U.S. patent application number 09/822767 was filed with the patent office on 2002-10-03 for premixed amiodarone parenteral solution and method for making the same.
Invention is credited to Doty, Mark J., Kipp, James E., Raghavan, Neervalur V., Rebbeck, Christine L..
Application Number | 20020143051 09/822767 |
Document ID | / |
Family ID | 25236911 |
Filed Date | 2002-10-03 |
United States Patent
Application |
20020143051 |
Kind Code |
A1 |
Doty, Mark J. ; et
al. |
October 3, 2002 |
Premixed amiodarone parenteral solution and method for making the
same
Abstract
A premix parenteral solution for intravenous administration
having amiodarone, as an active ingredient, solubilized in a
solution of distilled water and about 0.4-12 mg/ml of a non-ionic
surfactant to a concentration range of from 0.2 to 6 mg/ml is
disclosed. The solution optionally may include an osmotic agent. No
dilution of the solution is required before administering to a
patient and the sterile packaged solution has an initial pH within
the range of from about 2.9 to about 3.2, preferably about 3.1.
Additionally, a method for producing an amiodarone solution
suitable for intravenous administration is further disclosed.
Inventors: |
Doty, Mark J.; (Grayslake,
IL) ; Rebbeck, Christine L.; (Algonquin, IL) ;
Kipp, James E.; (Wauconda, IL) ; Raghavan, Neervalur
V.; (Northbrook, IL) |
Correspondence
Address: |
Mark J. Buonaiuto, Esq.
BAXTER INTERNATIONAL INC.
Corporate Counsel, Law Department
One Baxter Parkway, DF2-2E
Deerfield
IL
60015
US
|
Family ID: |
25236911 |
Appl. No.: |
09/822767 |
Filed: |
March 29, 2001 |
Current U.S.
Class: |
514/469 ;
514/23 |
Current CPC
Class: |
A61K 31/343 20130101;
A61P 9/06 20180101; A61K 9/0019 20130101; A61K 47/26 20130101 |
Class at
Publication: |
514/469 ;
514/23 |
International
Class: |
A61K 031/343; A61K
031/70 |
Claims
We claim:
1. A parenteral solution for intravenous administration comprising:
amiodarone, as an active ingredient, solubilized in a solution of
distilled water and a non-ionic surfactant to a concentration range
of from 0.2 to 6 mg/ml.; optionally, an osmotic agent; and wherein
the solution requires no dilution before administering and has a pH
within the range of from about 2.9 to about 3.2.
2. The parenteral solution of claim 1 wherein the osmotic agent is
selected from the group consisting of dextrose, mannitol, sorbitol,
glycerol, amino acids such as glycine, and salts such as sodium
chloride.
3. The parenteral solution of claim 1 wherein the quantity of
non-ionic surfactant is in the range of from about 0.4 to about 12
mg/ml.
4. The parenteral solution of claim 3 wherein the non-ionic
surfactant is selected from the group consisting of an ethoxylated
polysorbate such as polysorbate 80, an ethylene oxide/propylene
oxide copolymer, a polyethoxylated castor oil, and a polyethylene
glycol hydroxystearate such as SOLUTOL.RTM. HS-15.
5. The parenteral solution of claim 4 wherein the non-ionic
surfactant is polysorbate 80.
6. The parenteral solution of claim 4 wherein the non-ionic
surfactant is a polyethylene glycol hydroxystearate.
7. The parenteral solution of claim 1 wherein the pH of the
solution is about 3.1.
8. The parenteral solution of claim 2 wherein the pH of the
solution is about 3.1.
9. The parenteral solution of claim 3 wherein the pH of the
solution is about 3.1.
10. The parenteral solution of claim 4 wherein the pH of the
solution is about 3.1.
11. A parenteral solution for intravenous administration
comprising: amiodarone, as an active ingredient, solubilized in a
solution of distilled water and a non-ionic surfactant to a
concentration range of from 0.2 to 6 mg/ml.; optionally, an osmotic
agent; and wherein the solution is a sterilized premix.
