U.S. patent application number 16/836581 was filed with the patent office on 2020-07-16 for succinylcholine prefilled syringe, compositions and methods.
The applicant listed for this patent is Nevakar Inc.. Invention is credited to Prem Sagar Akasapu, Kumaresh Soppimath.
Application Number | 20200222314 16/836581 |
Document ID | / |
Family ID | 67903733 |
Filed Date | 2020-07-16 |
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United States Patent
Application |
20200222314 |
Kind Code |
A1 |
Soppimath; Kumaresh ; et
al. |
July 16, 2020 |
SUCCINYLCHOLINE PREFILLED SYRINGE, COMPOSITIONS AND METHODS
Abstract
Pre-filled syringes, pharmaceutical compositions, and kits and
methods relating to same allow for emergency administration of one
or more drugs from prefilled glass syringes to a patient via a
needleless connector. In preferred embodiments, the prefilled glass
syringe has a drug volume of at least 5 mL, has a Luer-lock, and
has a syringe tip with an internal channel that has a diameter of
about 1.7 mm. Such syringes advantageously allow storage of
emergency drugs without leaching of plastic materials and
degradation, and substantially improve the safety profile where the
syringe is attached to an IV line via a needleless connector.
Inventors: |
Soppimath; Kumaresh;
(Skillman, NJ) ; Akasapu; Prem Sagar; (Edison,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nevakar Inc. |
Bridgewater |
NJ |
US |
|
|
Family ID: |
67903733 |
Appl. No.: |
16/836581 |
Filed: |
March 31, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16272815 |
Feb 11, 2019 |
|
|
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16836581 |
|
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|
|
62642326 |
Mar 13, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/1452 20130101;
A61M 5/178 20130101; A61K 9/0019 20130101; A61K 47/02 20130101;
A61M 25/0097 20130101; A61M 5/3129 20130101; A61K 31/225 20130101;
A61K 47/12 20130101; A61K 31/137 20130101; A61M 39/10 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61M 5/145 20060101 A61M005/145; A61K 47/02 20060101
A61K047/02; A61M 25/00 20060101 A61M025/00; A61K 31/225 20060101
A61K031/225; A61M 5/31 20060101 A61M005/31; A61K 47/12 20060101
A61K047/12; A61M 5/178 20060101 A61M005/178; A61M 39/10 20060101
A61M039/10; A61K 31/137 20060101 A61K031/137 |
Claims
1. A method for intravenously administering succinylcholine to a
patient in need thereof, comprising: (a) providing a prefilled
glass syringe containing a succinylcholine composition, wherein the
succinylcholine composition has a pH of about 3.0 to about 4.5,
wherein the succinylcholine composition disposed in the glass
syringe contains not more than about 6% total impurities after
storage at 2-8.degree. C. for 12 months, followed by storage at
about 25.degree. C. for 14 days as determined by HPLC, and wherein
the syringe has a Luer-lock and a syringe tip with an internal
channel that has a diameter of 1.2-2.2 mm; (b) reversibly attaching
the syringe to a patient's intravenous line via the Luer-lock; (c)
delivering the succinylcholine composition from the syringe into
the patient's intravenous line; and (d) administering the
succinylcholine composition from the patient's intravenous line to
the patient.
2. The method of claim 1 wherein the internal channel has a
diameter of at least 1.3 mm.
3. The method of claim 1 wherein the internal channel has a
diameter of at least 1.5 mm.
4. The method of claim 1 wherein the internal channel has a
diameter of at least 1.7 mm.
5. The method of claim 1 wherein the internal channel has a
diameter of at least 1.9 mm.
6. The method of claim 1 wherein the internal channel has a
diameter of between 1.6-2.0 mm.
7. The method of claim 1, wherein the step of reversibly attaching
the syringe to a patient's intravenous line comprises attaching the
syringe to a needleless connector.
8. The method of claim 7 wherein the needleless connector has a
reversed internal blunt cannula.
9. The method of claim 1, wherein the glass syringe has a volume of
at least 5 mL.
10. The method of claim 1, wherein the succinylcholine composition
has an osmolality of about 260 to about 340 mOsm/kg.
11. The method of claim 1, wherein the succinylcholine chloride is
present in the succinylcholine composition in an amount of about 20
mg/mL and sodium chloride is present in the succinylcholine
composition in an amount of about 6 mg/mL.
12. The method of claim 1, wherein the succinylcholine composition
further comprises a pH adjusting agent, and wherein the pH of the
succinylcholine composition is about 3.6.
13. The method of claim 1, wherein the syringe has a glide force of
about 1 to about 20 N.
14. The method of claim 1, wherein the syringe has a break loose
force of about 10 to about 30 N.
15. The method of claim 1, wherein the syringe contains about 5 mL
of the succinylcholine composition, or wherein the syringe contains
about 10 mL of the succinylcholine composition.
16. The method of claim 1, wherein the succinylcholine composition
comprises succinylcholine chloride, sodium chloride, and water,
wherein the succinylcholine composition is substantially free of
preservatives.
17. A method for providing skeletal muscle relaxation to a patient
in need thereof, comprising: a) providing a prefilled glass syringe
containing a succinylcholine composition, wherein the
succinylcholine composition has a pH of about 3.0 to about 4.5,
wherein the succinylcholine composition disposed in the glass
syringe contains not more than about 6% total impurities after
storage at 2-8.degree. C. for 12 months, followed by storage at
about 25.degree. C. for 14 days, as determined by HPLC, and wherein
the syringe has a Luer-lock and a syringe tip with an internal
channel that has a diameter of about 1.2-2.2 mm; b) reversibly
attaching the syringe to a patient's intravenous line via the
Luer-lock; c) delivering the succinylcholine composition from the
syringe into the patient's intravenous line; and d) administering
the succinylcholine composition from the patient's intravenous line
to the patient.
18. The method of claim 17, wherein the step of reversibly
attaching the syringe to a patient's intravenous line comprises
attaching the syringe to a needleless connector that has a reversed
internal blunt cannula, and optionally wherein the succinylcholine
composition comprises succinylcholine chloride, sodium chloride,
and water, wherein the succinylcholine composition is substantially
free of preservatives.
