Note: Descriptions are shown in the official language in which they were submitted.
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1
Pharmaceutical containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol
and
providing delayed release of the active ingredient
This is a divisional application of Canadian Patent Application No. 2,464,578,
filed
October 22, 2002.
The invention relates to a slow-release pharmaceutical formulation, containing
3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol or a pharmaceutically
acceptable salt
thereof in a matrix.
The subject matter of this divisional application is directed to a slow-
release pharmaceutical
composition wherein the slow-release is achieved by means of a normal matrix
with a coating
which retards the release of active ingredient or by means of an osmotically
driven release
system.
The subject matter of the parent application has been restricted to a slow-
release pharmaceutical
composition wherein the slow-release is achieved by means of a slow-release
matrix. However,
it should be understood that the expression "the invention" and the like, when
used herein,
encompasses the subject matter of both the parent and this divisional
application.
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is known from EP 0 693 475
B1 as an
analgesic pharmaceutical composition and can be administered orally.
Conventional
formulations for the oral administration of 3-(3-dimethylamino-1-ethy1-2-
methyl-
propyl)phenol lead to fast release of the active ingredient in the
gastrointestinal tract, so its
analgesic action begins rapidly. At the same time, a rapid reduction in the
action is observed.
Therefore, the treatment of pronounced chronic pain with 3-(3-dimethylamino-1-
ethy1-2-
methyl-propyl)phenol formerly necessitated the administration of the
pharmaceutical
composition at relatively short intervals, for example four to eight times
daily to ensure an
adequately high concentration of active ingredient in the patient's blood
plasma. However,
the need for frequent dosing easily leads to errors in administration and to
undesirable
variations in concentration in the plasma which are detrimental to patient
compliance and the
therapeutic benefit, particularly when treating chronically painful
conditions. A form for
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la
pharmaceutical administration with slow release (retard formulation) for oral
administration
of the active ingredient, 3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol,
is therefore
desirable.
In the prior art, retard formulations are generally known for a large number
of different active
ingredients. Conventional forms of retardation include coating retardation and
matrix
retardation.
In the case of coating retardation, of the type described, for example, in DE
36 25 458 Al, the
nucleus of a pharmaceutical composition containing an active ingredient
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2
is provided with a coating which consists of one or more hydrophilic and/or
hydrophobic polymers and slows down release of the active ingredient.
In the case of matrix retardation, the active ingredient is contained in a
matrix which
is formed from one or more excipients and controls release of the active
ingredient.
DE 33 09 516 Al, for example, accordingly discloses a process for producing
matrix
formulations with hydroxypropylmethyl cellulose (HPMC) as excipient and slow
release, in part, of the active ingredient, the excipient making up not more
than one
third of the weight of the formulation and consisting of at least one
hydroxypropylmethyl cellulose having a methoxy content of 16 to 24% by weight,
a
hydroxypropyl content of 4 to 32% by weight and a numerically averaged
molecular
weight of at least 50,000. The formulations disclosed in DE 33 09 516 Al
contain
HPMCs having viscosities (in a 2% by weight aqueous solution at 20 C) between
15
and 30,000 cPs (15 to 30,000 inPa.$). Release behaviour which is independent
of the
pH of the dissolution medium is not disclosed in DE 33 09 516 Al.
An object of the present invention is accordingly to prepare a 3-(3-
dimethylamino-1-
ethy1-2-methyl-propyl)phenol-containing pharmaceutical formulation with slow
release of active ingredient.
This object is achieved by a slow-release pharmaceutical formulation,
containing 3-
(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol or a pharmaceutically
acceptable
salt thereof in a matrix with slow release of active ingredient, wherein the
matrix
contains 1 to 80% by weight, preferably 5 to 80% by weight, of one or more
hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix
forming
agents and has the following release rate in vitro, measured by the Ph. Eur.
Paddle
Method at 75 rpm in a buffer (to Ph. Eur.) at a pH of 6.8 at 37 C and detected
using
a UV spectrometer:
3 to 35% by weight (based on 100 by weight active ingredient) 3-(3-
dimethylamino-
1-ethy1-2-methyl-propyl)phenol released after 0.5 hours,
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to 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
1 hour,
to 75% by weight 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol released
after
2 hours,
5 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
3 hours,
30 to 97% by weight 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol released
after
6 hours,
more than 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
10 12 hours,
more than 70% by weight 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol
released after
18 hours,
more than 80% by weight 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol
released after
24 hours.
According to one aspect of the invention of the parent application, there is
provided a slow-release pharmaceutical composition comprising 3-(3-
dimethylamino-1 -
ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in
a matrix with
slow release of active ingredient, wherein the matrix comprises 1 to 80% by
weight of one
or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable
matrix
forming agents and has the following release rate in vitro, measured by the
Ph. Eur. Paddle
Method at 75 rpm in a buffer (to Ph. Eur.) at a pH of 6.8 at 37 C and detected
using a UV
spectrometer:
3 to 35% by weight (based on 100 by weight active ingredient) 3-(3-
dimethylamino-1 -
ethy1-2-methyl-propyl)phenol released after 0.5 hours,
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to 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
1 hour,
to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
2 hours,
5 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
3 hours,
30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
6 hours,
more than 50% by weight 3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol
released after
10 12 hours,
more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
18 hours,
more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
24 hours.