12. The parenteral solution of claim 11 wherein the pH of the
sterilized premix is in the range of from about 2.9 to about
3.2.
13. The parenteral solution of claim 12 wherein the pH of the
sterilized premix is about 3.1.
14. The parenteral solution of claim 11 wherein the sterilized
premix is refrigerated.
15. The parenteral solution of claim 14 wherein the sterilized
premix is maintained at a temperature within the range of from 3 to
about 10.degree. C.
16. A parenteral solution for intravenous administration
comprising: amiodarone, as an active ingredient, solubilized in a
solution of distilled water and a non-ionic surfactant and wherein
the solution requires no dilution before administering and has a
drug degradation over time of less than 3% per year at room
temperature.
17. The parenteral solution of claim 16 wherein the pH of the
solution is within the range of from about 2.9 to about 3.2.
18. The parenteral solution of claim 17 wherein the pH of the
solution is about 3.1.
19. A parenteral solution for intravenous administration
comprising: amiodarone, as an active ingredient, solubilized in a
solution of distilled water and a non-ionic surfactant to a
concentration range of from 0.2 to 6 mg/ml.; optionally, an osmotic
agent; and wherein the solution requires no dilution before
administering and has a rate of total impurity formation of less
than about 0.02% (w/v) total impurities/week at room
temperature.
20. The parenteral solution of claim 19 wherein the pH of the
solution is about 3.1.
21. The parenteral solution of claim 19 wherein the osmotic agent
is selected from the group consisting of dextrose, mannitol,
sorbitol, glycerol, amino acids such as glycine, and salts such as
sodium chloride.
22. The parenteral solution of claim 19 wherein the quantity of
non-ionic surfactant is in the range of from about 0.4 to about 12
mg/ml.
23. The parenteral solution of claim 22 wherein the non-ionic
surfactant is selected from the group consisting of an ethoxylated
polysorbate such as polysorbate 80, an ethylene oxide/propylene
oxide copolymer, a polyethoxylated castor oil, and a polyethylene
glycol hydroxystearate such as SOLUTOL.RTM. HS-15.
24. A parenteral solution for intravenous administration
comprising: amiodarone, as an active ingredient, solubilized in a
solution of distilled water and a non-ionic surfactant to a
concentration range of from 0.2 to 6 mg/ml.; optionally, an osmotic
agent; and wherein the solution requires no dilution before
administering and has a drug adsorption of less than 3% in a
plastic container which has a plastic surface area to solution
volume ratio of approximately 4 cm.sup.1at room temperature.
25. The parenteral solution of claim 24 wherein the pH of the
solution is about 3.1.
26. A parenteral solution for intravenous administration consisting
of: amiodarone, as an active ingredient, solubilized in a solution
of distilled water and about 0.4-12 mg/ml of a non-ionic surfactant
to a concentration range of from 0.2 to 6 mg/ml.; optionally, an
osmotic agent; and wherein the solution has a pH within the range
of from about 2.9 to about 3.2.
27. The parenteral solution of claim 26 wherein the pH of the
solution is about 3.1.
28. The parenteral solution of claim 27 wherein the osmotic agent
is selected from the group consisting of dextrose, mannitol,
sorbitol, glycerol, amino acids such as glycine, and salts such as
sodium chloride.
29. The parenteral solution of claim 27 wherein the non-ionic
surfactant is selected from the group consisting of an ethoxylated
polysorbate such as polysorbate 80, an ethylene oxide/propylene
oxide copolymer, a polyethoxylated castor oil, and a polyethylene
glycol hydroxystearate such as SOLUTOL.RTM.HS-15.
30. A parenteral solution for intravenous administration
comprising: amiodarone, as an active ingredient, solubilized in a
solution of distilled water and a non-ionic surfactant to a
concentration range of from 0.2 to 6 mg/ml.; optionally, an osmotic
agent; and wherein the solution requires no dilution before
administering and has minimal insoluble particle formation in a
plastic container at room temperature.
31. The parenteral solution of claim 30 wherein the pH of the
solution is about 3.1.
