U.S. patent application number 15/943175 was filed with the patent office on 2018-08-09 for prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol.
The applicant listed for this patent is GRUENENTHAL GMBH. Invention is credited to Johannes BARTHOLOMAEUS, Iris ZIEGLER.
Application Number | 20180221308 15/943175 |
Document ID | / |
Family ID | 26010444 |
Filed Date | 2018-08-09 |
United States Patent
Application |
20180221308 |
Kind Code |
A1 |
BARTHOLOMAEUS; Johannes ; et
al. |
August 9, 2018 |
PROLONGED RELEASE PHARMACEUTICAL COMPOSITION CONTAINING
3-(3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL)PHENOL
Abstract
A pharmaceutical formulation for prolonged release of the active
ingredient 3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol or a
pharmaceutically acceptable salt thereof in a matrix containing
between 1 and 80 wt % of at least one pharmaceutically acceptable
hydrophilic or hydrophobic polymer as a matrix forming agent and
exhibiting in vivo the following release rate: 3 to 35% by weight
(based on 100% by weight active ingredient)
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after
0.5 hours; 5 to 50% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1
hour; 10 to 75% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2
hours; 15 to 82% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3
hours; 30 to 97% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6
hours; more than 50% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12
hours; more than 70% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 18
hours, and more than 80% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24
hours.
Inventors: |
BARTHOLOMAEUS; Johannes;
(Aachen, DE) ; ZIEGLER; Iris; (Rott-Roetgen,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUENENTHAL GMBH |
Aachen |
|
DE |
|
|
Family ID: |
26010444 |
Appl. No.: |
15/943175 |
Filed: |
April 2, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15377628 |
Dec 13, 2016 |
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15943175 |
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15018529 |
Feb 8, 2016 |
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15377628 |
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13868635 |
Apr 23, 2013 |
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15018529 |
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13242800 |
Sep 23, 2011 |
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13868635 |
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10831368 |
Apr 26, 2004 |
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13242800 |
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PCT/EP02/11809 |
Oct 22, 2002 |
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10831368 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/136 20130101;
A61K 31/135 20130101; A61P 29/00 20180101; A61K 31/137 20130101;
A61K 9/5047 20130101; A61K 9/2054 20130101; A61P 25/04 20180101;
A61P 25/00 20180101; A61K 9/0053 20130101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 9/00 20060101 A61K009/00; A61K 31/135 20060101
A61K031/135; A61K 9/20 20060101 A61K009/20; A61K 9/50 20060101
A61K009/50; A61K 31/136 20060101 A61K031/136 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 24, 2001 |
DE |
10152469.2 |
Oct 16, 2002 |
DE |
10248309.4 |
Claims
1. A slow-release pharmaceutical formulation containing
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof as active ingredient in a
matrix, wherein the matrix contains 1 to 80% by weight of one or
more pharmaceutically acceptable hydrophilic or hydrophobic
polymers as 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.degree. C. and detected
using a UV spectrometer: 3 to 35% by weight (based on 100% by
weight active ingredient)
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after
0.5 hours, 5 to 50% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1
hour, 10 to 75% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2
hours, 15 to 82% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3
hours, 30 to 97% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6
hours, more than 50% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12
hours, more than 70% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 18
hours, and more than 80% by weight
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24
hours.
2. A pharmaceutical composition according to claim 1, wherein the
matrix forming agents comprise cellulose ethers, cellulose esters
or a mixture thereof having a viscosity of 10,000 to 150,000 mPas
in a 2% by weight solution at 20.degree. C.
3. A pharmaceutical composition according to claim 1, wherein the
matrix forming agents comprise cellulose ethers, cellulose esters
or a mixture thereof having a viscosity of 50,000 to 150,000 mPas
in a 2% by weight solution at 20.degree. C.
4. A pharmaceutical composition according to claim 1, wherein the
matrix forming agent comprises at least one substance selected from
the group consisting of hydroxypropylmethyl celluloses (HPMC),
hydroxyethyl celluloses, hydroxypropyl celluloses (HPC), methyl
celluloses, ethyl celluloses and carboxymethyl celluloses.
5. A pharmaceutical composition according to claim 1, wherein the
matrix forming agent comprises at least one substance selected from
the group consisting of hydroxypropylmethyl celluloses,
hydroxyethyl celluloses, hydroxypropyl celluloses and hydroxypropyl
celluloses.