Description
[0001] This application claims priority to allowed US patent
application with the Ser. No. 16/272,815, which was filed Feb. 11,
2019, which claims priority to US provisional patent application
with the Ser. No. 62/642,326, which was filed Mar. 13, 2018, the
contents of which are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present disclosure relates to kits, prefilled syringes,
pharmaceutical compositions and methods of use thereof,
particularly as it relates to prefilled glass syringes containing
emergency medication for administration through needleless
connectors.
BACKGROUND OF THE INVENTION
[0003] The background description includes information that may be
useful in understanding the present disclosure. It is not an
admission that any of the information provided herein is prior art
or relevant to the presently claimed invention, or that any
publication specifically or implicitly referenced is prior art.
[0004] All publications and patent applications herein are
incorporated by reference to the same extent as if each individual
publication or patent application were specifically and
individually indicated to be incorporated by reference. Where a
definition or use of a term in an incorporated reference is
inconsistent or contrary to the definition of that term provided
herein, the definition of that term provided herein applies and the
definition of that term in the reference does not apply.
[0005] Needleless devices for connecting intravenous (IV)
catheters, administration sets, and syringes have been developed
over the last decades and helped significantly reduce needlestick
injuries among health care providers. Unfortunately, the use of
needleless connectors has also been associated with an increase in
various complications such as catheter-related bloodstream
infection and catheter lumen occlusion. To circumvent at least some
of these problems, various improvements have been implemented. For
example, several simple needleless connectors use a split septum
and/or other non-moving parts to avoid backflow of blood into the
IV line while still allowing needleless access to the IV line. More
complex needleless connectors employ internal moving components
such as unidirectional valves to control the flow of fluids within
the connector. While simple connectors advantageously provide
simplicity of use and manufacture, negative fluid displacement or
reflux will often occur upon withdrawal of the cannula due to their
relatively large size. On the other hand, connectors with
mechanical valves are more complex and therefore less simple in
manufacture, but typically have no or only minor reflux.
[0006] A representative complex needleless connector is shown in
Prior Art FIG. 1, in which a syringe with a male luer tip 110 is
coupled to a needleless connector with a reversed internal blunt
cannula 120. Exemplary complex needleless connectors are described,
for example, in U.S. Pat. Nos. 9,205,243 and 9,750,926, and such
and similar connectors may further include a sealing member and
regulator acting as a second valve as is described, for example, in
US Publication Nos. 20180099137 and 20190001114. While such and
other complex needleless connectors eliminate the risk of
needlestick injuries and at least conceptually simplify operation,
catheter related blood stream infections have become more
prevalent.
[0007] Worse yet, and particularly in emergency settings where
certain drugs (e.g., adenosine, amiodarone, succinylcholine, etc.)
need to be administered without delay and interruption, complex
needleless connectors can contribute to catastrophic failure. In a
Drug Safety Communication, the FDA had more recently indicated that
pre-filled glass syringes can become clogged and malfunction during
the process of connecting them to pin-activated needleless IV
access systems (see Prior Art FIGS. 2A and 2B). Unfortunately, such
failure is not detected until after the syringe is inserted into
the pin-activated needleless i.v. access system. For example, the
action of inserting the syringe can cause the pin in the access
system to clog or break off in the syringe tip, thus preventing
delivery of the medication and necessitating placement of a new
i.v. access line. As a consequence, the FDA advised that the use of
needleless pre-filled glass syringes in emergency situations should
be avoided, if possible (see URL:
www.fda.gov/Drugs/DrugSafety/ucm254215.htm). Moreover, because of
recent adverse glass syringe connection events, the FDA has
recognized that demonstrating conformity to the ISO 11040-4
standard alone does not ensure that the glass syringes can be
properly connected to connecting devices. Therefore, sponsors who
seek to rely on conformity to the ISO 11040-4 standard in
submissions for glass syringe products should also submit
information from supplemental tests to demonstrate that the glass
syringe can be properly connected to connecting devices. Such safe
connection has been elusive and challenging, particularly for
prefilled glass syringes.
[0008] Thus, even though various methods of delivering emergency
medication from syringes via needleless connectors are known in the
art, all or almost all of them suffer from various disadvantages.
Consequently, there is a need to provide improved devices, kits,
and methods using glass syringes that improve safety and
reliability of drug administration in emergency settings.
SUMMARY OF THE INVENTION
[0009] Various devices, compositions, kits, and methods are
presented in which problems associated with emergency IV
administration of various drug compositions via needleless
connectors can be avoided. In especially preferred aspects, the
emergency drug composition comprises succinylcholine that is
contained in a prefilled glass syringe, and the syringe has a
Luer-lock and a syringe tip with an internal channel that has a
diameter of about 1.7 mm.
[0010] In one aspect of the inventive subject matter, the inventors
contemplate a method for intravenously administering
succinylcholine to a patient and/or providing skeletal muscle
relaxation to a patient in need thereof that includes the steps of
(a) providing a prefilled glass syringe containing a
succinylcholine composition, wherein the succinylcholine
composition comprises succinylcholine chloride, sodium chloride,
and water, wherein the succinylcholine composition is substantially
free of preservatives, and wherein the succinylcholine composition
has a pH of about 3.0 to about 4.5, and wherein the syringe has a
Luer-lock and a syringe tip with an internal channel that has a
diameter of about 1.7 mm; (b) reversibly attaching the syringe to a
patient's intravenous line via the Luer-lock; (c) delivering the
succinylcholine composition from the syringe into the patient's
intravenous line; and (d) administering the succinylcholine
composition from the patient's intravenous line to the patient.
[0011] In some embodiments, the step of reversibly attaching the
syringe to a patient's intravenous line comprises attaching the
syringe to a needleless connector, which may include a reversed
internal blunt cannula. Most typically, but not necessarily, the
glass syringe has a volume of at least 5 mL.