32. A method for producing an amiodarone solution suitable for
intravenous administration comprising the steps of: (1) providing,
as an active ingredient, an effective amount of an amiodarone
solution; (2) solubilizing the active ingredient in a
water/surfactant solution to create a premix solution; (3) diluting
and cooling the premix solution; (4) adjusting the pH of the premix
solution with a suitable pH adjuster to an initial pH within the
range of from about 2.9 to about 3.2; (5) diluting the premix
solution to the final active ingredient concentration; and (6)
filling suitable containers with the solution.
33. The method of claim 32 and further comprising the step of
mixing into the premix solution an osmotic agent.
34. The method of claim 33 wherein the osmotic agent is selected
from the group consisting of dextrose, mannitol, sorbitol,
glycerol, amino acids, inorganic salts, and any combination
thereof.
35. The method of claim 32 and further comprising the step of
sterilizing the premix solution either before or after the filling
step, by any suitable sterilization method.
36. The method of claim 32 wherein the pH of the premix solution is
adjusted to about 3.1.
Description
TECHNICAL FIELD
[0001] This invention relates generally to a premixed
pharmaceutical composition containing amiodarone for parenteral
administration. Particularly, the composition, and method for
making the same, provides an enhanced shelf-life and an improved
polymeric container compatibility over diluted formulations.
BACKGROUND ART
[0002] Amiodarone HCl
(2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]--
3,5-diiodophenyl]methanone hydrochloride, is a class III
antiarrhythmic agent that possesses electro physiologic
characteristics of all four Vaughan Williams classes. The
hydrochloride salt is currently marketed in ampoules suitable for
intravenous administration following dilution in dextrose
(CORDARONE.RTM. IV, Wyeth-Ayerst). Each milliliter of a
CORDARONE.RTM. ampoule contains 50 mg amiodarone HCl, 20.2 mg
benzyl alcohol, 100 mg polysorbate 80, and water for injection. The
pH of the commercial product after dilution in dextrose is
approximately 3.8-4.0.
[0003] One disadvantage of the prior art product is a required step
of admixing 1-6 ampoules in dextrose prior to administration. Since
amiodarone is used under emergency conditions to rapidly stabilize
a patient's acute ventricular arrhythmia, this dilution step
consumes valuable time that could be used instead to save the
patient. Other drawbacks of the admixing step include the
possibility of dosage error, needle sticks, and/or solution
contamination.
[0004] Another disadvantage of the prior art product is that the
diluted formulations have a limited shelf life at room temperature.
Generally, due to diminished sterility precautions brought about by
opening the sterile container of the concentrate, the resulting
diluted formulations must be used within 24 hours of dilution or be
discarded. Obviously, such discarded quantities of the product are
incurred costs which cannot be billed out by the health care
provider.
[0005] An additional disadvantage is that the diluted formulations
have been shown to be incompatible with certain polymeric materials
due to drug adsorption. This phenomenon creates dosing problems for
health care providers, or requires the use of special material
containers for dilution and delivery.
[0006] The product configuration and amiodarone formulations
described in the present invention overcome these disadvantages.
The ready-to-use premixed product configuration prevents loss of
emergency room time, avoids potential problems of contamination,
prevents needle sticks, decreases medical waste production, and
eliminates dosage errors. Such benefits are due to the fact that
medical personnel will be able to simply pull a prepared container
of the inventive composition off the shelf, as needed, for
immediate use. Moreover, the new premixed amiodarone formulations
have an enhanced shelf life and an improved compatibility with
polymeric container materials.
[0007] U.S. Pat. No. 6,143,778 issued Nov. 7, 2000, to Gautier et
al. discloses an amiodarone composition concentrate for parenteral
delivery after dilution. The disclosed composition requires a
physiologically acceptable buffer solution capable of solubilizing
the active principle and of maintaining the pH of the concentrated
composition between 2.4 and 3.8 (column 4, lines 8-54). Gautier et
al. take an approach to develop an amiodarone hydrochloride
formulation "which is at the same time concentrated, stable and
dilutable."(See column 1, lines 28-31, column 3, lines 34-39, and
lines 47-56). Gautier et al., therefore, focus on the stability and
admixing of the concentrate. The invention of this application
provides a premixed amiodarone hydrochloride formulation which does
not require dilution and does not utilize a buffer, not even for
solubilizing the active, before parenteral administration to a
patient.
