U.S. patent application number 15/078631 was filed with the patent office on 2016-09-29 for stable formulation for parenteral administration of tapentadol.
The applicant listed for this patent is Gruenenthal GmbH. Invention is credited to Ulrike BERTRAM, Ulrich REINHOLD, Marc SCHILLER, Stefanie STRAUB, Carlos van Hemelrijck, Eva WULSTEN.
Application Number | 20160279078 15/078631 |
Document ID | / |
Family ID | 55661386 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160279078 |
Kind Code |
A1 |
SCHILLER; Marc ; et
al. |
September 29, 2016 |
Stable Formulation for Parenteral Administration of Tapentadol
Abstract
The invention relates to an aqueous pharmaceutical composition
for parenteral administration comprising Tapentadol or a
physiologically acceptable salt thereof, wherein the concentration
of Tapentadol is within the range of from 0.10 to 8.00 mg/mL, based
on the weight of Tapentadol free base and based on the total volume
of the composition; and wherein the pH value of the composition is
buffered and within the range of from 4.0 to 6.0. The invention
also relates to a container comprising the pharmaceutical
composition and a process for the preparation thereof. The
invention also relates to a kit comprising the contained according
to the invention in a packaging. The pharmaceutical composition
according to the invention is particularly useful for treating
pain, especially acute pain, preferably in pediatric patients.
Inventors: |
SCHILLER; Marc; (Aachen,
DE) ; van Hemelrijck; Carlos; (Aachen, DE) ;
STRAUB; Stefanie; (Bad Vilbel, DE) ; WULSTEN;
Eva; (Willich, DE) ; BERTRAM; Ulrike; (Aachen,
DE) ; REINHOLD; Ulrich; (Aachen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gruenenthal GmbH |
Aachen |
|
DE |
|
|
Family ID: |
55661386 |
Appl. No.: |
15/078631 |
Filed: |
March 23, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/08 20130101; A61K
47/12 20130101; A61P 25/04 20180101; A61K 9/0019 20130101; A61K
31/137 20130101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 9/00 20060101 A61K009/00; A61K 47/12 20060101
A61K047/12; A61K 9/08 20060101 A61K009/08 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 27, 2015 |
EP |
15 161 487.2 |
May 28, 2015 |
EP |
15 169 730.7 |
Claims
1.-61. (canceled)
62. An aqueous pharmaceutical composition for parenteral
administration comprising Tapentadol or a physiologically
acceptable salt thereof, wherein the concentration of Tapentadol is
within the range of from 0.10 to 8.00 mg/mL, based on the weight of
Tapentadol free base and based on the total volume of the
composition; and wherein the pH value of the composition is
buffered and within the range of from 4.0 to 6.0.
63. The composition according to claim 62, which is stable upon
autoclaving and preferably exhibits an unaltered pH value upon
autoclaving.
64. The composition according to claim 63, which is stable upon
autoclaving for 20 minutes at 121.degree. C. and 2 bar and
preferably exhibits an unaltered pH value upon autoclaving under
these conditions.
65. The composition according to claim 62, wherein the content of
molecular oxygen in the composition is not more than 9.0 mg/L,
based on the total volume of the composition.
66. The composition according to claim 62, wherein the content of
molecular oxygen in the composition is not more than 0.2 mg/L,
based on the total volume of the composition.
67. The composition according to claim 62, wherein the pH value is
within the range of from 4.5 to 5.5, in particular before and after
autoclaving.
68. The composition according to claim 62, which comprises a buffer
comprising one or more conjugate bases and one or more conjugate
acids selected from the group consisting of citrate,
hydrogencitrate, dihydrogencitrate and citric acid.
69. The composition according to claim 62, which comprises a buffer
comprising one or more conjugate bases and one or more conjugate
acids and having a concentration of at least 0.5 mmol/L, based on
the total content of the one or more conjugate bases and the one or
more conjugate acids and based on the total volume of the
composition.
70. The composition according to claim 62, which comprises a buffer
comprising one or more conjugate bases and one or more conjugate
acids and having a concentration of not more than 1.5 mmol/L, based
on the total content of the one or more conjugate bases and the one
or more conjugate acids and based on the total volume of the
composition.
71. The composition according to claim 62, which comprises a buffer
comprising one or more conjugate bases and one or more conjugate
acids and having a concentration within the range of from 0.5 to
1.5 mmol/L, based on the total content of the one or more conjugate
bases and the one or more conjugate acids and based on the total
volume of the composition.
72. The composition according to claim 62, wherein Tapentadol is
present as Tapentadol hydrochloride.
73. The composition according to claim 62, wherein the
concentration of Tapentadol is within the range of 1.0.+-.0.5
mg/mL, based on the weight of Tapentadol free base and based on the
total volume of the composition.
74. The composition according to claim 62, which comprises an
isotonizing agent.
75. The composition according to claim 74, wherein the isotonizing
agent is sodium chloride.
76. The composition according to claim 62, which has a titration
acidity of not more than 1.8 mmol/L.
77. The composition according to claim 62, which does not contain
any antioxidant and/or chelating agent.
78. The composition according to claim 62, which does not contain
any preservative.
79. A container comprising the pharmaceutical composition according
to claim 62.
80. The container according to claim 79, which is a glass
ampoule.
81. The container according to claim 79, which comprises from 1.0
to 3.0 mL of the composition.
82. The container according to claim 79, which comprises the
composition as a liquid phase and a gaseous phase in a headspace
above the liquid phase, wherein the gaseous phase has a content of
molecular oxygen of not more than 2.5% Vbar.
Description
[0001] The invention relates to an aqueous pharmaceutical
composition for parenteral administration comprising Tapentadol or
a physiologically acceptable salt thereof, wherein the
concentration of Tapentadol is within the range of from 0.10 to
8.00 mg/mL, based on the weight of Tapentadol free base and based
on the total volume of the composition; and wherein the pH value of
the composition is buffered and within the range of from 4.0 to
6.0. The invention also relates to a container comprising the
pharmaceutical composition and a process for the preparation
thereof. The invention also relates to a kit comprising the
contained according to the invention in a packaging. The
pharmaceutical composition according to the invention is
particularly useful for treating pain, especially acute pain,
preferably in pediatric patients.
[0002] Various formulations for parenteral administration are known
from the prior art.
[0003] WO 01/22998 discloses a therapeutic calcitriol solution
which is suitable for packaging into pharmaceutical vials without
producing discoloration of the antioxidant component of the
solution.
[0004] WO 01/93830 relates to a method for obtaining aqueous
formulations with easily oxidizable active principles, notably
phenols, stable over prolonged period, which consists of subjecting
them to extreme deoxygenation by bubbling with an inert gas and/or
placing under vacuum, protecting them against possible resorption
of oxygen by keeping them under an inert gas atmosphere by filling,
under inert gas, into bottles previously cleared of air by
insufflation with inert gas, then subjecting them, whilst
stoppering, to low pressure as obtained in the bottle, of 65,000 Pa
maximum, and thus obtaining aqueous solutions having a residual
oxygen concentration in the solution below 2 ppm, and preferably of
the order of 1 ppm and even 0.5 ppm.
[0005] WO 02/072080 relates to parenterally administrable,
especially infusible, aqueous paracetamol solutions which are
stable in storage and free of particles and discoloration. Said
solutions contain a mixture of: a) between 1 and 17 grams of
paracetamol per liter, and b) between 0.01 and 0.17 grams of at
least one physiologically compatible antioxidant per liter,
selected from the group comprising ascorbic acid,
N-acetyl-L-cysteine and stabilizer compounds containing SH groups
which are different from N-acetyl-L-cysteine. The aqueous solution
is free of organic solvents and has a pH value of between 5.5 and
6.5 and an oxygen content of less than 0.5 milligrams per
liter.
[0006] WO 03/041687 a method for producing stabilized
antioxidant-free solutions based on phenolic substances which
consists in: deoxygenation of the solutions with an inert gas, and
in deoxygenation of gas holdups of the vessels, of the
manufacturing pipes and inerting of ampoules and flasks containing
the solute with a dense inert rare gas such as argon, at low
temperature and with pH adjusted above 3.0 and below 5.0 to obtain
stable solutions of phenolic substances containing not more than
0.02 ppm of oxygen in the solution, which is filtered by double
sterilizing filtration.
[0007] WO 2004/062689 discloses stabilized aqueous compositions of
tissue factor pathway inhibitor (TFPI) or TFPI variants that
comprise a solubilizing agent, an antioxidant, and a buffer. The
combination of a solubilizing agent and an antioxidant can lead to
a significant improvement in the storage life of TFPI or TFPI
variant compositions. The solubilizing agent and antioxidant
substantially counteract the effects of TFPI or TFPI variant
degradation through aggregation and oxidation.
[0008] WO 2008/135601 relates to a liquid formulation, stable to
oxidation, based on a phenolic active principle susceptible to
oxidation such as paracetamol in an aqueous solvent and to a method
for preparing such formulation. The formulation and the method are
characterized in that the active principle is admixed in the
aqueous solvent having a temperature between 60.degree. C. and
105.degree. C., a pH between 5.0 and 6.0 and an oxygen
concentration below 0.0002%.
[0009] WO 2009/124586 concerns a stable aqueous pharmaceutical
composition comprising
5-[(2RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl]-pyrimidi-
ne-2,4-diamine in form of the water soluble methanesulfonic acid
salt, a physiological sodium chloride solution, ethanol and
Povidone 12 PF, the liquid having a pH of over and above 4.8, but
not higher than 5.2, and wherein the oxygen amount is controlled to
be 0.8 ppm or less; which can be sterilized by filtration and/or by
heated treatment, stored for longer time periods and which can be
used for bolus injection or diluted for i.v. infusion.
