U.S. patent application number 13/410768 was filed with the patent office on 2013-01-24 for aqueous pharmaceutical formulation of tapentadol for oral administration.
This patent application is currently assigned to Gruenenthal GmbH. The applicant listed for this patent is Roger Carolus Augusta Embrechts, Sabine Karine Katrien Inghelbrecht, Ulrich REINHOLD, Marc Schiller, Eva Wulsten. Invention is credited to Roger Carolus Augusta Embrechts, Sabine Karine Katrien Inghelbrecht, Ulrich REINHOLD, Marc Schiller, Eva Wulsten.
Application Number | 20130022670 13/410768 |
Document ID | / |
Family ID | 44650617 |
Filed Date | 2013-01-24 |
United States Patent
Application |
20130022670 |
Kind Code |
A1 |
REINHOLD; Ulrich ; et
al. |
January 24, 2013 |
Aqueous Pharmaceutical Formulation of Tapentadol for Oral
Administration
Abstract
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.
Inventors: |
REINHOLD; Ulrich; (Aachen,
DE) ; Schiller; Marc; (Aachen, DE) ; Wulsten;
Eva; (Duesseldorf, DE) ; Inghelbrecht; Sabine Karine
Katrien; (Beerse, BE) ; Embrechts; Roger Carolus
Augusta; (Beerse, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
REINHOLD; Ulrich
Schiller; Marc
Wulsten; Eva
Inghelbrecht; Sabine Karine Katrien
Embrechts; Roger Carolus Augusta |
Aachen
Aachen
Duesseldorf
Beerse
Beerse |
|
DE
DE
DE
BE
BE |
|
|
Assignee: |
Gruenenthal GmbH
Aachen
DE
|
Family ID: |
44650617 |
Appl. No.: |
13/410768 |
Filed: |
March 2, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61449287 |
Mar 4, 2011 |
|
|
|
Current U.S.
Class: |
424/451 ;
514/654 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61K 47/12 20130101; A61K 47/02 20130101; A61K 9/08 20130101; A61K
9/0095 20130101; A61P 25/00 20180101; A61K 31/137 20130101; A61P
25/04 20180101 |
Class at
Publication: |
424/451 ;
514/654 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 9/48 20060101 A61K009/48; A61P 25/04 20060101
A61P025/04 |
Foreign Application Data
Date |
Code |
Application Number |
May 3, 2011 |
EP |
11 003 601.9 |
Claims
1. An aqueous pharmaceutical composition comprising water and
tapentadol or a physiologically acceptable salt thereof, wherein
said composition is orally administrable.
2. The composition according to claim 1, further comprising a
buffer.
3. The composition according to claim 2, wherein said composition
is buffered to a pH value within the range from 3.0 to 6.5.
4. The composition according to claim 1, wherein said composition
has a pH value within the range from 3.0 to 6.5.
5. The composition according to claim 1, wherein said composition
contains tapentadol in a concentration of 50 mg/mL or less, based
on the total volume of the composition.
6. The composition according to claim 1, wherein said composition
is free of any preservative.
7. The composition according to claim 1, further comprising a
preservative.
8. The composition according to claim 7, wherein said preservative
is selected from the group consisting of 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.
9. The composition according to claim 7, wherein the content of
said preservative is at most 5.0 wt.-%, based on the total weight
of the composition.
10. The composition according to claim 7, wherein the sum of the
concentration of tapentadol and the concentration of preservative
is 50 mg/mL or less, based on the total volume of the
composition.
11. The composition according to claim 7, wherein the preservative
content is at most 90% of the content that would be needed
according to Ph. Eur. in order to sufficiently preserve the
pharmaceutical composition in the absence of tapentadol.
12. The composition according to claim 1, wherein said composition
exhibits a shelf-life under accelerated storage conditions of at
least 3 months.
13. The composition according to claim 1, wherein said composition
is selected from the group consisting of syrups, drops, solutions,
dispersions, suspensions and emulsions.
14. A pharmaceutical dosage form comprising a pharmaceutical
composition according to claim 1.
15. The dosage form according to claim 14, wherein said dosage form
is selected from the group consisting of oral solutions, oral gels,
suspensions, emulsions and liquid or gel filled capsules.
16. The dosage form according to claim 15, wherein said dosage form
is adapted for administration to pediatric patients.
17. A method of treating pain in a subject in need thereof, said
method comprising administering to said subject a pharmaceutically
effective amount of a composition according to claim 1.
18. A method according to claim 17, wherein said pain is selected
from the group consisting of acute pain and chronic pain.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
patent application No. 61/449,287, filed Mar. 4, 2011, the entire
disclosure of which is incorporated herein by reference. Priority
is also claimed based upon European patent application no. EP 11
003 601.9, filed May 3, 2011, the entire disclosure of which is
likewise incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The invention relates to an aqueous pharmaceutical
composition containing tapentadol or a physiologically acceptable
salt thereof and being adapted for oral administration.
[0003] Tapentadol is a centrally-acting analgesic with a dual mode
of action as an agonist at the .mu.-opioid receptor and as a
norepinephrine reuptake inhibitor (cf. T. M. Tzschentke et al.,
Drugs of the future, 2006, 12, 1053-1061). Solid oral dosage forms
of tapentadol are known from the prior art, e.g. WO 02/067651, WO
03/035053, WO 2006/002886, WO 2007/128412, WO 2007/128413, WO
2008/110323, WO 2009/092601, WO 2009/067703, and US
2007-128412.
[0004] However, solid oral dosage forms containing tapentadol are
not satisfactory in every respect and there is a demand of
pharmaceutical formulations which have advantages compared to the
known solid oral dosage forms.
[0005] The stability of the active ingredient in the final product
is a primary concern to the formulator. In general, drug substances
are less stable in aqueous media than solid dosage forms, and it is
important to properly stabilize and preserve liquid aqueous
formulations such as solutions, suspensions, and emulsions.
Acid-base reactions, acid or base catalysis, oxidation, and
reduction can occur in these products. These reactions can arise
from drug substance-ingredient interactions, ingredient-ingredient
interactions or container-product interactions. For pH sensitive
compounds, any of these interactions may alter the pH and may cause
precipitation.
[0006] Oxidative labile drug substances or vitamins, essential
oils, and almost all fats and oils can be oxidized by
auto-oxidation. Such reactions can be initiated by heat, light,
peroxides, or other labile compounds or heavy metals such as copper
or iron.
[0007] The effect of trace metals can be minimized by using
chelating agents such as EDTA. Antioxidants may retard or delay
oxidation by rapidly reacting with free radicals as they are formed
(quenching). Common antioxidants include propyl, octyl and
dodecylesters of gallic acid, butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), ascorbic acid, sodium ascorbate,
monothioglycerol, potassium or sodium metabisulfite, propionic
acid, propyl gallate, sodium bisulfite, sodium sulfite, and the
tocopherols or vitamin E.
[0008] In addition to stabilization of pharmaceutical preparations
against chemical and physical degradation, liquid and semisolid
preparations, particularly multiple dosed preparations, must
usually be protected against microbial contamination. In contrast
to solid preparations, aqueous solutions, syrups, emulsions, and
suspensions often provide excellent growth media for microorganisms
such as molds, yeast, and bacteria (e.g. Pseudomonas Aeruginosa, E.
Coll, Salmonella spp., Staphylococcus aureus, Candida albicans,
Aspergillus niger). Contamination by these microorganisms may occur
during manufacturing or when a dose is taken from a multiple dosed
formulation. Growth of the microorganisms occurs when a sufficient
amount of water is present in the formulation.
[0009] Ophthalmic and injectable preparations are typically
sterilized by autoclaving or filtration. However, many of them
require the presence of an antimicrobial preservative to maintain
aseptic conditions throughout their stated shelf life, specifically
for multiple dosed preparations.
[0010] When a preservative is required, its selection is based upon
several considerations, in particular the site of use whether
internal, external or ophthalmic (for further details it can be
referred to e.g. Remington, The Science and Practice of Pharmacy,
21.sup.st edition, Lippincott Williams & Wilkins, 2005).
[0011] Many liquid formulations for oral administration,
particularly multiple dosed formulations, contain parabens as
preservatives, e.g. methyl paraben (methyl-4-hydroxybenzoate) and
propyl paraben (propyl-4-hydroxybenzoate). For example, in the
Federal Republic of Germany liquid oral formulations containing
parabens are commercialized under the trademarks: ben-u-ron.RTM.;
Cetirizin-ratiopharm.RTM.; Pipamperon HEXAL.RTM.; Sedotussin.RTM.;
TALOXA.RTM.; Truxal.RTM.; XUSAL.RTM.; talvosilen.RTM.; and
Timonil.RTM.. Other commercialized liquid formulations contain
sorbic acid or its potassium salt as preservative, e.g. ibuprofen
liquid formulations and morphine liquid formulations.
[0012] Because of the number of excipients and additives in these
preparations, it is recommended all the ingredients be listed on
the container to reduce the risks that confront hypersensitive
patients when these products are administered.
[0013] The preservatives benzalkonium chloride and potassium
sorbate are also widely used e.g. in nasal drops and sprays.
Recently, side effects resulting from mucosal damage caused by
benzalkonium chloride and potassium sorbate were reported (cf. C.
Y. Ho et al., Am J Rhinol. 2008, 22(2), 125-9). As far as
hypersensitivity reactions of preservatives in topical ophthalmic
therapies are concerned, quaternary ammoniums (benzalkonium
chloride) are commonly associated with irritant toxic reactions
whereas the organomercurials (thimerosal) and the alcohols
(chlorobutanol) have high associations, respectively, with allergic
responses (cf. J. Hong et al., Curr Opin Allergy Clin Immunol.
2009, 9(5), 447-53). Parabens have been implicated in numerous
cases of contact sensitivity associated with cutaneous exposure
(cf. M. G. Soni et al., Food Chem Toxicol. 2001, 39(6), 513-32) and
have been reported to exert a weak estrogenic activity (cf. S.
Oishi, Food Chem Toxicol. 2002, 40(12), 1807-13 and M. G. Soni et
al., Food Chem Toxicol. 2005, 43(7), 985-015).
[0014] Due to these undesired side effects of known preservatives,
it is desirable to provide pharmaceutical compositions for oral
administration that exhibit a sufficient shelf life and in use
stability in the absence of preservatives or at least in the
presence of comparatively low quantities thereof.