[0012] In other embodiments, the succinylcholine composition has an
osmolality of about 260 to about 340 mOsm/kg, and/or the
succinylcholine chloride is present in the succinylcholine
composition in an amount of about 20 mg/mL and the sodium chloride
is present in the succinylcholine composition in an amount of about
6 mg/mL. It is further contemplated that the succinylcholine
composition further comprises a pH adjusting agent (e.g.,
hydrochloric acid and/or sodium hydroxide), and/or that the pH of
the succinylcholine composition is about 3.6.
[0013] With respect to the syringe it is contemplated that the
syringe has a glide force of about 1 to about 20 N, and/or that the
syringe has a break loose force of about 10 to about 30 N. In
further embodiments, the syringe contains about 5 mL or about 10 mL
of the succinylcholine composition, which may be administered to
the patient at a rate of about 0.5 to about 10 mg per minute.
Preferably, the succinylcholine composition in the glass syringe
contains not more than about 6% total impurities after storage at
2-8.degree. C. for 15 months as determined by HPLC. Viewed from a
different perspective, the succinylcholine composition disposed in
the glass syringe contains not more than about 4%
succinylmonocholine chloride after storage at 2-8.degree. C. for 15
months as determined by HPLC, and/or the succinylcholine
composition disposed in the glass syringe contains not more than
about 1% succinic acid after storage at 2-8.degree. C. for 15
months as determined by HPLC.
[0014] In another aspect of the inventive subject matter, the
inventors contemplate a kit that comprises a prefilled glass
syringe containing a succinylcholine composition, wherein the
succinylcholine composition comprises succinylcholine chloride,
sodium chloride, and water, wherein the succinylcholine composition
is substantially free of preservatives, and wherein the
succinylcholine composition has a pH of about 3.0 to about 4.5.
Preferably, the syringe has a Luer-lock and a syringe tip with an
internal channel that has a diameter of about 1.7 mm.
[0015] Most typically, the glass syringe has a volume of at least 5
ml. Contemplated kits may further include an IV administration set
with at least one needleless connector (e.g., needleless connector
with a reversed internal blunt cannula).
[0016] With respect to contemplated succinylcholine compositions it
is typically preferred that the succinylcholine composition has an
osmolality of about 260 to about 340 mOsm/kg, and/or that the
succinylcholine chloride is present in the succinylcholine
composition in an amount of about 20 mg/mL and the sodium chloride
is present in the succinylcholine composition in an amount of about
6 mg/mL. Moreover it is contemplated that the succinylcholine
composition further comprises a pH adjusting agent (e.g.,
hydrochloric acid and/or sodium hydroxide) and that the pH of the
succinylcholine composition is about 3.6. In some embodiments, the
succinylcholine composition disposed in the glass syringe contains
not more than about 6% total impurities after storage at
2-8.degree. C. for 15 months as determined by HPLC, and in other
embodiments the succinylcholine composition disposed in the glass
syringe contains not more than about 4% succinylmonocholine
chloride after storage at 2-8.degree. C. for 15 months as
determined by HPLC. In further embodiments, the succinylcholine
composition disposed in the glass syringe contains not more than
about 1% succinic acid after storage at 2-8.degree. C. for 15
months as determined by HPLC.
[0017] Therefore, viewed from a different perspective, the
inventors also contemplate a kit that comprises a prefilled glass
syringe containing a drug for emergency medical administration,
wherein the glass syringe has a volume of at least 5 ml, wherein
the glass syringe has a luer-lock and a syringe tip with an
internal channel that has a diameter of about 1.7 mm, and wherein
the glass syringe and the drug are sterilized.
[0018] In particularly preferred aspects, the drug is
succinylcholine, ephedrine, amiodarone, adenosine, epinephrine,
atropine, methylprednisolone, metoprolol, diltiazem, or
procainamide, and contemplated kits may further include an IV
administration set with at least one needleless connector, and
particularly a needleless connector with a reversed internal blunt
cannula.
[0019] Viewed from yet another perspective, the inventors
contemplate a prefilled glass syringe containing a drug composition
for emergency medical administration of the drug through a
needleless connector, wherein the glass syringe has a volume of at
least 5 ml, wherein the glass syringe has a luer-lock, and wherein
the glass syringe has a syringe tip with an internal channel that
has a diameter of about 1.7 mm.
[0020] For example, suitable drug compositions include
succinylcholine, ephedrine, amiodarone, adenosine, epinephrine,
atropine, methylprednisolone, metoprolol, diltiazem, and
procainamide. For example, the drug composition may comprise
succinylcholine chloride, sodium chloride, and water, wherein the
succinylcholine composition is substantially free of preservatives,
and wherein the succinylcholine composition has a pH of about 3.0
to about 4.5.
[0021] Various objects, features, aspects, and advantages will
become more apparent from the following detailed description of
preferred embodiments, along with the accompanying drawing in which
like numerals represent like components.
BRIEF DESCRIPTION OF THE DRAWING
[0022] Prior Art FIG. 1 depicts a cross sectional view of an
exemplary known needleless connector with a reversed internal blunt
cannula attached to a syringe with a male luer tip.
[0023] Prior Art FIG. 2A depicts a damaged/clogged syringe tip
after disconnection from a needleless connector with a reversed
internal blunt cannula, and Prior Art FIG. 2B depicts a glass
syringe tip and broken off tip of a reversed internal blunt cannula
of a needleless connector.
[0024] FIG. 3 depicts a comparison between a conventional
attachment of a glass syringe to a needleless connector (left) and
an attachment of a wide mouth glass syringe to a needleless
connector (right) according to the inventive subject matter.
[0025] FIG. 4 depicts an exemplary connection between a syringe
according to the inventive subject matter to a needleless connector
with a reversed internal blunt cannula.
[0026] FIGS. 5A and 5B depict exemplary labels for prefilled
syringes.
