U.S. patent application number 15/867330 was filed with the patent office on 2018-05-17 for semisolid aqueous pharmaceutical composition containing tapentadol.
The applicant listed for this patent is Gruenenthal GmbH. Invention is credited to Roger Carolus Augusta EMBRECHTS, Ulrich FEIL, Sabine Karine Katrien INGHELBRECHT, Ulrich REINHOLD, Marc SCHILLER, Eva WULSTEN.
Application Number | 20180133174 15/867330 |
Document ID | / |
Family ID | 44652117 |
Filed Date | 2018-05-17 |
United States Patent
Application |
20180133174 |
Kind Code |
A1 |
REINHOLD; Ulrich ; et
al. |
May 17, 2018 |
Semisolid Aqueous Pharmaceutical Composition Containing
Tapentadol
Abstract
A semisolid aqueous pharmaceutical composition containing
tapentadol or a physiologically acceptable salt thereof.
Inventors: |
REINHOLD; Ulrich; (Aachen,
DE) ; SCHILLER; Marc; (Aachen, DE) ; WULSTEN;
Eva; (Willich, DE) ; INGHELBRECHT; Sabine Karine
Katrien; (Beerse, BE) ; EMBRECHTS; Roger Carolus
Augusta; (Beerse, BE) ; FEIL; Ulrich;
(Aschaffenburg, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gruenenthal GmbH |
Aachen |
|
DE |
|
|
Family ID: |
44652117 |
Appl. No.: |
15/867330 |
Filed: |
January 10, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15232841 |
Aug 10, 2016 |
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15867330 |
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|
13410837 |
Mar 2, 2012 |
9446008 |
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15232841 |
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61449329 |
Mar 4, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/137 20130101;
Y02A 50/30 20180101; Y02A 50/473 20180101; A61K 9/107 20130101;
A61K 47/14 20130101; A61K 9/06 20130101; A61K 47/06 20130101; Y02A
50/481 20180101; A61K 9/0014 20130101; A61K 47/10 20130101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 47/14 20060101 A61K047/14; A61K 9/00 20060101
A61K009/00; A61K 9/107 20060101 A61K009/107; A61K 47/06 20060101
A61K047/06; A61K 9/06 20060101 A61K009/06; A61K 47/10 20060101
A61K047/10 |
Foreign Application Data
Date |
Code |
Application Number |
May 3, 2011 |
EP |
11 003 603.5 |
Claims
1. A pharmaceutical composition comprising water and tapentadol or
a physiologically acceptable salt thereof, wherein said composition
is a semi-solid.
2. The pharmaceutical composition according to claim 1, wherein
said composition is adapted for topical or local
administration.
3. The pharmaceutical composition according to claim 1, wherein
said composition has an aqueous phase pH value of at least 5.5.
4. The pharmaceutical composition according to claim 1, wherein
said composition is selected from the group consisting of
ointments, creams, magmas, gels, emulsions, suspensions, lotions,
liniments, pastes, poultices, suspension gels and emulsion
gels.
5. The pharmaceutical composition according to claim 1, wherein
said composition is a bi-phasic formulation or a multi-phase
formulation.
6. The pharmaceutical composition according to claim 1, wherein
said composition has a tapentadol content amounting to at least
0.55 wt.-%, based on the total weight of the composition.
7. The pharmaceutical composition according claim 1, wherein said
composition is free of any preservative.
8. The pharmaceutical composition according to claim 1, wherein
said composition further comprises a preservative in an amount that
in the absence of tapentadol is insufficient to preserve the
pharmaceutical composition according to the Ph. Eur.
9. The pharmaceutical composition according to claim 8, wherein
preservative content is at most 5.0 wt.-%, based on the total
weight of the composition.
10. The pharmaceutical composition according to claim 1, wherein
said composition further comprises at least one substance selected
from the group consisting of lipids and surfactants.
11. The pharmaceutical composition according to claim 10, wherein
said composition comprises a lipid selected from the group
consisting of monoglycerides, diglycerides, triglycerides, and
mixtures of two or more thereof.
12. The pharmaceutical composition according to claim 10, wherein
said composition comprises a surfactant having an HLB value of at
least 12.
13. The pharmaceutical composition according to claim 1, wherein
said composition exhibits fluid characteristics of a pseudoplastic
fluid.
14. The pharmaceutical composition according to claim 1, wherein
said composition has a shelf-life under accelerated storage
conditions of at least 3 months.
15. A method of treating pain in a subject in need thereof, said
method comprising administering to said subject a
pharamacologically effective amount of a semi-solid composition
according to claim 1.
16. A method according to claim 15, wherein said pain is selected
from the group consisting of chronic pain and acute pain.
17. A method according to claim 15, wherein said pain is related to
rheumatic disorders, arthritic disorders, painful joints,
postoperative complaints, dental surgery, dermatitis, skin lesions,
skin cancer, mouth sores or athletic injuries.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/232,841, filed Aug. 10, 2016, which is a continuation of
U.S. application Ser. No. 13/410,837, filed Mar. 2, 2012, which
claims the benefit of U.S. provisional patent application No.
61/449,329, filed Mar. 4, 2011, and European patent application no.
EP 11 003 603.5, filed May 3, 2011, the entire disclosures of all
of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The invention relates to a semisolid aqueous pharmaceutical
composition containing tapentadol or a physiologically acceptable
salt thereof.
[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 02/67651, WO
03/035053, WO 2006/002886, WO 2007/128412, WO 2007/128413, WO
2008/110323, WO 2009/092601, WO 2009/067703, and US2010-272815. 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.
[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] For instance, the pain may be caused by a topical effect
that does not require systemic treatment. In this case, systemic
side effects may be avoided when tapentadol is applied topically
and/or locally. Typically, the drug may be applied directly to the
source of pain in a high dosage, thereby keeping the burden to
entire organism to a minimum. Consequently, there is a demand of
pharmaceutical formulations containing tapentadol for topical
and/or local administration.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] In addition to stabilization of pharmaceutical preparations
against chemical and physical degradation, liquid and semisolid
preparations, particularly multiple dose 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. Coli,
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 dose
formulation. Growth of the microorganisms occurs when a sufficient
amount of water is present in the formulation. Biphasic systems of
the O/W-type are especially prone to be excellent breeding grounds
for microorganisms.
[0010] 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 dose preparations.
[0011] 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).
[0012] Many liquid and semisolid formulations, particularly
multiple dose formulations and/or O/W-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 semi-solid formulations containing analgesics such as
ibuprofen and parabens are commercialized under the trademarks:
Dolgit.RTM., Ibutop.RTM. and Elacur.RTM..
[0013] Because of the number of excipients and additives in
pharmaceutical formulations, it is recommended all the ingredients
be listed on the container to reduce the risks that confront
hypersensitive patients when these products are administered.
[0014] Other commercialized pharmaceutical formulations contain
sorbic acid or its potassium salt (e.g. Mobilat.RTM.) or
benzalkonium chloride as preservative. 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).
[0015] Due to these undesired side effects of known preservatives,
it is desirable to provide pharmaceutical compositions for topical
and/or local administration that exhibit a sufficient shelf-life in
the absence of preservatives or at least in the presence of
comparatively low quantities thereof.
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.