[0015] WO 2008/110323 discloses a composition for parenteral
administration of 20 g
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
hydrochloride in 1 L water for injection purposes which has been
isotonized by addition of NaCl.
SUMMARY OF THE INVENTION
[0016] It is an object of the invention to provide pharmaceutical
formulations of tapentadol that have advantages over the
pharmaceutical formulations of the prior art. The pharmaceutical
formulations should not have the above preservative based side
effects that are typically observed with pharmaceutical
formulations containing preservatives such as allergic
reactions.
[0017] This object has been achieved by the invention as described
and claimed hereinafter. It has been surprisingly found that
tapentadol as such exhibits preservative properties and thus, when
formulating comparatively labile compositions, particularly aqueous
liquid or semisolid compositions, preservatives can be completely
omitted or at least need to be present in comparatively low amounts
in order to achieve the stated shelf life.
[0018] A first aspect of the invention relates to an aqueous
pharmaceutical composition containing tapentadol or a
physiologically acceptable salt thereof and being adapted for oral
administration.
[0019] 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). Thus, unless expressly states 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.
[0020] The composition according to the invention is aqueous. For
the purpose of the specification, the term "aqueous" means that its
water content is preferably above the typical water content of
solid pharmaceutical dosage forms which are humidified from the
atmosphere due to the more or less pronounced hygroscopic
properties of their constituents.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0021] Preferably, the water content of the composition is at least
0.5 wt.-%, more preferably at least 1.0 wt.-%, still more
preferably at least 2.0 wt.-%, yet more preferably at least 3.0
wt.-%, most preferably at least 4.0 wt.-% and in particular at
least 5.0 wt.-%, based on the total weight of the composition.
[0022] In a preferred embodiment, the water content of the
composition is at least 5 wt.-%, more preferably at least 10 wt.-%,
still more preferably at least 20 wt.-%, yet more preferably at
least 30 wt.-%, most preferably at least 40 wt.-% and in particular
at least 50 wt.-%, based on the total weight of the
composition.
[0023] In another preferred embodiment, the water content of the
composition is within the range of 35.+-.30 wt.-%, more preferably
35.+-.25 wt.-%, still more preferably 35.+-.20 wt.-%, yet more
preferably 35.+-.15 wt.-%, most preferably 35.+-.10 wt.-% and in
particular 35.+-.5 wt.-%, based on the total weight of the
composition.
[0024] In another preferred embodiment, the water content of the
composition is within the range of 45.+-.30 wt.-%, more preferably
45.+-.25 wt.-%, still more preferably 45.+-.20 wt.-%, yet more
preferably 45.+-.15 wt.-%, most preferably 45.+-.10 wt.-% and in
particular 45.+-.5 wt.-%, based on the total weight of the
composition.
[0025] In another preferred embodiment, the water content of the
composition is within the range of 55.+-.30 wt.-%, more preferably
55.+-.25 wt.-%, still more preferably 55.+-.20 wt.-%, yet more
preferably 55.+-.15 wt.-%, most preferably 55.+-.10 wt.-% and in
particular 55.+-.5 wt.-%, based on the total weight of the
composition.
[0026] In another preferred embodiment, the water content of the
composition is within the range of 65.+-.30 wt.-%, more preferably
65.+-.25 wt.-%, still more preferably 65.+-.20 wt.-%, yet more
preferably 65.+-.15 wt.-%, most preferably 65.+-.10 wt.-% and in
particular 65.+-.5 wt.-%, based on the total weight of the
composition.
[0027] In another preferred embodiment, the water content of the
composition is within the range of 75.+-.24 wt.-%, more preferably
75.+-.22 wt.-%, still more preferably 75.+-.20 wt.-%, yet more
preferably 75.+-.15 wt.-%, most preferably 75.+-.10 wt.-% and in
particular 75.+-.5 wt.-%, based on the total weight of the
composition.
[0028] In another preferred embodiment, the water content of the
composition is within the range of 85.+-.14 wt.-%, more preferably
85.+-.12 wt.-%, still more preferably 85.+-.10 wt.-%, most
preferably 85.+-.7.5 wt.-% and in particular 85.+-.5 wt.-%, based
on the total weight of the composition.
[0029] In still another preferred embodiment, the water content of
the composition is within the range of 95.+-.4.75 wt.-%, more
preferably 95.+-.4.5 wt.-%, still more preferably 95.+-.4 wt.-%,
yet more preferably 95.+-.3.5 wt.-%, most preferably 95.+-.3 wt.-%
and in particular 95.+-.2.5 wt.-%, based on the total weight of the
composition.
[0030] In a preferred embodiment, the water content of the
composition is within the range of from 75 to 99.99 wt.-%, more
preferably 80 to 99.98 wt.-%, still more preferably 85 to 99.95
wt.-%, yet more preferably 90 to 99.9 wt.-%, most preferably 95 to
99.7 wt.-% and in particular 96.5 to 99.5 wt.-%, based on the total
weight of the composition.
[0031] In a preferred embodiment, the composition has a viscosity
within the range of 15.+-.12 mPas, more preferably 15.+-.10 mPas,
still more preferably 15.+-.8 mPas, yet more preferably 15.+-.6
mPas, most preferably 15.+-.4 mPas, and in particular 15.+-.2
mPas.
[0032] In another preferred embodiment, the composition has a
viscosity within the range of 30.+-.28 mPas, more preferably
30.+-.20 mPas, still more preferably 30.+-.16 mPas, yet more
preferably 30.+-.12 mPas, most preferably 30.+-.8 mPas, and in
particular 30.+-.4 mPas.
[0033] In still another preferred embodiment, the composition has a
viscosity within the range of 60.+-.56 mPas, more preferably
60.+-.40 mPas, still more preferably 60.+-.32 mPas, yet more
preferably 60.+-.24 mPas, most preferably 60.+-.16 mPas, and in
particular 60.+-.8 mPas.
[0034] In yet another preferred embodiment, the composition has a
viscosity within the range of 120.+-.112 mPas, more preferably
120.+-.80 mPas, still more preferably 120.+-.64 mPas, yet more
preferably 120.+-.48 mPas, most preferably 120.+-.32 mPas, and in
particular 120.+-.16 mPas.
[0035] In another preferred embodiment, the composition has a
viscosity within the range of 240.+-.224 mPas, more preferably
240.+-.160 mPas, still more preferably 240.+-.128 mPas, yet more
preferably 240.+-.96 mPas, most preferably 240.+-.64 mPas, and in
particular 240.+-.32 mPas.
[0036] In still another preferred embodiment, the composition has a
viscosity within the range of 500.+-.400 mPas, more preferably
500.+-.300 mPas, still more preferably 500.+-.200 mPas, yet more
preferably 500.+-.150 mPas, most preferably 500.+-.100 mPas, and in
particular 500.+-.50 mPas.
[0037] A skilled person knows how to measure the viscosity of
pharmaceutical compositions. Preferably, the viscosity is measured
at room temperature.
[0038] Besides water, the composition according to the invention
may contain further solvents.
[0039] Further suitable solvents include all physiologically
acceptable substances that are normally liquid at ambient or room
temperatures. Preferably, the further solvent is water-soluble or
water-miscible. Further solvents may be selected from the group
consisting of propylene glycol, ethanol, poly(ethylene glycol) or
PEG, propylene carbonate, diethylene glycol monoethyl ether,
poloxamer, glycofurol, glycerol, and mixtures thereof. Further
solvents also include tensides (emulsifiers) and/or fats.
[0040] In a preferred embodiment, the composition contains a
tenside. In a preferred embodiment, the composition contains a
single tenside. In another preferred embodiment, the composition
contains a mixture of two or more tensides.
[0041] Preferably, the tenside has a hydrophilic-lipophilic balance
(HLB) of at least 10. More preferably, the hydrophilic-lipophilic
balance (HLB) is at least 12. Most preferably, the
hydrophilic-lipophilic balance (HLB) ranges within 14 and 16. The
tenside can be an ionic tenside, amphoteric tenside or non-ionic
tenside.
[0042] In a preferred embodiment, the tenside is ionic, in
particular anionic. Suitable anionic ionic tensides include but are
not limited to sodium lauryl sulfate (sodium dodecyl sulfate),
sodium cetyl stearyl sulfate, sodium dioctylsulfosuccinate
(docusate sodium); and the corresponding potassium or calcium salts
thereof.
[0043] In another preferred embodiment, the tenside is non-ionic.
Suitable non-ionic tensides include but are not limited to [0044]
polyoxyethylene-sorbitan-fatty acid esters, e.g. mono- and
tri-lauryl, palmityl, stearyl and oleyl esters, such as the type
known under the name "polysorbate" and commercially available under
the trade name "Tween.RTM." including the tensides tween 20
[polyoxyethylene(20)sorbitan monolaurate], tween 40
[polyoxyethylene(20)sorbitan monopalmitate], 60
[polyoxyethylene(20)sorbitan monostearate], tween 65
[polyoxyethylene(20)sorbitan tristearate], tween 80
[polyoxyethylene(20)sorbitan monooleate], tween 85
[polyoxyethylene(20)sorbitan trioleate], tween 21
[polyoxyethylene(4)sorbitan monolaurate] and tween 81
[polyoxyethylene(5)sorbitan monooleate]; [0045] polyoxyethylene
fatty acid esters, the fatty acid preferably having from about 8 to
about 18 carbon atoms, e.g. polyoxyethylene esters of
12-hydroxystearic acid, such as the type known and commercially
available under the trade name "Solutor"; [0046] polyoxyethylene
esters of alpha-tocopheryl succinate, e.g.
D-alpha-tocopheryl-PEG-1000-succinate (TPGS); [0047] polyglycolyzed
glycerides, such as the types known and commercially available
under the trade names "Gelucire.RTM." and "Labrasol.RTM."; [0048]
reaction products of a natural or hydrogenated castor oil and
ethylene oxide such as the various liquid tensides known and
commercially available under the trade name "Cremophor.RTM.";
[0049] glycerol fatty acid esters, e.g. mono- and tri-lauryl,
palmityl, stearyl and oleyl esters, such as for example glyceryl
monooleate 40, known and commercially available under the trade
name "Peceol.RTM.".
[0050] Examples of fats include glycerol monostearate, glycerol
monopalmitate, stearic acid, diglycol stearate, glycerol trioleate,
carnauba wax, bees wax, cetylstearyl alcohol and the like.
[0051] Preferably, however, water is the only liquid constituent of
the composition according to the invention.
