U.S. patent application number 10/179389 was filed with the patent office on 2003-06-05 for controlled release tramadol preparations with a storage-stable release profile and process for their production.
This patent application is currently assigned to Gruenenthal GmbH. Invention is credited to Bartholomaeus, Johannes Heinrich, Ziegler, Iris.
Application Number | 20030104061 10/179389 |
Document ID | / |
Family ID | 7894565 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030104061 |
Kind Code |
A1 |
Bartholomaeus, Johannes Heinrich ;
et al. |
June 5, 2003 |
Controlled release tramadol preparations with a storage-stable
release profile and process for their production
Abstract
A process for producing an oral, controlled release preparation
of tramadol or a physiologically compatible tramadol salt having a
storage stable active substance release profile by coating the
active substance preparation with an aqueous ethylcellulose
dispersion which contains at least one physiologically compatible,
lipophilic diester of a C.sub.6-C.sub.40 aliphatic or aromatic
dicarboxylic acid and a C.sub.6-C.sub.8 aliphatic alcohol as
plasticizer, and, during coating, drying the coating at
conventional temperatures, with the result that a storage stable
active substance release profile is obtained even without
subsequent heat treatment. Optionally, in order to increase the
active substance release profile without impairing the storage
stability of the preparation, a heat treatment may be performed at
temperatures of >35.degree. C. until a desired, increased active
substance release profile is achieved.
Inventors: |
Bartholomaeus, Johannes
Heinrich; (Aachen, DE) ; Ziegler, Iris;
(Rott-Roetgen, DE) |
Correspondence
Address: |
CROWELL & MORING LLP
INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
Gruenenthal GmbH
Aachen
DE
D-52078
|
Family ID: |
7894565 |
Appl. No.: |
10/179389 |
Filed: |
June 26, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10179389 |
Jun 26, 2002 |
|
|
|
09484017 |
Jan 18, 2000 |
|
|
|
6451350 |
|
|
|
|
Current U.S.
Class: |
424/470 |
Current CPC
Class: |
A61K 9/5073 20130101;
A61K 9/5047 20130101; A61P 29/00 20180101; A61K 9/5015 20130101;
A61P 25/04 20180101 |
Class at
Publication: |
424/470 |
International
Class: |
A61K 009/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 18, 1999 |
DE |
199 01 686.0 |
Claims
What is claimed is:
1. A process for producing an oral, controlled release preparation
of tramadol or a physiologically compatible salt of tramadol having
a storage stable active substance release profile, said process
comprising the step of coating a tramadol or physiologically
compatible tramadol salt preparation with an aqueous ethylcellulose
dispersion containing at least one physiologically compatible
plasticizer comprising a lipophilic diester of a C.sub.6-C.sub.40
aliphatic or aromatic dicarboxylic acid and a C.sub.1-C.sub.8
aliphatic alcohol, and drying the coating, whereby a storage stable
active substance release profile is obtained without subsequent
heat treatment.
2. A process according to claim 1, wherein said coating is dried
during coating at conventional drying temperatures.
3. A process according to claim 1, further comprising the step of
heat treating the tramadol preparation at temperatures of
>35.degree. C. until a desired, increased active substance
release profile is achieved without impairing the storage stability
of the preparation.
4. A process according to claim 1, wherein said plasticizer is a
diester of an C.sub.6-C.sub.30 aliphatic or aromatic dicarboxylic
acid and a C.sub.2-C.sub.6 aliphatic alcohol.
5. A process according to claim 4, wherein said plasticizer is a
diester of a C.sub.10-C.sub.16 aliphatic or aromatic dicarboxylic
acid and a C.sub.2-C.sub.5 aliphatic alcohol.
6. A process according to claim 5, wherein said plasticizer is
selected from the group consisting of dibutyl phthalate, diethyl
phthalate, dibutyl sebacate, and diethyl sebacate.
7. A process according to claim 5, wherein said plasticizer is
dibutyl sebacate.
8. A process according to claim 1, wherein the plasticizer is used
in an amount equal to 5 to 50 wt. % of the ethylcellulose.