[0010] WO 2011/071400 relates to stable liquid formulations of
paracetamol for pharmaceutical use and to a method of preparation
of stable paracetamol solutions.
[0011] WO 2013/144814 discloses a stable ready-to-use
pharmaceutical composition comprising pemetrexed or
pharmaceutically acceptable salts thereof, wherein the composition
is free from antioxidants, amino acids and chelating agents. Also
provided is a process for preparing a stable ready-to-use
pharmaceutical composition comprising the steps: i) purging inert
gas into a parenterally acceptable aqueous solvent until the
dissolved oxygen content of the solvent comes to less than 7 mg/L,
preferably less than 3 mg/L; ii) adding pemetrexed disodium under
stirring; iii) adjusting the pH of the resulting solution to
between 4 to 9; iv) optionally adding additional aqueous solvent;
wherein the composition is purged with inert gas throughout the
entire process.
[0012] Pharmaceutical dosage forms of Tapentadol are also known
from the prior art, e.g., WO 02/67651, WO 03/035053, WO
2006/002886, WO 2007/128412, WO 2007/128413, WO 2008/110323, WO
2009/067703, WO 2009/092601, US 2010/272815, and T. M. Tzschentke
et al., Drugs of the future, 31(12), 2006, 1053-1061.
[0013] WO 2012/119727 relates to an aqueous pharmaceutical
composition containing tapentadol or a physiologically acceptable
salt thereof and being adapted for oral administration. The
composition has excellent storage stability without relying on the
presence of high amounts of preservatives.
[0014] WO 2012/119728 discloses parenteral formulations for the
administration of Tapentadol. The concentration of Tapentadol in
these formulations is preferably below 100 mg/mL. The concentration
of Tapentadol in the exemplified formulations according to WO
2012/119728 is 15 mg/mL and 20 mg/mL, respectively. According to WO
2012/119728 Tapentadol exhibits antimicrobial properties. These
antimicrobial properties are more pronounced at higher pH values.
In consequence, preservatives may be omitted or their content in
the formulations may at least be decreased. The complete absence of
preservatives is preferred when the content of Tapentadol is
sufficiently high so that due to its preserving property the
desired shelf life or in use stability can be achieved by the
presence of Tapentadol itself. For that purpose, the concentration
of Tapentadol is preferably at least 10 mg/mL, based on the total
volume of the composition.
[0015] It has been found, however, that in diluted solutions the
dissolved Tapentadol tends to decomposition having a negative
impact on storage stability of parenteral formulations at such low
concentrations of Tapentadol.
[0016] It is an object of the invention to provide parenteral
formulations of Tapentadol that have advantages compared to the
parenteral formulations of Tapentadol of the prior art. The
parenteral formulations should contain Tapentadol or
physiologically acceptable salts thereof at comparatively low
concentrations but at the same time should have a good storage
stability and shelf life.
[0017] This object has been achieved by the subject-matter of the
patent claims.
[0018] It has been surprisingly found that in diluted solutions at
pH values in the range of 6 to 7.5 the otherwise chemically very
stable pharmacologically active ingredient Tapentadol is subject to
inacceptable chemical degradation. The inventors have unexpectedly
found that chemical stability can be substantially improved by
lowering the pH value and by increasing the buffer capacity in
order to provide an adjusted and robustly maintained pH value.
While conventional diluted solutions of Tapentadol are instable and
show a successive increase of the pH value after autoclaving and
long-term storage, the pH value of the composition according to the
invention remains substantially unchanged.
[0019] Therefore, it has been surprisingly found that at
comparative low concentrations of Tapentadol below 8.0 mg/mL,
especially below 5.0 mg/mL, particularly at concentrations of about
1.0 mg/mL, lowering the pH value of the pharmaceutical composition
for parenteral administration has a stabilizing effect so that
decomposition (degradation) of Tapentadol can be significantly
reduced or even suppressed, also under stress conditions after
repeated autoclaving. Thus, it appears that under certain
conditions antimicrobial effect of Tapentadol on the one hand (cf.
WO 2012/119728) and chemical stability of Tapentadol on the other
hand are both function of the pH value but in opposite
directions.
[0020] Further, it has been surprisingly found that even at pH
values of the composition within the range of from 4.0 to 6.0 and
even at such comparative low concentrations of Tapentadol, stable
pharmaceutical compositions for parenteral administration can be
provided that need neither a preservative nor an antioxidant and
are nevertheless storage stable for a long period of time. This is
particularly surprising, as the antimicrobial effect of Tapentadol
itself is a function of its concentration and of the pH value such
that the antimicrobial effect of Tapentadol should principally
decrease when its concentration and the pH value are comparatively
low.
[0021] Still further, it has been surprisingly found that the
composition remains chemically stable under the harsh conditions of
autoclaving, e.g. for at least 20 min at 2 bar and 121.degree. C.
Thus, the storage stability of the composition according to the
invention does not need to rely on the antimicrobial effect of
Tapentadol alone. Autoclaving achieves sufficient storage stability
against antimicrobial decontamination without the need for
preservatives.
[0022] Furthermore, it has been surprisingly found that Tapentadol
may be sufficiently stabilized against chemical decomposition by
degassing and providing the composition under an inert gas
atmosphere, respectively, e.g. by means of degassing with nitrogen
purge. The use of antioxidants can thus be avoided.
[0023] A first aspect of the invention relates to a stable aqueous
pharmaceutical composition for parenteral administration comprising
Tapentadol or a physiologically acceptable salt thereof, wherein
the concentration of Tapentadol is within the range of from 0.10 to
8.00 mg/mL, preferably within the range of from 0.10 to 5.00 mg/mL,
more preferably within the range of from 0.50 to 1.50 mg/mL, based
on the weight of Tapentadol free base and based on the total volume
of the composition; wherein the pH value of the composition is
buffered, preferably by a citrate buffer, and wherein the pH value
is within the range of from 4.0 to 6.0, preferably within the range
of from 4.5 to 5.5, in particular before and after autoclaving.
Thus, preferably the composition according to the invention has
undergone autoclaving, preferably at least for at least 20 minutes
at least at 2 bar and at least at 121.degree. C., and the pH value
before autoclaving as well as the pH value after autoclaving is
independently within the range of from 4.0 to 6.0, preferably
within the range of from 4.5 to 5.5.
[0024] The term "pharmaceutical composition" includes any
pharmaceutical preparation or formulation that is customized for
being administered to a human being or animal. Preferably, the
composition is an aqueous solution.
[0025] Unless expressly stated otherwise, all percentages are
weight percent, relative to the total weight of the pharmaceutical
composition according to the invention.
[0026] Unless expressly stated otherwise, all values in mL refer to
the total volume of the pharmaceutical composition according to the
invention.
[0027] Unless expressly stated otherwise, parameters and conditions
(such as temperature, pressure, relative humidity, volume, weight,
concentration, pH value, titration acidity, buffer capacity,
osmolarity, content of molecular oxygen, storage stability, color,
and the like) are determined and measured in accordance with the
requirements and recommendations as set forth in the European
Pharmacopoeia (Ph. Eur.). Unless expressly stated otherwise, all
references to Ph. Eur. refer to the version that is officially
valid in March 2015. General conditions are typically ambient
conditions.
[0028] For the purpose of the specification, the term "Tapentadol"
includes the free base
((1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol) as
well as any physiologically acceptable salt thereof, particularly
the hydrochloride
((1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
hydrochloride).
[0029] Thus, unless expressly stated otherwise, the term
"Tapentadol" does not only refer to the free base but also to any
physiologically acceptable salt. Further, unless expressly stated
otherwise, all amounts, contents and concentrations are equivalents
related to Tapentadol free base.
[0030] Preferably, Tapentadol is present in the composition
according to the invention as Tapentadol hydrochloride. In a
preferred embodiment, Tapentadol is present as solubilized
Tapentadol hydrochloride salt form A. Form A of Tapentadol
hydrochloride is known from the prior art. In this regard, it can
be referred to e.g. US 2007/0213405. Preferably, form A is
characterized by showing at least one or more X-ray lines (2-theta
values) in a powder diffraction pattern when measured using Cu
K.alpha. radiation selected from the list comprising 15.1.+-.0.2,
16.0.+-.0.2, 18.9.+-.0.2, 20.4.+-.0.2, 22.5.+-.0.2, 27.3.+-.0.2,
29.3.+-.0.2 and 30.4.+-.0.2
[0031] The concentration of Tapentadol is within the range of from
0.10 to 8.00 mg/mL, preferably within the range of from 0.10 to
5.00 mg/mL, more preferably within the range of from 0.50 to 1.50
mg/mL, based on the weight of Tapentadol free base and based on the
total volume of the composition. In preferred embodiments, said
concentration is within the range of 1.0.+-.0.8 mg/mL, or
1.0.+-.0.7 mg/mL, or 1.0.+-.0.6 mg/mL, or 1.0.+-.0.5 mg/mL, or
1.0.+-.0.4 mg/mL, or 1.0.+-.0.3 mg/mL, or 1.0.+-.0.2 mg/mL, or
1.0.+-.0.1 mg/mL.
[0032] The composition according to the invention is aqueous, i.e.
the composition comprises water which is typically water for
injection purposes, i.e. highly pure and sterile water.