[0052] The composition according to the invention is adapted for
oral administration. In this regard, oral administration includes
every administration through the oral cavity such as peroral,
sublingual, buccal, and the like. Preferably, oral administration
has the purpose of systemically administering tapentadol upon
swallowing.
[0053] 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 contains one or more physiologically acceptable
carriers, preferably water, and/or excipients. The pharmaceutical
composition may be a subunit of a pharmaceutical dosage form, e.g.
the liquid core of a capsule.
[0054] Preferably, the composition according to the invention is
buffered, i.e. contains one or more buffers and buffer systems
(i.e. conjugate acid-base-pairs), respectively. Preferred buffer
systems are derived from the following acids: organic acids such as
acetic acid, propionic acid, maleic acid, fumaric acid, malonic
acid, malic acid, mandelic acid, citric acid, tartric acid; or
inorganic acids such as phosphoric acid. Citric acid or citric acid
monohydrate are particularly preferred. When the buffer systems are
derived from any of the above acids, the buffer system constitutes
of said acid and its conjugate base.
[0055] It has been surprisingly found that the antimicrobial
activity of tapentadol depends upon the pH value.
[0056] Preferably, the composition has a pH value within the range
of from 3.0 to 6.5, more preferably 3.0 to 6.0, still more
preferably 3.0 to 5.5, yet more preferably 3.0 to 5.0, most
preferably 3.2 to 4.8 and in particular 3.4 to 4.6. Higher pH
values are also possible, e.g. 3.0 to 9.0, 3.0 to 8.5, 3.0 to 8.0
or 3.0 to 7.5.
[0057] In a preferred embodiment, the composition has a pH value
within the range of 3.0.+-.1.4 or 3.0.+-.1.3, more preferably
3.0.+-.1.2 or 3.0.+-.1.1, still more preferably 3.0.+-.1.0 or
3.0.+-.0.9, yet more preferably 3.0.+-.0.8 or 3.0.+-.0.7, even more
preferably 3.0.+-.0.6 or 3.0.+-.0.5, most preferably 3.0.+-.0.4 or
3.0.+-.0.3, and in particular 3.0.+-.0.2 or 3.0.+-.0.1.
[0058] In a preferred embodiment, the composition has a pH value
within the range of 3.5.+-.1.4 or 3.5.+-.1.3, more preferably
3.5.+-.1.2 or 3.5.+-.1.1, still more preferably 3.5.+-.1.0 or
3.5.+-.0.9, yet more preferably 3.5.+-.0.8 or 3.5.+-.0.7, even more
preferably 3.5.+-.0.6 or 3.5.+-.0.5, most preferably 3.5.+-.0.4 or
3.5.+-.0.3, and in particular 3.5.+-.0.2 or 3.5.+-.0.1.
[0059] In a preferred embodiment, the composition has a pH value
within the range of 4.0.+-.1.4 or 4.0.+-.1.3, more preferably
4.0.+-.1.2 or 4.0.+-.1.1, still more preferably 4.0.+-.1.0 or
4.0.+-.0.9, yet more preferably 4.0.+-.0.8 or 4.0.+-.0.7, even more
preferably 4.0.+-.0.6 or 4.0.+-.0.5, most preferably 4.0.+-.0.4 or
4.0.+-.0.3, and in particular 4.0.+-.0.2 or 4.0.+-.0.1.
[0060] In a preferred embodiment, the composition has a pH value
within the range of 4.5.+-.1.4 or 4.5.+-.1.3, more preferably
4.5.+-.1.2 or 4.5.+-.1.1, still more preferably 4.5.+-.1.0 or
4.5.+-.0.9, yet more preferably 4.5.+-.0.8 or 4.5.+-.0.7, even more
preferably 4.5.+-.0.6 or 4.5.+-.0.5, most preferably 4.5.+-.0.4 or
4.5.+-.0.3, and in particular 4.5.+-.0.2 or 4.5.+-.0.1.
[0061] In a preferred embodiment, the composition has a pH value
within the range of 5.0.+-.1.4 or 5.0.+-.1.3, more preferably
5.0.+-.1.2 or 5.0.+-.1.1, still more preferably 5.0.+-.1.0 or
5.0.+-.0.9, yet more preferably 5.0.+-.0.8 or 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.
[0062] In a preferred embodiment, the composition has a pH value
within the range of 5.5.+-.1.4 or 5.5.+-.1.3, more preferably
5.5.+-.1.2 or 5.5.+-.1.1, still more preferably 5.5.+-.1.0 or
5.5.+-.0.9, yet more preferably 5.5.+-.0.8 or 5.5.+-.0.7, even more
preferably 5.5.+-.0.6 or 5.5.+-.0.5, most preferably 5.5.+-.0.4 or
5.5.+-.0.3, and in particular 5.5.+-.0.2 or 5.5.+-.0.1.
[0063] In a preferred embodiment, the composition has a pH value
within the range of 6.0.+-.1.4 or 6.0.+-.1.3, more preferably
6.0.+-.1.2 or 6.0.+-.1.1, still more preferably 6.0.+-.1.0 or
6.0.+-.0.9, yet more preferably 6.0.+-.0.8 or 6.0.+-.0.7, even more
preferably 6.0.+-.0.6 or 6.0.+-.0.5, most preferably 6.0.+-.0.4 or
6.0.+-.0.3, and in particular 6.0.+-.0.2 or 6.0.+-.0.1.
[0064] In a preferred embodiment, the composition has a pH value
within the range of 6.5.+-.1.4 or 6.5.+-.1.3, more preferably
6.5.+-.1.2 or 6.5.+-.1.1, still more preferably 6.5.+-.1.0 or
6.5.+-.0.9, yet more preferably 6.5.+-.0.8 or 6.5.+-.0.7, even more
preferably 6.5.+-.0.6 or 6.5.+-.0.5, most preferably 6.5.+-.0.4 or
6.5.+-.0.3, and in particular 6.5.+-.0.2 or 6.5.+-.0.1.
[0065] In a preferred embodiment, the composition has a pH value
within the range of 7.0.+-.1.4 or 7.0.+-.1.3, more preferably
7.0.+-.1.2 or 7.0.+-.1.1, still more preferably 7.0.+-.1.0 or
7.0.+-.0.9, yet more preferably 7.0.+-.0.8 or 7.0.+-.0.7, even more
preferably 7.0.+-.0.6 or 7.0.+-.0.5, most preferably 7.0.+-.0.4 or
7.0.+-.0.3, and in particular 7.0.+-.0.2 or 7.0.+-.0.1.
[0066] In a preferred embodiment, the composition has a pH value
within the range of 7.5.+-.1.4 or 7.5.+-.1.3, more preferably
7.5.+-.1.2 or 7.5.+-.1.1, still more preferably 7.5.+-.1.0 or
7.5.+-.0.9, yet more preferably 7.5.+-.0.8 or 7.5.+-.0.7, even more
preferably 7.5.+-.0.6 or 7.5.+-.0.5, most preferably 7.5.+-.0.4 or
7.5.+-.0.3, and in particular 7.5.+-.0.2 or 7.5.+-.0.1.
[0067] In a preferred embodiment, the composition has a pH value
within the range of 8.0.+-.1.4 or 8.0.+-.1.3, more preferably
8.0.+-.1.2 or 8.0.+-.1.1, still more preferably 8.0.+-.1.0 or
8.0.+-.0.9, yet more preferably 8.0.+-.0.8 or 8.0.+-.0.7, even more
preferably 8.0.+-.0.6 or 8.0.+-.0.5, most preferably 8.0.+-.0.4 or
8.0.+-.0.3, and in particular 8.0.+-.0.2 or 8.0.+-.0.1.
[0068] In a preferred embodiment, the composition has a pH value
within the range of 8.5.+-.1.4 or 8.5.+-.1.3, more preferably
8.5.+-.1.2 or 8.5.+-.1.1, still more preferably 8.5.+-.1.0 or
8.5.+-.0.9, yet more preferably 8.5.+-.0.8 or 8.5.+-.0.7, even more
preferably 8.5.+-.0.6 or 8.5.+-.0.5, most preferably 8.5.+-.0.4 or
8.5.+-.0.3, and in particular 8.5.+-.0.2 or 8.5.+-.0.1.
[0069] In a preferred embodiment, the composition has a pH value
within the range of 9.0.+-.1.4 or 9.0.+-.1.3, more preferably
9.0.+-.1.2 or 9.0.+-.1.1, still more preferably 9.0.+-.1.0 or
9.0.+-.0.9, yet more preferably 9.0.+-.0.8 or 9.0.+-.0.7, even more
preferably 9.0.+-.0.6 or 9.0.+-.0.5, most preferably 9.0.+-.0.4 or
9.0.+-.0.3, and in particular 9.0.+-.0.2 or 9.0.+-.0.1.
[0070] Preferably, the concentration of the buffer and buffer
system, respectively, preferably citric acid or its monohydrate, is
adjusted to provide a sufficient buffer capacity.
[0071] Preferably, the content of the buffer and buffer system,
respectively, preferably citric acid or its monohydrate, is within
the range of from 0.0001 to 5.0 wt.-%, more preferably 0.0005 to
4.5 wt.-%, still more preferably 0.001 to 4.0 wt.-%, yet more
preferably 0.005 to 3.5 wt.-%, most preferably 0.01 to 3.0 wt.-%
and in particular 0.05 to 2.5 wt.-%, based on the total weight of
the composition.
[0072] In a preferred embodiment, the buffer and buffer system,
respectively, preferably citric acid or its monohydrate, has a
concentration within the range of 1.0.+-.0.6 mg/mL, more preferably
1.0.+-.0.5 mg/mL, still more preferably 1.0.+-.0.4 mg/mL, yet more
preferably 1.0.+-.0.3 mg/mL, most preferably 1.0.+-.0.2 mg/mL, and
in particular 1.0.+-.0.1 mg/mL, based on the total volume of the
composition.
[0073] In another preferred embodiment, the buffer and buffer
system, respectively, preferably citric acid or its monohydrate,
has a concentration within the range of 1.5.+-.0.6 mg/mL, more
preferably 1.5.+-.0.5 mg/mL, still more preferably 1.5.+-.0.4
mg/mL, yet more preferably 1.5.+-.0.3 mg/mL, most preferably
1.5.+-.0.2 mg/mL, and in particular 1.5.+-.0.1 mg/mL, based on the
total volume of the composition.