[0008] Discussion regarding diluted amiodarone concentrations
(i.e., admixtures) are set forth by Gautier et al., but no
information is provided discussing the long-term stability (1 year
or more) of the diluted product (column 5, lines 32-51). In the
only provided examples of a diluted form of the amiodarone, Gautier
et al. teach pH levels of around 4 (see examples 2, 4, and 6 of
Table, column 6, lines 45-53). Gautier et al. fail to appreciate
the criticality of a limited pH range of from about 2.9 to about
3.2, and specifically a pH of about 3.1 for long term stability and
container compatibility of a diluted premix formulation. By
focusing on the stability of a concentrate which is capable of
dilution for immediate use or discard, Gautier et al. ignore the
potential long term problems of the diluted product. That is,
outside of the very narrow pH range problems result in drug
degradation, particle formation, impurity formation, and container
incompatibility. By addressing and solving these problems, the
premix formulation of the present invention distinguishes over all
teaching by Gautier et al. of both a concentrate and a diluted
admix product.
[0009] Similarly, U.S. Pat. No. 5,234,949 issued Aug. 10, 1993, to
Ehrenpreis et al., teaches a parenteral solution of amiodarone in
acetate buffer. Ehrenpreis et al. teach a preferred pH in the range
of 3.5 to 3.8 (column 3, lines 53-54). This approach is contrary to
the claimed composition and methods of the present invention.
SUMMARY OF THE INVENTION
[0010] The present invention provides a new, ready-to-use premixed
formulation of amiodarone, or pharmaceutically acceptable salts
thereof, which are suitable for intravenous administration and
continuous infusion. Within a specific pH range of from about 2.9
to about 3.2, these formulations have an enhanced shelf life and
are more compatible with polymeric container materials.
[0011] In one aspect of the invention a parenteral solution for
intravenous administration is provided having amiodarone as an
active ingredient. The active is solubilized in a solution of
distilled water and about 0.4-12 mg/ml of a non-ionic surfactant to
a concentration range of from 0.2 to 6 mg/ml, wherein the solution
requires no dilution before administering and has a pH within the
range of from about 2.9 to about 3.2. Optionally, an osmotic agent
may also be added to the solution.
[0012] In still other aspects, at room temperature, the solution
exhibits drug degradation of less than 3% per year, drug loss due
to adsorption by polymeric material containers of less than 3%
given a plastic surface area to solution volume ratio of
approximately 4 cm.sup.-1, minimal insoluble particulate formation,
and a rate of total impurity formation of less than 0.02% (w/v)
total impurities/week.
[0013] In a method for producing an amiodarone solution suitable
for intravenous administration, the present invention discloses the
steps of providing, as an active ingredient, an effective amount of
an amiodarone solution. The active ingredient is solubilized in a
water/surfactant solution, then cooled before diluting the premix
solution. Optionally, an osmotic agent may be added to the solution
at this point. The pH is then adjusted with a suitable pH adjuster
to be within the range of from about 2.9 to about 3.2, most
preferably about 3.1. The premix is then further diluted to the
final active ingredient concentration. Proper containers are then
filled with the final solution which may be administered directly
to a patient without further dilution.
[0014] Other advantages and aspects of the present invention will
become apparent upon reading the following detailed description of
the invention in conjunction with the appended drawings and
claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] For further facilitating the understanding of the present
invention, four drawing figures are appended hereto, wherein:
[0016] FIG. 1 is a diagrammatic illustration comparing rates of
total impurity formation for diluted CORDARONE.RTM. product
(pH=3.9) and premixed amiodarone formulation (pH=3.0) at 25.degree.
C. in a glass container;
[0017] FIG. 2 is a diagrammatic illustration comparing the rates of
amiodarone active degradation over a period of five months to one
year for the diluted CORDARONE.RTM. product (pH=3.9) and premixed
amiodarone formulation (pH=3.0) at 25.degree. C. in a plastic
container.
