment, the mannitol may
be present in the solution in an amount ranging from about 45 mg/ml
to about 70 mg/ml, such as about 50, 55, 60 or 65 mg/ml, preferably
about 50 mg/ml. The sugar or sugar alcohol provides the solution
that is iso-osmolar and is chemically stable. The osmolality of the
solution is in the range of about 250-375 mOsm/kg, such as about
260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360 or 370
mOsm/kg, preferably in the range of 250-320 mOsm/kg. The sugar or
sugar alcohol according to the present disclosure does not include
sodium other than sodium hydroxide and/or a buffer component for
example, sodium hydrogen phosphate which may be used, if required,
in amounts sufficient to adjust the pH
[0039] The pH of the ready-to-administer solution of fentanyl or a
salt thereof, used in the method of the present disclosure is in
the range of about 3.5 to 7.5, such as about 4.0, 4.5, 5.0, 5.5,
6.0, 6.5 or 7.0, preferably between 3.5 to 6.0, most preferably
between 3.5 to 5.5. In one embodiment, the pH of the solution is
achieved and maintained in this range without the use of any pH
adjusting agent. In other embodiments, a suitable pH adjusting
agent and/or a buffer component may be used, if required, to adjust
the pH in a desired range. The pH adjusting agent that may be used,
if required, is selected from hydrochloric acid , citric acid,
acetic acid, tartaric acid, tromethamine, potassium hydroxide,
sodium hydroxide and the like and mixtures thereof. In preferred
embodiments, the ready-to-administer solution is free of a pH
adjusting agent or buffering agent.
[0040] In one preferred embodiment, the present disclosure provides
a sterile, ready-to-administer solution consisting essentially of
fentanyl citrate as the sole active ingredient, a sugar or sugar
alcohol and water for injection, the solution having a pH in the
range of 3.5 to 7.5 and the fentanyl citrate having a concentration
in the range of 0.005 to 0.1 mg/ml.
[0041] In one embodiment, the present disclosure provides a
sterile, ready-to-administer solution consisting essentially of
fentanyl citrate as the sole active ingredient, a sugar selected
from dextrose, glucose or fructose, and water for injection, the
solution having a pH in the range of 3.5 to 7.5 and the fentanyl
citrate having a concentration in the range of 0.005 to 0.1
mg/ml.
[0042] In one embodiment, the present disclosure provides a
sterile, ready-to-administer solution consisting essentially of
fentanyl citrate as the sole active ingredient, dextrose and water
for injection, the solution having a pH in the range of 3.5 to 5.5
and the fentanyl citrate having a concentration in the range of
0.005 to 0.075 mg/ml.
[0043] In one embodiment, the present disclosure provides a
sterile, ready-to-administer solution consisting essentially of
fentanyl citrate as the sole active ingredient, sugar alcohol
selected from mannitol or sorbitol, and water for injection, the
solution having a pH in the range of 3.5 to 7.5 and the fentanyl
citrate having a concentration in the range of 0.005 to 0.1
mg/ml.
[0044] In one preferred embodiment, it was found that the
ready-to-administer solution consisting essentially of fentanyl
citrate, dextrose, water and having a pH in the range of 3.5 to
5.5, showed better stability as compared to solutions that are
devoid of dextrose/tonicity adjusting agents or solutions that
contain other tonicity adjusting agents, such as sodium
chloride.
[0045] The ready-to-administer solution of fentanyl or a salt
thereof used in the method of the present disclosure is physically
and chemically stable when stored at room temperature for at least
12 months. The solution is chemically stable in that the assay of
the drug remains within the specified limit (90-110%) and content
of related compounds or impurities remains within a specified
limit, i.e., impurity A, B, C and D are not present in amounts of
more than 0.5% by weight, the highest unknown impurity is not more
than 0.2% by weight, and the total impurities is not more than 0.5%
by weight, upon storage at room temperature for the shelf life
period of at least 12 months. In preferred embodiments, the assay
values remain within the specified limit upon storage at room
temperature until 18 months, preferably until 24 months.