[0074] In still another preferred embodiment, the buffer and buffer
system, respectively, preferably citric acid or its monohydrate,
has a concentration within the range of 2.0.+-.0.6 mg/mL, more
preferably 2.0.+-.0.5 mg/mL, still more preferably 2.0.+-.0.4
mg/mL, yet more preferably 2.0.+-.0.3 mg/mL, most preferably
2.0.+-.0.2 mg/mL, and in particular 2.0.+-.0.1 mg/mL, based on the
total volume of the composition.
[0075] In yet another preferred embodiment, the buffer and buffer
system, respectively, preferably citric acid or its monohydrate,
has a concentration within the range of 2.5.+-.0.6 mg/mL, more
preferably 2.5.+-.0.5 mg/mL, still more preferably 2.5.+-.0.4
mg/mL, yet more preferably 2.5.+-.0.3 mg/mL, most preferably
2.5.+-.0.2 mg/mL, and in particular 2.5.+-.0.1 mg/mL, based on the
total volume of the composition.
[0076] A skilled person is fully aware that multiprotonic acids can
form more than a single buffer system. For example, citric acid is
a triprotonic acid so that it forms the conjugate acid-base pairs
citric acid-dihydrogencitrate, dihydrogencitrate-hydrogencitrate
and hydrogencitrate-citrate. In other words, any of citric acid,
dihydrogencitrate and hydrogencitrate can be the acid of a buffer
system with the conjugate base. For the purpose of the
specification, the expression "buffer and buffer system,
respectively" preferably refers to the quantity of both, the acid
and its conjugate base. Further, a skilled person is fully aware
that a buffer system, e.g. the conjugate system citric acid/sodium
dihydrogencitrate can be established either by adding citric acid
and an appropriate amount of sodium hydroxide or citric acid and
sodium dihydrogencitrate as such.
[0077] In a preferred embodiment, the content of tapentadol is
within the range of from 0.01 to 50 wt.-%, more preferably 0.05 to
45 wt.-%, still more preferably 0.1 to 40 wt.-%, yet more
preferably 0.5 to 35 wt.-%, most preferably 1.0 to 30 wt.-% and in
particular 5.0 to 25 wt.-%, based on the total weight of the
composition.
[0078] In another preferred embodiment, the content of tapentadol
is within the range of from 0.0001 to 5.0 wt.-%, more preferably
0.0005 to 4.5 wt.-%, still more preferably 0.001 to 4.0 wt.-%, yet
more preferably 0.005 to 3.5 wt.-%, most preferably 0.01 to 3.0
wt.-% and in particular 0.05 to 2.5 wt.-%, based on the total
weight of the composition. In a preferred embodiment, the content
of tapentadol is within the range of from 0.01 to 3.0 wt.-%, more
preferably 0.05 to 2.8 wt.-%, still more preferably 0.1 to 2.6
wt.-%, yet more preferably 0.2 to 2.4 wt.-%, most preferably 0.3 to
2.2 wt.-% and in particular 0.4 to 2.0 wt.-%, based on the total
weight of the composition.
[0079] Preferably, the concentration of tapentadol is equal or
below 200 mg/mL, more preferably equal or below 150 mg/mL, still
more preferably equal or below 100 mg/mL, yet more preferably equal
or below 75 mg/mL, and most preferably equal or below 50 mg/mL, and
in particular equal or below 30 mg/mL, based on the total volume of
the composition.
[0080] Preferably, the concentration of tapentadol is within the
range of from 0.5 to 200 mg/mL, more preferably within the range of
from 1.0 to 150 mg/mL, still more preferably within the range of
from 1.5 to 100 mg/mL, yet more preferably within the range of from
2.0 to 75 mg/mL, most preferably within the range of from 2.5 to 50
mg/mL, and in particular within the range of from 3.0 to 25 mg/mL
based on the total volume of the composition.
[0081] In a preferred embodiment, the concentration of tapentadol
is equal or below 20 mg/mL, based on the total volume of the
composition.
[0082] It has been found that the antimicrobial effect of
tapentadol, its preservative effect, is a function of the pH value.
Thus, at a given pH value a certain minimum concentration of
tapentadol is already sufficient in order to achieve the desired
preserving effect, while at another pH value another minimum
concentration of tapentadol is necessary in order to achieve the
same preserving effect. This minimum concentration for a given pH
value can be determined by routine experimentation.
[0083] In a preferred embodiment, the concentration of tapentadol
is within the range of 20.+-.6 mg/mL, more preferably 20.+-.5
mg/mL, still more preferably 20.+-.4 mg/mL, yet more preferably
20.+-.3 mg/mL, most preferably 20.+-.2 mg/mL, and in particular
20.+-.1 mg/mL, based on the total volume of the composition.
[0084] In another preferred embodiment, the concentration of
tapentadol is within the range of 17.5.+-.6 mg/mL, more preferably
17.5.+-.5 mg/mL, still more preferably 17.5.+-.4 mg/mL, yet more
preferably 17.5.+-.3 mg/mL, most preferably 17.5.+-.2 mg/mL, and in
particular 17.5.+-.1 mg/mL, based on the total volume of the
composition.
[0085] In another preferred embodiment, the concentration of
tapentadol is within the range of 15.+-.6 mg/mL, more preferably
15.+-.5 mg/mL, still more preferably 15.+-.4 mg/mL, yet more
preferably 15.+-.3 mg/mL, most preferably 15.+-.2 mg/mL, and in
particular 15.+-.1 mg/mL, based on the total volume of the
composition.
[0086] In still another preferred embodiment, the concentration of
tapentadol is within the range of 12.5.+-.6 mg/mL, more preferably
12.5.+-.5 mg/mL, still more preferably 12.5.+-.4 mg/mL, yet more
preferably 12.5.+-.3 mg/mL, most preferably 12.5.+-.2 mg/mL, and in
particular 12.5.+-.1 mg/mL, based on the total volume of the
composition.
[0087] In still another preferred embodiment, the concentration of
tapentadol is within the range of 10.+-.6 mg/mL, more preferably
10.+-.5 mg/mL, still more preferably 10.+-.4 mg/mL, yet more
preferably 10.+-.3 mg/mL, most preferably 10.+-.2 mg/mL, and in
particular 10.+-.1 mg/mL, based on the total volume of the
composition.
[0088] In yet another preferred embodiment, the concentration of
tapentadol is within the range of 7.5.+-.6 mg/mL, more preferably
7.5.+-.5 mg/mL, still more preferably 7.5.+-.4 mg/mL, yet more
preferably 7.5.+-.3 mg/mL, most preferably 7.5.+-.2 mg/mL, and in
particular 7.5.+-.1 mg/mL, based on the total volume of the
composition.
[0089] In a further preferred embodiment, the concentration of
tapentadol is within the range of 4.+-.3 mg/mL, more preferably
4.+-.2.5 mg/mL, still more preferably 4.+-.2 mg/mL, yet more
preferably 4.+-.1.5 mg/mL, most preferably 4.+-.1 mg/mL, and in
particular 4.+-.0.5 mg/mL, based on the total volume of the
composition.
[0090] In another preferred embodiment, the concentration of
tapentadol is equal or above 20 mg/mL, based on the total volume of
the composition.
[0091] In a preferred embodiment, the concentration of tapentadol
is within the range of 22.5.+-.6 mg/mL, more preferably 22.5.+-.5
mg/mL, still more preferably 22.5.+-.4 mg/mL, yet more preferably
22.5.+-.3 mg/mL, most preferably 22.5.+-.2 mg/mL, and in particular
22.5.+-.1 mg/mL, based on the total volume of the composition.
[0092] In another preferred embodiment, the concentration of
tapentadol is within the range of 25.+-.6 mg/mL, more preferably
25.+-.5 mg/mL, still more preferably 25.+-.4 mg/mL, yet more
preferably 25.+-.3 mg/mL, most preferably 25.+-.2 mg/mL, and in
particular 25.+-.1 mg/mL, based on the total volume of the
composition.
[0093] In another preferred embodiment, the concentration of
tapentadol is within the range of 27.5.+-.6 mg/mL, more preferably
27.5.+-.5 mg/mL, still more preferably 27.5.+-.4 mg/mL, yet more
preferably 27.5.+-.3 mg/mL, most preferably 27.5.+-.2 mg/mL, and in
particular 27.5.+-.1 mg/mL, based on the total volume of the
composition.
[0094] In still another preferred embodiment, the concentration of
tapentadol is within the range of 30.+-.6 mg/mL, more preferably
30.+-.5 mg/mL, still more preferably 30.+-.4 mg/mL, yet more
preferably 30.+-.3 mg/mL, most preferably 30.+-.2 mg/mL, and in
particular 30.+-.1 mg/mL, based on the total volume of the
composition.
[0095] In still another preferred embodiment, the concentration of
tapentadol is within the range of 32.5.+-.6 mg/mL, more preferably
32.5.+-.5 mg/mL, still more preferably 32.5.+-.4 mg/mL, yet more
preferably 32.5.+-.3 mg/mL, most preferably 32.5.+-.2 mg/mL, and in
particular 32.5.+-.1 mg/mL, based on the total volume of the
composition.
[0096] In yet another preferred embodiment, the concentration of
tapentadol is within the range of 35.+-.6 mg/mL, more preferably
35.+-.5 mg/mL, still more preferably 35.+-.4 mg/mL, yet more
preferably 35.+-.3 mg/mL, most preferably 35.+-.2 mg/mL, and in
particular 35.+-.1 mg/mL, based on the total volume of the
composition.
[0097] In a preferred embodiment, the composition 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.
[0098] 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. Sodium benzoate
is particularly preferred.
[0099] The complete absence of preservatives in the composition is
preferred when the content of tapentadol is sufficiently high so
that due to its preservative property the desired shelf life or in
use stability can be achieved by the presence of the drug itself.
Preferably, under these circumstances the concentration of
tapentadol is at least 10 mg/mL, at least 12.5 mg/mL, at least 15
mg/mL, or at least 17.5 mg/mL, based on the total volume of the
composition.
[0100] The complete absence of preservatives in the composition is
also preferred when the pH value of the aqueous composition is
sufficiently high so that due to its preservative property the
desired shelf life or in use stability can be achieved by the
presence of the drug itself. Preferably, under these circumstances
the pH value of the composition is at least 3.0, at least 3.5, at
least 4.0, or at least 4.5 mg/mL.