[0033] Preferably, the water content is at least 50 wt.-%, more
preferably at least 60 wt.-%, still more preferably at least 70
wt.-%, yet more preferably at least 80 wt.-%, most preferably at
least 85 wt.-% and in particular at least 90 wt.-%, based on the
total weight of the composition.
[0034] Preferably, the water content is at least 95 wt.-%, more
preferably at least 96 wt.-%, still more preferably at least 97
wt.-%, yet more preferably at least 98 wt.-%, most preferably at
least 99 wt.-% and in particular at least 99.5 wt.-%, based on the
total weight of the composition.
[0035] In preferred embodiments, the water content is within the
range of from 99.020.+-.0.970 wt.-%, or 99.020.+-.0.900 wt.-%, or
99.020.+-.0.800 wt.-%, or 99.020.+-.0.700 wt.-%, or 99.020.+-.0.600
wt.-%, or 99.020.+-.0.500 wt.-%, or 99.020.+-.0.400 wt.-%, or
99.020.+-.0.300 wt.-%, based on the total weight of the
composition.
[0036] Besides water, the composition according to the invention
may contain further solvents.
[0037] Further suitable solvents include all types of
physiologically acceptable hydrophilic solvents, preferably
selected from the group consisting of ethanol, glycerol, propylene
glycol, 1,3-butanediol and macrogol 300.
[0038] Preferably, however, the composition according to the
invention does not contain further solvents besides water.
[0039] The pH value of the composition according to the invention
is buffered, i.e. the composition comprises a buffer (i.e. a pair
of conjugate acid and conjugate base).
[0040] Preferred buffers are derived from the following acids:
organic acids such as acetic acid, propionic acid, maleic acid,
fumaric acid, lactic acid, malonic acid, malic acid, mandelic acid,
citric acid, tartric acid, succinic acid; or inorganic acids such
as phosphoric acid. When the buffer is derived from any of the
above acids, the buffer constitutes of said acid and its conjugate
base(s). Buffers derived from acetic acid, citric acid, lactic
acid, succinic acid or phosphoric acid are particularly
preferred.
[0041] A skilled person is fully aware that multiprotonic acids can
form more than a single pair of a conjugate acid and a conjugate
base. For example, citric acid is a triprotonic acid so that it
forms the following pairs of conjugate acid and conjugate base: (i)
citric acid-dihydrogencitrate, (ii)
dihydrogencitrate-hydrogencitrate, (iii) and
hydrogencitrate-citrate. In other words, any of citric acid,
dihydrogencitrate and hydrogencitrate can be the acid of a buffer
with the conjugate base. A skilled person is also fully aware that
the conjugate acids and conjugate bases are in equilibrium with one
another and that the predominant species that are present in a
mixture of citrate, hydrogencitrate, dihydrogencitrate and citric
acid can be determined on the basis of the pK.sub.A values and the
pH value of the composition.
[0042] For the purpose of the specification, the expression
"buffer" refers to the total quantity of conjugate acids and
conjugate bases. For example, when the buffer is derived from
citric acid, i.e. is a citrate buffer, the expression "buffer"
refers to the total quantity of citrate, hydrogencitrate,
dihydrogencitrate and citric acid.
[0043] Further, a skilled person is fully aware that a buffer, e.g.
citric acid as conjugate acid and sodium dihydrogencitrate as
conjugate base, can be established either by adding citric acid and
an appropriate amount of sodium hydroxide, or sodium citrate and an
appropriate amount of hydrochloric acid, or citric acid and sodium
dihydrogencitrate as such. Unless expressly stated otherwise,
"sodium citrate" is synonymous to "trisodium citrate". Sodium
citrate dihydrate (=trisodium citrate dihydrate) thus has the
linear formula HOC(COONa)(CH.sub.2COONa).sub.2.2H.sub.2O and a
relative molecular weight of 294.10 g/mol.
[0044] Accordingly, in case that the composition contains an
appropriate amount of Tapentadol in form of its hydrochloride, a
buffer can be established by adding sodium citrate, e.g. in form of
sodium citrate dihydrate. Nevertheless, Tapentadol and its
physiologically acceptable salts are not to be considered as
conjugate acid or conjugate base of the buffer.
[0045] Preferably, the concentration of the buffer, preferably
sodium citrate or its dihydrate, is adjusted to provide a
sufficient buffer capacity.
[0046] It has been surprisingly found that by adjusting the content
of buffer in the pharmaceutical composition, the shelf life can be
substantially improved, particularly the chemical stability of
Tapentadol in the composition at its comparatively low
concentrations, particularly also under conditions of autoclaving.
It has been found that an optimal buffer concentration can be found
that on the one hand provides sufficient stability of the
composition, but that on the other had does not entrain significant
amounts of material into the organism to be treated and does not
significantly change the pH value of the body fluids of the
organism to be treated.
[0047] Preferably, the composition according to the invention
comprises a buffer comprising one or more conjugate bases and one
or more conjugate acids selected from the group consisting of
citrate, hydrogencitrate, dihydrogencitrate and citric acid.
[0048] In preferred embodiments, the composition according to the
invention comprises a buffer comprising one or more conjugate bases
and one or more conjugate acids and having a concentration of at
least 0.015 wt.-%, more preferably at least 0.020 wt.-%, still more
preferably at least 0.025 wt.-%, and most preferably at least 0.030
wt.-%, based on the total weight of the one or more conjugate bases
and the one or more conjugate acids and based on the total weight
of the composition.
[0049] In preferred embodiments, the composition according to the
invention comprises a buffer comprising one or more conjugate bases
and one or more conjugate acids and having a concentration of not
more than 0.055 wt.-%, more preferably not more than 0.050 wt.-%,
still more preferably not more than 0.045 wt.-%, yet more
preferably not more than 0.040 wt.-%, and most preferably not more
than 0.035 wt.-%, based on the total weight of the one or more
conjugate bases and the one or more conjugate acids and based on
the total weight of the composition.
[0050] In preferred embodiments, the composition according to the
invention comprises a buffer comprising one or more conjugate bases
and one or more conjugate acids and having a concentration within
the range of from 0.015 to 0.055 wt.-%, more preferably within the
range of from 0.020 to 0.050 wt.-%, still more preferably within
the range of from 0.025 to 0.045 wt.-%, most preferably within the
range of from 0.030 to 0.045 wt.-%, based on the total weight of
the one or more conjugate bases and the one or more conjugate acids
and based on the total weight of the composition.
[0051] In a preferred embodiment, the content of the buffer,
preferably sodium citrate or its dihydrate, is within the range of
from 0.020.+-.0.018 wt.-%, or 0.020.+-.0.016 wt.-%, or
0.020.+-.0.014 wt.-%, or 0.020.+-.0.012 wt.-%, or 0.020.+-.0.010
wt.-%, or 0.020.+-.0.008 wt.-%, or 0.020.+-.0.006 wt.-%, or
0.020.+-.0.004 wt.-%, based on the total weight of the one or more
conjugate bases and the one or more conjugate acids and based on
the total weight of the composition.
[0052] In another preferred embodiment, the content of the buffer,
preferably sodium citrate or its dihydrate, is within the range of
from 0.030.+-.0.018 wt.-%, or 0.030.+-.0.016 wt.-%, or
0.030.+-.0.014 wt.-%, or 0.030.+-.0.012 wt.-%, or 0.030.+-.0.010
wt.-%, or 0.030.+-.0.008 wt.-%, or 0.030.+-.0.006 wt.-%, or
0.030.+-.0.004 wt.-%, based on the total weight of the one or more
conjugate bases and the one or more conjugate acids and based on
the total weight of the composition.
[0053] In still another preferred embodiment, the content of the
buffer, preferably sodium citrate or its dihydrate, is within the
range of from 0.040.+-.0.035 wt.-%, or 0.040.+-.0.030 wt.-%, or
0.040.+-.0.025 wt.-%, or 0.040.+-.0.020 wt.-%, or 0.040.+-.0.015
wt.-%, or 0.040.+-.0.010 wt.-%, or 0.040.+-.0.005 wt.-%, based on
the total weight of the one or more conjugate bases and the one or
more conjugate acids and based on the total weight of the
composition.
[0054] In yet another preferred embodiment, the content of the
buffer, preferably sodium citrate or its dihydrate, is within the
range of from 0.060.+-.0.035 wt.-%, or 0.060.+-.0.030 wt.-%, or
0.060.+-.0.025 wt.-%, or 0.060.+-.0.020 wt.-%, or 0.060.+-.0.015
wt.-%, or 0.060.+-.0.010 wt.-%, or 0.060.+-.0.005 wt.-%, based on
the total weight of the one or more conjugate bases and the one or
more conjugate acids and based on the total weight of the
composition.
[0055] In still another preferred embodiment, the content of the
buffer, preferably sodium citrate or its dihydrate, is within the
range of from 0.080.+-.0.035 wt.-%, or 0.080.+-.0.030 wt.-%, or
0.080.+-.0.025 wt.-%, or 0.080.+-.0.020 wt.-%, or 0.080.+-.0.015
wt.-%, or 0.080.+-.0.010 wt.-%, or 0.080.+-.0.005 wt.-%, based on
the total weight of the one or more conjugate bases and the one or
more conjugate acids and based on the total weight of the
composition.