[0046] The ready-to-administer solution used in the method of the
present disclosure is sterile. The term "sterile" or `sterilized`,
as used in the context of the present disclosure, means a solution
that has been brought to a state of sterility and has not been
subsequently exposed to microbiological contamination, i.e., the
sterility of the solution present in the container has not been
compromised. The solution complies with the sterility requirements
of the standard Pharmacopoeias, such as the United States
Pharmacopoeia (USP). Sterilization may be achieved by suitable
techniques, such as filtration sterilization, radiation
sterilization, or autoclaving. In one preferred embodiment, the
ready-to-administer solution of the present disclosure is subjected
to membrane filtration followed by filling into a suitable
container and terminal sterilization by autoclaving. In one
embodiment, the ready-to-administer solution present in one or more
containers is terminally sterilized by moist heat sterilization. In
one embodiment, the ready-to-administer solution present in one or
more containers has been sterilized by autoclaving. The autoclaving
is preferably carried out at 121.degree. C. for 15 minutes. In one
or more embodiments, the autoclaving may be carried out at
temperatures varying from about 110.degree. C. to 125.degree. C.
for a period of time varying from about 5 minutes to 60 minutes. It
was observed that the ready-to-administer solution of the present
disclosure contained in infusion container withstands the extreme
conditions of autoclaving and remains stable, physically and
chemically, even upon being subjected to autoclaving and subsequent
storage.
[0047] According to one aspect of the present disclosure, there is
provided a process for the manufacture of a ready-to-administer
solution of fentanyl as per the present invention, the process
comprising the steps of: [0048] a) preparing a solution of fentanyl
or a salt thereof and a sugar or a sugar alcohol in water; [0049]
b) adjusting the pH of the solution in the range of 3.5 to 7.5;
[0050] c) filtering the solution of step b); [0051] d) filling the
solution aseptically into an infusion container; and [0052] e)
sterilizing the solution of step d).
[0053] In specific embodiments, the process involves the steps of
purging nitrogen into water for injection to attain a dissolved
oxygen level of less than 1 ppm, adding dextrose into the water for
injection, followed by the addition of fentanyl or a salt thereof
to the above solution and checking the pH of the solution. If the
pH is outside the range of 3.5 to 7.5, a suitable pH adjusting
agent may be added so as to adjust the pH to the desired range.
Further steps include filtration of the above solution using a
membrane filter and aseptically filling the solution into an
infusion container, such as an infusion bag, followed by terminally
sterilizing the filled containers in an autoclave at 121.degree. C.
for 15 minutes. The process further optionally includes wrapping
the filled infusion container with an aluminum pouch, along with
the use of an oxygen scavenger.
[0054] In the context of this specification "comprising" is to be
interpreted as "including".
[0055] Aspects of the invention comprising certain elements are
also intended to extend to alternative embodiments "consisting" or
"consisting essentially" of the relevant elements.
[0056] Where technically appropriate, embodiments of the invention
may be combined.
[0057] Embodiments are described herein as comprising certain
features/elements. The disclosure also extends to separate
embodiments consisting or consisting essentially of said
features/elements.
[0058] Technical references such as patents and applications are
incorporated herein by reference.
[0059] Any embodiments specifically and explicitly recited herein
may form the basis of a disclaimer either alone or in combination
with one or more further embodiments.
[0060] Hereinafter, embodiments of the present disclosure will be
more specifically described by way of examples. The examples should
not be understood as limiting the scope of the present disclosure,
and are merely used as illustrations of specific embodiments of the
present disclosure.
EXAMPLES 1 AND 2
[0061] Ready-to-administer solutions of fentanyl citrate according
to specific embodiments of the present disclosure are given below
in Table 1.
TABLE-US-00002 TABLE 1 Ready-to-administer solutions of fentanyl
citrate. amount in mg/ml Ingredients Example 1 Example 2 Fentanyl
Citrate eq. to Fentanyl Base 0.05 0.01 Dextrose, monohydrate 50.0
50.0 Water for Injection q.s. to 1 ml q.s. to 1 ml
[0062] Water for injection was purged with nitrogen to attain a
dissolved oxygen level of less than 1 ppm. Dextrose was added to
the water for injection and dissolved. Purging with nitrogen was
continued. Fentanyl citrate was then added to the above solution.
The pH of the solution was checked and it was kept in the range of
pH 3.5 to 5.5 by adding a suitable pH adjusting agent when
required. The solution was filtered through a 0.2 micron membrane
filter and was filled into an infusion container (a bag) made from
a cycloolefin polymer. The filled infusion container was then
terminally sterilized in an autoclave at 121.degree. C. for 15
minutes. The infusion container was over wrapped with an aluminum
pouch along with an oxygen scavenger. This was charged for a
stability study and the assay value as well as known and highest
unknown impurity and total impurities were measured periodically.
The total impurities, known impurities including Impurity A, B, C
and Impurity D and any individual unknown impurity were analyzed by
HPLC or high performance liquid chromatography method. The mobile
phase was a mixture of potassium dihydrogen orthophosphate (a
buffer having a pH of about 3.2), acetonitrile and methanol; the
chromatographic column was Inertsil ODS 3V (250.times.4.6) mm 5.mu.
column and the chromatograms were recorded using UV spectroscopy.