[0017] A further object of the invention is to provide
pharmaceutical formulations containing tapentadol or a
physiologically acceptable salt thereof which do not have the
aforementioned preservative based side effects, such as allergic
reactions, typically observed with pharmaceutical formulations
containing preservatives.
[0018] An additional object of the invention is to provide
pharmaceutical formulations which are suitable for topical and/or
local administration of tapentadol.
[0019] These and other objects are achieved by the invention as
described and claimed hereinafter.
[0020] 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.
[0021] A first aspect of the invention relates to a semisolid
aqueous pharmaceutical composition containing tapentadol.
[0022] The term "pharmaceutical composition" includes any
pharmaceutical preparation or formulation that is customized for
being administered to a human being or animal.
[0023] For the purpose of this application 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.
DETAILED DESCRIPTION OF EMBODIMENTS
[0024] 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.
[0025] 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. Preferably, the content of tapentadol is
equal or less than 5.0 wt.-%, based on the total weight of the
composition.
[0026] In a preferred embodiment, the content of tapentadol is
within the range of 0.4.+-.0.35 wt.-%, more preferably 0.4.+-.0.3
wt.-%, still more preferably 0.4.+-.0.2 wt.-%, yet more preferably
0.4.+-.0.15 wt.-%, most preferably 0.4.+-.0.1 wt.-%, and in
particular 0.4.+-.0.05 wt.-%, based on the total weight of the
composition.
[0027] In another preferred embodiment, the content of tapentadol
is within the range of 0.6.+-.0.5 wt.-%, more preferably 0.6.+-.0.4
wt.-%, still more preferably 0.6.+-.0.3 wt.-%, yet more preferably
0.6.+-.0.2 wt.-%, most preferably 0.6.+-.0.1 wt.-%, and in
particular 0.6.+-.0.05 wt.-%, based on the total weight of the
composition.
[0028] In still another preferred embodiment, the content of
tapentadol is within the range of 0.8.+-.0.6 wt.-%, more preferably
0.8.+-.0.5 wt.-%, still more preferably 0.8.+-.0.4 wt.-%, yet more
preferably 0.8.+-.0.3 wt.-%, most preferably 0.8.+-.0.2 wt.-%, and
in particular 0.8.+-.0.1 wt.-%, based on the total weight of the
composition.
[0029] In yet another preferred embodiment, the content of
tapentadol is within the range of 1.0.+-.0.9 wt.-%, more preferably
1.0.+-.0.7 wt.-%, still more preferably 1.0.+-.0.5 wt.-%, yet more
preferably 1.0.+-.0.3 wt.-%, most preferably 1.0.+-.0.2 wt.-%, and
in particular 1.0.+-.0.1 wt.-%, based on the total weight of the
composition.
[0030] In a further preferred embodiment, the content of tapentadol
is within the range of 1.2.+-.1.0 wt.-%, more preferably 1.2.+-.0.8
wt.-%, still more preferably 1.2.+-.0.6 wt.-%, yet more preferably
1.2.+-.0.4 wt.-%, most preferably 1.2.+-.0.2 wt.-%, and in
particular 1.2.+-.0.1 wt.-%, based on the total weight of the
composition.
[0031] In a preferred embodiment, the content of tapentadol amounts
to at least 0.05, at least 0.10 or at least 0.15 wt.-%, more
preferably at least 0.20, at least 0.25 or at least 0.30 wt.-%,
still more preferably at least 0.35, at least 0.40 or at least 0.45
wt.-%, yet more preferably at least 0.50, at least 0.55 or at least
0.60 wt.-%, most preferably at least 0.65, at least 0.70 or at
least 0.75 wt.-%, and in particular at least 0.80, at least 0.85 or
at least 0.90 wt.-%, based on the total weight of the
composition.
[0032] Preferably, the tapentadol is homogeneously distributed in
the composition according to the invention. The content of
tapentadol of two segments of the composition having a volume of
0.1 mL each, deviate from one another by preferably not more than
.+-.10%, more preferably not more than more than .+-.7.5%, still
more preferably not more than .+-.5.0%, most preferably not more
than .+-.2.5%, and in particular not more than .+-.1.0%.
[0033] Preferably, the composition according to the invention is
characterized by a comparatively homogeneous distribution of
density. Preferably, the densities of two segments of the
pharmaceutical composition having a volume of 0.1 mL each, deviate
from one another by not more than .+-.10%, more preferably not more
than more than .+-.7.5%, still more preferably not more than
.+-.5.0%, most preferably not more than .+-.2.5%, and in particular
not more than .+-.1.0%.
[0034] The composition according to the invention is aqueous. For
the purpose of this application, the term "aqueous" means that its
water content is preferably above the typical water content of
solid pharmaceutical compositions which are humidified from the
atmosphere due to the more or less pronounced hygroscopic
properties of their constituents.
[0035] 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.
[0036] In a 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.
[0037] 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.
[0038] In still 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.
[0039] In yet 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.
[0040] The pharmaceutical composition according to the invention is
semisolid at room temperature. A skilled person knows how to
distinguish semisolid pharmaceutical compositions from solid
pharmaceutical compositions and from liquid pharmaceutical
compositions. The term "semisolid" is well accepted in the art. For
the purpose of this application, the term "semisolid" preferably
has the meaning as used in the Eur. Ph.
[0041] Preferably, the semisolid preparation becomes liquid at a
temperature of at most 100.degree. C., more preferably of at most
95.degree. C., still more preferably of at most 90.degree. C., yet
more preferably of at most 85.degree. C., most preferably of at
most 80.degree. C. and in particular of at most 75.degree. C.
[0042] According to the Eur. Ph. semisolid preparations can be
systematically divided into oinments (hydrophobic, hydrophilic and
absorption ointments), creams (hydrophobic and hydrophilic), gels
(hydrophobic and hydrophilic), pastes, poultices and plasters.
Thus, the composition according to the invention is preferably
selected from the group consisting of oinments, creams, gels,
pastes, poultices and plasters.
[0043] Ointments are lipid-based semisolid preparations which do
not necessarily contain an aqueous phase and appear homogeneous. In
simplified terms, they are characterized as single-phase
preparations, although liquid and/or solid particles may be
dispersed therein. Typical base formulations for hydrophobic
ointments contain hard paraffin, soft paraffin, vegetable oils,
animal fats, hydrogenated oils, synthetic oily materials, partially
synthetic glycerides and/or waxes. Hydrophobic ointments can only
absorb small amounts of water. Hydrophilic ointments and absorption
ointments further contain emulsifiers that increase their potency
to absorb water. Hydrophilic ointments are based on formulations
that are soluble in water. They often contain a polyethylene
glycol.
[0044] Creams are bi-phasic or multiple-phase systems that contain
an aqueous and lipid phase. They often have an opaque appearance as
contrasted with translucent ointments. Creams contain at least one
surfactant (emulsifier) whose hydrophilicity determines whether the
cream is hydrophobic (e. g., w/o-type), hydrophilic (e. g.,
o/w-type) or ambiphilic. A cream's phase characteristics are often
complex. For instance, creams may contain more phases than only the
aqueous and lipid phase, e. g. an aqueous phase and two lipid
phases. Or it may further contain solid particles or the lipid
phase may be solid itself. Therefore, creams are usually not
classified as emulsions. They may, however, be referred to as
emulsoid.