DETAILED DESCRIPTION
[0027] The inventors have now discovered that various emergency
medications can be rapidly and safely administered through a
needleless connector (that is typically fluidly coupled to an IV
line into a patient) without the attendant risk of clogging or
breakage that has been encountered in the past. More particularly,
the inventors discovered that the likelihood of breakage can be
significantly reduced by using a syringe having a widened inner
diameter of a syringe tip. Advantageously, the inventors observed
that such a widened inner diameter substantially increased the
tolerance of the tip to angled insertion into a needleless
connector and so dramatically decreased the likelihood of damaging
static or moving internals of the needleless connector. Moreover,
the inventors observed that such widening did not cause significant
mechanical weakening of the syringe tip that could otherwise lead
to chipping or breaking of the tip where a glass syringe is
used.
[0028] For example, FIG. 3 exemplarily depicts on the left hand a
conventional syringe 300 that has a syringe tip 310 having an
internal diameter 320 (here: 1.1 mm). The syringe also includes a
luer lock connector 330 that is releasably coupled to matching luer
lock of a needleless connector 340 (internals not shown) of an IV
line. In contrast, on the right hand syringe 301 is shown having a
syringe tip 311 with a significantly larger internal diameter 321
(here: 1.7 mm). The syringe also includes a luer lock connector 331
that is releasably coupled to matching luer lock of a needleless
connector 341 (internals not shown) of an IV line. As should be
readily apparent, the wider internal diameter accommodates angled
insertion of the syringe tip 311 without jamming or breaking the
internals (such as a reversed internal blunt cannula). FIG. 4
schematically illustrates one such embodiment in which syringe 401
has a syringe tip 411 with a significantly larger internal
diameter. As can be seen, the reversed internal blunt cannula 442
of needleless connector 441 does not contact the internal walls of
syringe tip 411. Instead, due to the wider inner diameter of the
tip, an annular void space between the outer surface of the
reversed internal blunt cannula and the internal walls of syringe
tip is present that reduces or even entirely eliminates the risk of
breakage or jamming of the front end of the reversed internal blunt
cannula. FIGS. 5A and 5B depict exemplary labels for prefilled
syringes according to the inventive subject matter.
[0029] Notably, despite the loss of a sealing surface (i.e., the
outside surface of reversed internal blunt cannula against internal
wall of the syringe tip) the connection between the syringe and the
needleless connector nevertheless remained fluidly sealed by
compression of elastic member 444 against the front end of the
syringe tip and further by sealing engagement between the outer
surface of the syringe tip 411 and the inner surface of the front
portion of the connector that receives the syringe tip 411. Even at
elevated pressure, these remaining surfaces maintained a
fluid-tight contact that allowed rapid delivery of fluids through
the connection.
[0030] Most preferably, the syringe for use in conjunction with the
teachings herein may be a glass syringe (e.g., borosilicate glass),
and in less preferred embodiments also a syringe manufactured from
a polymeric material such as polypropylene or polyethylene.
Moreover, it is preferred that the syringe has a volume of at least
5 mL or at least 10 mL, however, smaller volumes are also expressly
contemplated. In one embodiment, the syringe has a volume of 5 mL.
In another embodiment, the syringe has a volume of 10 mL. With
respect to the tip it typically preferred that the tip is a
centrally located tip, but eccentric tips are also deemed suitable.
Most typically, the syringe tip will have an outer diameter, angle,
and length that accommodate standard hub dimensions of luer lock
needles and other luer lock equipment. Standards for luer lock
connections are described in ISO 80369 and in DIN and EN standard
1707:1996 and 20594-1:1993, incorporated by reference herein.
[0031] For example, a typical tip of a syringe for luer-type
connection will have a cone shaped configuration acting as the male
portion of the luer lock with an overall length of about 7.5 mm
from proximal to distal end (with respect to the barrel) of the
tip, the proximal end of the tip having an outer diameter of about
4.45 mm and the distal end of the tip having an outer diameter of
about 4.00 mm. Thus, a taper angle (relative to a hypothetical axis
running through the center of the barrel and tip) of the tip walls
between 0.5 degree and 5.0 degree are generally deemed suitable.
However, the actual taper angle will in most cases correspond to
the female luer lock counterpart such that the outer surface of the
male and inner surface of the female connector will sealingly
coupled the male and female portions (i.e., have the same angle
along at least 70% of the length of the male tip).
[0032] With respect to the overall length of the tip as measured
from proximal to distal end it is generally preferred that the
length will be between about 8.5 mm to about 6.0 mm, however,
various longer and shorter lengths are also deemed suitable for use
herein. For example, suitable lengths include those between 5.5 mm
and 7.0 mm, and between 6.0 mm and 8.0 mm, and between 7.0 mm and
9.0 mm. However, lengths of equal or less than 8.0 mm are generally
preferred. With respect to the inner diameter of the tip it is
generally preferred that the inner diameter is constant from the
proximal to the distal end of the tip. Most typically the inner
diameter will be about 1.7 mm, however various other inner
diameters are also deemed suitable for use herein. For example,
alternative inner diameters will generally be greater than 1.1 mm,
or greater than 1.3 mm, or greater than 1.5 mm, or greater than 1.7
mm, or greater than 1.9 mm, or even greater. Thus, suitable inner
diameters will be between 1.2-2.2 mm, or between 1.4-2.0 mm, or
between 1.6-1.8 mm, or between 1.3-1.6 mm, or between 1.5-1.9 mm,
or between 1.6-2.0 mm. Viewed from a different perspective, the
inner diameter and/or the length of the tip will be selected such
that the syringe and tip can be inserted into the needleless
connector at an angle (with respect to a hypothetical central axis
extending through the barrel and the tip of the syringe and a
hypothetical central axis longitudinally extending through the
needleless connector) without the reversed internal blunt cannula
contacting the inner surface of the tip. In some embodiments, such
angle will be 5 degrees, or 7 degrees, or 10 degrees, or 12.5
degrees, or 15 degrees, or 20 degrees, or even higher. While not
limiting to the inventive subject matter, contemplated syringes may
have a fixed or a rotating (typically polymeric) lock portion.