The assay of drug was also analysed by HPLC or high performance
liquid chromatography method. The mobile phase was a mixture of
ammonium acetate buffer (having a pH of about 3.2), methanol,
acetonitrile and glacial acetic acid; the chromatographic column
was Inertsil ODS 3V (250.times.4.6) mm 5.mu. column and the
chromatograms were recorded by UV spectroscopy using a ultraviolet
spectrophotometer.
[0063] The percentage transmittance of the solution was measured by
UV (ultraviolet) spectroscopy using a UV spectrophotometer at a
wavelength of 650 nm, wherein the transmittance of 1 cm layer of
sample at 650 nm was measured using a suitable UV spectrophotometer
against water blank. The pH of the solution was measured by a
calibrated pH meter at 25.degree. C..+-.2.degree. C. The osmolality
of the solution was measured by an osmometer.
[0064] The results for stability testing at various time points
upon storage of the solution of Example 1, at 25.degree. C. and
40.degree. C. are shown below in Table 2.
TABLE-US-00003 TABLE 2 Observations of stability testing: Highest
Assay of Unknown Total % T fentanyl Imp. A Imp. B Imp. C Imp. D
Imp. Imp. @ 650 nm Osmolality Storage Time Limit NMT NMT NMT NMT
NMT NMT NLT (mOsm) Condition (M) 90-110% 0.5% 0.5% 0.5% 0.5% 0.2%
0.5% 95% 250-350 25.degree. C. 0 M 100.06 ND 0.004 ND ND 0.008
0.019 100 265 40% 12 M 102.13 ND ND ND ND 0.013 0.017 98.851 272
relative humidity 40.degree. C. 1 M 101.73 ND 0.013 ND ND 0.046
0.059 100 268 25% 6 M 101.14 ND 0.005 ND ND ND 0.005 100 269
relative humidity M--Month; Imp.--Impurity; % T--% Transmittance;
NMT--Not more than; NLT--Not Less than; ND--Not detected
[0065] The results for stability testing upon storage of the
solution of Example 2, at 25.degree. C. and 40.degree. C. are shown
below in Table 3.
TABLE-US-00004 TABLE 3 Observations of stability testing: Assay of
Highest Total % T @ fentanyl Imp. A Imp. B Imp. C Imp. D Unknown
Imp. 650 nm Osmolality Storage Time Limit NMT NMT NMT NMT Imp. NMT
NLT (mOsm) Condition (M) 90-110% 0.5% 0.5% 0.5% 0.5% NMT 0.2% 0.5%
95% 250-350 25.degree. C.; 0 M 99.7 ND 0.003 ND ND 0.019 0.022
99.709 272 40% 12 M 101.51 ND ND ND ND 0.036 0.045 100 274 relative
humidity 40.degree. C.; 1 M 101.71 ND 0.006 ND ND 0.009 0.015 100
271 25% 6 M 100.58 ND 0.01 ND ND ND 0.01 99.916 274 relative
humidity M--Month; Imp.--Impurity; % T--% Transmittance; NMT--Not
more than; NLT--Not Less than; ND--Not detected
[0066] As can be seen from Tables 2 and 3 above, the
ready-to-administer solutions of fentanyl citrate of the present
disclosure, when filled, autoclaved, and stored in an infusion
container, remained physically and chemically stable upon storage
at room temperature (25.degree. C.; 40% relative humidity) for at
least 12 months. There occurred no drop in the assay of fentanyl
citrate and no substantial increase in the impurities level, and
the values remained within the desired specified limits. It was
observed that the assay of fentanyl remained almost unchanged upon
storage, wherein the values are maintained within the range of
95%-105%. The total impurities remained less than 0.1% by weight of
fentanyl; the highest unknown impurity remained less than 0.1% by
weight and other known impurities (Impurity A, B, C, D) were either
undetected or remained below 0.1% by weight. Further, it was
observed that the solution remained physically stable, such that no
precipitation or crystallization or color change took place upon
storage, and the value of the percentage transmittance of the
solution remained greater than 90%, preferably greater than 95%
upon long term storage at room temperature. Surprisingly, the
solution also remained chemically stable upon storage at the
accelerated stability testing condition of 40.degree. C., 25%
relative humidity for a period of 6 months, which correlates to a
room temperature shelf life stability for 24 months. The
ready-to-administer solution of fentanyl citrate according to the
present disclosure thus shows long term stability and room
temperature shelf life stability of 24 months.
* * * * *