[0056] In a particularly preferred embodiment, the content of the
buffer, preferably sodium citrate or its dihydrate, is within the
range of from 0.032.+-.0.030 wt.-%, 0.032.+-.0.026 wt.-%,
0.032.+-.0.024 wt.-%, 0.032.+-.0.020 wt.-%, 0.032.+-.0.016 wt.-%,
0.032.+-.0.012 wt.-%, 0.032.+-.0.008 wt.-%, 0.032.+-.0.004 wt.-%,
based on the total weight of the one or more conjugate bases and
the one or more conjugate acids and based on the total weight of
the composition.
[0057] When the buffer is neither sodium citrate nor its dihydrate,
but a different buffer, the content of said different buffer
preferably amounts to an equivalent content that is necessary to
achieve the same buffer capacity at the given pH value as if the
buffer would be sodium citrate or its dihydrate in the above
content in wt.-%.
[0058] In preferred embodiments, the composition according to the
invention comprises a buffer comprising one or more conjugate bases
and one or more conjugate acids and having a concentration of at
least 0.5 mmol/L, more preferably at least 0.6 mmol/L, still more
preferably at least 0.7 mmol/L, yet more preferably at least 0.8
mmol/L, and most preferably at least 0.9 mmol/L, based on the total
content of the one or more conjugate bases and the one or more
conjugate acids and based on the total volume of the
composition.
[0059] In preferred embodiments, the composition according to the
invention comprises a buffer comprising one or more conjugate bases
and one or more conjugate acids and having a concentration of not
more than 1.5 mmol/L, more preferably not more than 1.4 mmol/L,
still more preferably not more than 1.3 mmol/L, and most preferably
not more than 1.2 mmol/L, based on the total content of the one or
more conjugate bases and the one or more conjugate acids and based
on the total volume of the composition.
[0060] In preferred embodiments, the composition according to the
invention comprises a buffer comprising one or more conjugate bases
and one or more conjugate acids and having a concentration within
the range of from 0.5 to 1.5 mmol/L, more preferably within the
range of from 0.6 to 1.4 mmol/L, still more preferably within the
range of from 0.7 to 1.3 mmol/L, and most preferably within the
range of from 0.8 to 1.2 mmol/L, based on the total content of the
one or more conjugate bases and the one or more conjugate acids and
based on the total volume of the composition
[0061] The buffered pH value of the composition according to the
invention is within the range of from 4.0 to 6.0, preferably within
the range of from 4.5 to 5.5.
[0062] In a preferred embodiment, the composition has a buffered pH
value within the range of 4.5.+-.0.5, more preferably 4.5.+-.0.4,
still more preferably 4.5.+-.0.3, yet more preferably 4.5.+-.0.2,
and in particular 4.5.+-.0.1.
[0063] In another preferred embodiment, the composition has a
buffered pH value within the range of 5.0.+-.1.0, more preferably
5.0.+-.0.9, still more preferably 5.0.+-.0.8, yet more preferably
5.0.+-.0.7, even more preferably 5.0.+-.0.6 or 5.0.+-.0.5, most
preferably 5.0.+-.0.4 or 5.0.+-.0.3, and in particular 5.0.+-.0.2
or 5.0.+-.0.1.
[0064] In still another preferred embodiment, the composition has a
buffered pH value within the range of 5.5.+-.0.5, more preferably
5.5.+-.0.4, still more preferably 5.5.+-.0.3, yet more preferably
5.5.+-.0.2, and in particular 5.5.+-.0.1.
[0065] Preferably, the content of molecular oxygen of the
composition, i.e. the content of dissolved molecular oxygen, is not
more than 9.0 mg/L, more preferably not more than 7.0 mg/L, still
more preferably not more than 5.0 mg/L, yet more preferably not
more than 3.0 mg/L, and most preferably not more than 1.0 mg/L,
based on the total volume of the composition.
[0066] Preferably, the content of molecular oxygen in the
composition is not more than 0.2 mg/L, more preferably 0.1 mg/L,
still more preferably 0.05 mg/L, based on the total volume of the
composition.
[0067] In preferred embodiments, the content of molecular oxygen in
the composition is not more than 0.20 mg/L, or 0.18 mg/L, or 0.16
mg/L, or 0.14 mg/L, or 0.12 mg/L, or 0.10 mg/L, or 0.09 mg/L, or
0.08 mg/L, or 0.07 mg/L, or 0.006 mg/L, or 0.05 mg/L, or 0.04 mg/L,
or 0.03 mg/L, or 0.02 mg/L.
[0068] In preferred embodiments, the content of molecular oxygen in
the composition is not more than 0.048 mg/L, or 0.046 mg/L, or
0.044 mg/L, or 0.042 mg/L, or 0.040 mg/L, or 0.038 mg/L, or 0.036
mg/L, or 0.034 mg/L, or 0.032 mg/L, or 0.030 mg/L, or 0.028 mg/L,
or 0.026 mg/L, or 0.024 mg/L, or 0.022 mg/L, or 0.020 mg/L, or
0.018 mg/L, or 0.016 mg/L, or 0.014 mg/L, or 0.012 mg/L, or 0.010
mg/L.
[0069] The composition according to the invention is preferably
packaged in containers, e.g. in glass ampoules. The inner space of
the container typically comprises at least two phases, namely a
liquid phase and a gaseous phase (headspace). As far as the content
of molecular oxygen is concerned, the oxygen content in the liquid
phase and the oxygen content in the headspace are typically
equilibrated. Thus, measuring the content of molecular oxygen in
the gaseous phase of the headspace allows drawing conclusions also
concerning the content of dissolved molecular oxygen of the liquid
phase, i.e. the aqueous composition as such.
[0070] In preferred embodiments--when filling 2.0 ml of the
composition into a closed glass ampoule having an inner volume of
3.0 ml and containing pure nitrogen gas such that the filled
ampoule comprises the composition as a liquid phase and a gaseous
phase in a headspace above the liquid phase, and allowing the gas
dissolved in the liquid phase and the gas in the gaseous phase to
equilibrate--the gaseous phase has a content of molecular oxygen of
not more than 2.5% Vbar, more preferably not more than 2.4% Vbar,
still more preferably not more than 2.3% Vbar, yet more preferably
not more than 2.2% Vbar, even more preferably not more than 2.1%
Vbar, and most preferably not more than 2.0% Vbar. In preferred
embodiments, under the given conditions, the gaseous phase has
preferably a content of molecular oxygen of not more than 1.8%
Vbar, more preferably not more than 1.6% Vbar, still more
preferably not more than 1.4% Vbar, yet more preferably not more
than 1.2% Vbar, even more preferably not more than 1.0% Vbar, and
most preferably not more than 0.8% Vbar.
[0071] Suitable methods for adjusting and determining the oxygen
content of aqueous pharmaceutical compositions are known to the
skilled person and suitable measuring devices are commercially
available. The oxygen content can be reduced by purging the
composition with an inert gas such as nitrogen and/or by subjecting
the composition to reduced pressure and/or by purging the headspace
of the composition with an inert gas such as nitrogen. Preferably,
the oxygen content in the headspace is determined by means of an
electrochemical oxygen sensor, e.g. a Head Space Analyzer
Orbisphere 510, Hach Lange.
[0072] It has been surprisingly found that by reducing the oxygen
content of the pharmaceutical composition, the shelf life can be
substantially improved, particularly the chemical stability of
Tapentadol in the composition at its comparatively low
concentrations.
[0073] The osmolarity of the composition depends on the content of
its constituents and is preferably adjusted during the manufacture
of the composition by the addition of an appropriate amount of an
isotonizing agent, preferably sodium chloride. Other isotonizing
agents such as mannitol or sorbitol can also be added alternatively
or additionally. Ionic isotonizing agents are preferred.
[0074] Thus, preferably the composition according to the invention
comprises an isotonizing agent, more preferably sodium
chloride.
[0075] Preferably, the content of the sodium chloride is not more
than 1.0 wt.-%, more preferably not more than 0.8 wt.-%, still more
preferably not more than 0.6 wt.-%, yet more preferably not more
than 0.4 wt.-%, most preferably not more than 0.2 wt.-%, and in
particular not more than 0.1 wt.-%, based on the total weight of
the composition.
[0076] In preferred embodiments, the content of the sodium chloride
is within the range of from 0.848.+-.0.800 wt.-%, or 0.848.+-.0.700
wt.-%, or 0.848.+-.0.600 wt.-%, or 0.848.+-.0.500 wt.-%, or
0.848.+-.0.400 wt.-%, or 0.848.+-.0.300 wt.-%, or 0.848.+-.0.200
wt.-%, or 0.848.+-.0.100 wt.-%, based on the total weight of the
composition.
[0077] Preferably, the composition according to the invention does
not contain any preservative. For the purpose of the specification,
a "preservative" preferably refers to any substance that is usually
added to pharmaceutical compositions in order to preserve them
against microbial degradation or microbial growth. In this regard,
microbial growth typically plays an essential role, i.e. the
preservative serves the main purpose of avoiding microbial
contamination. As a side aspect, it may also be desirable to avoid
any effect of the microbes on the active ingredients and
excipients, respectively, i.e. to avoid microbial degradation.
[0078] Representative examples of preservatives include
benzalkonium chloride, benzethonium chloride, benzoic acid, sodium
benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium
chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol,
cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol,
phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,
propylene glycol, sodium propionate, thimerosal, methyl paraben,
ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben,
benzyl paraben, sorbic acid, and potassium sorbate.
[0079] Preferably, the composition according to the invention does
not contain any chelating agents such as EDTA or its sodium or
calcium salts. However, the composition according to the invention
may contain a citrate buffer and under these circumstances, citric
acid and its salts are to be considered as a buffer and not as a
chelating agent, though it is known that citric acid and its salt
also have a certain degree of chelating capacity.