Still further, it is contemplated that contemplated syringes will
have a tip cap rubber surface contact area of equal or more than
2.4 mm.sup.2, and more preferably equal or more than 4.8 mm.sup.2.
In still further contemplated embodiments, the syringe has a glide
force of about 1 to about 30 N, about 1 to about 20N, or about 1 to
about 10N. In other embodiments, the syringe has a break loose
force of about 10 to about 30 N or about 15 to 25N. Exemplary
syringes are commercially available, for example, from Becton
Dickinson under the brand name Hylok or LLEC (Luer Lock extended
channel), which are commonly used for viscous materials such as
dermal fillers.
[0033] It should be recognized that the syringes contemplated
herein will be particularly suitable for use with drug compositions
that are administered in an emergency setting where administration
must be performed promptly and without interruption necessitated by
clearing a clogged line, reconnecting a malfunctioning syringe,
and/or preparing a new vascular access. Typical drugs for use with
the syringes presented herein include those used in
cardiac/vascular emergencies, pulmonary emergencies, anaphylaxis,
etc. Consequently, suitable drugs include succinylcholine,
ephedrine, amiodarone, adenosine, epinephrine, atropine,
methylprednisolone, metoprolol, diltiazem, and procainamide. In
most embodiments, the syringes will be prefilled with a volume of
the drug, typically at a volume of at least 1 mL, or at least 5 mL,
or at least 10 mL, or about 5 mL or about 10 mL. As will be readily
appreciated, the emergency drug in such products will be present at
a pharmaceutically effective concentration to treat any emergency
condition. Suitable formulation types of the drug compositions
include solutions with single, binary, or higher solvent systems,
dispersed systems (e.g., preferably emulsions or suspensions)
[0034] Of course, it should also be appreciated that the prefilled
syringe may be provided with an IV administration set or other bags
or tubing that will most typically comprise at least one needleless
connector that may or may not have a reversed internal blunt
cannula. Still further, it should be noted that the prefilled
syringe will typically be sterilized using terminal sterilization,
e-beam or gamma ray radiation, ethylene oxide, etc.
[0035] Moreover, it should be recognized that contemplated
prefilled glass syringes are especially advantageous for drug
compositions that are sensitive to components that would otherwise
leach from a plastic syringe (such as plasticizers, dyes, metals,
etc.), particularly where the pH of the drug composition is in the
acidic range (e.g., equal or less than 5.0, or equal or less than
4.5, or equal or less than 4.0, or equal or less than 3.5), where
the drug is sensitive to oxygen ingress, or where the composition
comprises a solvent that is incompatible with polymers used in
plastic syringes such as polypropylene or polyethylene. Therefore,
and viewed form a different perspective, contemplated systems and
methods will also advantageously help improve chemical stability of
otherwise relatively labile compounds (e.g., succinylcholine) under
refrigeration conditions (about 2.degree. C. to about 8.degree. C.,
or about 5.degree. C.) and at room temperature (about 25.degree.
C.).
[0036] For example, the stability of a succinylcholine composition
in a glass syringe will typically be increased such that total
impurities are equal or less than 12%, or equal or less than 10%,
more typically equal or less than 8%, even more typically equal or
less than 6%, or equal or less than 4%, or equal or less than 2%
after storage at 2-8.degree. C. for 12, 15, 18, or 24 months as
determined HPLC as is described in more detail below. Thus, total
impurities will preferably be in the range of between 1-3%, or
between 2-5%, or between 4-8%, or between 5-10% after storage at
2-8.degree. C. for 15 months as determined HPLC. Additionally, it
is contemplated that after storage of a succinylcholine composition
in a glass syringe at 2-8.degree. C. for 12, 15, 18, or 24 months,
no more than 8%, or no more than 6%, or no more than 4%, or no more
than 2% of succinylmonocholine chloride (as primary degradation
product) are present. Thus, succinylmonocholine chloride may be
present after storage of a succinylcholine composition in a glass
syringe at 2-8.degree. C. for 12, 15, 18, or 24 months in a range
of between 1-3%, or between 2-5%, or between 4-8%, or between
5-10%.
[0037] In further contemplated aspects, improved stability is also
contemplated where the succinylcholine composition is stored in a
glass syringe at about 25.degree. C. For example,
succinylmonocholine chloride may be present after storage of a
succinylcholine composition in a glass syringe at about 25.degree.
C. for 14-60 days (or for 7-14 days, or for 14-21 days, or for
21-28 days, or for 28-40 days, or for 40-60 days) in a range of
between 1-3%, or between 2-5%, or between 4-8%, or between 5-10%,
particularly where the prefilled syringe was not previously
subjected extended storage at 2-8.degree. C. In such cases, for
example where the previous refrigerated storage was between 1-3
months, the succinylmonocholine chloride may be present after
subsequent storage about 25.degree. C. for 14-60 days (or for 7-14
days, or for 14-21 days, or for 21-28 days, or for 28-40 days, or
for 40-60 days) in a range of between 2-5%, or between 4-8%, or
between 5-10%. Likewise, where the previous refrigerated storage
was between 3-6 months, the succinylmonocholine chloride may be
present after subsequent storage about 25.degree. C. for 14-50 days
(or for 7-14 days, or for 14-21 days, or for 21-28 days, or for
28-40 days, or for 40-50 days) in a range of between 3-6%, or
between 5-9%, or between 8-12%, and where the previous refrigerated
storage was between 6-15 months, the succinylmonocholine chloride
may be present after subsequent storage about 25.degree. C. for
14-40 days (or for 7-14 days, or for 14-21 days, or for 21-28 days,
or for 28-40 days) in a range of between 3-7%, or between 5-10%, or
between 8-12%.
[0038] In some embodiments, the drug composition comprises a drug
for emergency medical administration, a toncity agent, optionally
one or more pH adjusting agents, and water.
