Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
BASF AktlengesellsccAao222g62l 1998-o3-ll 0.Z. 0050/47837
Solid, at least two-phase formulations of an opioid analgesic
with delayed release
5 Descripti~n
The present invention relates to solid, at least two-phase
form~ tions of at least one opioid analgesic, where each of the
two phases contains at least one opioid, with an in vitro release
10 rate det~rm;ne~ by the Ph.Eur. paddle method of more than 50% by
weight after one hour. The invention furthe --e relates to a
process for producing such formulations.
Opioid drug forms disclosed to date release the active ingredient
15 either with no delay or with classical slowing of release. Such
forms with classical slowing of release have either a coating
which acts to slow release or contain a homogeneous phase of the
active ingredient in an ancillary substance matrix. One-stage
release profiles are accordingly achieved. However, the
20 disadvantage of classical slowing of release is that release o~
the active ingredient starts relatively slowly, which also
results in delayed onset of the analgesic effect. Another
disadvantage of slowing release by means of a coating is that
dose dumping may occur if the coating is damaged by the
- 25 peristalsis in the digestive tract. This may result in an init:ial
dose so large as to be outside the therapeutic range.
Thus, EP-A 271 193 describes hydromorphone formulations for
A~; n; stration twice a day which contain the active ingredient in
30 a matrix and with which up to 42.5% by weight of the active
ingredient are released after one hour. Formulations of this t~rpe
consist of a homogeneous phase.
EP-A 543 541 describes preparations of the active ingredient
35 flutamide which have a rapid release phase as outer shell and a
core which has a release-slowing coating.
It is an object of the present invention to find drug forms which
permit both a rapid rise in level of the active ingredient for
40 rapidly ~;m; n; ~hing severe pain and a slow release for pro~onged
pain control.
we have found that this object is achieved by dosage forms which
display at least biphasic release of the active ingredient. The
45 solid, at least two-phase drug forms for oral ~m; n; ~tration,
where each phase comprises at least one opioid analgesic, show an
in vitro release rate measured by the Ph.Eur. p~l~ method of
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more than 50% of the active ingredient after one hour. Preferred
drug forms have a release rate of from 55 up to 80% after one
hour, up to 85% a~ter two hours, 60 to 95% after four hours and
from 65 to l00~ after eight hours. Particularly preferred release
5 rates are from 56 to 70% in the first hour. The drug forms are
particularly in~en~ed for Al' ; n; ctration twice a day. Unless
otherwise mentioned, the in vitro release rates are det~r~;ned by
the Ph. Eur. paddle method at l00 rpm in 0.l N HCl at 37~C with W
detection at 270 nm.
Opioid analgesics for the purpose of this invention are:
morphine, codeine, ethylmorphine, dihydrocodeine, hydLc -rphone,
oxycodone, hydroco~one, thebacon, levorphanol, pethidine,
15 ketobe~i~e, levomethadone, normethadone, fenpipramide,
dextromoramide, clofenadol, pentazocine, tili~;ne~ naloxone,
piritramide, fentanyl, nefopam, tramadol and buprenorphine or
their physiologically tolerated salts.
20 Preferred opioids are:
codeine, dihydrocodeine, hydrocodone, hydromorphone, morphine,
dihydromorphine, oxymorphone, tramadol or mixtures thereof.
Very particularly preferred opioids are selected from the group
25 of hydromorphone, morphine, tramadol or their physiologically
tolerated salts.
The claimed drug forms comprise therapeutically effective amoun1s
of the opioid active ingredients. In the case of tramadol, 50 -
30 l000 mg of tramadol hydrochloride are employed per drug form,preferably l00 to 600 mg. This preferably comprises 5 - 50~ by
weight in the IR phase and 50 - 95% by weight in the SR phase.
In the case of morphine or its physiologically tolerated salts
35 such as morphine sulfate or morphine hydrochloride, l0 mg, 30 mg,
60 mg, l00 mg, 200 mg or 500 mg of active ingredient are employe
per drug form, preferably comprising l - 20% by weight in the I~.
phase and 80 - 99% by weight in the SR phase.
40 In the case of hydromorphone, the drug forms comprise l - 150 mg,
preferably 2 - 60 mg, in particular 2 - 30 mg, preferably
comprising l - 15% by weight in the IR phase and 85 - 99% by
weight in the SR phase.
45 The drug forms consist of at least two phases, each phase
comprising at least one opioid in a matrix. The opioids can be
identical or different. The various phases each display a
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different release profile, one phase being rapid release (IR
phase; instant release) and intended to achieve a rapid onset of
the analgesic effect, while the other phase shows slow release
(SR phase, sustained release), in order to achieve an additi~
5 prolonged effect.