[0045] Gels are semisolid systems in which a liquid is solidified
by a gelling agent which forms three-dimensional crosslinked
network within the liquid. The liquid may be aqueous (hydrophobic
gel, oleogel) or lipid-based (hydrophilic gel, hydrogel). Gels
typically exhibit no flow when in the steady-state.
[0046] Creams and ointments may also contain thickening agents and
the classification is not in each and every case unambigous. For
instances, there are semisolid systems that can both be classified
as o/w-creams or hydrogels, and are thus also referred to as
emulsion gels.
[0047] Pastes are lipid-based preparations which contain a high
amount of solid particles dispersed therein. They usually contain
only a small amount of water. Preparations of this type that
contain a high amount of water are usually referred to as
poultices.
[0048] In common parlance, free-running aqueous multiple-phase
preparations that are suspensions of solid particles in hydrophilic
solvents or emulsions are also referred to as lotions.
[0049] Preferably, the composition according to the invention is
selected from the group consisting of ointments, creams, magmas,
gels, emulsions, suspensions, lotions, liniments, pastes,
poultices, suspension gels and emulsion gels.
[0050] In a preferred embodiment, the composition according to the
invention is an emulsoid preparation such as a cream or lotion. The
emulsoid preparation may be hydrophilic, hydrophobic or
amphiphilic.
[0051] For the purpose of this application, the term "hydrophilic
emulsoid preperation" refers to any emulsoid preparation in which
the aqueous phase represents the external phase, including
bi-phasic preparations of the w/o-type and multiple-phase
preparations of the w/o/w-type.
[0052] For the purpose of this application, the term "hydrophobic
emulsoid preparation" refers to any bi-phasic emulsoid preparation
in which the lipid phase represents the external phase, including
biphasic preparations of the w/o-type.
[0053] Preferably, the emulsoid preparation is hydrophilic. In
particular, the emulsoid preparation is of the o/w-type
(oil-in-water) or w/o/w-type (w/o emulsoid preparation in
water).
[0054] In another preferred embodiment, the composition according
to the invention is a suspensoid preparation, preferably selected
from the group consisting of sustained release suspensions, gels
and magmas, and lotions.
[0055] In a preferred embodiment, the aqueous composition according
to the invention is a single phase formulation. In another
preferred embodiment, the composition according to the invention is
a two-phase or multi-phase formulation. Preferably, the composition
contains at least one aqueous phase and at least one lipid
phase.
[0056] In a preferred embodiment, the aqueous phase and the lipid
phase form a bicoherent system.
[0057] In another preferred embodiment, the aqueous phase and the
lipid phase form an emulsoid or suspendoid system, in which they
may independently of each other be present as dispersed phase
and/or coherent phase.
[0058] If the emulsoid system contains a solid phase, two or three
coherent phases may be present. For example, the lipid phase may be
dispersed in an aqueous phase and contain a second aqueous phase
dispersed therein (w/o/w-type). Preferably, the emulsoid system
contains at least one aqueous coherent phase.
[0059] The semisolid aqueous pharmaceutical composition according
to the invention contains tapentadol. Preferably, the tapentadol is
dispersed in the composition. In particular, the tapentadol is
dissolved in an aqueous phase, which may either represent the
composition's single phase or be part of multiple-phase system.
[0060] In a preferred embodiment, the aqueous phase of the
composition has a pH value of at least 5.50, more preferably at
least 5.75, still more preferably at least 6.00, yet more
preferably at least 6.25, even more preferably at least 6.50, most
preferably at least 6.75, and in particular at least 7.00.
[0061] In a preferred embodiment, the pH value of the aqueous phase
of the composition is at least 5.4, more preferably at least 5.5,
still more preferably at least 5.6, yet more preferably at least
5.7, most preferably at least 5.8 and in particular at least 5.9.
Preferably, the pH value is within the range of from 5.4 to 6.5,
more preferably 5.5 to 6.3, still more preferably 5.4 to 6.0.
[0062] In a preferred embodiment, the pH value is within the range
of 5.7.+-.0.3, more preferably 5.7.+-.0.25, still more preferably
5.7.+-.0.2, most preferably 5.7.+-.0.15, and in particular
5.7.+-.0.1.
[0063] In a preferred embodiment, the pH value is within the range
of 6.0.+-.0.6, more preferably 6.0.+-.0.5, still more preferably
6.0.+-.0.4, even more preferably 6.0.+-.0.3, most preferably
6.0.+-.0.2, and in particular 6.0.+-.0.1.
[0064] In a preferred embodiment, the pH value is within the range
of 6.5.+-.1.0, more preferably 6.5.+-.0.9, still more preferably
6.5.+-.0.8, yet more preferably 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 pH value is 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 pH value is 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 pH value is 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 pH value is 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] It has been surprisingly found that tapentadol exhibits a
pH-dependent antimicrobial effect. Thus, the pH value of the
aqueous phase of the composition according to the invention is
preferably adjusted to a value within the physiologically
acceptable range where the antimicrobial effect of tapentadol is
maximized.
[0070] In a preferred embodiment, the concentration of tapentadol
is equal or below 20 mg/mL, based on the total volume of all
aqueous phases within the composition.
[0071] In a 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 all aqueous phases
within the composition.
[0072] 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 all aqueous
phases within the composition.
[0073] 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 all
aqueous phases within the composition.
[0074] 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 all aqueous
phases within the composition.
[0075] 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 all aqueous
phases within the composition.
[0076] 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 0.6.+-.1 mg/mL, and in
particular 0.6.+-.0.05 mg/mL, based on the total volume of all
aqueous phases within the composition.
[0077] In another preferred embodiment, the concentration of
tapentadol is equal or above 20 mg/mL, based on the total volume of
all aqueous phases within the composition.
[0078] 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 all aqueous phases
within the composition.
[0079] 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 all aqueous
phases within the composition.
[0080] 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 all
aqueous phases within the composition.
[0081] 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 all aqueous
phases within the composition.
[0082] 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 all
aqueous phases within the composition.
[0083] 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 all aqueous
phases within the composition.
[0084] In a preferred embodiment, the composition does not contain
any preservative. For the purpose of this application, 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.
[0085] 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.
[0086] 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
aqueous phase.
[0087] For the purpose of this application there is a distinction
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.
[0088] 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.
[0089] It has been surprisingly found that aqueous tapentadol
compositions containing sodium benzoate show less total degradation
products compared with aqueous tapentadol compositions containing
parabens. Thus, sodium benzoate is a particularly preferred
preservative according to the invention.
[0090] Preferably, the preservative is contained in such an amount
that in absence of tapentadol would not sufficiently preserve the
pharmaceutical composition according to the Ph. Eur.
[0091] 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.-% or
at most 0.2 wt.-%, based on the total weight of the aqueous
phase.
[0092] 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.
[0093] 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 aqueous
phase.
[0094] 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
aqueous phase.
[0095] 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
aqueous phase.
[0096] 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
aqueous phase.
[0097] 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 8.0 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 aqueous phase.
[0098] 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.
[0099] Preferably, the sum of the concentration of tapentadol and
the concentration of preservative is below 30 mg/mL, based on the
total volume of the aqueous phase.