6. A pharmaceutical composition according to claim 1, wherein said
composition contains from 0.5 to 85% by weight active ingredient
and from 8 to 40% by weight matrix forming agents.
7. A pharmaceutical composition according to claim 1, wherein said
composition comprises from 3 to 70% by weight active ingredient and
from 10 to 35% by weight matrix forming agents.
8. A pharmaceutical composition according to claim 7, wherein said
composition comprises from 8 to 66% by weight active ingredient and
from 10 to 30% by weight matrix forming agents.
9. A pharmaceutical composition according to claim 1, wherein a
peak plasma level of the active ingredient is obtained in vivo 2 to
10 hours after administration of the composition.
10. A pharmaceutical composition according to claim 9, wherein the
peak plasma level of the active ingredient is obtained in vivo 3.5
to 6 hours after administration of the composition.
11. A pharmaceutical formulation according to claim 1, wherein the
active ingredient comprises (+)-(1S,2
S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof.
12. A pharmaceutical formulation according to claim 1, wherein the
active ingredient comprises
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof.
13. A tablet for twice daily oral administration of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, said tablet
containing a pharmaceutical formulation according to claim 1.
14. A slow-release pharmaceutical formulation containing
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof as active ingredient in a
matrix, wherein the matrix contains 1 to 80% by weight of one or
more pharmaceutically acceptable hydrophilic or hydrophobic
polymers as matrix forming agents and comprises cellulose ethers
cellulose esters or a mixture thereof having a viscosity of 3,000
to 150,000 mPas in a 2% by weight aqueous solution at 20.degree.
C.
15. A pharmaceutical composition according to claim 14, wherein the
matrix Ruining agents comprise cellulose ethers, cellulose esters
or a mixture thereof having a viscosity of 10,000 to 150,000 mPas
in a 2% by weight solution at 20.degree. C.
16. A pharmaceutical composition according to claim 14, wherein the
matrix forming agents comprise cellulose ethers, cellulose esters
or a mixture thereof having a viscosity of 50,000 to 150,000 mPas
in a 2% by weight solution at 20.degree. C.
17. A pharmaceutical composition according to claim 14, wherein the
matrix forming agent comprises at least one substance selected from
the group consisting of hydroxypropylmethyl celluloses (HPMC),
hydroxyethyl celluloses, hydroxypropyl celluloses (HPC), methyl
celluloses, ethyl celluloses and carboxymethyl celluloses.
18. A pharmaceutical composition according to claim 14, wherein the
matrix forming agent comprises at least one substance selected from
the group consisting of hydroxypropylmethyl celluloses,
hydroxyethyl celluloses, hydroxypropyl celluloses and hydroxypropyl
celluloses.
19. A pharmaceutical composition according to claim 14, wherein
said composition contains from 0.5 to 85% by weight active
ingredient and from 8 to 40% by weight matrix forming agents.
20. A pharmaceutical composition according to claim 14, wherein
said composition comprises from 3 to 70% by weight active
ingredient and from 10 to 35% by weight matrix forming agents.
21. A pharmaceutical composition according to claim 20, wherein
said composition comprises from 8 to 66% by weight active
ingredient and from 10 to 30% by weight matrix forming agents.
22. A pharmaceutical composition according to claim 14, wherein a
peak plasma level of the active ingredient is obtained in vivo 2 to
10 hours after administration of the composition.
23. A pharmaceutical composition according to claim 22, wherein the
peak plasma level of the active ingredient is obtained in vivo 3.5
to 6 hours after administration of the composition.
24. A pharmaceutical formulation according to claim 14, wherein the
active ingredient comprises (+)-(1 S,2
S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof.
25. A pharmaceutical formulation according to claim 14, wherein the
active ingredient comprises
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof.
26. A tablet for twice daily oral administration of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, said tablet
containing a pharmaceutical formulation according to claim 14.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
13/242,800, filed Sep. 23, 2011, which in turn was a continuation
of co-pending application Ser. No. 10/831,368, filed Apr. 26, 2004,
now abandoned, which in turn was a continuation of international
patent application no. PCT/EP02/11809, filed Oct. 22, 2002,
designating the United States of America, and published in Gelman
as WO 03/035053, the entire disclosure of which is incorporated
herein by reference. Priority is claimed based on Federal Republic
of Germany patent application nos. DE 101 52 469.2, filed Oct. 24,
2001, and DE 102 48 309.4, filed Oct. 16, 2002.
BACKGROUND OF THE INVENTION
[0002] The present 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.