The control of release can in each case be achieved by the
composition of the matrix of the individual phases. This matrix
can consist of low molecular weight ancillary substAnc~s and~or
10 polymeric binders. The release is not controlled by a
release-slowing coating.
Rapid release matrices may, for example, be obt~;n~ by the
following compositions of ancillary substances:
a) suitable polymeric binders are synthetic or semisynthetic
polymers such as water-soluble homo- or copolymers of
N-vinylpyrrolidone (NVP) with Fikentscher K values up to 30,
with preferred comonomers being vinyl esters, especially
vinyl acetate, also hydroxyalkylcelluloses such as
hydroxypropylcellulose, alkylcelluloses such as
ethylcellulose, as well as polyethylene glycols, preferably
those having molecular weights of from 1000 to 20000. Also
suitable are methacrylic acid copolymers (Eudragit types) 03
polyvinyl alcohol. Also suitable as binders are natural
polymers such as starch or else starch derivatives such as
hydroxyethyl starch, oxidized starches or pregelatini~e~
starches.
30 b) suitable bulking agents are sugars, for example lactose,
glucose or sucrose, sugar alcohols such as maltitol,
mannitol, sorbitol, xylitol and isomalt, also degraded
starches such as dextrins, especially maltodextrin. Also
suitable are microcrystalline cellulose or inorganic salts
such as calcium phosphate, dicalcium phosphate or sodium
chlorider and, where appropriate, also alkali metal
carbonates such as Na2CO3.
c) suitable disintegrants are sodium starch glycolate,
crosslinked polyvinylpyrrolidone, crosslinked
carboxymethylcellulose, bentonites, alginates or
croscarmellose.
. .,
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BA~F Aktiengesellschaft 960833 O.Z. 0050~47837
d) suitable water-soluble wetting agents or water-soluble
surfactants are sodium lauryl sulfate, sorbitan fatty acid
esters, salts of bile acids and similar phAr~ceu~ic~lly
acceptable surface-active substances.
e) further phA ~eutical additives such as colors and~or
- flavors.
The various components can be employed in the matrix in the
lO following amounts:
a) 0 - 80% by weight
b) 0 - 99% by weight
c) 1 - 8% by weight
15 d) 0.1 - ~0% by weight
e) 0.1 - 5~ by weight
The stated amounts are based on the total amount of the ancillary
substances ~a) to (e), with the amounts of a) and b) being chosen
~ 20 in each case so that the total amount of 100% by weight results.
The slow-release phase may comprise the following ingredients:
Suitable polymeric binders are:
A) soluble homo- and copolymers of NVP with K values from 10 l:o
100, preferred comonomers being vinyl esters such as vinyl
propionate or, in particular, vinyl acetate, also polyvinyl
alcohol, polyvinyl acetate, partially hydrolyzed polyvinyl
acetate,
s) alkylcelluloses such as methylcellulose or ethylce~tllo~e,
hydroxyalkylcelluloses such as hydroxypropylcellulose,
hydroxyethylcellulose, and hydroxypropylmethylcellulose,
furthermore cellulose esters such as cellulose acetate,
cellulose acetate propionate, cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate phthalate and
uncrosslinked carboxymethylcellulose,
C) methacrylic acid copolymers, with ethyl acrylate being
preferred as comonomer, A~;noAlkyl methacrylate copolymers.
It is also possible to employ mixtures of polymers A), B) and/or
45 C), for example mixtures of 0 - 90% by weight of A), 10 - 70% by
weight of B) and 0 - 20% by weight of C).
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Each of the phases may furthermore contain additional
pharmaceutical ancillary substances such as lubricants, fl~vor
improvers, emulsifiers etc.
5 The drug forms may also comprise more than two opioid-cont~ining
phases when a more pronounced gradation of the slow release is to
be achieved. The drug forms may furthermore additionally contain
nonopioid-cont~in;ng phases which may comprise other analgesics
such as nonsteroidal antiinflammatory analgesics.
The drug forms according to the invention are preferably in the
form of open multilayer tablets in which each phase forms a
layer. The drug forms may also be in the form of closed 1~ in~ted
tablets in which the rapid release phase forms the outer coati~g
15 while the core is formed by one or more slow-release phases.
Suitable multiphase drug forms are also inlay tablets (bull-eye
tablets) or multiparticulate forms in which individual granule:~,
pellets or other particles which correspond to the slow-release
phase are incorporated into a rapid-release phase.
Suitable for producing the drug forms according to the invention
are, inter alia, conventional tableting processes, for example
processes in which the individual phases in each case are
compressed together in the form of granules or pellets. In these
25 cases, the individual phases with their different release
characteristics are ret~ine~ It is possible in this way to
obtain monolayer or multilayer tablets.