[0039] In some embodiments, the drug for emergency medical
administration is succinylcholine, selected from the group
consisting of ephedrine, amiodarone, adenosine, epinephrine,
atropine, methylprednisolone, metoprolol, diltiazem, and
procainamide, and pharmaceutically acceptable salts thereof. In
preferred embodiments, the drug for emergency medical
administration is succinylcholine or a pharmaceutically acceptable
salt thereof, and most preferably, succinylcholine chloride. In
some embodiments, the drug for emergency medical administration is
present in the composition in a therapeutically effective amount.
In some embodiments, the drug for emergency medical administration
is succinylcholine chloride and the succinylcholine chloride is
present in the composition in an amount of about 10 to about 30
mg/mL, about 15 to about 25 mg/mL, or about 20 mg/mL.
[0040] In some embodiments, the tonicity agent is selected from the
group consisting of dextrose, mannitol, potassium chloride, and
sodium chloride. In preferred embodiments, the tonicity agent is
sodium chloride. In some embodiments, the tonicity agent is present
in the composition in an amount sufficient to provide an isotonic
solution. In some embodiments, the tonicity agent is present in the
composition in an amount sufficient to provide an osmolality of
about 260 to about 340 mOsm/kg. In some embodiments, the tonicity
agent is sodium chloride and the sodium chloride is present in the
composition in an amount of about 4 to about 7 mg/mL, about 5 to
about 6 mg/mL, about 5 mg/mL, or about 6 mg/mL.
[0041] In some embodiments, the pH adjusting agents are selected
from the group consisting of acidifying agents, alkalizing agents,
and buffering agents. In some embodiments, the pH adjusting agent
is selected from the group consisting of citric acid, acetic acid,
hydrochloric acid, sodium hydroxide, sodium citrate, potassium
hydroxide, and potassium citrate. In preferred embodiments, pH
adjusting agent is hydrochloric acid and/or sodium hydroxide. In
some embodiments, the pH adjusting agent is present in the
composition in an amount sufficient to provide a pH of about 3 to
about 4.5, about 3 to about 4, about 3.5 to about 4.5, or about 3.5
to about 4, or about 3.6.
EXAMPLES
Example 1: Succinylcholine Composition
[0042] In one example, where the drug composition comprises
succinylcholine, a 5 mL or 10 mL glass syringe (e.g., syringes with
inner tip diameter of 1.7 mm) can be filled with a composition as
shown in Table 1 where the composition has a pH of about 3.0 to
about 4.5. Tonicity is adjusted to about 260 to about 340 mOsm/kg,
and in preferred aspects, the succinylcholine chloride is present
in the succinylcholine composition in an amount of about 20 mg/mL
and the sodium chloride is present in the succinylcholine
composition in an amount of about 5.50-6.00 mg/mL.
TABLE-US-00001 TABLE 1 Ingredient Grade Function Qty/mL
Succinylcholine Chloride USP Active ingredient 20.0 mg Sodium
Chloride USP Tonicity agent 5.56 mg Hydrochloric Acid NF pH
adjuster q.s. for pH adjustment to about pH 3.6 Sodium Hydroxide NF
pH adjuster q.s. for pH adjustment to about pH 3.6 Water for
Injection USP Vehicle q.s. to 1.0 mL 5 ml per Syringe 10 ml per
Syringe
Example 2: Stability of a Succinylcholine Composition at 25.degree.
C.
[0043] Advantageously, thusly prefilled glass syringes afford
relatively high stability and purity throughout extended periods of
storage despite the acidic pH of the solution.
[0044] Three batches of the succinylcholine composition of Example
1 in a 5 mL Becton Dickinson LLEC glass syringe with inner tip
diameter of 1.7 mm were prepared and stability was tested over 3
months of storage at 25.degree. C. and 60% relative humidity.
Content of succinylcholine chloride, impurities succinylmonocholine
chloride, succinic acid, unidentified impurity 1, unidentified
impurity 2, and total impurities were measured at 0, 1, 2, and 3
months by HPLC according to Example 4 below. Unidentified impurity
1 and unidentified impurity 2 are referenced in the USP monograph
for impurity detection in succinylcholine, First Supplement to USP
39-NF 34. Appearance, pH, osmolality, and particulate content were
also measured at 0, 1, 2, and 3 months. The results are included in
Table 2 below.
TABLE-US-00002 TABLE 2 Impurity Impurity Total P .gtoreq. 10 P
.gtoreq. 25 Osmolality Month Batch Appearance* pH SCC SMCC SA 1 2
impurities .mu.m .mu.m (mOsm/kg) 0 1 complies 3.9 99.3% 0.5%
<LOQ <LOQ <LOQ 0.5% 34 0 314 0 2 complies 3.9 99.8% 0.4%
ND 0.2% <LOQ 0.4% 25 0 313 0 3 complies 3.9 97.6% 0.4% ND
<LOQ 0.2% 0.4% 65 1 312 1 1 complies 3.4 93.5% 2.5% 0.1% 0.2% ND
2.7% -- -- -- 1 2 complies 3.4 94.8% 2.3% 0.1% <LOQ 0.1% 2.4% --
-- -- 1 3 complies 3.4 94.5% 2.2% 0.1% <LOQ <LOQ 2.3% -- --
-- 2 1 complies 3.3 93.8% 4.0% 0.3% 0.5% 0.1% 4.3% -- -- -- 2 2
complies 3.3 93.8% 3.9% 0.3% 0.3% 0.3% 4.2% -- -- -- 2 3 complies
3.3 93.8% 3.8% 0.2% 0.3% 0.3% 4.0% -- -- -- 3 1 complies 3.3 91.6%
4.9% 0.4% 0.2% <LOQ 5.4% 75 1 316 3 2 complies 3.3 92.7% 4.9%
0.4% 0.1% <LOQ 5.3% 63 0 318 3 3 complies 3.3 92.6% 4.8% 0.4%
0.1% <LOQ 5.2% 133 0 316 ND = not detected; *Clear, colorless
solution essentially free of visible particles; SCC:
Succinylcholine chloride; SMCC: Succinylmonocholine chloride; SA:
Succinic acid: P: Particle; >LOQ = that the amount detected is
less than the limit of quantitation of the HPLC method. -- = not
measured.