According to another aspect of the invention of the parent application, there
is provided a slow-release pharmaceutical composition comprising 3-(3-
dimethylamino- 1 -
ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in
a matrix with
slow release of active ingredient, wherein the matrix comprises 1 to 80% by
weight of one
or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable
matrix
forming agents and, as pharmaceutically acceptable matrix forming agents,
comprises
cellulose ethers and/or cellulose esters having a viscosity of 3,000 to
150,000 mPa.s in a 2%
by weight aqueous solution at 20 C.
According to yet another aspect of the invention of the parent application,
there
is provided a tablet for the twice daily oral administration of 3-(3-
dimethylamino-1 -ethyl-2-
methyl-propyl)phenol comprising a pharmaceutical composition as described
herein.
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3b
According to one aspect of the invention of the present divisional
application,
there is provided a slow-release pharmaceutical composition comprising 3-(3-
dimethylamino-
1-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof
as active
ingredient in a matrix coated with a material controlling the slow release of
the active
ingredient in an aqueous medium, the coating material comprising a water-
insoluble wax, a
polymethacrylate or a water-insoluble cellulose, wherein the active ingredient
has the
following release rate in vitro, measured by the Ph. Eur. Paddle Method at 75
rpm in a buffer
(to Ph. Eur.) at a pH of 6.8 at 37 C and detected using a UV spectometer:
3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-
dimethylamino-1-
1 0 ethyl-2-methyl-propyl)phenol released after 0.5 hours,
5 to 50% by weight 3-(3-dimethylamino-1 -ethy1-2-methyl-propyl)phenol released
after
1 hour,
to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
2 hours,
15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
3 hours,
30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
6 hours,
more than 50% by weight 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol
released after
12 hours,
more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
18 hours, and
more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
24 hours.
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3c
According to another aspect of the invention of the present divisional
application, there is provided a slow-release pharmaceutical composition
comprising
3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a pharmaceutically
acceptable salt
thereof as active ingredient in an oral osmotically driven release system,
wherein surfaces of
the oral osmotically driven release system that are in contact or that are
contactable with a
release medium are provided with a semipermeable-coating, so that the surfaces
are
permeable to the release medium but substantially impermeable to the active
ingredient,
wherein one or both of the surface and the coating comprise at least one
opening for releasing
the active ingredient, wherein the active ingredient has the following release
rate in vitro,
measured by the Ph. Eur. Paddle Method at 75 rpm in a buffer (to Ph. Eur.) at
a pH of 6.8 at
37 C and detected using a UV spectometer:
3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-
dimethylamino-l-
ethy1-2-methyl-propyl)phenol released after 0.5 hours,
5 to 50% by weight 3-(3-dimethylamino- 1 -ethy1-2-methyl-propyl)phenol
released after
1 hour,
10 to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
2 hours,
15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
3 hours,
30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released
after
6 hours,
more than 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
12 hours,
more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
18 hours, and
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more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol
released after
24 hours.
Throughout this specification, the composition described is sometimes referred
to as a "formulation".
It has surprisingly been found that the formulation according to the
invention releases the active ingredient, 3-(3-dimethylamino-1-ethy1-2-methyl-
propyl)phenol, slowly when administered orally and is therefore suitable for
administration
at intervals of at least 12 hours. The formulation according to the invention
therefore
allows pain therapy, during which the analgesic, 3-(3-dimethylamino-1-ethy1-2-
methyl-
1 0 propyl)phenol, only has to be administered once daily, for example at
24 hour intervals, or
twice daily, preferably at 12 hourly intervals, in order to ensure an adequate
concentration
of the active ingredient in the plasma. A corresponding
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duration of efficacy and the maintenance of an adequate level in the blood
plasma
are demonstrated by simulation studies and experimental investigations.
It is particularly surprising that the formulation according to the invention
not only
ensures long-lasting therapeutic efficacy over a relatively long period (at
least 12
hours) owing to the slow release, but at the same time allows the active
ingredient to
start flowing rapidly in the plasma when the pharmaceutical composition is
first
administered, leading to a rapid onset of pain relief in the patient.
Therefore, the pain
suffered by a patient can rapidly be alleviated when the formulation according
to the
invention is administered without the analgesic action quickly fading again.
The
formulation according to the invention therefore combines properties of a
formulation with immediate release of active ingredient ¨ rapid pain relief
due to
adequately high concentration of active ingredient just after administration
of the
pharmaceutical composition ¨ with properties of a formulation having slow
release
long-lasting analgesic action owing to an adequately high level of active
ingredient
over a prolonged time. By taking the analgesic in the formulation according to
the
invention, the patient can effectively combat his pain acutely and, at the
same time,
treat it effectively over a prolonged period without further measures and
merely by
regular administration at 12 (or 24) hourly intervals.
The active ingredient of the formulation according to the invention is
contained in a
slow release matrix. It is also conceivable, however, that the active
ingredient is
contained in a matrix with conventional release behaviour and the slow release
is
achieved by a retarding coating.
In a further possibility the slow release behaviour is achieved by an
osmotically
driven release system.