The drug forms according to the invention are preferably produced
30 by a melt extrusion process, in which case the active ingredients
are mixed with the ancillary substances in the melt and extruded
through one or more dies or breaker plates, and then the still
the ~plastic materials are subjected to shaping. This process is
preferably carried out in the absence of solvents. Particularly
35 suitable for producing open or closed l~in~ted tablets is the
coextrusion process in which the compositions int~n~e~ for the
individual phases are melted and extruded separately, after which
the still plastic strands, ribbons or layers are brought together
and shaped. A coextrusion process of this type is described, for
40 example, in DE 195 39 361. Alternatively, it is also possible to
produce multilayer tablets by combining melts in an injection
molding process, applying successive layers in the mold, or by
2-component injection molding.
45 Production preferably takes place in twin-screw extruders with or
without kneading disks.
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It is furthermore possible to incorporate one of the phases in
solid form into the other phase in the form of a melt or a still
plastic material. ~he precondition for this is that the solid
phase does not dissolve in the melt, which can be achieved by
5 suitable choice of the ancillary substance, or by one matrix
being coated or dusted with powder before incorporation into the
other.
Solid, at least two-phase drug forms which can be produced by the
lO process according to the invention are, in particular, tablets,
preferably oblong tablets, coated tablets, pastilles or pelle1s.
The drug forms can also be provided with a taste-masking coatLng.
The opioid drug forms obtained according to the invention
15 display, because they are composed of a rapid-release phase and
at least one slow-release phase, release kinetics which are
particularly desirable for strong analgesics. Forms of this type
can be produced particularly straightforwardly and reliably by
the process according to the invention.
A~; ni ~tration of the dosage forms according to the invention
achieves not only a rapid onset of the analgesic effect but also
a long-lasting pain control. It was surprising that plasma le~els
in the pain-relevant range could be achieved even after 5 h.
In the case of tramadol, blood plasma levels of 90 - 200 mg~ml,
preferably lO0 - 180 mg/ml, particularly preferably llO -
165 mg/ml, are achieved 5 hours after a single ~l~nin;~tration
under fasting conditions.
The compositions mentioned in the following Examples are
preferably coextruded in a Werner ~ Pfleiderer ZSK 30 twin-screw
extruder with an output of 2 kg/hour in each case. The shaping of
the still plastic extrudate takes place as described in EP-A 240
35 906 by calendering.
Formulation l:
Extruder l:
l kg of a mixture of 40% by weight of tramadol HCl, 15% by weight
of ethylcellulose (Ethocel NlO0), 35% by weight of isomalt, 7% by
weight of polyvinylpyrrolidone K30 and 3% by weight of
hydrogenated castor oil (Cutina HR) were mixed in a twin-screw
45 extruder.
BASF AktiengesellscAao~t2962l 9998-o3-11 O.Z. 0050/47837
Section t~reratures: 44, 80, 121, 99, 92, 82 ~C
Die: 80 ~C
Extruder 2:
1 kg of a mixture of 35% by weight of tramadol HCl, 34~ by weight
of hydroxypropylmethylcellulose (Methocel RlOOM) and 31% by
weight of hydroxypropylcellulose (Klucel EF) were mixed in
twin-screw extruder.
Section temr~ratures: 44, 80, 121, 99, 92, 8Z~C
Die: 80 ~C
The drug forms displayed the following in vitro release.
Time in minutes % by weight of active ingredient relea$ed
71.9
120 81.9
180 87.9
240 90 9
300 95.6
360 97.0
420 97 5
480 98.0
3 Example 2:
Extruder 1:
1 kg of a mixture of 40% by weight of tramadol HCl, 15% by weight
of ethylcellulose, 35% by weight of isomalt, 7~ by weight of
polyvinylpyrrolidone K30 and 3% by weight of hydrogenated castor
oil were mixed in a twin-screw extruder.
Section t~ _~ratures 44, 80, 121, 99, 92, 82 ~C
Die: 80~C
Extruder 2:
. .,
1 kg of a mixture of 52% by weight of tramadol HCl, 36~ by weigllt
of hydroxypropylmethylce~lulose and 12% by weight of
hydroxypropylcellulose were mixed in a twin-screw extruder.
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Section temperatures: 43, 78, 123, 124, 131, 131 ~C
Die: 131~C
The tablets displayed the following in vitro release:
Time in minutes% by weight of active ingredient
58.5
120 70.4
180 81.3
240 88.8
300 93.8
360 96.2
420 97 0
480 97,5
20 The release rate was measured by the Ph.Eur. paddle method in
0.1 N HCl at 100 rpm und 37 ~C with UV detection at 270 nm.
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