[0080] Preferably, the composition according to the invention does
not contain any antioxidants. Examples of antioxidants that are
preferably not contained in the composition according to the
invention include but are not limited to [0081] propyl, octyl and
dodecylesters of gallic acid, [0082] butylated hydroxyanisole
(BHA), butylated hydroxytoluene (BHT), [0083] ascorbic acid, sodium
ascorbate, [0084] monothioglycerol, [0085] potassium or sodium
metabisulfite, [0086] propionic acid, [0087] propyl gallate, [0088]
sodium bisulfite, sodium sulfite, and [0089] the tocopherols or
vitamin E.
[0090] Preferably, the composition according to the invention
contains neither any preservative nor any antioxidant.
[0091] In a preferred embodiment, the composition according to the
invention essentially consists of Tapentadol, buffer, isotonizing
agent and water.
[0092] Particularly preferred embodiments A.sup.1 to A.sup.8 of the
composition according to the invention are summarized in the table
here below:
TABLE-US-00001 A.sup.1 A.sup.2 A.sup.3 A.sup.4 Tapentadol [mg/mL]
1.0 .+-. 0.8 1.0 .+-. 0.7 1.0 .+-. 0.6 1.0 .+-. 0.5 buffer [wt.-%]
0.032 .+-. 0.030 0.032 .+-. 0.026 0.032 .+-. 0.024 0.032 .+-. 0.020
sodium chloride [wt.-%] 0.848 .+-. 0.800 0.848 .+-. 0.700 0.848
.+-. 0.600 0.848 .+-. 0.500 water [wt.-%] 99.020 .+-. 0.970 99.020
.+-. 0.900 99.020 .+-. 0.800 99.020 .+-. 0.700 oxygen headspace [%
Vbar] .ltoreq.2.5% .ltoreq.2.4% .ltoreq.2.3% .ltoreq.2.2% pH value
5.0 .+-. 1.0 5.0 .+-. 0.9 5.0 .+-. 0.8 5.0 .+-. 0.7 A.sup.5 A.sup.6
A.sup.7 A.sup.8 Tapentadol [mg/mL] 1.0 .+-. 0.4 1.0 .+-. 0.3 1.0
.+-. 0.2 1.0 .+-. 0.1 buffer [wt.-%] 0.032 .+-. 0.016 0.032 .+-.
0.012 0.032 .+-. 0.008 0.032 .+-. 0.004 sodium chloride [wt.-%]
0.848 .+-. 0.400 0.848 .+-. 0.300 0.848 .+-. 0.200 0.848 .+-. 0.100
water [wt.-%] 99.020 .+-. 0.600 99.020 .+-. 0.500 99.020 .+-. 0.400
99.020 .+-. 0.300 oxygen headspace [% Vbar] .ltoreq.2.1%
.ltoreq.2.1% .ltoreq.2.0% .ltoreq.2.0% pH value 5.0 .+-. 0.6 5.0
.+-. 0.6 5.0 .+-. 0.5 5.0 .+-. 0.5
[0093] Preferably, the composition according to the invention has a
titration acidity of not more than 1.8 mmol/L, more preferably not
more than 1.7 mmol/L, still more preferably not more than 1.6
mmol/L, yet more preferably not more than 1.5 mmol/L, and most
preferably not more than 1.4 mmol/L.
[0094] Preferably, the composition according to the invention has a
titration acidity within the range of from 1.0 to 1.8 mmol/L, more
preferably 1.4 to 1.8 mmol/L. Especially in pediatric patients
titration acidity is an important parameter in view of the lower
blood volume.
[0095] Preferably, titration acidity is determined at a CO.sub.2
partial pressure of 0 mm Hg under Argon at 37.degree. C. When
titrating the composition according to the invention under these
conditions with 0.01 M NaOH up to an endpoint of pH 7.4.
[0096] In a preferred embodiment, particularly when the composition
has a pH value within the range of 5.0.+-.0.5, the titration
acidity is preferably within the range of 1.20.+-.0.20 mmol/L, more
preferably 1.20.+-.0.10 mmol/L.
[0097] In another preferred embodiment, particularly when the
composition has a pH value within the range of 4.5.+-.0.5, the
titration acidity is preferably within the range of 1.60.+-.0.20
mmol/L, more preferably 1.60.+-.0.10 mmol/L.
[0098] In order to satisfy high quality requirements for infusion
and injection solutions, respectively, the composition has to
exhibit a physiologically acceptable osmolarity and a
physiologically acceptable pH.
[0099] Isotonic sodium chloride solution (saline), for instance,
contains 0.9 wt.-% of sodium chloride and exhibits an osmolarity of
0.308 osmol/L, which is close to the osmolarity of blood.
[0100] Preferably, the composition has an osmolarity of at least
0.20 or at least 0.22 osmol/L, more preferably of at least 0.23
osmol/L, still more preferably of at least 0.24 osmol/L, yet more
preferably of at least 0.25 osmol/L, most preferably of at least
0.26 osmol/L, and in particular of at least 0.27 osmol/L.
[0101] Preferably, the composition has an osmolarity of not more
than 0.36 osmol/L, more preferably of not more than 0.34 osmol/L,
still more preferably of not more than 0.32 osmol/L, yet more
preferably of not more than 0.31 osmol/L, most preferably of not
more than 0.30 osmol/L and in particular of not more than 0.29
osmol/L.
[0102] In preferred embodiments, the composition has an osmolarity
of 0.28.+-.0.08 osmol/L, more preferably of 0.28.+-.0.06 osmol/L,
still more preferably of 0.28.+-.0.04 osmol/L, yet more preferably
of 0.28.+-.0.03 osmol/L, most preferably of 0.28.+-.0.02 osmol/L,
and in particular of 0.28.+-.0.01 osmol/L.
[0103] Another aspect of the invention relates to a container
comprising the pharmaceutical composition according to the
invention, wherein the container is preferably a closed and
airtight container. All preferred embodiments that have been
defined above in connection with the composition according to the
invention analogously also apply to the container according to the
invention.
[0104] The container according to the invention comprises a
distinct volume of the composition according to the invention that
is adapted for parenteral administration to the patient. As the
aqueous composition according to the invention is typically liquid,
it is preferably provided in a container. Prior to parenteral
administration, the composition according to the invention is then
removed, completely (single dosage) or partially (multiple dosage)
from the container.
[0105] Preferably, the container is a glass ampoule. Preferably,
the container is made from glass of quality type I that satisfies
the requirements of Ph. Eur. for parenteral formulations.
[0106] Preferably, the container comprises the composition as a
liquid phase and a gaseous phase in a headspace above the liquid
phase, wherein the gaseous phase has a content of molecular oxygen
of not more than 2.5% Vbar, more preferably not more than 2.4%
Vbar, still more preferably not more than 2.3% Vbar, yet more
preferably not more than 2.2% Vbar, even more preferably not more
than 2.1% Vbar, and most preferably not more than 2.0% Vbar. In
preferred embodiments, under the given conditions, the gaseous
phase has preferably a content of molecular oxygen of not more than
1.8% Vbar, more preferably not more than 1.6% Vbar, still more
preferably not more than 1.4% Vbar, yet more preferably not more
than 1.2% Vbar, even more preferably not more than 1.0% Vbar, and
most preferably not more than 0.8% Vbar.
[0107] The container according to the invention may comprise a
single dose of Tapentadol or may be multiple dosed. For the purpose
of the specification "multiple dosed" preferably means that the
container encompasses more than a single dosage unit.
[0108] In a preferred embodiment, the container contains the
composition according to the invention in a quantity exceeding a
single administration dose (dosage unit). Under these
circumstances, the container comprises multiple dosage units, i.e.
is customized for more than a single administration, preferably by
injection.
[0109] For example, when the container comprises a multiple dosed
injection solution, its overall volume is more than the volume that
is to be typically administered at once. Instead, the multiple
dosed injection solution is customized for being divided into a
multitude of dosage units that are to be administered over a
treatment interval typically encompassing several days. The
individual dosage units may preferably be separated from the
multiple dosage unit by means of a syringe. A typical example for a
container according to the invention that comprises multiple dosage
units is a preferably sterilized glass container sealed with a
septum. Said glass container contains a volume of the
pharmaceutical composition well exceeding the individual volume of
an individual dosage unit that is intended for at once
administration to the patient. For example, when the container has
a total volume of 250 mL and the prescribed dosage unit is 25 mL
once daily, at day 1 of the treatment interval the patient takes 25
mL so that 225 mL remain in the container; at day 2 of the
treatment interval the patient takes another 25 mL so that 200 mL
remain in the container; and so on, until at day 10 the entire
amount is taken by the patient.
[0110] Preferably, the container contains at least 2, more
preferably at least 3, even more preferably at least 5, yet more
preferably at least 10, most preferably at least 12, and in
particular at least 15 individual dosage units.
[0111] In another preferred embodiment, the container comprises a
single dosage unit, i.e. only one individual dosage unit. Under
these circumstances, the container preferably comprises from 1.0 to
3.0 mL of the composition.
[0112] Preferably, the individual dosage units have a volume of
0.25 mL to 3.0 mL, more preferably of 0.5 mL to 2.75 mL, still more
preferably of 0.75 mL to 2.5 mL, and most preferably of 1.0 mL to
2.0 mL.