[0101] For the purpose of the specification, it is preferably
distinguished between shelf life and in-use stability. Shelf life
preferably refers to the storage stability of a closed container of
the pharmaceutical composition. In-use stability preferably refers
to the storage container that contains a multiple dose preparation
which has been utilized for the first time. Typically, the
shelf-life of a multiple dose preparation is much longer than its
in-use stability.
[0102] In another preferred embodiment, the composition
additionally contains a preservative, which is preferably selected
from the group consisting of 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.
[0103] It has been surprisingly found that aqueous tapentadol
compositions containing sodium benzoate show a lower decrease in
preservative at 50.degree. C. and less degradation products
compared with aqueous tapentadol compositions containing parabens.
Thus, sodium benzoate is a particularly preferred preservative
according to the invention.
[0104] Preferably, the content of the preservative is at most 5.0
wt.-%, more preferably at most 4.0 wt.-%, still more preferably at
most 3.0 wt.-%, yet more preferably at most 2.0 wt.-%, most
preferably at most 1.0 wt.-% and in particular at most 0.5 wt.-%,
based on the total weight of the composition.
[0105] In a preferred embodiment, the preservative, preferably
benzoic acid or its sodium salt, has a concentration within the
range of 1.0.+-.0.6 mg/mL, more preferably 1.0.+-.0.5 mg/mL, still
more preferably 1.0.+-.0.4 mg/mL, yet more preferably 1.0.+-.0.3
mg/mL, most preferably 1.0.+-.0.2 mg/mL, and in particular
1.0.+-.0.1 mg/mL, based on the total volume of the composition.
[0106] In another preferred embodiment, the preservative,
preferably benzoic acid or its sodium salt, has a concentration
within the range of 1.5.+-.0.6 mg/mL, more preferably 1.5.+-.0.5
mg/mL, still more preferably 1.5.+-.0.4 mg/mL, yet more preferably
1.5.+-.0.3 mg/mL, most preferably 1.5.+-.0.2 mg/mL, and in
particular 1.5.+-.0.1 mg/mL, based on the total volume of the
composition.
[0107] In still another preferred embodiment, the preservative,
preferably benzoic acid or its sodium salt, has a concentration
within the range of 2.0.+-.0.6 mg/mL, more preferably 2.0.+-.0.5
mg/mL, still more preferably 2.0.+-.0.4 mg/mL, yet more preferably
2.0.+-.0.3 mg/mL, most preferably 2.0.+-.0.2 mg/mL, and in
particular 2.0.+-.0.1 mg/mL, based on the total volume of the
composition.
[0108] In yet another preferred embodiment, the preservative,
preferably benzoic acid or its sodium salt, has a concentration
within the range of 2.5.+-.0.6 mg/mL, more preferably 2.5.+-.0.5
mg/mL, still more preferably 2.5.+-.0.4 mg/mL, yet more preferably
2.5.+-.0.3 mg/mL, most preferably 2.5.+-.0.2 mg/mL, and in
particular 2.5.+-.0.1 mg/mL, based on the total volume of the
composition.
[0109] The additional presence of a preservative in the composition
is preferred when the content of tapentadol is too low so that due
to its preservative property the desired shelf life or in use
stability cannot be achieved by the presence of the drug itself. As
already mentioned above, the preservative property of tapentadol is
a function of the pH value and thus, at one pH value the addition
of another preservative might be necessary, whereas at another pH
value it can be completely omitted. Preferably, under these
circumstances the concentration of tapentadol is at most 12.5
mg/mL, at most 10 mg/mL, at most 8 mg/mL, at most 7.5 mg/mL, at
most 5.0 mg/mL, at most 4.0 mg/mL, at most 3.0 mg/mL or at most 2.5
mg/mL, based on the total volume of the composition.
[0110] In a preferred embodiment, the relative weight ratio of
tapentadol to the preservative is within the range of from 10:1 to
0.25:1, more preferably 9:1 to 0.33:1, still more preferably 8:1 to
0.5:1, yet more preferably 7:1 to 0.66:1, most preferably 6:1 to
0.75:1 and in particular 5:1 to 1:1. Preferably, the relative
weight ratio of tapentadol to the preservative is within the range
of from 5:1 to 1:1, more preferably 4.5:1 to 1:1, still more
preferably 4:1 to 1:1, yet more preferably 3.5:1 to 1:1, most
preferably 3:1 to 1:1 and in particular 2.5:1 to 1:1.
[0111] Preferably, the sum of the concentration of tapentadol and
the concentration of preservative is equal or below 50 mg/mL,
preferably equal or below 20 mg/mL, based on the total volume of
the composition.
[0112] In a preferred embodiment, the sum of the concentration of
tapentadol and the concentration of preservative is within the
range of 4.0.+-.3.5 mg/mL, more preferably 4.0.+-.3.0 mg/mL, still
more preferably 4.0.+-.2.5 mg/mL, yet more preferably 4.0.+-.2.0
mg/mL, most preferably 4.0.+-.1.5 mg/mL, and in particular
4.0.+-.1.0 mg/mL, based on the total volume of the composition.
[0113] In another preferred embodiment, the sum of the
concentration of tapentadol and the concentration of preservative
is within the range of 6.0.+-.3.5 mg/mL, more preferably 6.0.+-.3.0
mg/mL, still more preferably 6.0.+-.2.5 mg/mL, yet more preferably
6.0.+-.2.0 mg/mL, most preferably 6.0.+-.1.5 mg/mL, and in
particular 6.0.+-.1.0 mg/mL, based on the total volume of the
composition.
[0114] In still another preferred embodiment, the sum of the
concentration of tapentadol and the concentration of preservative
is within the range of 8.0.+-.3.5 mg/mL, more preferably 8.0.+-.3.0
mg/mL, still more preferably 8.0.+-.2.5 mg/mL, yet more preferably
8.0.+-.2.0 mg/mL, most preferably 8.0.+-.1.5 mg/mL, and in
particular 8.0.+-.1.0 mg/mL, based on the total volume of the
composition.
[0115] In a preferred embodiment, the content of the preservative
is at most 90%, more preferably at most 80%, still more preferably
at most 70%, yet more preferably at most 60%, most preferably at
most 50% and in particular at most 40% of the content that would be
needed according to Ph. Eur. in order to sufficiently preserve the
pharmaceutical composition in the absence of tapentadol, either
concerning its shelf-life or, in case of multiple dosed
preparations, optionally concerning its in-use stability.
Sufficient preservation according to Ph. Eur. is preferably defined
as in the experimental section (e.g. for molds and yeasts log
reduction of 1 after 14 and no increase after 28 days).
[0116] 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 E. coli,
S. aureus, Ps. Aeruginosa, S. spp., C. albicans, and/or A. niger,
preferably satisfying the requirement of log reduction of 1 after
14 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.
[0117] Preferably, the composition according to the invention
exhibits a shelf-life under accelerated storage conditions of at
least 1 month, more preferably at least 2 months, still more
preferably at least 3 months, yet more preferably at least 4
months, most preferably at least 5 months and in particular at
least 6 months. Preferably, the shelf life is determined according
to Ph. Eur., particularly as described in the experimental section.
Accelerated storage conditions preferably mean 40.degree. C./75%
relative humidity.
[0118] Preferably, the composition 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.
[0119] Preferably, the composition according to the invention is a
multiple dosed 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.
[0120] Preferably, the composition according to the invention is
liquid or semisolid.
[0121] Preferably, the composition according to the invention is
selected from the group consisting of syrups, drops, solutions,
dispersions, suspensions and emulsions. Emulsions may be of
o/w-type (oil-in-water) or w/o-type (water-in-oil).
[0122] When the pharmaceutical composition is a solution, it may be
selected from the group consisting of aromatic waters, aqueous
acids, diluted acids, douches, enemas, gargles, mouthwashes,
juices, and irrigation solutions.
[0123] Preferably, the composition belongs to the group of sweet
and other viscid aqueous solutions encompassing syrups, honeys,
mucilages, and jellies.
[0124] Other examples of compositions according to the invention
include collodions, elixirs, glycerins, liniments and spirits.
[0125] In a preferred embodiment, the composition according to the
invention is an emulsion, preferably selected from the group
consisting of conventional emulsions, multiple emulsions,
microemulsions and liposomes.
[0126] In another preferred embodiment, the composition according
to the invention is a suspension, preferably selected from the
group consisting of sustained release suspensions, gels and magmas,
and lotions.
[0127] Preferably, the composition is a multiple dosed form, i.e.
customized for more than a single administration. For the purpose
of the specification "multiple dosed" preferably means that the
composition encompasses more than a single dosage unit. For
example, when the composition is a multiple dosed oral solution,
its overall volume is more than the volume that is to be typically
orally administered at once. Instead, the multiple dosed oral
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. For example, when the multiple
dosed oral dosage form that is contained in a storage 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 storage container; at day 2 of the
treatment interval the patient takes another 25 mL so that 200 mL
remain in the storage container; and so on, until at day 10 the
entire amount is taken by the patient.
[0128] In a preferred embodiment the composition according to the
invention is ready to use, i.e. does not require particular
treatment steps such as dissolution in a solvent before it may be
orally administered to the patient.
[0129] A skilled person recognizes that the aqueous composition
according to the invention may alternatively be commercialized as a
precursor in form of a dry powder that is to be dissolved or
dispersed in an appropriate amount of water prior to the first
use.
[0130] Preferably, the composition according to the invention
additionally comprises a taste-enhancing component.
[0131] In a preferred embodiment, the taste-enhancing component
comprises at least one sweetener, preferably selected from the
group comprising cyclamate (E 952), saccharin (E 954) or sodium
saccharin, aspartame (E 951), sucralose (E 955), neotame,
thaumatine (E 957), neohesperidine (E 959), acesulphame potassium
(acesulphame K, E 950) and acesulphame-aspartame salt (E 962), and
sorbitol (E 420). Sucralose is particularly preferred.
[0132] Preferably, the content of the sweetener amounts to
preferably .ltoreq.20% by wt., more preferably .ltoreq.15% by wt.,
still more preferably .ltoreq.10% by wt., most preferably
.ltoreq.5.0% by wt., and in particular .ltoreq.1.0%, based on the
total weight of the composition.
[0133] In a preferred embodiment, the concentration of the
sweetener, preferably sucralose, is within the range of 2.0.+-.1 .5
mg/mL, more preferably 2.0.+-.1.25 mg/mL, still more preferably
2.0.+-.1.0 mg/mL, yet more preferably 2.0.+-.0.75 mg/mL, most
preferably 2.0.+-.0.5 mg/mL, and in particular 2.0.+-.0.25 mg/mL,
based on the total volume of the composition.