[0018] FIG. 3 is a diagrammatic illustration comparing percentages
of drug adsorption at 25.degree. C. after a period of five months
to one year in a plastic container for diluted CORDARONE.RTM.
product (pH=3.9) and premixed amiodarone formulation (pH=3.0);
and
[0019] FIG. 4 is a diagrammatic illustration comparing particle
counts (USP 788) after a period of one to two months and a period
of four to five months for diluted CORDARONE.RTM. product (pH=3.9)
and premixed amiodarone formulation (pH=3.0 and 2.5) in a plastic
container.
DETAILED DESCRIPTION
[0020] While this invention is susceptible of embodiment in many
different forms, this disclosure will describe in detail preferred
embodiments of the invention. The present disclosure is to be
considered as an example of the principles of the invention, and is
not intended to limit the broad aspect of the invention to the
embodiments illustrated.
[0021] According to the present invention, there is provided
premixed parenteral formulations containing as an active ingredient
a substituted benzofuran drug. The active ingredient has the
following structural formula: 1
[0022] where R.sub.i represents one or more groups selected from
alkyl, aryl, alkoxy, aryloxy or halogen substituents; R.sub.1
represents an alkyl, aryl, alkoxy, aryloxy or halogen substituent,
X.sub.j includes one or more iodo or bromo substituents on the
phenyl ring; R.sub.2 represents a dialkylamino group such as
N,N-dimethylamino or N,N-diethylamino; R.sub.2 can also be a
1-substituted heterocycle such as 1-morpholinyl, 1-piperazinyl, or
1-piperadinyl.
[0023] Amiodarone and/or one or more pharmaceutically acceptable
salts thereof, are preferred for use in the present invention.
Amiodarone has the following structural formula: 2
[0024] Suitable amiodarone is sold by ISOCHEM, France. The
preferred concentration of amiodarone is about 0.2-6 mg/ml. The
formulations also contain approximately 0.4-12 mg/ml of a non-ionic
surfactant, such as an ethoxylated polysorbate (e.g., polysorbate
80), an ethylene oxide/propylene oxide copolymer, a polyethoxylated
castor oil, and/or a polyethylene glycol hydroxystearate such as
PEG-660 12-hydroxy stearate. The non-ionic surfactant is preferably
either polysorbate 80 (TWEEN.sub.80.RTM.) or polyethylene glycol
hydroxystearate (SOLUTOL.RTM. HS-15). The solutions can also
optionally include an osmotic agent such as dextrose, mannitol,
sorbitol, glycerol, amino acids such as glycine, or salts such as
sodium chloride. The solutions have a pH preferably within the
range of from about 2.9 to about 3.2, with an initial pH of about
3.1 being the optimal pH for the solution. This initial pH range is
preferred because the parenteral formulations are particularly
stable, demonstrating a low percentage of drug degradation (See
FIGS. 1 and 2), minimal drug adsorption to polymeric container
materials (See FIG. 3), and minimal particle formation (See FIG.
4).
[0025] The present invention also provides a method for producing
amiodarone solutions suitable for intravenous administration. The
method comprises the steps of: (1) providing an effective
ingredient or ingredients of an amiodarone solution; (2) providing
distilled water; (3) providing a non-ionic surfactant, such as
TWEEN.sub.80.RTM. or SOLUTOL.RTM. HS-15; (4) mixing an effective
amount of the non-ionic surfactant with heated, distilled water;
(5) solubilizing an effective amount of the active ingredient in
the heated water/surfactant solution; (6) cooling and diluting the
solution; (7) adjusting the initial pH of the solution with a
suitable pH adjuster to be within the range of from approximately
2.9 to approximately 3.2; (8) diluting the solution to the final
active ingredient concentration; (9) filling suitable containers
with the solution. The pH may change slightly from the initial pH,
but should remain within the stated range.
[0026] Optionally, the method can also include the step of mixing
into the solution an osmotic agent such as dextrose, mannitol,
sorbitol, glycerol, amino acids, inorganic salts, and any
combination of these osmotic adjusters. Further, the method can
also include the step of sterilizing the solution either before or
after the filling step, by any suitable sterilization method
including heat, radiation or preferably through filter membrane
sterilization.