[0100] In a preferred embodiment, the sum of the concentration of
tapentadol and the concentration of preservative is within the
range of 20.+-.15 mg/mL, more preferably 20.+-.17.5 mg/mL, still
more preferably 20.+-.15 mg/mL, yet more preferably 20.+-.10 mg/mL,
most preferably 20.+-.7.5 mg/mL, and in particular 20.+-.5 mg/mL,
based on the total volume of the aqueous phase.
[0101] In another preferred embodiment, the sum of the
concentration of tapentadol and the concentration of preservative
is within the range of 15.+-.12.5 mg/mL, more preferably 15.+-.10
mg/mL, still more preferably 15.+-.7.5 mg/mL, yet more preferably
15.+-.5 mg/mL, and most preferably 15.+-.3 mg/mL, and in particular
10.+-.1 mg/mL, based on the total volume of the aqueous phase.
[0102] In still another preferred embodiment, the sum of the
concentration of tapentadol and the concentration of preservative
is within the range of 10.+-.8 mg/mL, more preferably 10.+-.6
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 aqueous phase.
[0103] 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 dose
preparations, optionally concerning its in-use stability. The
criteria for sufficient preservation according to Ph. Eur. are met,
if (a) the concentrations of viable bacteria are reduced to not
more than 0.1% of the initial concentrations by the fourteenth day;
and (b) the concentration of each test microorganism remains at or
below these designated levels during the remainder of the 28-day
test period. These criteria are more specifically defined in the
experimental section.
[0104] Preferably, after 2 days a log 2 reduction is achieved,
after 7 days a log 3 reduction is achieved, and thereafter no
increase can be observed.
[0105] 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,
preferably 3 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.
[0106] 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.+-.2.degree.
C./75% relative humidity.
[0107] 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.
[0108] Preferably, the composition according to the invention is a
multiple dose 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.
[0109] Preferably, the composition according to the invention
further contains at least one lipid. In one preferred embodiment,
the composition contains one lipid. In another preferred
embodiment, the composition contains a mixture of at least two
lipids.
[0110] In a preferred embodiment, the lipid is selected from the
group consisting of [0111] saturated C.sub.8 to C.sub.18 fatty
acids, such as myristic acid and stearic acid; [0112] unsaturated
C.sub.8 to C.sub.18 fatty acids and their esters, such as oleic
acid and ethyl oleate; [0113] mixtures of saturated and unsaturated
C.sub.8 to C.sub.18 fatty acids, including vegetable oils such as
soybean oil and peanut oil; hydrogenated oils such as hydrogenated
castor oil; and animal fats; and [0114] glycerides of fatty acids,
including monoglycerides, diglycerides, triglycerides, and mixtures
thereof; preferably of C.sub.6 to C.sub.12 fatty acids, more
preferably of C.sub.6 to C.sub.10 fatty acids, such as the
caprylic/capric triglyceride mixtures, most preferably medium-chain
triglycerides according to Ph. Eur. or USP, e.g. known and
commercially available under the trade names "Captex.RTM." and
Miglyol.RTM."; [0115] propylene glycol fatty acid esters such as
propylene glycol monocaprylate (known and commercially available
under the trade name "Capryol.RTM."); [0116] waxes including wool
wax, carnauba wax, bees wax and mixtures of saturated C.sub.18 to
C.sub.32 hydrocarbons such as hard paraffin and soft paraffin (e.
g. white petroleum jelly).
[0117] Preferably, the lipid is a C.sub.8-C.sub.18-fatty acid ester
of a monoalcohol (e.g. C.sub.1-C.sub.12-alkylalcohols), a
di-C.sub.8-C.sub.18-fatty acid ester of a dialcohol (e.g. ethylene
glycol or propylene glycol) or tri-C.sub.8-C.sub.18-fatty acid
ester of a trialcohol (e.g. glycerol). Especially preferred are
medium-chain triglycerides according to Ph. Eur. or USP such as
said caprylic/capric triglyceride mixtures.
[0118] Preferably, the content of the lipid in the composition is
within the range of from 0.1 wt.-% to 90 wt.-%, preferably from 1
wt.-% to 80 wt.-%, more preferably from 5 wt.-% to 70 wt.-%, still
more preferably from 10 wt.-% to 50 wt.-%, yet more preferably from
15 wt.-% to 45 wt.-%, and most preferably from 20 wt.-% to 40
wt.-%, based on the content of all lipids contained in the
composition.
[0119] In a preferred embodiment, the lipid is semisolid or solid
at room temperature; i. e. the lipid is a wax or hard fat.
Preferably, the semisolid or solid lipid has a melting point of at
most 100.degree. C., more preferably of at most 95.degree. C.,
still more preferably of at most 90.degree. C., and most preferably
of at most 85.degree. C., even more preferably of at most
80.degree. C., and most preferably of at most 75.degree. C.
[0120] In another preferred embodiment, the lipid is liquid at room
temperature; i. e. the lipid is an oil. Preferably, the oil has a
density within the range of 0.94.+-.0.07 g/cm.sup.3, more
preferably 0.94.+-.0.06 g/cm.sup.3, still more preferably
0.94.+-.0.05 g/cm.sup.3, yet more preferably 0.94.+-.0.04
g/cm.sup.3, even more preferably 0.94.+-.0.03 g/cm.sup.3, most
preferably 0.94.+-.0.02 g/cm.sup.3, and in particular 0.94.+-.0.01
g/cm.sup.3. Preferably, the pure oil has a viscosity at 20.degree.
C. measured in accordance with Ph. Eur. 2.2.8, within the range of
30.+-.9 mPas, more preferably 30.+-.8 mPas, still more preferably
30.+-.7 mPas, yet more preferably 30.+-.6 mPas, even more
preferably 30.+-.5 mPas, most preferably 30.+-.4 mPas, and in
particular 30.+-.3 mPas.
[0121] In an especially preferred embodiment, the composition
contains both an oil and a wax. For example, the composition may
contain a liquid triglyceride mixture and soft paraffin.
Preferably, the relative weight ratio of the oil to wax is within
the range of from 30:1 to 1:30, more preferably 20:1 to 1:20, still
more preferably 10:1 to 1:15, yet more preferably 5:1 to 1:10, most
preferably 1:1 to 1:7.5 and in particular 1:2 to 1:5.
[0122] Preferably, the composition according to the invention
further contains a surfactant. The surfactant may act as an
emulsifier, wetting agent, solubiliser and/or detergent. In one
preferred embodiment, the surfactant acts as an O/W emulsifier. In
another preferred embodiment, the surfactant acts as a W/O
emulsifier.
[0123] In a preferred embodiment, the composition contains a single
surfactant. In another preferred embodiment, the composition
contains a mixture of two or more surfactants.
[0124] Preferably, the surfactants contained in the composition
have a weighted average HLB value of at least 10, in particular a
HLB value within 11 and 14.
[0125] The surfactant may be an ionic surfactant, amphoteric
surfactant or non-ionic surfactant.
[0126] In a preferred embodiment, the surfactant is ionic, in
particular anionic. Suitable anionic ionic surfactants 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.
[0127] In another preferred embodiment, the surfactant is cationic.