[0134] In a preferred embodiment, the concentration of the
sweetener, preferably sucralose, is within the range of 2.5.+-.1.5
mg/mL, more preferably 2.5.+-.1.25 mg/mL, still more preferably
2.5.+-.1.0 mg/mL, yet more preferably 2.5.+-.0.75 mg/mL, most
preferably 2.5.+-.0.5 mg/mL, and in particular 2.5.+-.0.25 mg/mL,
based on the total volume of the composition.
[0135] In a preferred embodiment, the taste-enhancing component
comprises at least one flavoring agent. Flavoring agents are known
to the person skilled in the art. In this context, reference can be
made, for example, to the European Commission: Decision of the
Commission concerning a register of flavouring agents used in or on
foodstuffs, of 23 Feb. 1999; last consolidated version dated
29.03.06. Natural or nature-identical flavorings of fruit are
particularly preferred. Examples of suitable flavoring agents are
orange flavor, blood orange flavor, lemon flavor, lime flavor,
grapefruit flavor, strawberry flavor, raspberry flavor,
blackcurrant flavor, redcurrant flavor, pineapple flavor, blueberry
flavor, cherry flavor, woodruff flavor, vanilla flavor and mixtures
thereof, such as wild berry flavor or strawberry-vanilla flavor.
Raspberry flavor is particularly preferred.
[0136] In a preferred embodiment, the concentration of the
flavoring agent, preferably raspberry flavor, is within the range
of 2.0.+-.1.5 mg/mL, more preferably 2.0.+-.1.25 mg/mL, still more
preferably 2.0.+-.1.0 mg/mL, yet more preferably 2.0.+-.0.75 mg/mL,
most preferably 2.0.+-.0.5 mg/mL, and in particular 2.0.+-.0.25
mg/mL, based on the total volume of the composition.
[0137] The compositions may include one or more further excipients
selected from the group comprising wetting agents, emulsifying
agents, isotonizing agents, surfactant components, solubilizing
agents, thickening agents, colorant agents, and antioxidant
components.
[0138] A wetting agent or surfactant component can be included in
the liquid compositions of the present invention that, when used,
includes one or more quaternary ammonium compounds, such as
benzalkonium chloride, benzethonium chloride and cetylpyridinium
chloride; TPGS, dioctyl sodium sulfosuccinate; polyoxyethylene
alkylphenyl ethers, such as nonoxynol 9, nonoxynol 10, and
octoxynol 9; poloxamers (polyoxyethylene and polyoxypropylene block
copolymers); polyoxyethylene fatty acid glycerides and oils, such
as polyoxyethylene (8) caprylic/capric mono- and diglycerides,
polyoxyethylene (35) castor oil and polyoxyethylene (40)
hydrogenated castor oil; polyoxyethylene alkyl ethers, such as
polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid
esters, such as polyoxyethylene (40) stearate; polyoxyethylene
sorbitan esters, such as polysorbate 20 and polysorbate 80;
propylene glycol fatty acid esters, such as propylene glycol
laureate; sodium lauryl sulfate; fatty acids and salts thereof,
such as oleic acid, sodium oleate and triethanolamine oleate;
glyceryl fatty acid esters, for example glyceryl monostearate;
sorbitan esters, such as sorbitan monolaurate, sorbitan monooleate,
sorbitan monopalmitate and sorbitan monostearate; tyloxapol;
lecithin; stearyl triethanolamine; laurylaminopropionic acid; and
mixtures thereof. Such surfactant component or wetting agent, if
present, will typically together form about 0.25 wt.-% to about 15
wt.-%, preferably about 0.4 wt.-% to about 10 wt.-%, and more
preferably about 0.5 wt.-% to about 5 wt.-%, of the total weight of
the composition.
[0139] A thickening agent or viscosity-enhancing agent can be
included to generally thicken the liquid composition, which
typically improves the mouth-feel of the composition, and/or to
help coat the lining of the gastrointestinal tract. While any
suitable thickening agent can be included in the compositions of
the present invention, a preferred thickening agent, when used,
includes one or more of acacia, alginic acid bentonite, carbomer,
carboxymethyl-cellulose calcium or sodium, cetostearyl alcohol,
methyl cellulose, ethylcellulose, glycerin, gelatin guar gum,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethyl-cellulose, maltodextrin, polyvinyl alcohol,
povidone, propylene carbonate, propylene glycol alginate, sodium
alginate, sodium starch glycolate, starch tragacanth, and xanthan
gum, and any combination thereof. More preferred thickening agents
are glycerin, hydroxypropylmethylcellulose, and xanthan gum, and
any combination thereof. Such a thickening agent, if present, will
typically form about 0.1 wt.-%to 20 wt.-%, preferably about 0.3
wt.-%to about 15 wt.-%, and more preferably about 0.5 wt.-%to 4
wt.-%, of the total weight of the composition.
[0140] A colorant agent, when included, can provide the
compositions with a more aesthetic and/or distinctive appearance.
Colorant agents preferable for inclusion in the present invention
include one or more water-soluble synthetic organic food additives
(e.g., food dyes such as food red dye Nos. 2 and 3, food yellow dye
Nos. 4 and 5 and food blue dye Nos. 1 and 2), water-insoluble lake
dyes (e.g., aluminum salts of the above water-soluble synthetic
organic food additives, etc.), and natural pigments (e.g.,
beta-carotene, chlorophyll, iron oxide red, etc.). Such a colorant
agent, if present, will typically form about 0.001 wt.-% to about 1
wt.-%, preferably about 0.001 wt.-% to about 0.5 wt.-%, and more
preferably about 0.0075 wt.-% to about 0.25 wt.-%, of the total
weight of the composition.
[0141] Examples of a suitable antioxidant component, if used,
include one or more of the following: sulfites; ascorbic acid;
ascorbates, such as sodium ascorbate, calcium ascorbate, or
potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylene
diamine tetraacetic acid (EDTA) or its sodium or calcium salts;
tocopherol; gallates, such as propyl gallate, octyl gallate, or
dodecyl gallate; vitamin E; and mixtures thereof. The antioxidant
component provides long term stability to the liquid compositions.
Addition of the antioxidant component can help enhance and ensure
the stability of the compositions and renders the compositions
stable even after six months at 40.degree. C. A suitable amount of
the antioxidant component, if present, is about 0.01 wt.-% to about
3 wt.-%, preferably about 0.05 wt.-% to about 2 wt.-%, of the total
weight of the composition.
[0142] Solubilizing and emulsifying agents can be included to
facilitate more uniform dispersion of the active ingredient or
other excipient that is not generally soluble in the liquid
carrier. Examples of a suitable emulsifying agent, if used,
includes, for example, gelatin, egg yolk, casein, cholesterol,
acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,
cetostearyl alcohol, cetyl alcohol, and mixtures thereof. Examples
of a suitable solubilizing agent include glycol, glycerin,
D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane,
cholesterol, triethanolamine, sodium carbonate, sodium citrate,
sodium salicylate, sodium acetate, and mixtures thereof.
Preferably, the solubilizing agent includes glycerin. The
solubilizing or emulsifying agent is/are generally present in an
amount sufficient to dissolve or disperse the active ingredient,
i.e. tapentadol, in the carrier. Typical amounts when a
solubilizing or an emulsifier are included are from about 1 wt.-%
to about 80 wt.-%, preferably about 20 wt.-% to about 65 wt.-%, and
more preferably about 25 wt.-% to about 55 wt.-%, of the total
weight of the composition.
[0143] A suitable isotonizing agent, if used, includes sodium
chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures
thereof. A suitable amount of the isotonizing agent, when included,
is typically about 0.01 wt.-% to about 15 wt.-%, more preferably
about 0.3 wt.-% to about 4 wt.-%, and more preferably about 0.5
wt.-% to about 3 wt.-%, of the total weight of the composition.
[0144] Particularly preferred embodiments E.sup.1 to E.sup.8 of
compositions according to the invention are summarized in the
following table:
TABLE-US-00001 E.sup.1 E.sup.2 E.sup.3 E.sup.4 tapentadol
.ltoreq.50 mg/mL .ltoreq.50 mg/mL .ltoreq.30 mg/mL .ltoreq.30 mg/mL
buffer optional 0-5.0 0.001-4.0 wt. % 0.05-2.5 wt. % 0.05-2.5 wt. %
preservative wt. % optional 0-3.0 wt. % 0-1.0 wt. % --
taste-enhancing sweetener and/or .ltoreq.1.0 wt. % 2.0 .+-. 1.5
mg/mL component flavoring agent sweetener sweetener and and
.ltoreq.1.0 wt. % 2.0 .+-. 1.5 mg/mL flavoring agent flavoring
agent water .gtoreq.5 wt. % .gtoreq.50 wt. % 85-99.5 wt. % 90-99.9
wt. % E.sup.5 E.sup.6 E.sup.7 E.sup.8 tapentadol .ltoreq.20 mg/mL
.ltoreq.25 mg/mL 20 .+-. 5 mg/mL 1-10 mg/mL buffer 0.05-2.5 wt. %
0.05-1.0 wt. % 2.0 .+-. 0.6 mg/mL 2.0 .+-. 0.6 mg/mL citric acid or
its citric acid or its citric acid or its monohydrate monohydrate
monohydrate preservative 0.01-0.5 wt. % 0-0.5 wt. % -- 2.5 .+-. 0.5
mg/mL sodium benzoate sodium benzoate taste-enhancing 2.0 .+-. 1.5
mg/mL 2.0 .+-. 1.5 mg/mL 2.0 .+-. 1.0 mg/mL 2.0 .+-. 1.0 mg/mL
component sweetener sucralose sucralose sucralose and and and and
2.0 .+-. 1.5 mg/mL 2.0 .+-. 1.5 mg/mL 2.0 .+-. 1.0 mg/mL 2.0 .+-.
1.0 mg/mL flavoring agent flavoring agent raspberry flavor
raspberry flavor water 90-99.9 wt. % 90-99.9 wt. % 98 .+-. 1.5 wt.
% 98 .+-. 1.5 wt. %
[0145] Other particularly preferred embodiments F.sup.1 to F.sup.8
of compositions according to the invention are summarized in the
following table:
TABLE-US-00002 F.sup.1 F.sup.2 F.sup.3 F.sup.4 tapentadol 4.7 .+-.