If the formulation according to the invention contains a slow release matrix,
the
matrix contains 1 to 80% by weight of one or more hydrophilic or hydrophobic
polymers as pharmaceutically acceptable matrix forming agents, for example
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rubbers, cellulose ethers, cellulose esters, acrylic resins, materials derived
from
proteins, fats, waxes, fatty alcohols or fatty acid esters. When using
hydrophilic
polymers as matrix forming agents, it is preferable for the matrix to comprise
5 to
80% by weight matrix forming agents.
5
The present invention also relates to a pharmaceutical formulation which
contains 3-
(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a pharmaceutically
acceptable
salt thereof in a matrix with slow release of active ingredient, wherein the
matrix
contains 1 to 80% by weight, in particular 5 to 80 by weight, of one or more
hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix
forming
agents and which is characterised in that as pharmaceutically acceptable
matrix
forming agents, comprises cellulose ethers and/or cellulose esters having a
viscosity
of 3,000 to 150,000 mPas in a 2% by weight aqueous solution at 20 C. (The
viscosity is determined using a Pharm. Eu. capillary viscosimeter). The
compositions have the above-mentioned release profile according to the
invention.
Preferred pharmaceutically acceptable matrix forming agents include cellulose
ethers and/or cellulose esters having a viscosity between 10,000, in
particular 50,000
mPas, and 150,000 mPas in a 2% by weight aqueous solution at 20 C.
Particularly suitable pharmaceutically acceptable matrix forming agents
selected
from the group comprising hydroxypropylmethyl celluloses (HPMC), hydroxyethyl
celluloses, hydroxypropyl celluloses (HPC), methyl celluloses, ethyl
celluloses and
carboxymethyl celluloses and are selected, in particular, from the group
comprising
= HPMCs, hydroxyethyl celluloses and HPCs. HPMCs having a viscOsity of approx.
100,000 mPas, measured in a 2% by weight aqueous solution at 20 C are most
preferred.
The active ingredient, 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol,
exists as
such, i.e. as a free base, but also in the form of a pharmaceutically
acceptable salt,
for example as hydrochloride. Preparation of the free base is known from EP 0
693
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475 Al. Where EP 0 693 475 Al does not also disclose the preparation of
pharmaceutically acceptable salts such as hydrochloride, these may be obtained
from
the free base by processes generally known from the prior art.
3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol has two centres of
asymmetry,
so the compound can exist in the form of four different stereoisomers. In the
formulation according to the invention 3-(3-dimethylamino-1-ethy1-2-methyl-
propyl)phenol can exist as a mixture of all four diastereomers in any ratio,
but also
as a mixture of two or three of the four stereoisomers or in pure stereoisomer
form.
Preferred stereoisomers include (+)-(1S,2S)-3-(3-dimethylamino-l-ethy1-2-
methyl-
propyl)phenol and (-)-(1R,2R)-3-(3-dimethylamino-l-ethyl-2-methyl-
propyl)phenol,
which, in the formulation according to the invention, can exist as a mixture,
in
particular as a 1:1 mixture (racemate) or particularly preferably in pure
isomer form.
For the purposes of the present invention, therefore, the term "active
ingredient"
denotes 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol as a mixture of
various
stereoisomers thereof or as one pure stereoisomer thereof as a free base or in
the
form of a pharmaceutically acceptable salt respectively.
In the pharmaceutical compositions according to the invention, the slow
release
active ingredient content is preferably between 0.5 and 85% by weight and the
content of pharmaceutically acceptable matrix forming agents between 8 and 40%
by weight. Particularly preferred pharmaceutical compositions have a slow
release
active ingredient content between 3 and 70% by weight, in particular between 8
and
66% by weight, and a content of pharmaceutically acceptable matrix forming
agents
between 10 and 35% by weight, in particular between 10 and 30% by Weight. If
the =
enantiomer-pure (+)-(1S,2S)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol
(or a mixture of the (+) and (-) enantiomers with a large excess of the (+)
enantiomer) is used as active ingredient, it is particularly preferred if the
active
ingredient content lies at the lower limit, i.e. between 0.5 and 25% by weight
(based
on the total weight). If the enantiomer-pure (-)-(1R,2R)-3-(3-dimethylamino-l-
ethyl-
' 2-methyl-propyl)phenol (or a mixture of the (+) and (-) enantiomers
with a large
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excess of the (-) enantiomer) is used as active ingredient, it is particularly
preferred
if the active ingredient content lies between 16 and 66% by weight.
Further components of the matrix of the formulation according to the invention
may
optionally be digestible long-chain (i.e. with 8 to 50 carbon atoms,
preferably 12 to
50 carbon atoms) unsubstituted or substituted hydrocarbons such as fatty
alcohols,
fatty acid glyceryl esters, mineral and vegetable oils as well as waxes,
hydrocarbons
having a melting point between 25 and 90 C being preferred. Fatty alcohols
are
particularly preferred and lauryl alcohol, myristyl alcohol, stearyl alcohol,
cetyl
alcohol and cetylstearyl alcohol are more particularly preferred. Their
content in the
matrix is 0 to 60% by weight. The matrix can alternatively or additionally
contain
polyethylene glycols in a content of 0 to 60% by weight.