Suitable cationic ionic surfactants include but are not limited to
quaternary ammonium compounds, such as benzalkonium chloride,
benzethonium chloride, cetylpyridinium chloride, cetyl
trimethylammoniom bromide, cetyl trimethylammoniom chloride,
5-bromo-5-nitro-1,3-dioxane, dimethyldioctadecylammonium chloride
and dimethyldioctadecylammonium bromide; and hydrohalide salts of
amines, such as octenidine dihydrochloride.
[0128] In still another preferred embodiment, the surfactant is
amphoteric. Suitable amphoteric surfactants include the group of
phospholipids, e. g. lecithine.
[0129] In yet another preferred embodiment, the surfactant is
non-ionic. Suitable non-ionic surfactants include but are not
limited to [0130] polyoxyethylene-sorbitan-fatty acid esters, e.g.
mono- and tri-lauryl, palmityl, stearyl and oleyl esters, such as
the type known under the name "polysorbat" and commercially
available under the trade name "Tween.RTM." including the
surfactants 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]; [0131]
polyoxyethylene-glycerol-fatty acid esters, e.g. mono- and
tri-lauryl, palmityl, stearyl and oleyl esters, such as the type
known and commercially available under the trade name "Tagat.RTM."
[0132] polyoxyethylene fatty acid esters, the fatty acid preferably
having from about 8 to about 18 carbon atoms, such as diglycol
stearate, glycol stearate, glycol distearate and mixtures of
polyoxyethylene esters of 12-hydroxystearic acid, such as the type
known and commercially available under the trade name
"Solutol.RTM."; [0133] polyoxyethylene esters of alpha-tocopheryl
succinate, e. g. D-alpha-tocopheryl-PEG-1000-succinate (TPGS);
[0134] polyglycolyzed glycerides, such as the types known and
commercially available under the trade names Gelucire.RTM." and
"Labrasol.RTM."; [0135] reaction products of a natural or
hydrogenated castor oil and ethylene oxide such as the various
liquid surfactants known and commercially available under the trade
name "Cremophor.RTM."; [0136] glycerol fatty acid esters, e.g.
mono- and tri-lauryl, palmityl, stearyl and oleyl esters, including
diglycol stearate, glycerol monostearate, glycerol monopalmitate
and glycerol trioleate; [0137] fatty alcohols or sterols including
cetyl alcohol, stearyl alcohol, cetylstearyl alcohol and
cholesterol.
[0138] In a particularly preferred embodiment, the pharmaceutical
composition according to the invention comprises a surfactant or
mixture of different surfactants obtainable by esterifying
saturated or unsaturated C.sub.12-C.sub.18-fatty acids, optionally
bearing a hydroxyl group, with glycerol and optionally, a
polyethylene glycol; wherein the polyethylene glycol preferably
comprises 10 to 40 ethylene oxide units (--CH.sub.2CH.sub.2O--).
Especially preferred surfactants that are contained in the
composition according to the invention are non-ionic surfactants
having a hydrophilic-lipophilic balance (HLB) of at least 10, in
particular non-ionic surfactants having an HLB value of at least
12, more in particular non-ionic surfactant's having an HLB value
within 14 and 16. Examples for this type of surfactants are the
surfactants "Tween.RTM. 80", "Solutol.RTM. HS 15" and "Tagat.RTM.
S2".
[0139] In another preferred embodiment the pharmaceutical
composition according to the invention contains at least one
surfactant having a HLB value of at least 10 (hydrophilic
surfactant) and at least one surfactant having a HLB value below 10
(lipophilic surfactant). For example, the composition may contain
macrogol-20-glycerolhydroxystearat 40 (e.g., Tagat.RTM. S2) and/or
cetyl alcohol as the hydrophilic surfactant component and glycerol
monostearate as the lipophilic surfactant component.
[0140] Preferably, the hydrophilic surfactant is selected from
[0141] the group consisting of macrogolhydroxystearate,
macrogolglycerylhydroxystearate and macrogolglyceryllaurate,
wherein the macrogol moiety preferably comprises 15 to 45 ethylene
oxide units; and/or [0142] the group consisting of cetyl alcohol,
stearyl alcohol and cetylstearyl alcohol.
[0143] Preferably, the lipophilic surfactant is selected from the
group consisting of glycerol monostearate, glycerol monopalmitate
and glycerol trioleate.
[0144] Preferably, the relative weight ratio of the surfactant
having a HLB value of at least 10 (hydrophilic surfactant) and the
surfactant having a HLB value below 10 (lipophilic surfactant) is
greater than or equal to 1.
[0145] Preferably, the relative weight ratio of the surfactant
having a HLB value of at least 10 (hydrophilic surfactant) and the
surfactant having a HLB value below 10 (lipophilic surfactant) is
within the range of 20:1 to 1:15, more preferably 15:1 to 1:10,
still more preferably 12:1 to 1:8, yet more preferably 10:1 to 1:6,
even more preferably 7:1 to 1:5, most preferably 5:1 to 1:2 and in
particular 4:1 to 1:1.
[0146] In a preferred embodiment, the content of the surfactant is
at least 0.1 wt.-%, more preferably at least 1 wt.-%, still more
preferably at least 2 wt.-%, or at least 3 wt.-%, yet more
preferably at least 5 wt.-%, or at least 7 wt.-%, most preferably
at least 10 wt.-%, or at least 12 wt.-%, and in particular at least
14 wt.-%, or at least 15 wt.-%, based on the total weight of the
composition.
[0147] In a preferred embodiment, the content of the surfactant
ranges preferably from 0.1 wt.-% to 95 wt.-%, more preferably from
1 wt.-% to 80 wt.-%, still more preferably from 2.5 wt.-% to 70
wt.-%, yet more preferably from 5 wt.-% to 50 wt.-%, most
preferably from 7.5 wt.-% to 30 wt.-%, and in particular from 10
wt.-% to 25 wt.-%, based on the total weight of the
composition.
[0148] In a preferred embodiment, the relative weight ratio of the
surfactant to the lipid is within the range of from 20:1 to 1:20,
more preferably 10:1 to 1:10, still more preferably 7.5:1 to 1:5,
yet more preferably 6:1 to 1:2, most preferably 5:1 to 1:1 and in
particular 3.5:1 to 1.5:1.
[0149] The composition according to the invention may further
contain a hydrophilic solvent. The hydrophilic solvent 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.
[0150] The composition according to the invention may be 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, or organic bases such as trometamol.
Buffer systems derived from citric acid, phosphoric acid or
trometamol 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.
[0151] Persons skilled in the art will be 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 this application, 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.
[0152] Liquid and semisolid compositions can be characterized by
their viscosity and flow behavior and classified as follows.
[0153] Newtonian fluids exhibit ideal flow characteristics; i. e.
the relation between shear stress and shear rate is linear and
their viscosity does thus not depend on the shear rate. Pure
liquids usually exhibit Newtonian fluid characteristics.
[0154] Most semisolid compositions, however, show a non-linear
relation between shear stress and shear rate. They are referred to
as non-Newtonian fluids or structurally viscous fluids. According
to their different correlations between shear stress and shear
rate, they are classified as pseudoplastic, dilatant fluid, Bingham
plastic or Casson plastic.
[0155] Pseudoplastic fluids exhibit a decreasing viscosity as the
applied shear rate is increased. Examples are creams that contain
anisometric solid particles.