[0113] In a preferred embodiment, the individual dosage units have
a volume of 1.0.+-.0.9 mL, more preferably of 1.0.+-.0.75 mL, still
more preferably 1.0.+-.0.5 mL, yet more preferably of 1.0.+-.0.4
mL, even more preferably of 1.0.+-.0.2 mL, most preferably of
1.0.+-.0.15 mL, and in particular of 1.0.+-.0.1 mL.
[0114] In another preferred embodiment, the individual dosage units
have a volume of 2.0.+-.0.9 mL, more preferably of 2.0.+-.0.75 mL,
still more preferably 2.0.+-.0.5 mL, yet more preferably of
2.0.+-.0.4 mL, even more preferably of 2.0.+-.0.2 mL, most
preferably of 2.0.+-.0.15 mL, and in particular of 2.0.+-.0.1
mL.
[0115] In still another preferred embodiment, the individual dosage
units have a volume of 3.0.+-.0.9 mL, more preferably of
3.0.+-.0.75 mL, still more preferably 3.0.+-.0.5 mL, yet more
preferably of 3.0.+-.0.4 mL, even more preferably of 3.0.+-.0.2 mL,
most preferably of 3.0.+-.0.15 mL, and in particular of 3.0.+-.0.1
mL.
[0116] The one or more individual dosage units that are contained
in the container may be customized for administration once, twice,
thrice, four times, five times, six times or even more frequently,
optionally in regular time intervals.
[0117] The composition that is contained in the container may also
be customized for a continual administration, preferably by
infusion. Preferably, the composition that is contained in the
container is adapted for a continual administration for at least 30
minutes or 45 minutes, more preferably for at least 1 h or 2 h,
still more preferably for at least 3 h or 4 h, yet more preferably
for at least 6 h or 8 h, most preferably for at least 10 h, and in
particular for at least 12 h.
[0118] Tapentadol is administered in a therapeutically effective
amount. The amount that constitutes a therapeutically effective
amount varies according to the condition being treated, the
severity of said condition and the patient being treated.
[0119] Preferably, the amount of Tapentadol that is contained in
the individual dosage unit is preferably within the range of from
0.2 to 0.6 mg/kg body weight.
[0120] In a preferred embodiment, the amount of Tapentadol that is
contained in the individual dosage unit is preferably within the
range of from 10 mg to 250 mg, more preferably within the range of
from 15 mg to 200 mg, still more preferably within the range of
from 20 mg to 150 mg, yet more preferably within the range of from
30 mg to 130 mg, and most preferably within the range of from 40 mg
to 115 mg, and in particular within the range of from 50 mg to 100
mg.
[0121] In another preferred embodiment, the amount of Tapentadol
that is contained in the individual dosage unit is preferably
within the range of from 0.1 mg to 60 mg, more preferably within
the range of from 0.1 mg to 55 mg, still more preferably within the
range of from 0.2 mg to 50 mg.
[0122] Preferably, the container according to the invention
comprises Tapentadol in an amount within the range of from 1.00 mg
to 3.00 mg, based on the weight of Tapentadol free base.
[0123] Preferably, the daily dose of Tapentadol is not more than
250 mg, more preferably not more than 225 mg, yet more preferably
not more than 200 mg, still more preferably not more than 175 mg,
and in particular not more than 150 mg.
[0124] Preferably, the daily dose of Tapentadol is at least 15 mg,
more preferably at least 20 mg, yet more preferably at least 25 mg,
still more preferably at least 30 mg, most preferably at least 35
mg, and in particular at least 40 mg.
[0125] The composition according to the invention, particularly
when it is contained in the container according to the invention,
has an excellent shelf life and storage stability. Thus,
preferably, the composition according to the invention is stable
upon storage.
[0126] Preferably, the composition according to the invention is
stable upon storage under accelerated storage conditions at
40.degree. C. and 75% relative humidity for at least 3 months, more
preferably at least 6 months. Preferably, stability criteria are in
accordance with Ph. Eur. and EMEA guidelines, respectively,
preferably according to the edition that is valid in March
2015.
[0127] In preferred embodiments, the pH value of the composition
after storage under accelerated storage conditions at 40.degree. C.
and 75% relative humidity for at least 3 months, more preferably at
least 6 months, does not relatively differ by more than .+-.0.4 pH
units, more preferably by not more than .+-.0.3 pH units, more
preferably by not more than .+-.0.2 pH units, from the initial pH
value of the composition prior to storage.
[0128] Preferably, the composition is colorless before storage and
after storage under accelerated storage conditions at 40.degree. C.
and 75% relative humidity for at least 3 months, more preferably at
least 6 months. Preferably, the composition is colorless before
storage and during/after storage, in particular during/after a
storage time of more than three months, preferably of more than 6
months, more preferably of more than 12 months, most preferably of
at least for twenty-four months.
[0129] In preferred embodiments, the composition has a content of
decomposition products of Tapentadol after storage under
accelerated storage conditions at 40.degree. C. and 75% relative
humidity for at least 3 months, more preferably at least 6 months,
of not more than 1.0 wt.-%, more preferably not more than 0.9
wt.-%, still more preferably not more than 0.8 wt.-%, yet more
preferably not more than 0.7 wt.-%, even more preferably not more
than 0.6 wt.-%, and most preferably not more than 0.5 wt.-%,
relative to the total content of Tapentadol that was originally
contained in the composition prior to storage and based on the
weight of Tapentadol free base. Decomposition products of
Tapentadol are preferably analyzed by HPLC.
[0130] For the purpose of the specification, it may additionally be
distinguished between shelf life and in-use stability. Shelf life
preferably refers to the storage stability of a closed container.
In-use stability preferably refers to the storage container that
contains a multiple dosage unit preparation which has been utilized
for the first time. Typically, the shelf life of a multiple dosage
unit preparation is much longer than its in-use stability.
Preferably, stability criteria are in accordance with Ph. Eur. and
EMEA guidelines, respectively, preferably according to the edition
that is valid in March 2015.
[0131] Preferably, the composition according to the invention,
particularly when it is contained in the container according to the
invention, exhibits a shelf life under ambient conditions of at
least 6 month, more preferably at least 12 months, still more
preferably at least 15 months, yet more preferably at least 18
months, most preferably at least 21 months and in particular at
least 24 months.
[0132] Preferably, the composition according to the invention,
particularly when it is contained in the container according to the
invention, is provided as a multiple dosage unit preparation that
exhibits an in-use stability under ambient conditions of at least 1
week, more preferably at least 2 weeks, still more preferably at
least 3 weeks, yet more preferably at least 4 weeks, most
preferably at least 5 weeks and in particular at least 6 weeks.
[0133] It has been surprisingly found that even at comparatively
low concentrations of Tapentadol pH value and content of molecular
oxygen can be controlled such that undesired decomposition
reactions of Tapentadol can be reduced. No additional excipients
are needed for stabilization.
[0134] Preferably, the composition according to the invention
exhibits an antimicrobial robustness that complies with the
requirements of the Ph. Eur., preferably in its version for 2010.
Preferably, antimicrobial robustness is achieved against S. aureus,
Ps. Aeruginosa, S. spp., C. albicans, and/or A. niger, preferably
satisfying the requirement of log reduction of 1, preferably 3
after 7 and no increase after 28 days. In a particularly preferred
embodiment, antimicrobial robustness is achieved against bacteria
satisfying the requirement of log reduction of 3 after 14 days and
against molds and yeast of log reduction of 1 after 14 days.
[0135] The composition according to the invention, particularly
when it is contained in the container according to the invention,
exhibits an excellent autoclavability, i.e. it can be subjected to
autoclaving under suitable conditions for a suitable period of time
without causing significant degradation of Tapentadol under the
typically drastic conditions of autoclaving. Preferably, the
composition is stable upon autoclaving and preferably exhibits an
unaltered pH value upon autoclaving.
[0136] Preferably, the composition is stable upon autoclaving for
20 minutes at 121.degree. C. and 2 bar. Preferably, the composition
is stable upon autoclaving for 20 minutes at 121.degree. C. and 2
bar and preferably exhibits an unaltered pH value upon autoclaving
under these conditions.
[0137] Preferably, stability criteria are in accordance with Ph.
Eur. and EMEA guidelines, respectively, preferably according to the
edition that is valid in March 2015.
[0138] In preferred embodiments, the composition according to the
invention, particularly when it is contained in the container
according to the invention, has a content of decomposition products
of Tapentadol after autoclaving of not more than 0.05 wt.-%, more
preferably not more than 0.04 wt.-%, and most preferably not more
than 0.03 wt.-%, relative to the total content of Tapentadol that
was originally contained in the composition prior to autoclaving
and based on the weight of Tapentadol free base.
[0139] Preferably, the pharmaceutical composition according to the
invention is for use in the treatment of pain.
[0140] Accordingly, a further aspect of the invention relates to a
method for the treatment of pain comprising the parenteral
administration of a therapeutically effective amount of the
pharmaceutical composition according to the invention as described
above, that may be provided in the container according to the
invention as described above, to a subject in need thereof.
[0141] Furthermore, the invention also relates to the use of
Tapentadol or a physiologically acceptable salt thereof for the
manufacture of the pharmaceutical composition according to the
invention as described above or of the container containing the
pharmaceutical composition according to the invention as described
above, for the treatment of pain. Preferably, Tapentadol is
employed as Tapentadol hydrochloride polymorph form A. Form A of
Tapentadol hydrochloride is known from the prior art. In this
regard, it can be referred to e.g. US 2007/0213405. Form A is
preferably characterized by showing at least one or more X-ray
lines (2-theta values) in a powder diffraction pattern when
measured using Cu K.alpha. radiation selected from the list
comprising 15.1.+-.0.2, 16.0.+-.0.2, 18.9.+-.0.2, 20.4.+-.0.2,
22.5.+-.0.2, 27.3.+-.0.2, 29.3.+-.0.2 and 30.4.+-.0.2
[0142] The pain may either be chronic pain or acute pain. Acute
pain is preferred.