The pharmaceutical formulations according to the invention can also contain,
as
further components, pharmaceutically acceptable auxiliaries such as fillers,
for
example lactose, microcrystalline cellulose (MCC) or calcium hydrogen
phosphate
as well as sliding agents, lubricants and flow regulators such as talcum,
magnesium
stearate, stearic acid and/or highly dispersed silicon dioxide, of which the
total
content in the tablet is between 0 and 80% by weight, preferably between 5 and
65%
by weight.
The release rate of an active ingredient from an administrable form is often
dependent on the pH of the release medium. This can vary in a pH range from
less
than 1 to about 8 as the pharmaceutical composition passes through the
gastrointestinal tract. These variations can vary from one person to another.
One and
the same person can also have a different pH/time profile during passage
through the
gastrointestinal tract from one administration to another. If the release rate
of the
active ingredient from the pharmaceutical composition is dependent on the pH,
this
can lead to different release rates in vivo and therefore different
biocompatibility.
However, the release profiles of the active ingredient (in the form of the
base or a
pharmaceutically acceptable salt thereof) from a pharmaceutical formulation
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8
according to the invention are surprisingly dependent on the pH which can
occur
physiologically during passage through the gastrointestinal tract. The release
profiles
with an ambient pH of 1.2, 4.0 and 6.8 are identical to one another and also
comparative to the release during a pH/time profile of pH 1.2 over pH 2.3 and
pH
6.8 to pH 7.2.
It has been found that it is immaterial for achieving the slow release of
active
ingredient from the formulation according to the invention which preferably
exists in
tablet form, whether a water-soluble filler, for example lactose, an insoluble
filler
which does not swell in an aqueous medium, for example calcium hydrogen
phosphate, or an insoluble filler which swells in an aqueous medium, for
example
microcrystalline cellulose, is used as filler with otherwise unchanged values
and
unchanged composition of the tablet, based on the active ingredient, the
matrix
forming agent and the optional components. All these pharmaceutical
compositions
exhibit mutually corresponding release behaviour.
It is also surprising that, in the compositions according to the invention
with a given
amount of active ingredient, the quantity of matrix forming agent and the
quantity of
optional components can each vary over a relatively large range without
affecting
the therapeutic efficacy of at least 12 h or with twice daily administration
(providing
that the above-mentioned limits to the quantity of active ingredient, matrix
forming
agent and further optional components are adhered to). Efficacy over at least
12 h is
ensured, for example, with an active ingredient content of approx. 32.25% by
weight
(based on the weight of the total composition) in a composition of approx.
12.9% by
weight HPMC having a viscosity of 100,000 mPa.s as matrix forming agent and a
=
content of, for example MCC as filler of approx. 52.6% by weight and also in a
composition of approx. 25.8% by weight of the same HPMC and approx. 39.7% by
weight MCC (or lactose monohydrate) with otherwise identical amounts of
sliding
agent, lubricant and flow regulators. The same applies to compositions
according to
the invention with a higher or lower active ingredient content within the
specified
limits.
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It has also extremely surprisingly been found that, when the pharmaceutical
formulations according to the invention with slow release of the active
ingredient are
administered to human volunteers, biocompatibility which is the same as in
formulations with immediate release of active ingredients is unexpectedly
achieved
despite the high first-pass effect for the active ingredient..
Compositions according to the invention of which the tma, value in the in vivo
plasma concentration/time graph is between 2 and 10 h, in particular between
3.5
and 6 h and more particularly preferably between 4 and 5.5 h after oral
administration of the composition, i.e. of which the peak plasma level occurs
in said
periods, are also preferred.
The formulation according to the invention contains the active ingredient, 3-
(3-
dimethylamino-l-ethy1-2-methyl-propyl)phenol as such and/or as a
pharmaceutically acceptable salt in an amount conventionally of 2.5 to 800 mg,
in
particular 5 to 400 mg, more particularly preferably 10 to 250 mg (weight of
the
active ingredient 3-(3-dimethylamino- 1 -ethyl-2-methyl-
propyl)phenol as
hydrochloride) per dose unit, the release behaviour of the formulation
according to
the invention not being affected by the exact amount of the active ingredient
providing the above-mentioned limits are adhered to. Owing to the different
active
strength of the two particularly preferred enantiomers (+)-(1S,2S)-3-(3-
dimethylamino-1-ethy1-2-methyl-propyl)phenol and (-
)-(1R,2R)-3-(3-
dimethylamino- 1 -ethyl-2-methyl-propyl)phenol, it is preferred if the
stronger (+)-
(1S,25)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol exists in an arnount
of
2.5 to 80 mg, in particular 5 to 40 mg and more particularly preferably in an
amount
of 10 to 25 mg active ingredient (based on the hydrochloride) in the
formulations
according to the invention, while the (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
methyl-propyl)phenol preferably exists in an amount of 25 to 800 mg, in
particular
50 to 400 mg and more particularly preferably in an amount of 100 to 250 mg
active
ingredient (based on the hydrochloride) in the formulations according to the
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invention, more specifically on condition that the above-mentioned limits are
adhered to.
In the scope of this invention, pharmaceutically acceptable salts of the
active
5 ingredient are salts of the active ingredient which are physiologically
acceptable for
pharmaceutical use, in particular when administered to mammals and/or humans.