4.2 mg/mL 4.7 .+-. 2.1 mg/mL 4.7 .+-. 4.2 mg/mL 4.7 .+-. 2.1 mg/mL
buffer (pH 3.5-4.5) 1.7 .+-. 1.5 mg/mL 1.7 .+-. 0.8 mg/mL 1.7 .+-.
1.5 mg/mL 1.7 .+-. 0.8 mg/mL citric acid or its citric acid or its
citric acid or its citric acid or its monohydrate monohydrate
monohydrate monohydrate preservative 2.4 .+-. 2.0 mg/mL 2.4 .+-.
1.0 mg/mL 2.4 .+-. 2.0 mg/mL 2.4 .+-. 1.0 mg/mL sodium benzoate
sodium benzoate taste-enhancing 2.0 .+-. 1.7 mg/mL 2.0 .+-. 0.8
mg/mL 2.0 .+-. 1.7 mg/mL 2.0 .+-. 0.8 mg/mL component sweetener and
sweetener and sucralose and sucralose and 2.0 .+-. 1.7 mg/mL 2.0
.+-. 0.8 mg/mL 2.0 .+-. 1.7 mg/mL 2.0 .+-. 0.8 mg/mL flavoring
agent flavoring agent flavoring agent flavoring agent water 90-99.9
wt.-% 90-99.9 wt.-% 90-99.9 wt.-% 90-99.9 wt.-% F.sup.5 F.sup.6
F.sup.7 F.sup.8 tapentadol 23.3 .+-. 18.0 mg/mL 23.3 .+-. 9.0 mg/mL
23.3 .+-. 18.0 mg/mL 23.3 .+-. 9.0 mg/mL buffer (pH 3.5-4.5) 2.0
.+-. 1.7 mg/mL 2.0 .+-. 0.8 mg/mL 2.0 .+-. 1.7 mg/mL 2.0 .+-. 0.8
mg/mL citric acid or its citric acid or its citric acid or its
citric acid or its monohydrate; and monohydrate; and monohydrate;
and monohydrate; and 0.5 .+-. 0.3 mg/ml 0.5 .+-. 0.2 mg/ml 0.5 .+-.
0.3 mg/ml 0.5 .+-. 0.2 mg/ml alkali hydroxide alkali hydroxide
alkali hydroxide alkali hydroxide preservative -- -- -- --
taste-enhancing 2.5 .+-. 2.0 mg/mL 2.5 .+-. 1.0 mg/mL 2.5 .+-. 2.0
mg/mL 2.5 .+-. 1.0 mg/mL component sweetener and sweetener and
sucralose and sucralose and 2.0 .+-. 1.7 mg/mL 2.0 .+-. 0.8 mg/mL
2.0 .+-. 1.7 mg/mL 2.0 .+-. 0.8 mg/mL flavoring agent flavoring
agent flavoring agent flavoring agent water 90-99.9 wt.-% 90-99.9
wt.-% 90-99.9 wt.-% 90-99.9 wt.-%
[0146] A further aspect of the invention relates to a
pharmaceutical dosage form comprising the pharmaceutical
composition according to the invention. All preferred embodiments
that are described above in connection with the composition
according to the invention also apply to the dosage form according
to the invention.
[0147] Preferably, the dosage form is selected from the group
consisting of oral solutions, oral gels, suspensions, emulsions,
liquid or gel filled capsules, liquid-filled lozenges, metered
liquid dosing devices, atomizers, nebulizers, sprays, and
liquid-releasing, edible capsules.
[0148] Compared to solid dosage forms, liquid dosage forms have
several advantages. They can be exactly dose, e.g. according to the
body weight of the patients, which can be particularly important in
pediatric patients. Further, they can be administered by means of
probes, e.g. when the patient is young or has problems to
swallow.
[0149] Furthermore, liquid dosage forms tend to have a faster
release, i.e. the concentration of the active ingredient in the
serum or plasma increases faster than after adminsitration of a
solid dosage form (rapid onset), even if the solid dosage form is
qualified as immediate release disage form (IR). Such rapid onset
is particularly desirable in the treatment of pain, since pain
relief is to be achieved as fast as possible.
[0150] Preferably, the dosage form according to the invention is
adapted for administration once daily, twice daily, thrice daily,
four times daily, five times daily, six times daily or even more
frequently.
[0151] In a preferred embodiment the dosage form according to the
invention is adapted for administration to pediatric patients. For
the purpose of the specification, pediatric patients preferably
encompass infants, children, and adolescents. Preferably the upper
age limit of such patients is 12, 13, 14, 15, 16, 17, 18, 19, 20 or
21.
[0152] In this regard the surprising preservative properties of
tapentadol are even more beneficial, as the drug approval
authorities have set stricter standards as to the presence of
preservative in medicaments for pediatric patients. Further, as
tapentadol is suitable for treating pain in patients suffering from
serious diseases, e.g. for treating cancer pain, such patients
including pediatric patients are usually simultaneously treated
with other medicaments, e.g. chemotherapeutics, that have severe
side effects. Under these circumstances, it is even more desirable
to not expose such pediatric patients to preservatives, if
avoidable.
[0153] A further aspect of the invention relates to the
pharmaceutical composition according to the invention as described
above or the pharmaceutical dosage form according to the invention
as described above for use in the treatment of pain.
[0154] A still further aspect of the invention relates to the use
of tapentadol for the manufacture of the pharmaceutical composition
according to the invention as described above or of the
pharmaceutical dosage form according to the invention as described
above for the treatment of pain.
[0155] A yet further aspect of the invention relates to a method
for the treatment of pain comprising the oral administration of the
pharmaceutical composition according to the invention as described
above or of the pharmaceutical dosage form according to the
invention as described above to a subject in need thereof.
[0156] Preferably, the pain is selected from the group consisting
of inflammatory pain, neuropathic pain, acute pain, chronic pain,
visceral pain, migraine pain and cancer pain.
[0157] Another aspect of the invention relates to the use of
tapentadol or a physiologically acceptable salt thereof as
preservative.
EXAMPLES
[0158] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
Example 1
Determination of Antimicrobial Effective Concentration of
Tapentadol Hydrochloride
[0159] It has been revealed in initial studies that tapentadol
hydrochloride at a concentration of 10 mg/mL free base exhibits a
high antimicrobial activity and a high activity against yeast. The
activity against mold (Aspergillus niger) is lower but still within
the limits of the requirements of the Pharm. Eur. The activity of
tapentadol hydrochloride against Aspergillus niger has been
evaluated at lower drug concentrations and at pH 4.0 and 5.0 in
formulations containing citric acid as buffer system and
hydrochloric acid and sodium hydroxide to adjust the pH.
Results:
[0160] At pH 5 there is a better antimicrobial activity of
tapentadol hydrochloride than at pH 4 after 14 and 28 days (see
Table 1).
TABLE-US-00003 TABLE 1 log reduction Aspergillus niger 14 and 28
days after inoculation tapentadol eq. positive 14 28 Ex. (mg/mL) pH
control, log days days 1-1 2 4 5.2 +0.1 0.1 1-2 2 5 0.2 0.4 1-3 4 4
0.3 0.4 1-4 4 5 1.2 1.7 1-5 6 4 0.8 1.2 1-6 6 5 1.3 1.8 1-7 8 4 1.2
1.6 1-8 8 5 1.5 2.3 1-9 10 4 1.5 1.9 1-10 10 5 1.5 2.4
[0161] The requirements of Pharm. Eur. for oral solutions (log
reduction of 1 after 14 and no increase after 28 days concerning
mold A. niger) are met at pH 4 for tapentadol concentrations of
equal or above 8 mg/mL and at pH 5 for concentrations equal or
above to 4 mg/mL.
Conclusion:
[0162] At pH 4 minimal concentration of 8 mg/mL tapentadol is
needed to meet the requirements of the Eur. Pharm. with regard to
Aspergillus niger. There is a concentration limit of 4-8 mg/mL for
antimicrobial effectiveness of tapentadol depending on the pH.
Example 2
[0163] Antimicrobial Robustness testing of 20 mg/mL Tapentadol Oral
Solution
[0164] The 20 mg/mL solution of tapentadol has been subjected to an
antimicrobial robustness testing. As the drug substance tapentadol
hydrochloride acts as the preservative, the antimicrobial activity
of the formulation was determined at 100% and 90% of drug substance
at three different pH levels (target, upper and lower
limit--3.5-4-4.5). The following compositions of the formulation
were used for the antimicrobial robustness testing (Table 2):
TABLE-US-00004 TABLE 2 Composition of the formulations
(concentrations in mg/mL) 100% drug substance 90% drug substance
Example 2-1 2-2 2-3 2-4 2-5 2-6 tapentadol HCl 23.3 23.3 23.3 20.97
20.97 20.97 citric acid monohydrate 2 2 2 2 2 2 sucralose 2.5 2.5
2.5 2.5 2.5 2.5 raspberry flavor 2 2 2 2 2 2 NaOH ad pH 4 3.5 4.5 4
3.5 4.5 purified water q.s. ad 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL
[0165] The testing results revealed that the 20 mg/mL tapentadol
oral solution has a high antibacterial effect and a high effect on
inhibition of growth of C. albicans at all three tested pH levels,
even at lower concentration of 90%. The effect on A. niger is lower
but meets for both concentrations the requirements of the Pharm.
Eur. and USP, showing the overall spectrum of tapentadol
hydrochloride as a preservative.
Example 3
[0166] Antimicrobial Robustness Testing of 4 mg/mL Tapentadol Oral
Solution (Lower Concentration of Sodium Benzoate)
[0167] The 4 mg/mL solution of tapentadol has also been subjected
to an antimicrobial robustness testing. In this concentration the
antimicrobial effect of the drug substance tapentadol hydrochloride
is not sufficiently pronounced. Therefore, sodium benzoate has been
used as a preservative in the formulation. The antimicrobial
activity of the formulation was determined with 100% at target pH
of 4 and with 80% of sodium benzoate at the pH limits of 3.5 and
4.5. The following compositions of the formulation were used for
the antimicrobial robustness testing (Table 3).
TABLE-US-00005 TABLE 3 Composition of the formulations
(concentrations in mg/mL) Example 3-1 3-2 3-3 tapentadol 4.66 4.66
4.66 sodium benzoate 1.77 1.42 1.42 citric acid monohydrate 1.31
1.31 1.31 sucralose 2 2 2 raspberry flavor 2 2 2 NaOH ad pH 4.0 3.5
4.5 purified water q.s. ad 1 mL 1 mL 1 mL
[0168] The testing results revealed that the 4 mg/mL tapentadol
oral solution including 1.77 mg/mL sodium benzoate at target pH did
not comply with the requirements of USP and Pharm. Eur. as an
increase of Ps. Aeruginosa from day 14 to day 28 has been
observed.