[0143] Preferably, the pain is selected from the group consisting
of inflammatory pain, neuropathic pain, visceral pain, labor pain,
cancer pain, perioperative and post-operative pain.
[0144] In a preferred embodiment, the pain is cancer pain,
preferably neuropathic pain being induced by the cancer, including
neuropathic pain as a direct result of the cancer on peripheral
nerves, or as a side effect of chemotherapy, surgery or radiation
injury.
[0145] In another preferred embodiment, the pain is perioperative
or post-operative (post-surgical) pain.
[0146] In still another preferred embodiment, the pharmaceutical
composition according to the invention is for use in emergency pain
management.
[0147] Preferably, the composition according to the invention is
for use in the treatment of pain in mammals. Preferably, the
mammals are humans. Preferably, the humans are pediatric
patients.
[0148] For the purpose of the specification, pediatric patients
preferably encompass premature infants, newborn infants, infants,
children up to the age of 2, children, and adolescents. Preferably,
the upper age limit of the pediatric patients is 1, 2, 3, 4, 5, 6,
8, 10, 12, 14, 16 or 17. Preferably, the lower body weight limit of
the pediatric patients is 30 kg or 25 kg, more preferably 20 kg or
15 kg, still more preferably 10 kg or 7.5 kg, yet more preferably 5
kg or 3 kg, most preferably 2 kg or 1 kg, and in particular 500
g.
[0149] In a preferred embodiment, the composition is adapted for
parenteral administration to children having a body weight of 10 to
15 kg, 16 to 20 kg, 21 to 25 kg, 26 to 30 kg, 31 to 35 kg, 36 to 40
kg and/or 41 to 45 kg. In another preferred embodiment, the
composition is adapted for parenteral administration to infants or
children having a body weight of below 0.5 kg, 0.6 kg to 0.9 kg,
1.0 kg to 1.9 kg, 2.0 kg to 2.9 kg, 3.0 kg to 3.9 kg, 4.0 kg to 4.9
kg, 5.0 kg to 5.9 kg, 6.0 kg to 8.0 kg and/or 8.1 kg to 9.9 kg.
[0150] In a preferred embodiment, the pediatric patients are
newborn infants. Preferably, the pharmaceutical composition
according to the invention is for use in the treatment of acute
pain in newborn infants.
[0151] In another preferred embodiment, the pediatric patients are
premature infants. Preferably, the pharmaceutical composition
according to the invention is for use in the treatment of acute
pain in premature infants.
[0152] Preferably, composition according to the invention,
particularly when it is contained in the container according to the
invention, is a parenteral formulation selected from the group
consisting of injection solutions, injection suspensions, infusion
solutions, infusion suspensions, and depot formulations, such as
depot injection solutions, depot injection suspensions, implants
and infusion pumps.
[0153] Compared to oral formulations, parenteral formulations have
several advantages, especially when the patient is young or has
problems to swallow. They can be exactly dosed, e.g. according to
the body weight of the patients, which can be particularly
important in pediatric patients. Further, they can be administered
by infusion continually over an extended period of time (e. g. 24
h), e. g. by means of an infusion pump.
[0154] In a preferred embodiment, the parenteral formulation
according to the invention is an infusion solution or infusion
suspension.
[0155] In another preferred embodiment, the parenteral formulation
is an injection solution or injection suspension, which preferably
is a single dosage unit form or multiple dosage unit form. Multiple
dosage unit injection solutions are preferably contained in an
injection vial, whereas single dosage unit forms are preferably
contained in a single-use syringe.
[0156] In still another preferred embodiment, the parenteral
formulation is an implantable device, such as an implantable
infusion pump.
[0157] In a preferred embodiment, the parenteral formulation
according to the invention is a depot formulation (retard
formulation).
[0158] Preferably, the depot formulation is an infusion solution or
infusion suspension, preferably customized for an intramuscular or
subcutaneous administration.
[0159] Preferably, the depot formulation further contains
viscosity-enhancing excipients, such as methylcellulose, gelatine,
and polyvidon (polyvinylpyrrolidon) preferably having a molecular
weight of not more than 40,000 g/mol. By choosing the appropriate
type and the appropriate amount of the viscosity-enhancing
excipient, the depot effect of the depot formulation may be
influenced.
[0160] Preferably, the depot formulation is capable of releasing
the drug over time period of at least 12 h or 14 h, more preferably
at least 16 h or 18 h, still more preferably at least 20 h, yet
more preferably at least 24 h, most preferably at least 36 h, and
in particular at least 48 h.
[0161] The depot formulation is preferably administered for use in
the treatment of acute pain and/or post-surgical pain.
[0162] In a preferred embodiment, the composition according to the
invention, particularly when it is contained in the container
according to the invention, is adapted for local administration. In
this regard, local administration includes every administration of
the composition to a site which is identical to the site of
disorder and/or at least is located nearby. In particular, the
local administration has the purpose of delivering Tapentadol
directly to the desired site of action, thereby avoiding systemic
side-effects. Under these circumstances, the systemic concentration
of Tapentadol is preferably kept at a sub-therapeutic
concentration; i.e. during the treatment, the systemic
concentration of Tapentadol never reaches the level that is
required for exhibiting a therapeutic effect when the drug is only
administered systemically.
[0163] In another preferred embodiment, the composition according
to the invention, particularly when it is contained in the
container according to the invention, is adapted for systemic
administration. In this embodiment the administration of the
composition preferably has the purpose of inducing a systemic
action of Tapentadol.
[0164] The composition according to the invention is adapted for
parenteral administration, preferably by injection or infusion.
[0165] The composition according to the invention is adapted for
parenteral administration of Tapentadol. The parenteral
administration may proceed by infusion or injection.
[0166] Infusion solutions or suspensions may be administered
continuously, intermittently or patient-controlled. For the
administration, infusion devices such as implantable infusion
pumps, non-implantable infusion pumps and spinal pumps may be
used.
[0167] The administration of the composition may proceed
intramuscularly, intravenously, subcutaneously, epidurally,
intrathecally, intraspinally and/or intracerebroventricularly.
Intraveneous administration is particularly preferred.
[0168] In a preferred embodiment, the administration proceeds
intraspinally, either intrathecally or epidurally, preferably by
infusion. The intraspinal administration is especially suitable for
treating pain selected from perioperative pain, post-operative
pain, labor pain and cancer pain. The dosage of the intraspinal
administration may be controlled by means of an infusion pump,
either by the patient or by the selection of an appropriate steady
or intermittent infusion rate.
[0169] In another preferred embodiment, the administration proceeds
intramuscularly, intravenously or subcutaneously. This type of
administration is especially preferred for the local or regional
treatment of pain in distal extremities.
[0170] Depot formulations are preferably administered
intramuscularly or subcutaneously.
[0171] Another aspect of the invention relates to a process for the
preparation of the pharmaceutical composition according to the
invention or of the container according to the invention,
respectively, which process comprises the step of [0172] (a)
preparing a mixture comprising Tapentadol or a physiologically
acceptable salt thereof, water and a buffer.
[0173] In a preferred embodiment, Tapentadol is employed as
Tapentadol hydrochloride polymorph form A, which is preferably
characterized by showing at least one or more X-ray lines (2-theta
values) in a powder diffraction pattern when measured using Cu
K.alpha. radiation selected from the list comprising 15.1.+-.0.2,
16.0.+-.0.2, 18.9.+-.0.2, 20.4.+-.0.2, 22.5.+-.0.2, 27.3.+-.0.2,
29.3.+-.0.2 and 30.4.+-.0.2.
[0174] Preferably, in the course of manufacturing the composition
according to the invention and the container according to the
invention, respectively, the intermediate mixtures that are
obtained after the process steps are purged with inert gas,
preferably nitrogen, in order to discharge dissolved oxygen and to
avoid entrainment of oxygen from the gas atmosphere above the
composition.
[0175] Preferably, step (a) of the process according to the
invention comprises a substep relating to the addition of every
constituent to the composition, which substep comprises adding,
dissolving/mixing and purging with inert gas, preferably
nitrogen.
[0176] Thus, step (a) of the process according to the invention
preferably comprises [0177] the substep (a.sub.1) of providing
water for injections and purging with inert gas; [0178] the substep
(a.sub.2) of adding buffer, preferably sodium citrate dihydrate,
dissolving, and purging with inert gas; [0179] the substep
(a.sub.3) of adding Tapentadol, preferably Tapentadol
hydrochloride, dissolving, and purging with inert gas; [0180] the
substep (a.sub.4) of adding isotonizing agent, preferably sodium
chloride, dissolving, and purging with inert gas; [0181] the
substep (a.sub.5) of adding acid, preferably hydrochloric acid,
mixing, and purging with inert gas; and [0182] the substep
(a.sub.6) of adding further water for injections, mixing, and
purging with inert gas.
[0183] Substeps (a.sub.1) to (a.sub.6) may be performed in
numerical order or in any other order.