[0045] As illustrated by Table 2 above, the succinylcholine
composition in the glass syringe contained not more than about 6%
total impurities after storage at 25.degree. C. for 3 months as
determined by HPLC. Likewise, with respect to degradation it was
determined that the succinylcholine composition in the glass
syringe contained not more than about 4% succinylmonocholine
chloride (as primary degradation product) after storage at
25.degree. C. for 3 months as determined by HPLC, and that the
succinylcholine composition in the glass syringe contained not more
than about 1% succinic acid after storage at 25.degree. C. for 3
months as determined by HPLC.
Example 3: Stability of a Succinylcholine Composition at 5.degree.
C.
[0046] Stability of the three batches of Example 2 was also tested
over 3 months of storage at 5.degree. C. Content of succinylcholine
chloride, impurities succinylmonocholine chloride, succinic acid,
unidentified impurity 1, unidentified impurity 2, and total
impurities were measured at 0 and 3 months by HPLC according to
Example 4 below. Unidentified impurity 1 and unidentified impurity
2 are referenced in the USP monograph for impurity detection in
succinylcholine, First Supplement to USP 39-NF 34. Appearance, pH,
osmolality, and particulate content were also measured at 0 and 3
months. The results are included in Table 3 below.
TABLE-US-00003 TABLE 3 Impurity Impurity Total P .gtoreq. 10 P
.gtoreq. 25 Osmolality Month Batch Appearance* pH SCC SMCC SA 1 2
impurities .mu.m .mu.m (mOsm/kg) 0 1 complies 3.9 99.3% 0.5%
<LOQ <LOQ <LOQ 0.5% 34 0 314 0 2 complies 3.9 99.8% 0.4%
ND 0.2% <LOQ 0.4% 25 0 313 0 3 complies 3.9 97.6% 0.4% ND
<LOQ 0.2% 0.4% 65 1 312 3 1 complies 3.7 98.3% 1.1% <LOQ 0.2%
<LOQ 1.1% 66 0 310 3 2 complies 3.6 98.9% 0.9% <LOQ 0.1%
<LOQ 0.9% 88 1 311 3 3 complies 3.7 99.3% 0.9% <LOQ 0.1%
<LOQ 0.9% 63 0 310 ND = not detected; *Clear, colorless solution
essentially free of visible particles; SCC: Succinylcholine
chloride; SMCC: Succinylmonocholine chloride; SA: Succinic acid: P:
Particle; >LOQ = that the amount detected is less than the limit
of quantitation of the HPLC method. -- = not measured.
[0047] As illustrated by Table 3 above, the succinylcholine
composition in the glass syringe contained not more than about 2%
total impurities after storage at 5.degree. C. for 3 months as
determined by HPLC. Likewise, with respect to degradation it was
determined that the succinylcholine composition in the glass
syringe contained not more than about 2% succinylmonocholine
chloride (as primary degradation product) after storage at
5.degree. C. for 3 months as determined by HPLC, and that the
succinylcholine composition in the glass syringe contained not more
than about 1% succinic acid after storage at 5.degree. C. for 3
months as determined by HPLC.
Example 4: Analytic Protocols
[0048] In general, analytic protocols for succinylcholine are well
known in the art, and the following TLC and HPLC protocols are
suitable for use herein (which are based on the USP
monographs):
[0049] Analytic Protocol (TLC):
[0050] Standard solution: 1 mg/mL of USP Succinylcholine Chloride
RS in water; Sample solution: 1 mg/mL of succinylcholine chloride
in water; Adsorbent: 0.25-mm layer of chromatographic silica gel
with an application volume of 1 mcL. The plate is run with a
developing solvent system that consists of acetone and 1 N
hydrochloric acid (1:1). Analysis is performed by running standard
and sample solution in parallel. Sample and standard spots are
detected by heating the plate to 105.degree. C. for 5 min, followed
by cooling and spraying with potassium bismuth iodide test solution
and subsequent heating to 105.degree. C. for another 5 min.
[0051] Analytic Protocol (HPLC) for Succinylcholine:
[0052] Mobile phase: Prepare a 1 in 10 solution of 1 N aqueous
tetramethylammonium chloride in methanol. Adjust with hydrochloric
acid to a pH of about 3.0.
[0053] Standard solution: 8.8 mg/mL of USP Succinylcholine.
Succinylcholine Chloride Chloride RS prepared as follows. Transfer
a suitable amount of USP Succinylcholine Chloride RS to a suitable
volumetric flask and dissolve in 40% of the total volume of water.
Dilute with Mobile phase to volume while mixing.
[0054] Sample solution: 8.8 mg/mL of Succinylcholine Chloride
prepared as follows. Transfer a suitable amount of Succinylcholine
Chloride to a suitable volumetric flask and dissolve in 40% of the
total volume of water. Dilute with Mobile phase to volume while
mixing.
[0055] Conventional HPLC system is operated using UV detection at
214 nm and a 4-mm.times.25-cm, 10 .mu.m L3 packing (normal phase,
silica) at a flow rate of 0.75 ml/min.
[0056] Analysis is performed on standard and sample solutions and
percentage of succinylcholine chloride is calculated using the
following equation:
Result=(r.sub.U/r.sub.S).times.(C.sub.S/C.sub.U).times.100, where
r.sub.U is peak response from the sample solution, r.sub.S is peak
response from the standard solution, C.sub.S is concentration of
USP Succinylcholine Chloride RS in the standard solution (mg/mL),
and C.sub.U is concentration of Succinylcholine Chloride in the
sample solution (mg/mL).
[0057] Analytic Protocol (HPLC) for impurities:
[0058] Buffer: 3.85 g/L of anhydrous sodium 1-pentanesulfonate, 2.9
g/L of sodium chloride, and 1% (v/v) of 1 N sulfuric acid in
water.
[0059] Mobile phase: Acetonitrile and Buffer (5:95).
[0060] Standard solution: 0.05 mg/mL of USP Succinylmonocholine
Chloride RS in Mobile phase.
[0061] Sample solution: Sample solution: 10 mg/mL of
Succinylcholine Chloride in mobile phase.