Pharmaceutically acceptable salts of this type may be formed, for example,
with
inorganic or organic acids.
10 The pharmaceutical formulations according to the invention can exist both
as a
simple tablet and as a coated tablet, for example as a film tablet or dragee.
The
tablets are conventionally round and biconvex, but oblong tablet shapes which
allow
the tablet to be divided are also possible. Granules, spheroids, pellets or
microcapsules which are poured into sachets or capsules or may be compressed
to
disintegrating tablets are also possible.
One or more coating layers may be used for the coated tablets. Suitable
coating
materials include known hydroxypropylmethyl celluloses having a low viscosity
of
approx. 1 to 100 rnPa-s and a low molecular weight of < 10,000 (for example
Pharrnacoat 606 with a viscosity of 6 mPa.s in a 2% by weight aqueous solution
at
20 C), which only slightly influence the release profile of the pharmaceutical
compositions according to the invention. Diffusion coatings known to a person
skilled in the art and based, for example, on swellable but water-insoluble
poly(meth)acrylates lead to modulation of the slow release of the active
ingredients
from pharmaceutical formulations according to the invention. The tablet core
which
contains the active ingredient, releases the active ingredient slowly and has
an active
ingredient content preferably between 0.5 and 85% by weight, particularly
preferably between 3 and 70% by weight and more particularly preferably
between 8
and 66% by weight, can be sheathed with additional active ingredient which is
released as an initial dose without retardation by various processes known to
a
- person skilled in the art, for example dragee production, spraying from
solutions or
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11
suspensions or by application of powder, but without this being absolutely
essential
for the desired slow release with a simultaneous rapid initial flow of the
active
ingredient for rapid pain relief on first administration of the pharmaceutical
formulation according to the invention. Multilayered and shell-type tablets
represent
further embodiments, in which 3-(3-dimethylamino-l-ethy1-2-methyl-
propyl)phenol
or a pharmaceutically acceptable salt thereof is released slowly in one or
more layers
of the multilayer tablet with an active ingredient content preferably between
0.5 and
85% by weight, particularly preferably between 3 and 70% by weight and more
particularly preferably between 8 and 66% by weight or in the core of the
shell-type
tablet with an active ingredient content preferably between 0.5 and 85% by
weight,
particularly preferably between 3 and 70% by weight and more particularly
preferably between 8 and 66% by weight by a pharmaceutically acceptable matrix
forming agent and the release of the active ingredient takes place without
retardation
in one or more layers of the multilayer tablet or the outer shell layer of the
shell-type
tablets. Multilayer and shell-type tablets can contain one or more coatings
which are
free from active ingredients.
Instead of a slow release matrix in the slow release pharmaceutical
formulation, it is
also possible to use a normal release matrix with a coating which retards
release of
the active ingredient. For example, the active ingredient can be contained in
a
conventional matrix of microcrystalline cellulose and optionally further
pharmaceutical auxiliaries such as binders, fillers, sliding agents,
lubricants and flow
regulators, which are covered or coated with a material controlling the slow
release
of the active ingredient in an aqueous medium. Suitable coating agents
include, for
example, water-insoluble waxes and polymers such as polymethacrylates
(Eudragit
=
or the like) or water-insoluble celluloses, in particular ethyl cellulose. The
coating
material can optionally also contain water-soluble polymers such as polyvinyl
pyrrolidone, water-soluble celluloses such as hydroxypropylmethyl cellulose or
hydroxypropyl cellulose, other water-soluble agents such as Polysorbate 80 or
hydrophilic pore-forming agents such as polyethylene glycol, lactose or
mannitol.
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12
In addition or by way of supplement to the possibilities of a slow release
matrix in
the pharmaceutical formulation with slow release or a normal release matrix
with a
coating which retards the release of the active ingredient, an osmotically
driven
release system can also be used to achieve a slow release. With a, preferably
oral,
release system of this type, at least one, preferably all, surface(s) of the
release
system, preferably that/those which is/are, or may come into contact with the
release
medium, are semi-permeable, preferably provided with a semi-permeable coating,
so
the surface(s) is/are permeable to the release medium but substantially,
preferably
completely, impermeable to the active ingredient, the surface(s) and/or
optionally
the coating comprising at least one opening to release the active ingredient.
The
active ingredient 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof, preferably (+)-(15,2S)-3-(3-
dimethylarnino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable
salt thereof and/or (-)-(1R,2R)-3-(3-dimethylamino-l-ethyl-2-methyl-
propyl)phenol
or a pharmaceutically acceptable salt thereof or a mixture thereof can, but
does not
have to, be present in a matrix. This is preferably taken to mean a system in
tablet
form with a delivery opening, an osmotic pharamaceutical composition core, a
semi-
permeable membrane and a polymeric part which exerts pressure. A good and
preferred example of a system of this type is the OROS system from ALZA
Corporation, USA, of which the Internet site or other items of product
information
contain(s) details on the OROS system. In particular, these are also the OROS
Push-PullTM system, the OROS Delayed Push-PullTm system, the OROS Multi-
Layer PushPullTM system, the OROS Push-Stick System and in certain cases the
LOROSTM. Embodiments and examples of the actual production of osmotically
driven release systems can be found in US patents US 4,765,989, US 4,783,337
and
US 4, 612, 008.