[0169] Both formulations containing 80% preservative at the pH
limits did comply, however, the obtained log reduction of 3.3 for
E. coli is borderline.
Example 4
[0170] Antimicrobial Robustness Testing of 4 mg/mL Tapentadol Oral
Solution (Higher Concentration of Sodium Benzoate)
[0171] Based on the obtained results the test was repeated using a
formulation containing a higher preservative concentration of 2.36
mg/mL instead of 1.77 mg/mL sodium benzoate.
[0172] The above study of example 3 was repeated using a
formulation of 4 mg/mL tapentadol and 2.36 mg/mL sodium benzoate
(corresponding to 2 mg/mL benzoic acid). The antimicrobial activity
of the formulation was determined with 100% at target pH of 4 and
with 80% of sodium benzoate at the pH limits of 3.5 and 4.5. The
following compositions of the formulation were used for the
antimicrobial robustness testing (Table 4).
TABLE-US-00006 TABLE 4 Composition of the formulations
(concentrations in mg/mL) Example 4-1 4-2 4-3 tapentadol 4.66 4.66
4.66 sodium benzoate 2.36 1.89 1.89 citric acid monohydrate 1.7 1.7
1.7 sucralose 2 2 2 raspberry flavor 2 2 2 NaOH ad pH 4.0 3.5 4.5
purified water q.s. ad 1 mL 1 mL 1 mL
[0173] The testing results revealed that all requirements from USP
and Pharm. Eur. are fulfilled at target pH 4 and 100% sodium
benzoate as well as for the other two formulations (pH limits at
80% sodium benzoate). Therefore, it can be concluded that 2.36
mg/mL sodium benzoate (corresponding to 2 mg/mL benzoic acid) is
sufficient to provide antimicrobial efficacy for a 4 mg/mL
tapentadol hydrochloride oral solution.
Example 5
[0174] In Use Stability Study with 20 mg/mL Tapentadol Oral
Solution
[0175] For oral solution of tapentadol intended to be used as a
multiple dosed form, an in-use stability study was performed with
the focus on microbial stability. Therefore, during a period of 4
weeks approx. 1 mL of product was taken out 2 times on every
working day in a non-controlled environment simulating the home
conditions for patients. The test was performed on a total amount
of 10 bottles. The solution was removed in a representative way (by
dosing pipette) and the bottles were stored at room temperature
after each removal. After the period of 4 weeks, a microbial count
was performed on the residual solution of all tested bottles.
[0176] No microbial growth was observed for all bottles showing the
overall good antimicrobial properties of tapentadol hydrochloride
in a 20 mg/mL oral solution. It could be demonstrated that the
formulation shows a sufficient antimicrobial effect coming from the
incorporated drug substance.
Example 6
[0177] Screening Chemical Stability of 10 mg/mL Tapentadol Oral
Solution
[0178] Chemical properties of a preliminary formulation containing
tapentadol hydrochloride in the concentration of 10 mg/mL have been
evaluated at different temperatures over a storage period of 6
months. As preservatives sodium benzoate was used in the one
formulation approach, whereas methyl- and propyl parabens were used
in a separate formulation approach.
Results:
[0179] After 1, 3 and 6 months at room temperature (25.degree. C.)
and high temperature (50.degree. C.) the 10 mg/mL solution was
evaluated with regard to the parameters assay of API tapentadol,
degradation products as well as assay of the preservatives. The API
assay remains stable within the 6 months storage duration. For the
parabene formulation a degradation product was observed after 3
months with increased level at higher temperature.
Conclusion:
[0180] The formulation containing sodium benzoate showed less
degradation products compared with the parabens formulation.
Therefore, sodium benzoate was used as selected preservative for
further development.
Example 7
[0181] Chemical Stability of 4 and 20 mg/mL Tapentadol Oral
Solution
[0182] To investigate the chemical stability of tapentadol oral
solutions in different concentrations (4 and 20 mg/mL), stability
studies were performed over 3 months evaluating the following
parameters appearance, assay of tapentadol, degradation, assay
preservative (only for the 4 mg/mL formulation) and pH at
25.degree. C./60% RH, 40.degree. C./75% RH and 50.degree. C. In
addition, for the 4 mg/mL solution 2 weeks cycling studies (from
-15.degree. C. to 30.degree. C. as well as from 5.degree. C. to
40.degree. C.) were performed.
Results:
[0183] No stability trends for both formulations (4 and 20 mg/mL)
of tapentadol oral solution independent on the used flavor
(raspberry or masking flavor) are obvious after 3 months storage
time showing the good stability of the API tapentadol hydrochloride
in solution.
Example 8
[0184] Antimicrobial effect of tapentadol at pH 3 and pH 8
[0185] A tapentadol solution with a concentration of 15 mg/mL
tapentadol (free base) was prepared. The pH-value was adjusted to
the target value of 3 or 8 using citric acid and 1N NaOH solution,
respectively. No additional buffer system was added. To ensure the
placebo solution shows no antimicrobial effect itself, a placebo
solution pH 8 was prepared, with focus on the same pH-value, even
though a different amount of 1N NaOH solution was used for pH
adjustment.
[0186] The formulations were prepared, filled in glass bottles and
sterilized in an autoclave for 30 min at 121.degree. C. and 2 bars.
The sterilized glass bottles were spiked with Staphylococcus aureus
(Staph. aureus), Pseudomonas aeruginosa (Ps. aerouginosa),
Aspergillus niger (Asp. niger) and Candida albicans for the test
"Efficacy of antimicrobial preservation" on the basis of Ph. Eur.
6.6 monograph 5.1.3.
[0187] The Ph. Eur. test acceptance criteria for parenteral
preparations are given in Table (NI=no increase, NR=no recover).
The A criteria express the recommended efficacy to be achieved, in
justified cases where the A criteria cannot be attained for example
for reasons of an increased risk of adverse reaction, the B
criteria must be satisfied. To reduce the amount of experiments for
this first set up of pH-value experiments, the test points at 6 and
24 hours were replaced by a test point at 30 min (table 5).
TABLE-US-00007 TABLE 5 Acceptance criteria for parenteral
preparations for "Efficacy of antimicrobial preservation" (Ph.
Eur.) Log reduction Test criteria 6 h 24 h 7 d 14 d 28 d Bacteria A
2 3 -- -- NR B -- 1 3 -- NI Fungi A -- -- 2 -- NI B -- -- -- 1
NI
[0188] The results for the microbial testing of the solutions are
given for each bacteria / fungi in Tables 6 to 9.
TABLE-US-00008 TABLE 6 Microbial growth of Staph. aureus Microbial
count Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Spiked amount
7.4 .times. 10.sup.5 1.7 .times. 10.sup.6 1.6 .times. 10.sup.6 of
bacteria/fungi 30 min 8.3 .times. 10.sup.5 8 .times. 10.sup.5 2.5
.times. 10.sup.6 7 days 2.8 .times. 10.sup.5 < .times. 10.sup.2
2.3 .times. 10.sup.3 14 days not tested < .times. 10.sup.2 <
.times. 10.sup.2 28 days not tested < .times. 10.sup.2 <
.times. 10.sup.1 Test criteria A failed passed passed Test criteria
B failed passed passed
TABLE-US-00009 TABLE 7 Microbial growth of Ps. aeruginosa Microbial
count Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Spiked amount
1.4 .times. 10.sup.6 1.7 .times. 10.sup.6 1.6 .times. 10.sup.6 of
bacteria/fungi 30 min 1.6 .times. 10.sup.6 < .times. 10.sup.4
4.5 .times. 10.sup.5 7 days 8.8 .times. 10.sup.6 < .times.
10.sup.2 2 .times. 10.sup.3 14 days not tested < .times.
10.sup.2 < .times. 10.sup.2 28 days not tested < .times.
10.sup.2 < .times. 10.sup.2 Test criteria A failed passed passed
Test criteria B failed passed passed
TABLE-US-00010 TABLE 8 Microbial growth of Asp. niger Microbial
count Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Spiked amount
4.2 .times. 10.sup.5 5.4 .times. 10.sup.5 3.9 .times. 10.sup.5 of
bacteria/fungi 30 min 4.3 .times. 10.sup.5 6 .times. 10.sup.5 4.5
.times. 10.sup.5 7 days 6.3 .times. 10.sup.5 4.5 .times. 10.sup.2 8
.times. 10.sup.4 14 days not tested 0.3 .times. 10.sup.2 4.1
.times. 10.sup.5 28 days not tested 1.8 .times. 10.sup.1 4.5
.times. 10.sup.5 Test criteria A failed passed failed Test criteria
B failed passed failed
TABLE-US-00011 TABLE 9 Microbial growth of Candida albicans
Microbial count Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Spiked
amount 2 .times. 10.sup.5 1.7 .times. 10.sup.5 2.4 .times. 10.sup.5
of bacteria/fungi 30 min 2.5 .times. 10.sup.5 < .times. 10.sup.4
2 .times. 10.sup.5 7 days 3.4 .times. 10.sup.6 < .times.
10.sup.2 1.3 .times. 10.sup.3 14 days not tested < .times.
10.sup.2 1.8 .times. 10.sup.3 28 days not tested < .times.
10.sup.2 2.5 .times. 10.sup.3 Test criteria A failed passed failed
Test criteria B failed passed failed
[0189] In the absence of additional preservatives, the tapentadol
solution pH 3 is not sufficiently preserved according to Ph. Eur.
(crit. A and B) for Asp. niger and Cand. albicans, whereas the
tapentadol solution pH 8 passed the crit. A and B for all tested
bacteria and funghi. The placebo pH 8 solution shows no
preservative effect of the solution itself, so that the
antimicrobial effect of the formulation containing tapentadol HCl
is a consequence of the added amount of tapentadol HCl. Considering
this results a clear dependency of the pH-value on the preserving
effect of the tapentadol HCl solution could be shown.
[0190] The tapentadol HCl solution with a higher pH value of 8 has
an improved antimicrobial effect compared to the pH 3 solution, so
a clear dependency of the pH--value of the solution on the
preserving effect of tapentadol was found.
[0191] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the described embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations within the scope of the appended
claims and equivalents thereof.
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