[0003] 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is known
from European patent no. EP 693,475 as an analgesic pharmaceutical
composition and can be administered orally. Conventional
formulations for oral administration of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol lead to rapid
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-ethyl-2-methyl-propyl)phenol formerly required
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. It is therefore desirable
to have a slow release pharmaceutical composition (retard
formulation) for oral administration of the active ingredient,
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol.
[0004] 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.
[0005] In coating retardation as described, for example, in
published German patent application no. DE 36 25 458, the nucleus
of a pharmaceutical composition containing an active ingredient is
provided with a coating which consists of one or more hydrophilic
and/or hydrophobic polymers and slows down release of the active
ingredient.
[0006] In 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. Published German patent
application no. DE 33 09 516, 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 A1 contain HPMCs having
viscosities (in a 2% by weight aqueous solution at 20.degree. C.)
between 15 and 30,000 cPs (15 to 30,000 mPas). Release behavior
which is independent of the pH of the dissolution medium is not
disclosed in DE 33 09 516 A1.
SUMMARY OF THE INVENTION
[0007] Accordingly, it is an object of the present invention to
provide a pharmaceutical formulation which achieves slow release of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol.
[0008] This object and other objects are achieved in accordance
with the present invention by a slow-release pharmaceutical
formulation containing
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof in a matrix with slow
release of active ingredient, in which 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.degree. C. and detected using a UV
spectrometer: [0009] 3 to 35% by weight (based on 100% by weight
active ingredient) of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after
0.5 hours; [0010] 5 to 50% by weight of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1
hour; [0011] 10 to 75% by weight of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2
hours; [0012] 15 to 82% by weight of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3
hours; [0013] 30 to 97% by weight of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6
hours; [0014] more than 50% by weight of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12
hours; [0015] more than 70% by weight of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 18
hours, and [0016] more than 80% by weight of
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24
hours. It has surprisingly been found that the formulation
according to the invention releases the active ingredient,
3-(3-dimethylamino-1-ethyl-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 enables pain therapy, during which the
analgesic, 3-(3-dimethylamino-1-ethyl-2-methyl-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 duration of efficacy and the
maintenance of an adequate level in the blood plasma are
demonstrated by simulation studies and experimental
investigations.
[0017] 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) due to the slow
release of the active ingredient, 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
due to maintenance of 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.
[0018] 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 be contained in a
matrix with conventional release behavior and the slow release be
achieved by a retarding coating.
[0019] In a further possibility the slow release behavior is
achieved by an osmotically driven release system.
[0020] 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 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.
[0021] The present invention also relates to a pharmaceutical
formulation which contains
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof in a matrix with slow
release of active ingredient, in which 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 comprise cellulose ethers and/or
cellulose esters having a viscosity (determined using a Pharm. Eu.
capillary viscosimeter) of 3,000 to 150,000 mPas in a 2% by weight
aqueous solution at 20.degree. C. as pharmaceutically acceptable
matrix forming agents. These compositions have the above-mentioned
release profile according to the invention.
[0022] 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.degree. C.
[0023] Particularly suitable pharmaceutically acceptable matrix
forming agents may be selected from the group consisting of
hydroxypropylmethyl celluloses (HPMC), hydroxyethyl celluloses,
hydroxypropyl celluloses (HPC), methyl celluloses, ethyl celluloses
and carboxymethyl celluloses and are selected, in particular, from
the group consisting of HPMCs, hydroxyethyl celluloses and HPCs.
HPMCs having a viscosity of approx. 100,000 mPas, measured in a 2%
by weight aqueous solution at 20.degree. C. are most preferred.
[0024] The active ingredient,
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, exists as such,
i.e. as a free base, but also in the form of pharmaceutically
acceptable salts, for example as a hydrochloride. Preparation of
the free base is known from published European patent application
no. EP 693,475. Where EP 693,475 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 in the art.
[0025] 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol has two
asymmetric centers, so the compound can exist in the form of four
different stereoisomers. In the formulation according to the
invention 3-(3-dimethylamino-1-ethyl-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 (+)-(1 S,2
S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and
(-)-(1R,2R)-3-(3-dimethylamino-1-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-1-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.
[0026] 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
enantiomerically pure (+)-(1 S,2
S)-3-(3-dimethylamino-1-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
enantiomerically pure
(-)-(1R,2R)-3-(3-dimethylamino-1-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 between 16 and 66%
by weight.