[0062] Conventional HPLC system is operated using UV detection at
214 nm and a 4.6-mm.times.25-cm, L1 packing (octadecyl silane
chemically bonded to porous silica or ceramic micro-particles, 1.5
to 10 .mu.m in diameter) at a flow rate of 0.75 ml/min.
[0063] Analysis is performed on standard and sample solutions and
percentage of succinylcholine chloride is calculated using the
following equation:
Result=(r.sub.U/r.sub.S).times.(C.sub.S/C.sub.U).times.(1/F).ti-
mes.100, where r.sub.U is peak response from the sample solution,
r.sub.S is peak response from the standard solution, C.sub.S is
concentration of USP Succinylcholine Chloride RS in the standard
solution (mg/mL), C.sub.U is concentration of Succinylcholine
Chloride in the sample solution (mg/mL), and F is the relative
response factor.
Example 5: Syringe Parameters
[0064] Break loose force and glide force were also measured in
quintuplicate at each time point in Examples 2 and 3 above. The
results are included in Table 4 below:
TABLE-US-00004 TABLE 4 Break Loose Force Glide Force Month
Temperature Batch (Newtons) (Newtons) 0 25.degree. C. 1 16, 16, 16,
16, 13 6, 24, 6, 20, 5 0 25.degree. C. 2 13, 16, 14, 18, 15 5, 11,
6, 7, 11 0 25.degree. C. 3 16, 14, 18, 18, 24 14, 13, 9, 6, 7 1
25.degree. C. 1 16, 19, 21, 18, 16 6, 6, 21, 17, 12 1 25.degree. C.
2 19, 17, 13, 16, 17 28, 6, 8, 9, 6 1 25.degree. C. 3 18, 21, 15,
15, 21 8, 23, 16, 12, 7 2 25.degree. C. 1 20, 18, 19, 17, 22 5, 6,
7, 4, 6 2 25.degree. C. 2 23, 19, 16, 19, 17 5, 10, 6, 5, 6 2
25.degree. C. 3 16, 18, 16, 21, 21 9, 6, 8, 11, 10 3 25.degree. C.
1 22, 19, 19, 19, 18 9, 12, 8, 8, 6, 9 3 25.degree. C. 2 15, 19,
18, 22, 19 6, 7, 16, 13, 8 3 25.degree. C. 3 25, 25, 22, 14, 17 6,
9, 6, 6, 6 3 5.degree. C. 1 23, 16, 19, 20, 18 23, 7, 6, 33, 7 3
5.degree. C. 2 20, 17, 20, 22, 10 9, 6, 18, 7, 6 3 5.degree. C. 3
15, 17, 18, 16, 20 9, 26, 6, 7, 8
[0065] As used herein, the term "administering" a pharmaceutical
composition or drug refers to both direct and indirect
administration of the pharmaceutical composition or drug, wherein
direct administration of the pharmaceutical composition or drug is
typically performed by a health care professional (e.g., physician,
nurse, etc.), and wherein indirect administration includes a step
of providing or making available the pharmaceutical composition or
drug to the health care professional for direct administration
(e.g., via injection, infusion, oral delivery, topical delivery,
etc.).
[0066] In some embodiments, the drug composition in the prefilled
syringe is administered to a patient via the patient's intravenous
line. In some embodiments, the drug composition in the prefilled
syringe is administered to the patient by reversibly attaching the
syringe to the patient's intravenous line via the Luer-lock,
delivering the drug composition from the syringe into the patient's
intravenous line, and administering the drug composition from the
patient's intravenous line to the patient. The succinylcholine drug
composition is typically administered to the patient at a rate
sufficient to cause the desired skeletal muscle relaxation. In some
embodiments, the succinylcholine drug composition is administered
to the patient at a rate of about 0.5 to about 10 mg per minute or
about 2 to about 5 mg per minute, or about 2.5 to about 4.3 mg per
minute. In some embodiments, the succinylcholine drug composition
is administered to the patient in an amount of about 0.01 to about
3 mg/kg, about 0.04 to about 0.07 mg/kg, about 0.3 to about 1.1
mg/kg, about 0.6 mg/kg, 1 mg/kg, or 2 mg/kg.
[0067] In some embodiments, the present invention encompasses a
method for providing skeletal relaxation comprising administering
the succinylcholine drug composition in a prefilled syringe to a
patient in need thereof via the patient's intravenous line. In some
embodiments, the succinylcholine drug composition is administered
as an adjunct to general anesthesia, to facilitate tracheal
intubation, or to provide skeletal muscle relaxation during surgery
or mechanical ventilation.
[0068] The recitation of ranges of values herein is merely intended
to serve as a shorthand method of referring individually to each
separate value falling within the range. Unless otherwise indicated
herein, each individual value is incorporated into the
specification as if it were individually recited herein. All
methods described herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(e.g., "such as") provided with respect to certain embodiments
herein is intended merely to better illuminate the full scope of
the present disclosure, and does not pose a limitation on the scope
of the invention otherwise claimed. The term "about" where used in
conjunction of a numeric value refers to a range of +/-10% of that
numeric value, inclusive. No language in the specification should
be construed as indicating any non-claimed element essential to the
practice of the claimed invention.
[0069] It should be apparent to those skilled in the art that many
more modifications besides those already described are possible
without departing from the full scope of the concepts disclosed
herein. The disclosed subject matter, therefore, is not to be
restricted except in the scope of the appended claims. Moreover, in
interpreting both the specification and the claims, all terms
should be interpreted in the broadest possible manner consistent
with the context. In particular, the terms "comprises" and
"comprising" should be interpreted as referring to elements,
components, or steps in a non-exclusive manner, indicating that the
referenced elements, components, or steps may be present, or
utilized, or combined with other elements, components, or steps
that are not expressly referenced. Where the specification claims
refers to at least one of something selected from the group
consisting of A, B, C . . . and N, the text should be interpreted
as requiring only one element from the group, not A plus N, or B
plus N, etc.
* * * * *
References