[0156] Dilatant fluids exhibit an increasing viscosity as the
applied shear rate is increased. Examples of this type are pastes
having a high content of solid material.
[0157] Plastic fluids are not able to flow at low shear stresses.
However, after a certain shear stress value, the so-called shear
stress yield, has been reached, they may show an ideal plastical
flow behavior (Bingham plastic fluid) or non-ideal flow behavior
(Casson plastic fluid). Examples are gels in which the polymeric
structure formed by the gelling agent has to be broken by a certain
amount of shear stress before flowing may occur. Once the structure
has been broken and the shear stress is further increased, the
fluid may for example behave as a liquid and exhibit Newtonian
characteristics. Once the shear stress is removed, the fluid
usually regains its plastic flow characteristics, most often,
however, with time lag (thixotropic fluid).
[0158] Fluids may also show a combination of the above-mentioned
flow characteristics. For example, a fluid may exhibit a Newtonian
fluid behavior at low shear stresses and a pseudoplastic fluid
behavior at high shear stresses.
[0159] The viscosity and flow behavior of a liquid or semisolid
composition can be experimentally determined by means of a
rotational viscosimeter.
[0160] Preferably, the composition according to the invention
exhibits a viscosity of a most 10.sup.12 mPas, more preferably of
at most 10.sup.10 mPas, still more preferably of at most 10.sup.9
mPas, yet more preferably of at most 10.sup.8, most preferably of
at most 10.sup.7 mPas, and in particular of 10.sup.6 mPas. In a
preferred embodiment, the viscosity is within the pange of from 1
to 100 Pas, more preferably 5 to 20 Pas, when measured in
accordance with Eur. Ph.
[0161] In a preferred embodiment, the composition according to the
invention exhibits Newtonian fluid characteristics.
[0162] In another preferred embodiment, the composition exhibits
non-Newtonian fluid characteristics.
[0163] Preferably, the semisolid composition is selected from the
group of pseudoplastic fluids, dilatant fluids and plastic
fluids.
[0164] In a preferred embodiment, the semisolid composition
exhibits the fluid characteristics of a dilatant fluid.
[0165] In another preferred embodiment, the semisolid composition
exhibits the fluid characteristics of a plastic fluid. The plastic
fluid may be a Bingham plastic fluid or a Casson plastic fluid.
Preferably, the plastic fluid also exhibits viscoelastic
properties.
[0166] In still another preferred embodiment, the semisolid
composition exhibits the fluid characteristics of a pseudoplastic
fluid. Preferably, the viscosity curve of the pseudoplastic fluid
resembles the one of a Newtonian at low shear stresses and/or at
high shear stresses.
[0167] Preferably, at low shear stresses of at most 50 Pa and
25.degree. C., the viscosity does not change by at most 40%, more
preferably at most 30%, still more preferably at most 20%, most
preferably at most 10%.
[0168] Preferably, at low shear stresses of at most 100 Pa and
25.degree. C., the viscosity does not change by at most 40%, more
preferably at most 30%, still more preferably at most 20%, most
preferably at most 10%.
[0169] Preferably, at a shear rate of 40 s.sup.-1 and 25.degree.
C., the composition exhibits a viscosity within the range of from 1
mPas to 110.sup.12 mPas, more preferably within the range of from 2
mPas to 110.sup.11 mPas, still more preferably within the range of
from 5 mPas to 110.sup.10 mPas, yet more preferably within the
range of from 10 mPas to 110.sup.9 mPas, most preferably within the
range of from 50 mPas to 110.sup.6 mPas, and in particular within
the range of from 10.sup.2 mPas to 110.sup.4 mPas.
[0170] Preferably, at a shear rate of 80 s.sup.-1 and 25.degree.
C., the composition exhibits a viscosity within the range of from 1
mPas to 110.sup.12 mPas, more preferably within the range of from 2
mPas to 110.sup.11 mPas, still more preferably within the range of
from 5 mPas to 110.sup.10 mPas, yet more preferably within the
range of from 10 mPas to 110.sup.9 mPas, most preferably within the
range of from 50 mPas to 110.sup.6 mPas, and in particular within
the range of from 10.sup.2 mPas to 110.sup.4 mPas.
[0171] Preferably, at a shear rate of 120 s.sup.-1 and 25.degree.
C., the composition exhibits a viscosity within the range of from 1
mPas to 110.sup.12 mPas, more preferably within the range of from 2
mPas to 110.sup.11 mPas, still more preferably within the range of
from 5 mPas to 110.sup.10 mPas, yet more preferably within the
range of from 10 mPas to 110.sup.9 mPas, most preferably within the
range of from 50 mPas to 110.sup.6 mPas, and in particular within
the range of from 10.sup.2 mPas to 110.sup.4 mPas.
[0172] Preferably, at a shear rate of 160 s.sup.-1 and 25.degree.
C., the composition exhibits a viscosity within the range of from 1
mPas to 110.sup.12 mPas, more preferably within the range of from 2
mPas to 110.sup.11 mPas, still more preferably within the range of
from 5 mPas to 110.sup.10 mPas, yet more preferably within the
range of from 10 mPas to 110.sup.9 mPas, most preferably within the
range of from 50 mPas to 110.sup.6 mPas, and in particular within
the range of from 10.sup.2 mPas to 110.sup.4 mPas.
[0173] In a preferred embodiment, at a shear rate of 40 s.sup.-1
and 25.degree. C., the composition exhibits a viscosity of
preferably at least 4,850 mPas, more preferably of at least 4,900
mPas, still more preferably of at least 4,950 mPas, yet more
preferably of at least 5,000 mPas, most preferably of at least
5,100 mPas, and in particular of at least 5,200 mPas.
[0174] In a preferred embodiment, at a shear rate of 80 s.sup.-1
and 25.degree. C., the composition exhibits preferably a viscosity
of at least 2,250 mPas, more preferably of at least 2,300 mPas,
still more preferably of at least 2,350 mPas, yet more preferably
of at least 2,400 mPas, most preferably of at least 2,450 mPas, and
in particular of at least 2,500 mPas.
[0175] In a preferred embodiment, at a shear rate of 120 s.sup.-1
and 25.degree. C., the composition exhibits a viscosity of
preferably at least 1,600 mPas, more preferably of at least 1,650
mPas, still more preferably of at least 1,700 mPas, yet more
preferably of at least 1,750 mPas, most preferably of at least
1,800 mPas, and in particular of at least 1,850 mPas.
[0176] In a preferred embodiment, at a shear rate of 160 s.sup.-1
and 25.degree. C., the composition exhibits a viscosity of
preferably at least 1,300 mPas, more preferably of at least 1,350
mPas, still more preferably of at least 1,400 mPas, yet more
preferably of at least 1,450 mPas, and most preferably of at least
1,500 mPas.
[0177] The composition according to the invention may be
transparent, translucent or opaque.
[0178] In a preferred embodiment, the composition is translucent
having a visible light transmission of least 10%, more preferably
of at least 20%, even more preferably of at least 30%, yet more
preferably of at least 50%, still more preferably of at least 70%,
most preferably of at least 80%, and in particular of at least
90%.
[0179] In a preferred embodiment, the composition is translucent
having a visible light transmission of at most least 90%, more
preferably of at most 80%, even more preferably of at most 70%, yet
more preferably of at most 50%, still more preferably of at most
30, most preferably of at most 20%, and in particular of at most
10%.