The compositions according to the invention may be produced, for example, by
the
following general processes: the components of the composition (active
ingredient, =
matrix forming agent and optional components) are weighed in in succession and
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13
then screened on a conventional screening machine. The Quadro Comil U10
screening machine, for example, can be used here, a conventional screen size
being
approx. 0.813 mm. The screened material is then mixed in a container mixer,
for
example in a Bohle container mixer; typical operating conditions are: duration
approx. 15 min 45 s at a speed of 20 1 rpm. The powder mixture obtained is
subsequently compressed to a tablet on a tablet press. A Korsch EKO tablet
press,
for example, with a round die curved in the form of a dragee with a diameter
of 10
mm can be used for this purpose. Alternatively, the powder mixture can be
compacted and the compacts subsequently screened (Comill 3 mm friction
macerating sieve and subsequent 1.2 mm round hole screen), the resultant
granules
then being compressed in the above-described manner with addition of lubricant
(for
example magnesium stearate) for example on an EKO tablet press with 10 mm
round dies. Granulation can also be carried out by wet granulation using
aqueous or
organic solvents. Aqueous solvents with or without suitable binder are
preferred.
The production process can readily be adapted to the respective requirements
and
the desired form of administration by procedures well known in the prior art.
The production of pharmaceutical formulations according to the invention is
characterised by high repeatability of the release properties of the
compositions
obtained, which contain 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof. The release profile of
pharmaceutical
compositions according to the invention has proven to be stable for a storage
time of
at least one year under conventional storage conditions according to ICH Q1AR
Stability Testing Guidelines.
With once or twice daily administration of a pharmaceutical formulation
according
to the invention by the patient, good therapeutic efficacy is reliably
achieved in the
case of continuously strong pain.
=
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Examples
The examples serve to illustrate the present invention and preferred
embodiments,
but should not restrict its scope of protection.
Example 1
Matrix tablets with the following composition per tablet
(-)-(1R,2R)3-(3-di methylami no-1 -ethyl-2-methyl-prop yl)phenol hydrochloride
100 mg
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 80
mg
100,000 mPa-s
Microcrystalline cellulose (Avicel PH 102 from FMC)
123 mg
Highly dispersed silicon dioxide 4
mg
Magnesium stearate 3
mg
=
Total amount
310 mg
were produced in the following manner in a batch size of 1,000 tablets:
all components were weighed in and screened on a Quadro Comil U10 screening
machine using a screen size of 0.813 mm, mixed in a container mixer (Bohle LM
40) for 15 min 15 s at a speed of 20 1 rpm and pressed on a Korsch EKO
eccentric press to tablets curved in the manner of dragees with a diameter of
10 mm,
a radius of curvature of 8 mm and an average tablet weight of 310 mg.
The in vitro release was determined by the Ph. Eur. Paddle Method at 75 rpm in
900
ml pH 6.8 buffer according to Ph. Eur. at 37 C and with detection using a UV
spectrometer, and is reproduced in the following table.
. Time (min) Total amount of active
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ingredient released [%]
0 0
30 18
60 27
120 41
180 5= 0
240 5= 9
360 71
480 80
600 87
720 9= 3
Example 2
3,000 matrix tablets with the following composition per tablet
5
(-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride 200
mg
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 80 mg
100,000 mPa.s
Microcrystalline cellulose (Avicel PH 102 from FMC) 23
mg
Highly dispersed silicon dioxide 4
mg
Magnesium stearate 3
mg
Total amount
310 mg
=
were produced by a process similar to that described in Example 1.
The in vitro release was determined as in Example 1.
Time (min) Total amount of active
ingredient released [%]
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16
0 0
30 19
60 30
120 46
180 58
240 68
360 84
480 93
720 99
Example 3
Matrix tablets with the following composition per tablet
(-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol hydrochloride 100
mg
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 40 mg -
100,000 mPa.s
Microcrystalline cellulose (Avicel PH 102 from FMC)
163 mg
Highly dispersed silicon dioxide 4
mg
Magnesium stearate 3
mg
Total amount
310 mg
were produced by a process similar to that described in Example 1 in a batch
size of
3,000 tablets.
The in vitro release was determined as an Example 1; in addition, the release
was
determined under otherwise identical conditions at a stirring speed of 50 rpm
and
100 rpm.
Time (min) Total amount of active
Total amount of active Total amount of active
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17
ingredient released PY0] ingredient released ingredient
released [%1
at 50 rpm [%] at 100 rpm
at 75 rpm
0 0 0 0
30 20 20 21
60 35 33 35
120 54 51 53
180 67 63 66
¨240 76 73 76
360 89 87 89
480 97 95 97
600 100 100 100
Example 4
Matrix tablets with the following composition per tablet
(-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol 100 mg
hydrochloride
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg
Shinetsu, 100,000 mPa-s
Lactose monohydrate 230 (Megglel 123 mg
Highly dispersed silicon dioxide 4 mg
Magnesium stearate 3 mg
.Total amount 310 mg
=
were produced by a process similar to that described in Example 1 in a batch
size of
200 tablets.
The in vitro release was determined as in Example 1.