[0027] Further components of the matrix of the formulation
according to the invention may optionally include 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.degree. and 90.degree. C. are 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 may be 0 to 60%
by weight. The matrix can alternatively or additionally contain
polyethylene glycols in a content of 0 to 60% by weight.
[0028] 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 glidants, 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 may be between 0
and 80% by weight, preferably between 5 and 65% by weight.
[0029] The release rate of an active ingredient from an
administrable form frequently depends 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 also 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. Thus, 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.
[0030] Surprisingly, however, the release profiles of the active
ingredient (either in the form of the base or of a pharmaceutically
acceptable salt thereof) from a pharmaceutical formulation
according to the invention are independent of 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 in comparison to the release
during a pH/time profile from pH 1.2 via pH 2.3 and pH 6.8 to pH
7.2.
[0031] 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 a corresponding release behavior.
[0032] 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 hours or with
twice daily administration (providing that the above-mentioned
limits on the quantity of active ingredient, matrix forming agent
and further optional components are adhered to). Efficacy over at
least 12 hours is assured, 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 mPas as matrix forming agent and a
content of approx. 52.6% by weight of, for example, MCC as filler
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 glidant, 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.
[0033] 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, a 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.
[0034] Compositions according to the invention which have a
t.sub.max value in the in vivo plasma concentration/time graph of
between 2 and 10 hours, in particular between 3.5 and 6 hours and
more particularly preferably between 4 and 5.5 hours after oral
administration of the composition, i.e. compositions which yield
peak plasma levels during said periods, are also preferred.
[0035] As active ingredient, the formulation according to the
invention contains
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as such and/or as
a pharmaceutically acceptable salt in an amount typically 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 behavior of the formulation according to
the invention is not affected by the exact amount of the active
ingredient provided that the above-mentioned limits are adhered to.
Due to the different active strength of the two particularly
preferred enantiomers
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, it
is preferred if the stronger
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol
exists in an amount 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 is present 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 invention, more specifically on
condition that the above-mentioned limits are adhered to.
[0036] Within the scope of this invention, the term
"pharmaceutically acceptable salt" of the active ingredient refers
to a salt of the active ingredient which is 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.
[0037] 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 typically 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 within the
scope of the invention.
[0038] 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 mPas and a low molecular weight of <10,000 (for example
Pharmacoat 606 with a viscosity of 6 mPas in a 2% by weight aqueous
solution at 20.degree. C.), which only slightly influence the
release profile of the pharmaceutical compositions according to the
invention. Diffusion coatings known to persons 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. The tablet
core can be sheathed with additional active ingredient which is
released as an initial dose without retardation by various
processes known to persons skilled in the art, for example dragee
production, spraying from solutions or 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-1-ethyl-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.
[0039] 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,
glidants, 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.
[0040] As an alternative or a supplement to the possibilities of a
slow release matrix in the prolonged release pharmaceutical
formulation or of 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
release system of this type, preferably an oral system, at least
one, preferably all, surface(s) of the release system, preferably
those which are in contact or which may come into contact with the
release medium, are semi-permeable, preferably provided with a
semi-permeable coating, so the surfaces are permeable to the
release medium but substantially, and preferably completely,
impermeable to the active ingredient, whereby the surface and/or
optionally the coating comprises at least one opening for releasing
the active ingredient. The active ingredient
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof, preferably (+)-(1
S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
pharmaceutically acceptable salt thereof and/or
(-)-(1R,2R)-3-(3-dimethylamino-1-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 pharmaceutical composition core, a semi-permeable membrane
and a polymeric part which exerts pressure. A useful example of
such a system is the OROS.RTM. system from ALZA Corporation, USA,
details of which are available on the Alza Corporation internet
site and/or in product literature of Alza Corporation. These
include in particular the OROS.RTM. Push-Pull.TM. system, the
OROS.RTM. Delayed Push-Pull.TM. system, the OROS.RTM. Multi-Layer
Push-Pull.TM. system, the OROS.RTM. Push-Stick System and in
certain cases the L-OROS.TM.. Embodiments and examples of the
actual production of osmotically driven release systems can be
found in U.S. Pat. Nos. 4,765,989; 4,783,337 and 4,612,008, the
complete disclosures of which are incorporated herein by
reference.