[0180] The compositions may include one or more further excipients
selected from the group consisting of thickening agents, gelling
agents, antioxidants, fragrances, chelating agents and penetration
enhancers.
[0181] A thickening agent, viscosity-enhancing agent or gelling
agent can be included to generally thicken the liquid composition.
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, carboxymethylcellulose calcium or sodium, cetostearyl
alcohol, methyl cellulose, ethylcellulose, glycerin, gelatin, guar
gum, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, locust bean gum, maltodextrin,
pectin, polyacrylic acid and its derivatives (carbomers), polyvinyl
alcohol, polyvinylpyrrolidone, povidone, propylene carbonate,
propylene glycol alginate, sodium alginate, sodium starch
glycolate, starch, highly dispersed silicium dioxide, tragacanth,
tragant and xanthan gum, and any combination thereof. More
preferred thickening agents are carbomer, cellulose derivatives
such as sodium carboxymethyl cellulose and methyl cellulose,
galactomannans such as guar gum and locust bean gum, sodium
alginate, 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.
[0182] 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; butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), and mixtures thereof. Addition of
the antioxidant component can help enhance and ensure the stability
of the composition and render the composition 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.
[0183] The composition according to the invention may further
contain a fragrance. Suitable fragrances include lavender oil, rose
oil, lemon oil and almond oil.
[0184] Examples of a suitable chelating agent, if used, include
citric acid, maleic acid and ethylenediaminetetraacetic acid (EDTA)
and its sodium or calcium salts.
[0185] The composition according to the invention may contain a
penetration enhancer that improves the transdermal drug delivery.
Suitable penetration enhancers include cyclodextrins, ethanol,
oleic acid, lecithin, propylene glycol, Fatty acid esters of
propylene glycol (e. g. propylene glycol dipelargonate),
polyethylene glycole, and terpenes such as nerolidol, geraniol,
carvacrol, eucalyptol, menthol, limonene, linalool and cineol.
[0186] Preferably, the pharmaceutical composition is for the
treatment of acute or chronic pain.
[0187] In a preferred embodiment, the pain is related to wounds,
burns, ulcers or abcesses of the skin and/or mucous membranes.
[0188] In another preferred embodiment, the pain is related to bone
disorders, joint disorders and/or muscle disorders.
[0189] Preferably, the pain is related to rheumatic disorders,
arthritic disorders, painful joints, postoperative complaints,
dental surgery, skin inflammation (dermatitis), skin lesions, skin
cancer, mouth sores and/or athletic injuries.
[0190] In a preferred embodiment, administration of the composition
proceeds topically and/or locally. In this regard, topical and/or
local administration includes every administration of the
composition to a site which is identical to the site of pain and/or
at least is located nearby. In particular, the topical and/or local
administration has the purpose of delivering tapentadol directly to
the desired site of action, thereby avoiding systemic
side-effects.
[0191] Preferably, the systemic concentration of tapentadol is 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 applied systemically.
[0192] The composition may be applied topically to the skin,
cornea, rectal tissue, nasal mucosa, vagina, buccal tissue,
urethral membrane and/or external ear lining.
[0193] In another preferred embodiment, the administration of the
composition has the purpose of inducing a systemic mode of
action.
[0194] Preferably, the composition 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.
[0195] In a preferred embodiment the composition according to the
invention is adapted for administration to pediatric, geriatric
and/or pregnant patients.
[0196] For the purpose of this application, 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.
[0197] For the purpose of this application, geriatric patients
preferably encompass patients with a lower age limit of 60,
preferably 62, more preferably 64, even more preferably 66, yet
more preferably 68, and in particular 70.
[0198] In this regard the surprising preservative properties of
tapentadol are even more beneficial, as the drug approval
authorities have recommended 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.
[0199] In this regard the topical and/or local treatment of pain is
also beneficial, since the systemic concentration of tapentadol may
be kept at a sub-therapeutic level and systemic side effects that
burden the entire organism may be avoided. To keep the systemic
concentration of a drug at a low level is especially crucial in the
treatment of particularly pediatric, geriatric and/or pregnant
patients.
[0200] Preferably, the composition is a multiple dose form, i.e.
customized for more than a single administration. For the purpose
of this application, "multiple dose" preferably means that the
composition encompasses more than a single dosage unit. For
example, when the composition is a multiple dose cream, its overall
volume is more than the volume that is to be typically administered
at once. Instead, the multiple dose cream 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 dose composition that
is contained in a storage container has a total volume of 20 mL and
the prescribed dosage unit approx. 2 mL once daily, at day 1 of the
treatment interval the patient takes 2 mL so that 18 mL remain in
the storage container; at day 2 of the treatment interval the
patient takes another 2 mL so that 16 mL remain in the storage
container; and so on, until at day 10 the entire amount is taken by
the patient.
[0201] In a preferred embodiment, the semisolid aqueous composition
according to the invention is ready to use, i.e. does not require
particular treatment steps such as dispersing in a liquid medium
before it may be administered to the patient.
[0202] Persons skilled in the art will recognize that the aqueous
semisolid composition according to the invention may alternatively
be commercialized as a precursor in form of a dry powder that is to
be dispersed in an appropriate amount of water prior to the first
use.
[0203] 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.
[0204] 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.
[0205] In a preferred embodiment, the composition is made by
melting its semisolid and/or solid ingredients, optionally in
presence of other ingredients, and mixing them with the remaining
ingredients to form a homogeneous mixture.
[0206] In another preferred embodiment, the composition is made by
separately preparing [0207] the aqueous phase containing the
tapentadol, water and preferably a surfactant; and [0208] the lipid
phase containing the lipid, and optionally other ingredients such
as surfactants, waxes and/or lubricants; and mixing the two phases
thereafter, preferably at an increased temperature at which both
phases are liquid.
[0209] In still another preferred embodiment, the composition is
prepared by triturating two or more of the ingredients.
[0210] In yet another preferred embodiment, the composition is
prepared by means of an ointment mill.
[0211] A yet further aspect of the invention relates to a method
for the treatment of pain comprising the topical and/or local
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.
[0212] In a particular preferred embodiment, the composition
according to the invention is a composition: [0213] wherein the
content of tapentadol is within the range of from 0.01 to 50 wt.-%;
and/or [0214] wherein the water content is at least 0.5 wt.-%;
and/or [0215] which contains a surfactant having a HLB value of at
least 10; and/or [0216] which contains a lipid, preferably a
triglyceride; and/or [0217] which contains a wax selected from wool
wax, carnauba wax, bees wax, hard paraffin, soft paraffin and white
petroleum jelly; [0218] which does not contain any preservative;
and/or [0219] which is a biphasic or multiple-phase system
containing at least one aqueous and at least one lipid phase, and
the aqueous phase is preferably a coherent phase; and/or [0220]
which is a non-Newtonian fluid; and/or [0221] which exhibits the
fluid characteristics of a pseudoplastic fluid; and/or [0222] which
is adapted for topical and/or local administration; and/or [0223]
which is adapted for administration to pediatric, geriatric and/or
pregnant patients. [0224] whose preparation includes melting of
semisolid and/or solid ingredients.