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18
Time (min) Total amount of active
ingredient released [%]
0 0
30 16
60 26
120 39
180 49
240 57
360 71
480 81
600 87
720 92
Example 5
Matrix tablets with the following composition per tablet
(-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol 100
mg
hydrochloride
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 40
mg
Shinetsu, 100,000 mPa.s
Cellactose 80 (Meggle) 163
mg
Highly dispersed silicon dioxide 4
ma
0
Magnesium stearate 3
ma
Total amount 310
mg
were produced by a process similar to that described in Example 1 in a batch
size of
100 tablets.
The in vitro release was determined as an Example I.
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19
Time (min) Total amount of active
ingredient released [%]
0 0
30 18
60 31
120 48
180 61
240 71
360 84
480 91
600 95
720 97
Example 6
Matrix tablets with the following composition per tablet
(-)-(1R,2R)3-(3-dimethylamino- 1-ethy1-2-methyl-propyl)phenol 100
mg
hydrochloride
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80
mg
Shinetsu, 100,000 mPa.s
Ludipress (BASF) 123
mg
Highly dispersed silicon dioxide 4
mg
Magnesium stearate 3
mg
Total amount 310
mg
were produced by a process similar to that described in Example 1 in a batch
size of
100 tablets.
The in vitro release was determined as in Example 1.
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Time (min) Total amount of active
ingredient released [%]
0 0
17
60 27
120 40
180 51
240 59
360 72
480 82
600 89
720 93
Example 7
Matrix tablets with the following composition per tablet
5
(-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride
50 mg
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 40
mg
100,000 mPa-s
Microcrystalline cellulose (Avicel PH 102 from FMC)
163 mg
Lactose 200 (Meggle) 50
mg
Highly dispersed silicon dioxide 4
mg
Magnesium stearate 3
mg
Total amount
310 mg
were produced by a process similar to that described in Example 1 in a batch
size of
200 tablets.
10 The in vitro release was determined as in Example 1.
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21
Time (min) Total amount of active
ingredient released r/01
0 0
30 18
60 31
120 49
180 61
240 70
360 82
480 90
600 94
720 96
Example 8
Matrix tablets with the following composition per tablet
(-)-(1R,2R)3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol 100
hydrochloride mg
Cellactose (Meggle) 72.5
mg
TM 12.5
Hydroxyethyl cellulose (Natrosol 250 HX from Herkules)
mg
130
Cutina HR (Henkel)
. mg
=
Talcum 3 mg
Magnesium stearate 2 mg
Total amount 320
mg
were produced as follows in a batch size of 200 tablets:
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22
the active ingredient, Cellactose, Natrosol and Cutina were mixed then heated
to
TPA
80 C in a drying oven and granulated in a Kenwood Chef kitchen mixer. The
cooled
granules were screened through a 1 mm screen. After blending with magnesium
stearate and talcum, the granules were pressed on a EKO eccentric press
(Korsch) to
6 x 15 mm size oblong tablets with a breaking notch.
The in vitro release was determined as in Example 1.
=
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Time (min) Total amount of active
ingredient released ro]
0 0
30 28
60 39
120 56
180 68 =
240 80
360 97
390 99
Example 9
Matrix tablets with the following composition per tablet
(+)-(IS,2S)3-(3-dimethylarnino-l-ethyl-2-methyl-propyl)phenol 10
mg
hydrochloride
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80
mg
Shinetsu, 100,000 mPa.s
Microcrystalline cellulose (Avicel PH 102 from FMC) 213
mg
Lactose 200 (Meggle) 50
mg
Highly dispersed silicon dioxide 4
mg
Magnesium stearate 3
mg
Total amount 310
mg
were produced by a process similar to that described in Example 1 in a batch
size of
100 tablets.
The in vitro release was determined as in Example 1.
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Time (min) Total amount of active
ingredient released [%]
0 0
30 15
60 24
120 36
180 44
240 51
360 61
480 69
600 75
720 79
Example 10
Matrix tablets with the following composition per tablet
(-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol
100 mg
hydrochloride
Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80
mg
Shinetsu, 100,000 mPa.s
Microcrystalline cellulose (Avicel PH 102 from FMC) 63
mg
Highly dispersed silicon dioxide 4
mg
Magnesium stearate 3
mg
Total amount
250 mg
were produced by a process similar to that described in Example 1 in a batch
size of
100 tablets.
The in vitro release was determined under the following conditions:
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(A) application of the Ph. Eur. Paddle Method at 75 rpm in 900 ml pH 7.2
buffer
to USP 22 at 37 C and with detection using a UV spectrometer;
(B) application of the Ph. Eur. Paddle Method at 75 rpm, a pH of 1.2 being
5 adjusted from 0 to 30 min, a pH of 2.3 from 30 to 120 min, a pH of 6.5
from 120 to
180 min and a pH of 7.2 for the remaining test period. The table shows the
results
for both experimental conditions:
Time (min) Total amount of active Total amount of
active
ingredient released [%) ingredient released
[Vol
under condition (A) under condition (B)
0 0 0
19 20
60 29 30
120 43 44
180 54 55
240 63 65
360 78 80
480 - 87 90
600 94 97
720 98 100
10 The experiment shows that the release behaviour of the formulations
according to
the invention is independent of the pH of the release medium.