[0041] The compositions according to the invention may be produced,
for example, by the following general processes: weighed amounts of
the components of the composition (active ingredient, matrix
forming agent and optional components) successively introduced and
then screened on a conventional screening machine, for example a
Quadro Comil U10 screening machine using, for example, a
conventional screen size of approx. 0.813 mm. The screened material
is then mixed in a container mixer, for example a Bohle container
mixer. Typical mixer operating conditions are: duration approx. 15
min.+-.45 seconds at a speed of 20.+-.1 rpm. The resulting powder
mixture is subsequently compressed to a tablet on a tablet press,
for example a Korsch EKO tablet press with a round die curved in
the form of a dragee having a diameter of 10 mm. 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 resulting 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 a 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 to
persons skilled in the art.
[0042] The production of pharmaceutical formulations according to
the invention is characterized by high repeatability of the release
properties of the resulting compositions containing
3-(3-dimethylamino-1-ethyl-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.
[0043] 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.
BRIEF DESCRIPTION OF THE DRAWING
[0044] FIG. 1 is a graph of average serum concentrations achieved
by differing pharmaceutical formulations in a clinical trial.
EXAMPLES
[0045] The following examples serve to illustrate the present
invention and preferred embodiments, but do not restrict its
scope.
Example 1
[0046] A batch of 1,000 matrix tablets was produced as described
below having with the following composition per tablet:
TABLE-US-00001 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 80 mg 100,000 from Shinetsu, 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
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 minutes.+-.15 seconds 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.degree. C. and with detection using a UV spectrometer, and is
reproduced in the following table:
TABLE-US-00002 Total amount of active Time ingredient released
(min) [%] 0 0 30 18 60 27 120 41 180 50 240 59 360 71 480 80 600 87
720 93
Example 2
[0047] Using a process similar to that described in Example 1,
3,000 matrix tablets were produced having the following composition
per tablet:
TABLE-US-00003 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 200
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 80 mg 100,000 from Shinetsu, 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
[0048] The in vitro release was determined as in Example 1.
TABLE-US-00004 Total amount of active Time ingredient released
(min) [%] 0 0 30 19 60 30 120 46 180 58 240 68 360 84 480 93 720
99
Example 3
[0049] Using a process similar to that described in Example 1, a
batch of 3,000 matrix tablets were produced having the following
composition per tablet:
TABLE-US-00005 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 40 mg 100,000 from Shinetsu, 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
The in vitro release was determined as in Example 1. In addition,
the release was determined under otherwise identical conditions at
stirring speeds of 50 and 100 rpm.
TABLE-US-00006 Total amount of Total amount of Total amount of
active ingredient active ingredient active ingredient Time released
[%] released [%] released [%] (min) at 50 rpm at 75 rpm at 100 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
[0050] Using a process similar to that described in Example 1, a
batch of 200 matrix tablets was produced having the following
composition per tablet:
TABLE-US-00007 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 80 mg 100,000 from Shinetsu, 100,000 mPa s Lactose
monohydrate 230 (Meggle) 123 mg Highly dispersed silicon dioxide 4
mg Magnesium stearate 3 mg Total amount 310 mg
The in vitro release was determined as in Example 1.
TABLE-US-00008 Total amount of active Time ingredient released
(min) [%] 0 0 30 16 60 26 120 39 180 49 240 57 360 71 480 81 600 87
720 92
Example 5
[0051] Matrix tablets with the following composition per tablet
TABLE-US-00009 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 40 mg 100,000 from Shinetsu, 100,000 mPa s
Cellactose 80 (Meggle) 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 100 tablets.
[0052] The in vitro release was determined as an Example 1.
TABLE-US-00010 Total amount of active Time ingredient released
(min) [%] 0 0 30 18 60 31 120 48 180 61 240 71 360 84 480 91 600 95
720 97
Example 6
[0053] Matrix tablets with the following composition per tablet
TABLE-US-00011 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 80 mg 100,000 from 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.
[0054] The in vitro release was determined as in Example 1.
TABLE-US-00012 Total amount of active Time ingredient released
(min) [%] 0 0 30 17 60 27 120 40 180 51 240 59 360 72 480 82 600 89
720 93
Example 7
[0055] Matrix tablets with the following composition per tablet
TABLE-US-00013 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 50
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 40 mg 100,000 from Shinetsu, 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.
[0056] The in vitro release was determined as in Example 1.