BRIEF DESCRIPTION OF THE DRAWING
[0225] FIG. 1 is a graph showing the viscosity curves of semi-solid
compositions according to the invention measured at 25.degree. C.
by a rotational viscosimeter.
EXAMPLES
[0226] The following examples further illustrate the invention but
are not be construed as limiting its scope.
Example 1
[0227] Creams were formulated according to the following
compositions.
TABLE-US-00001 TABLE 1 Ingredients [wt.-%] C-1 I-1 I-2 Aqueous
Phase Tapentadol HCl 0.0 0.6 1.25 Macrogol-20-glycerol-monostearate
(Tagat S2) 7.0 7.0 7.0 Purified water 50.0 49.4 48.75 Lipid phase
Glycerolmonostearate 4.0 4.0 4.0 Cetyl alcohol 6.0 6.0 6.0 Miglyol
.RTM. 812 7.5 7.5 7.5 White petroleum jelly 25.5 25.5 25.5
[0228] In the creams the aqueous phase represented the coherent
phase (o/w-type), so that the formulation should be principally
sensitive to microbial contamination. The formulations were stored
in amber glass container.
[0229] Assuming that tapentadol hydrochloride is only present in
the aqueous phase, its concentration therein amounts to 12.0 mg/mL
(10.3 mg/mL tapentadol) for the inventive formulation I-1 and 25.0
mg/mL (21.46 mg/mL tapentadol) for the inventive formulation
I-2.
[0230] The formulations were spiked with Staphylococcus aureus
(Staph. aureus), Pseudomonas aeruginosa (Ps. aerouginosa),
Aspergillus niger (Asp. niger) and Candida albicans and their
efficacy of antimicrobial preservation was evaluated according to
the test "efficacy of antimicrobial preservation" as recommended by
the Ph. Eur. The test acceptance criteria for the preparations
according to the Ph. Eur. are given in Tables 2 and 3. The criteria
A express the recommended efficacy to be achieved. In justified
cases where the criteria A cannot be attained, for example for
reasons of an increased risk of adverse reaction, the criteria B
must be satisfied.
TABLE-US-00002 TABLE 2 Acceptance criteria for topical preparations
("Efficacy of antimicrobial preservation" test, Ph. Eur.) Log
reduction Test criteria 2 d 7 d 14 d 28 d Bacteria A 2 3 -- NI B --
-- 3 NI Fungi A -- -- 2 NI B -- -- 1 NI (NI = no increase, NR = no
recover)
TABLE-US-00003 TABLE 3 Acceptance criteria for parenteral
preparations ("Efficacy of antimicrobial preservation" test, 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
(NI = no increase, NR = no recover)
[0231] The "efficacy of antimicrobial preservation" tests revealed
that the placebo cream did not show any preservative effect of the
formulation itself. The antimicrobial effect of the formulation
containing tapentadol HCl is thus a consequence of presence of
tapentadol. Moreover, it was demonstrated that the efficacy of
antimicrobial preservation depends on the amount of tapentadol; the
inventive formulation I-1 containing 10.3 mg tapentadol per mL of
the aqueous phase was preserved by tapentadol to a certain extent,
but Staph. aureus (crit. A and B) and Aps. niger (crit. A) were not
sufficiently reduced during the test time according to the test
parameters. The inventive formulation I-2 (21.6 mg tapentadol per
mL of the aqueous phase), however, was sufficiently preserved by
tapentadol even for all tested bacteria/fungi.
CONCLUSION
[0232] The experiments using different concentrations of tapentadol
in the cream show that the concentration where the preservative
effect of tapentadol starts is between 12 and 25 mg of tapentadol
HCl in 100 mL of the aqueous phase. In a suitable concentration
tapentadol can thus be used as a preservative for creams.
Example 2
[0233] The viscosity curves of example compositions I-1 and I-2
according to the invention were determined as follows:
[0234] The experiments were conducted with a Haake RotoVisco RV1
device (sensor C60/1.degree. together with thermocontroler DC30,
Haake) at 25.0.+-.0.1.degree. C. The material (1.0 mL) was placed
between the stator and the rotor and the gap distance of which was
adjusted to 0.052 mm. The material was tempered at 25.0.degree. C.
before the experiment was started. The viscosity curve was
determined with the software RheoWin 3 and the viscosity values
(n=4) at different shear stresses (.DELTA.=40 s.sup.-1) were taken
to characterize the inventive samples. The viscosity curves are
depicted in FIG. 1 and the calculated viscosity values are listed
in the following table.
TABLE-US-00004 TABLE 4 viscosity shear stress t shear rate [mPa s]
[Pa] [s] [1/s] I-1 I-2 I-1 I-2 I-1 I-2 40.000 4790.6 5457.8 191.59
218.26 161.80 122.39 80.000 2189.0 2722.7 175.11 217.80 197.81
158.39 120.00 1532.3 1917.9 183.87 230.14 233.81 194.39 160.00
1219.2 1533.4 195.07 245.34 269.79 230.38
[0235] In both cases the viscosity decreased with increasing shear
rate, i. e. both fluids exhibited a pseudoplastic flow
behavior.
Example 3
Antimicrobial Effect of Tapentadol at pH 3 and pH 8
[0236] 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.
[0237] 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. The Ph. Eur. test acceptance criteria for
parenteral preparations are given in Table 1 (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-00005 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
[0238] The results for the microbial testing of the solutions are
given for each bacteria/fungi in Tables 6 to 9.
TABLE-US-00006 TABLE 6 Microbial growth of Staph. aureus Microbial
count Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Spiked amount of
7.4 .times. 10.sup.5 1.7 .times. 10.sup.6 1.6 .times. 10.sup.6
bacteria/fungi 30 min 8.3 .times. 10.sup.5 .sup. 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 .sup. < .times. 10.sup.2 28 days not tested <
.times. 10.sup.2 .sup. < .times. 10.sup.1 Test criteria A failed
passed passed Test criteria B failed passed passed
TABLE-US-00007 TABLE 7 Microbial growth of Ps. aeruginosa Microbial
count Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Spiked amount of
1.4 .times. 10.sup.6 1.7 .times. 10.sup.6 1.6 .times. 10.sup.6
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 .sup. 2 .times. 10.sup.3 14 days not tested < .times.
10.sup.2 .sup. < .times. 10.sup.2 28 days not tested <
.times. 10.sup.2 .sup. < .times. 10.sup.2 Test criteria A failed
passed passed Test criteria B failed passed passed
TABLE-US-00008 TABLE 8 Microbial growth of Asp. niger Microbial
count Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Spiked amount of
4.2 .times. 10.sup.5 5.4 .times. 10.sup.5 3.9 .times. 10.sup.5
bacteria/fungi 30 min 4.3 .times. 10.sup.5 .sup. 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 .sup. 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-00009 TABLE 9 Microbial growth of Candida albicans
Microbial count Placebo pH 8 Tapentadol pH 8 Tapentadol pH 3 Spiked
amount of .sup. 2 .times. 10.sup.5 1.7 .times. 10.sup.5 2.4 .times.
10.sup.5 bacteria/fungi 30 min 2.5 .times. 10.sup.5 < .times.
10.sup.4 .sup. 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
[0239] 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.
[0240] 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.
[0241] 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.
* * * * *