Example 11
15 Pellets having the following composition
(-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol
100 mg
hydrochloride
Low-substituted hydroxypropyl cellulose (L-HPC LH 31 from Shinetsu) 75
mg
=
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26
Aquacoat (aqueous ethyl cellulose dispersion from FMC) (calculated as 20 mg
dry substance)
Microcrystalline cellulose (Avicel PH 101 from FMC) 75 mg
Dibutyl sebacate (DBS) 4 mg
Tween 80 0.4 mg
Total amount 274.4
mg
were produced in the following manner:
The active ingredient, Avicel and L-HPC were mixed for 10 minutes in a
planetary
mixer (Kenwood K Mixer) and then granulated with water. The moist granules
were
extruded in a Nica extruder with a 0.8 x 0.8 mm matrix and then rounded for 10
min
in the Nica spheronizer at 500 rpm (1 kg loading). The pellets were dried
overnight
in a drying oven at 50 C and then classified into screen fractions.
Pellets measuring 0.6 to 1.0 mm (yields about 95%) were coated in the WSG
(smooth GPCG1 with a Wurster insert) at incoming air temperatures of 60 C
(product temperature 40 C) with an aqueous dispersion of Aquacoat and DBS
(20%,
calculated on Aquacoat solids content), so they had an increase in weight of
9.8%
(based on the original weight). The dispersion was produced in accordance with
the
manufacturer's instructions (FMC), the DBS together with the Tween 80 being
homogenised in a proportion of the water and then being added to the dilute
Aquacoat dispersion. The final dispersion had a solids content of 20% by
weight and
was stirred for at least 3 h. The coated pellets were dried in the WSG And
tempered
in the drying oven (2 h at 60 C). The release was tested as in Example 1, but
by the
basket method at 100 rpm.
Time (min) Total amount of active
ingredient released (%]
0 0
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27
30 5
60 15
120 28
180 43
240 56
360 73
480 82
600 87
720 90
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28
Clinical trial
In a monocentric, open, randomised individual dose four-way crossover trial,
various forms of administration of (-)-(1R,2R)-3-(3-dimethylamino-l-ethy1-2-
methyl-propyl)phenol hydrochloride (active ingredient) were administered to
sixteen
healthy male white subjects aged from 18 to 45 years, to determine
pharmacokinetic
data. Data was determined experimentally by HPLC analysis.
The following were administered:
"Capsule 100 mg": capsules with immediate release of the active ingredient and
100 mg of active ingredient
"Capsule 25 mg": capsules with immediate release of the active
ingredient and
25 mg of active ingredient
"Tablet 100 mg": tablet according to Example 1(100 mg of active
ingredient)
"Tablet 200 mg": tablet according to Example 2 (200 mg of active
ingredient)
(The capsules were white-opaque hard gelatine capsules of size 0 EL with a
filling
of 360 mg, which were made up as follows:
"Capsule 100 mg": 100 mg (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
methyl-
propyl)phenol hydrochloride, 152 mg microcrystalline cellulose, 8 mg Aerosil,
20
mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl starch type A
from Avebe);
"Capsule 25 mg": 25 mg (-)-(1R,2R)-3-(3-dimethylamino-l-ethy1-2-
methyl-
propyl)phenol hydrochloride, 227 mg microcrystalline cellulose, 8 mg Aerosil,
20
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29
mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl starch type A
from Avebe))
The essential pharmacokinetic data are shown in the following table and the
characteristic of the experimentally determined average serum concentration in
Fig.
1.
Parameter "Capsule 25 "Capsule 100 "Tablet 100 "Tablet
200
me, me,
AUC 69 14 318 66 300 51 667
141
[ng=h/m1]
C[ng/m1] 14 4 64 19 23 5 51 13
trnax [h] 1.2 0.4 1.5 0.9 4.6
1.3 4.8 1.1
MRT* [h] 5.8 0.7 5.9 0.9
10.7 1.5 10.3 1.1
HVD** 35 1.2 3.6 1.1 12.4 2.8
11.9 2.3
*MRT = "Mean Residence Time"
**}{VD = "Half Value Duration"
On the one hand, a comparison of "Capsule 100 mg" and "Tablet 100 mg"
immediately shows that the formulations according to the invention excellently
fulfil
the task of providing a pharmaceutical formulation containing a 3-(3-
dimethylamino-l-ethy1-2-methyl-propyl)phenol with slow release of active
ingredient. On the other hand, when "Tablet 100 mg" is compared with "Tablet
200
mg" there is also very advantageous dose proportionality in the release
behaviour.
However, this also shows that the two compositions according to the invention,
"Tablet 100 mg" and "Tablet 200 mg" release the active ingredient in a
discernible
amount but more slowly at the beginning than the two formulations with
immediate
release; with the two retarded formulations, however, the plasma level is
higher than
1.0 ng/ml after only one hour and still sufficiently high after 16 h to ensure
an
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analgesic action. Simulation studies for "Tablet 100 mg" also showed that,
with
repeated administration of the pharmaceutical composition at 12 hourly
intervals,
serum levels are achieved which do not fall below 20 ng/ml, so good analgesic
efficacy is ensured by twice daily administration. This represents great
progress for
5 the treatment, in particular of chronic painful conditions, and
allows a significant
improvement in patient compliance.