TABLE-US-00014 Total amount of active Time ingredient released
(min) [%] 0 0 30 18 60 31 120 49 180 61 240 70 360 82 480 90 600 94
720 96
Example 8
[0057] Matrix tablets with the following composition per tablet
TABLE-US-00015 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100
mg propyl)phenol hydrochloride Cellactose (Meggle) 72.5 mg
Hydroxyethyl cellulose (Natrosol 250 HX from Herkules) 12.5 mg
Cutina HR (Henkel) 130 mg Talcum 3 mg Magnesium stearate 2 mg Total
amount 320 mg
were produced as follows in a batch size of 200 tablets. The active
ingredient, Cellactose, Natrosol and Cutina were mixed then heated
to 80.degree. 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.times.15 mm size oblong tablets with a breaking notch.
[0058] The in vitro release was determined as in Example 1.
TABLE-US-00016 Total amount of active Time ingredient released
(min) [%] 0 0 30 28 60 39 120 56 180 68 240 80 360 97 390 99
Example 9
[0059] Matrix tablets with the following composition per tablet
TABLE-US-00017 (+)-(1S,2S)3-(3-dimethylamino-1-ethyl-2-methyl- 10
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 80 mg 100,000 from 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.
[0060] The in vitro release was determined as in Example 1.
TABLE-US-00018 Total amount of active Time ingredient released
(min) [%] 0 0 30 15 60 24 120 36 180 44 240 51 360 61 480 69 600 75
720 79
Example 10
[0061] Matrix tablets with the following composition per
tablet:
TABLE-US-00019 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100
mg propyl)phenol hydrochloride Hydroxypropylmethyl cellulose
(Metolose 90 SH 80 mg 100,000 from 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.
[0062] The in vitro release was determined under the following
conditions:
(A) application of the Ph. Eur. Paddle Method at 75 rpm in 900 ml
pH 7.2 buffer to USP 22 at 37.degree. 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 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:
TABLE-US-00020 Total amount of active Total amount of active
ingredient released ingredient released Time [%} [%} (min) under
condition (A) under condition (B) 0 0 0 30 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
The experiment shows that the release behavior of the formulations
according to the invention is independent of the pH of the release
medium.
Example 11
[0063] Pellets were produced as described below having the
following composition:
TABLE-US-00021 (-)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100
mg propyl)phenol hydrochloride Low-substituted hydroxypropyl
cellulose (L-HPC LH 75 mg 31 from Shinetsu) Aquacoat (aqueous ethyl
cellulose dispersion from FMC) 20 mg (calculated as 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
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.times.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.degree. C. and then classified
into screen fractions.
[0064] 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.degree. C. (product temperature 40.degree.
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 homogenized 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 hours. The coated pellets were dried in the
WSG and tempered in the drying oven (2 hours at 60.degree. C.). The
release was tested as in Example 1, but by the basket method at 100
rpm.
TABLE-US-00022 Total amount of active Time ingredient released
(min) [%] 0 0 30 5 60 15 120 28 180 43 240 56 360 73 480 82 600 87
720 90
Clinical Trial
[0065] In a monocentric, open, randomized individual dose four-way
crossover trial, various forms of administration of
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-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:
[0066] "Capsule 100 mg": capsules with immediate release of the
active ingredient and 100 mg of active ingredient
[0067] "Capsule 25 mg": capsules with immediate release of the
active ingredient and 25 mg of active ingredient
[0068] "Tablet 100 mg": tablet according to Example 1 (100 mg of
active ingredient)
[0069] "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:
[0070] "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);
[0071] "Capsule 25 mg": 25 mg
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol
hydrochloride, 227 mg microcrystalline cellulose, 8 mg Aerosil, 20
mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl
starch type A from Avebe))
[0072] The essential pharmacokinetic data are shown in the
following table and the characteristic of the experimentally
determined average serum concentration in FIG. 1.
TABLE-US-00023 "Capsule "Capsule "Tablet "Tablet Parameter 25 mg"
100 mg" 100 mg" 200 mg" AUC [ng h/ml] 69 .+-. 14 318 .+-. 66 300
.+-. 51 667 .+-. 141 C.sub.max [ng/ml] 14 .+-. 4 64 .+-. 19 23 .+-.
5 51 .+-. 13 t.sub.max [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** 3.5 .+-. 1.2 3.6 .+-. 1.1 12.4 .+-. 2.8 11.9 .+-.
2.3 *MRT = "Mean Residence Time" **HVD = "Half Value Duration"
[0073] 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-1-ethyl-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 behavior.
[0074] 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 10 ng/ml after only one hour and still sufficiently high after
16 hours to ensure an 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 the treatment, in particular of chronic painful
conditions, and allows a significant improvement in patient
compliance.
[0075] 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 my 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.
* * * * *