[0027] When prepared using the disclosed methods, at room
temperature, the present premix solution exhibits drug degradation
of less than 3% per year, drug loss due to adsorption by polymeric
material containers of less than 3% given a plastic area to
solution volume ratio of approximately 4 cm.sup.-1, minimal
insoluble particulate formation, and a rate of total impurity
formation of less than 0.02% (w/v) total impurities/week. These
surprising results are a striking improvement over the currently
available commercial product requiring dilution before
administration.
[0028] The following is a non-limiting example of the present
invention and should not be construed in a manner to narrow the
scope of the present invention.
EXAMPLE
PREPARATION OF AMIODARONE PREMIXED FORMULATION
[0029] To a 20-L jacketed tank reactor was added 6 L of distilled,
deionized water. To this was added 54 g of Tween 80 and the mixture
was brought to 55.degree. C. 27 g of amiodarone hydrochloride was
added to the mixture and agitated to dissolution. The mixture was
cooled to 30.degree. C., and 681 g of anhydrous dextrose was added
and agitated to dissolution. The mixture was diluted to 13.5L and
the solution pH was adjusted to 3.0 with 1 N sodium hydroxide
and/or 1 N hydrochloric acid. The solution is then diluted to 15 L
with distilled, deionized water. This provides a solution having an
approximate drug concentration of 1.8 mg/mL and a pH=3.0.
[0030] Amiodarone formulations prepared as described above were
found to be more stable than the currently marketed CORDARONE.RTM.
product following dilution. FIG. 1 shows the rate of formation of
total impurities in the diluted CORDARONE.RTM. product (pH=3.9)
versus the new premixed amiodarone formulation (pH=3.0) at
25.degree. C. Both formulations were stored in a glass container.
Under these conditions, the rate of total impurity formation in the
CORDARONE.RTM. product and the new amiodarone premix is found to be
approximately 0.142% and 0.016% (w/v) total impurities/week,
respectively. FIG. 2 shows the rate of amiodarone active
degradation over a period of five months to one year for the
diluted CORDARONE.RTM. product following admixing (pH=3.9) and
premixed amiodarone formulation (pH=3.0) at 25.degree. C. in a
plastic container. Consequently, the new premixed amiodarone
formulation is significantly more chemically stable than the
currently marketed CORDARONE.RTM. product following admixing stored
under the same conditions.
[0031] Amiodarone formulations prepared as described were also
found to be more compatible with polymeric container materials in
comparison to the currently marketed diluted CORDARONE.RTM.
product. FIG. 3 shows the percentage loss of amiodarone due to
adsorption after a period of five months to one year storage in a
plastic container at 25.degree. C. The drug concentration,
polysorbate 80 concentration, container configuration, and solution
volume were virtually identical for both formulations. Under these
conditions, the percentage of drug adsorption for the
CORDARONE.RTM. product (pH=3.9) and the new amiodarone premix
formulations (pH=3.0) is found to be approximately 4.3% and 1.6%,
respectively. Consequently, significantly less drug binding to the
polymeric material is observed with the new premixed amiodarone
formulation.
[0032] Amiodarone formulations prepared as described above also
formed less particulate matter over time in comparison to the
currently marketed CORDARONE.RTM. product following admixing. FIG.
4 shows the 5 .mu.m particle counts measured by the light
obscuration particle count test (USP 788) after a period of one to
two months and four to five months in a plastic container at 25
.degree. C. for the marketed CORDARONE.RTM. product following
admixing (pH=3.9) and the new premixed amiodarone formulations
(pH=3.0 and 2.5). The least number of particles were observed in
the more preferred pH range (pH=2.9-3.2) for the present invention.
Similar trends were observed in the 2 .mu.m and 10 .mu.m particle
size channels.
[0033] While the specific embodiments have been illustrated and
described, numerous modifications come to mind without
significantly departing from the spirit of the invention and the
scope of protection is only limited by the scope of the
accompanying claims.
* * * * *