[0184] Preferably, the process according to the invention comprises
one or more additional steps selected from the group consisting of
[0185] (b) purging the mixture with an inert gas; and/or [0186] (c)
filtering the mixture through a filter, preferably of an average
pore size of not more than 1.0 .mu.m, more preferably not more than
0.5 .mu.m, still more preferably not more than 0.2 .mu.m; and/or
[0187] (d) filling the mixture into a suitable container,
preferably a glass ampoule; and/or [0188] (e) autoclaving the
mixture at elevated temperature and elevated pressure, preferably
at 121.degree. C. and 2 bar for at least 20 minutes.
[0189] Preferably, steps (b), (c), (d) and/or (e) are performed in
alphabetical order.
[0190] The invention also relates to a composition or a container
that is obtainable by the process according to the invention as
described above.
[0191] Another aspect of the invention relates to a kit comprising
the container according to the invention as described above and a
packaging, wherein the container is packaged by the packaging. The
container may be regarded as a primary packaging of the
composition, whereas the packaging may be regarded as a secondary
packaging of said primary packaging.
[0192] Thus, when the composition according to the invention is
contained in a container such as a glass ampoule, said container is
preferably further packaged by a packaging. Preferably, the
packaging contains printed information and/or provides a barrier to
light.
[0193] Preferably, the packaging is made of a material that is
intransparent to visual light.
[0194] Preferably, the packaging is disposable. Suitable packaging
materials are known to the skilled person and include but are not
limited to paper, cardboard, plastics, and metal foil. Preferably,
the packaging comprises or essentially consists of cardboard.
[0195] Preferably, the composition which is contained in the
container and packaged by the packaging is photostable.
[0196] In preferred embodiments, the content of decomposition
products of Tapentadol in the composition after subjecting the kit
for 24 hours to UV radiation at 540 Wh/m.sup.2 and an illumination
of 1320 kL.times.h is not more than 0.05 wt.-%, more preferably not
more than 0.04 wt.-%, and most preferably not more than 0.03 wt.-%,
relative to the total content of Tapentadol that was originally
contained in the composition prior to subjecting the composition to
UV radiation and based on the weight of Tapentadol free base.
[0197] Another aspect of the invention relates to the use of
Tapentadol or a physiologically acceptable salt thereof for the
preparation of a pharmaceutical composition according to the
invention as described above or of a container according to the
invention as described above. Preferably, Tapentadol is employed as
Tapentadol hydrochloride polymorph form A, which is preferably
characterized by showing at least one or more X-ray lines (2-theta
values) in a powder diffraction pattern when measured using Cu
K.alpha. radiation selected from the list comprising 15.1.+-.0.2,
16.0.+-.0.2, 18.9.+-.0.2, 20.4.+-.0.2, 22.5.+-.0.2, 27.3.+-.0.2,
29.3.+-.0.2 and 30.4.+-.0.2.
[0198] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
EXAMPLE 1
Preparation of Composition and Container
[0199] The following pharmaceutical composition (50 L) was prepared
and subsequently filled into glass ampoules (2.00 mL):
TABLE-US-00002 amount per ampoule wt.-% Tapentadol HCl 2.33 mg
equivalent weight relative to 2.00 mg 0.0997 Tapentadol free base
sodium citrate dihydrate 0.64 mg 0.0319 sodium chloride 17.00 mg
0.8475 hydrochloric acid solution 1N ~2.18 mg q.s. sodium hydroxide
solution 1N q.s. q.s. water ad 2.00 mL pH value 5.0 .+-. 0.5 total
volume 2.00 mL total weight 2006 mg
[0200] Water for injection was weighed in a stainless steel
container and purged with nitrogen. Sodium citrate dihydrate was
weighed in a suitable container and subsequently added to the water
for injection while purging. Tapentadol hydrochloride for
parenteral use was weighed in a suitable container and subsequently
added to the sodium citrate solution while purging with nitrogen.
Sodium chloride was weighed in a suitable container and
subsequently added to the solution while purging with nitrogen.
[0201] The pH value was measured and adjusted to 5.0 by using IN
hydrochloric acid. If necessary, IN sodium hydroxide solution was
added to readjust the pH to the target value. The remaining water
was added to the solution while purging with nitrogen. The pH value
was measured again.
[0202] The solution was filtered using a filter with 0.2 .mu.m
pores (Fluorodyne.RTM. KA3DFLP1, polyvinylidene fluoride, Pall).
The filtered solution was filled (Fill and seal-machine AFV 6015,
Bausch & Strobel) into cleaned (Washing machine AWU 8000,
Bausch & Strobel) and sterilized (Sterilization tunnel DST
8000, Bausch & Strobel) type I clear glass ampoules while
gassing with nitrogen. The ampoules were closed by a welding and
cutting process (Fill and seal-machine AFV 6015, Bausch &
Strobel).
[0203] The fill weight of the ampoules was measured and the
ampoules were autoclaved at 121.degree. C., 2 bar for 20 minutes
(Belimed autoclave IV, Belimed). The ampoules were cleaned from the
outside (Washing machine DAR150, Seidenader), visually controlled
(EISAI AIM 287, Eisai) and subjected to a leak test at high voltage
(Densok HDB II, Nikka-Densok).
[0204] The thus obtained compositions in the containers were stable
upon autoclaving and had an excellent shelf life.
EXAMPLE 2
Storage Stability (pH, Color, Decomposition of Tapentadol)
[0205] A pharmaceutical composition according to the invention and
a comparative composition were prepared in accordance with Example
1. The relevant information concerning the two compositions are
summarized here below:
TABLE-US-00003 comparative inventive sodium citrate dihydrate 0.15
wt.-% 0.03 wt.-% (2.76 g in (7.36 g in 18.46 kg) 23.07 kg) pH range
according to specification 6.0 to 7.5 4.5 to 5.5 content of
molecular oxygen in headspace according to specification 5% Vbar 2%
Vbar measured 0.7% Vbar
[0206] The storage stability was investigated. The results are
summarized in the table here below:
Comparative Composition 1:
TABLE-US-00004 [0207] purity, .SIGMA. pH decomposition color of
solution value products start -- colorless 7.2 0.06% 1 25.degree.
C./60% r.h. colorless 7.1 0.20% 40.degree. C./75% r.h. colorless
7.1 0.58% 3 25.degree. C./60% r.h. colorless 7.5 0.38% 30.degree.
C./75% r.h. colorless 7.5 0.62% 40.degree. C./75% r.h. Sample 1:
BG7 7.7 1.51% Sample 2: <GG6, >GG7 6 25.degree. C./60% r.h.
colorless 7.5 0.51% 30.degree. C./75% r.h. colorless 7.6 0.93%
40.degree. C./75% r.h. GG4 7.6 2.88%
Inventive Composition 1:
TABLE-US-00005 [0208] purity, .SIGMA. pH decomposition color of
solution value products start -- colorless 5.2 n.d. 1 25.degree.
C./60% r.h. colorless 5.2 n.d. 40.degree. C./75% r.h. colorless 5.2
n.d. 3 25.degree. C./60% r.h. colorless 5.1 <0.05% 40.degree.
C./75% r.h. colorless 5.2 <0.05% 6 25.degree. C./60% r.h.
colorless 5.0 40.degree. C./75% r.h. colorless 5.1 9 25.degree.
C./60% r.h. colorless 4.9 12 25.degree. C./60% r.h. colorless 5.0
18 25.degree. C./60% r.h. colorless 5.1
[0209] Regarding the color of the solution, the codes BG7, GG4, GG6
and GG7 refer to The Munsell Book of Color (Munsell Color Macbeth
Division of Kollmorgan Instruments Corporation).
EXAMPLE 3
Storage Stability (Photostability)
[0210] The inventive composition according to Example 1 in 2 ml
clear glass ampoules (glass type I) (primary packaging) was
subjected to a photostability test according to ICH Q1B
investigating color, clarity and degradation (Illumination at 250
W/m.sup.2). Irradiation was performed up to 24 h corresponding to
540 Wh/m2 and 1320 kL.times.h (ICH Q1B requirement: not less than
200 Wh/m2 and not less than 1200 kL.times.h). In parallel, the
primary packaging was placed into a cardboard box as secondary
packaging.
[0211] The experimental results are summarized in the table here
below:
TABLE-US-00006 2 hours 4 hours 6 hours 8 hours UV: 45 UV: 90 UV:
135 UV: 180 24 hours Wh/m.sup.2, Wh/m.sup.2, Wh/m.sup.2,
Wh/m.sup.2, 24 hours irradiation Illum: Illum: Illum: Illum: UV:
540 Wh/m.sup.2, on window 0 hours 110 kL .times. h 220 kL .times. h
330 kL .times. h 440 kL .times. h Illum: 1320 kL .times. h sill
packaging primary primary primary primary primary primary secondary
primary color and clear -- -- -- -- clear -- -- clarity colorless
colorless solution solution sum of n.d. n.d. 0.12 0.23 0.31 1.00
n.d. 0.25 degradation products n.d. = not detectable or below
reporting threshold -- test not performed
[0212] As demonstrated by the above data, color did not change over
24 hours. The degradation products increased. After 8 h irradiation
the degradation products were still within specification but failed
the limits after 24 hours. 24 h irradiation in the secondary
packaging cardboard box, however, did not result in any changes
compared to the initial testing.
[0213] In addition, Tapentadol 1 mg/mL solution for injection
packaged in ampules was submitted over 4 days to a total of 24 h
day light irradiation on a window sill in order to evaluate the
comparability between artificial irradiation and normal daylight.
The extent of degradation is similar to 6 h artificial irradiation
(UV: 135 Wh/m.sup.2, Illumination: 330 kL.times.h). The secondary
packaging, however, provided sufficient light protection.
* * * * *