9. A process according to claim 8, wherein the plasticizer is used
in an amount equal to 10 to 40 wt. % of the ethylcellulose.
10. A process according to claim 9, wherein the plasticizer is used
in an amount equal to 10 to 30 wt. % of the ethylcellulose.
11. A process according to claim 1, wherein the ethylcellulose
dispersion has an ethylcellulose concentration of from 3 wt. % to
35 wt. %.
12. A process according to claim 11, wherein the ethylcellulose
dispersion has an ethylcellulose concentration of from 10 wt. % to
30 wt. %.
13. A process according to claim 1, wherein the controlled release
coating is dried at a temperature of from 40 to 80.degree. C.
14. A process according to claim 13, wherein the controlled release
coating is dried at a temperature of from 50 to 70.degree. C.
15. A process according to claim 1, further comprising the step of
applying a protective coating of water-soluble polymer and talcum
prior to coating with the controlled release coating.
16. A process according to claim 15, wherein said water-soluble
polymer is hydroxypropylmethylcellulose or
hydroxypropylcellulose.
17. A process according to claim 15, wherein the protective coating
produces an increase in weight of 1 to 10 wt. %.
18. A process according to claim 17, wherein the protective coating
produces an increase in weight of 2.5 to 5 wt. %.
19. A, process according to claim 1, wherein said preparation is a
tramadol hydrochloride preparation.
20. A process according to claim 1, wherein said tramadol or
physiologically compatible tramadol salt preparation is a
multiparticulate preparation.
21. A process according to claim 20, wherein said multiparticulate
preparation is comprised of microtablets, granules, pellets or
crystals.
22. A process according to claim 20, wherein the multiparticulate
preparation is comprised of particles having an average particle
size of 0.3 to 2.5 mm.
23. An oral, controlled release active substance preparation having
a storage stable active substance release profile, wherein said
active substance is tramadol or a physiologically compatible salt
of tramadol, said active substance preparation being coated with a
coalesced ethylcellulose coating obtained by coating a substrate
containing the active substance with an aqueous ethylcellulose
dispersion containing a plasticizer comprised of a lipophilic
diester of a C.sub.6-C.sub.40 aliphatic or aromatic dicarboxylic
acid and a C.sub.1-C.sub.8 aliphatic alcohol, and only drying the
coating at conventional temperature, whereby a storage stable
active substance release profile is obtained.
24. A controlled release preparation according to claim 23, wherein
the active substance release profile is increased by subsequent
heat treatment at temperatures of >35.degree. C. without
affecting storage stability of the preparation.
25. A controlled release preparation according to claim 23, wherein
said preparation is a multiparticulate preparation.
26. A controlled release preparation according to claim 25, wherein
said multiparticulate preparation is in the form of microtablets,
granules, pellets or crystals.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to preferably
multi-particulate, oral tramadol preparations, having a controlled
active substance release profile which is established in a
storage-stable manner by an ethylcellulose coating containing
plasticizer even without heat treatment.
[0002] Multiparticulate, controlled release tramadol preparations
having a controlled release coating of ethylcellulose are known in
the prior art. DE-A-196 30 035 accordingly describes
multiparticulate tramadol preparations in the form of pellets which
are provided with a controlled release coating of ethylcellulose.
To this end, accretion pellets are coated with one or more
ethylcellulose membrane layers which are applied from solutions in
organic solvents. This production method has the disadvantage that
the organic solvents must be recovered on environmental grounds,
thus rendering this process somewhat costly. It is moreover
disadvantageous to use organic solvents in the production of
pharmaceuticals.
[0003] Where controlled release coatings of aqueous ethylcellulose
dispersions are applied onto substrates, it is generally recognized
by experts that, once produced, such coatings do not usually
provide storage-stable active substance release profiles. Such
ethylcellulose coatings are indeed known to have a tendency to
"post-filming", i.e. active substance release is increasingly
delayed over storage. In order to overcome this problem, elaborate
heat treatment processes at elevated temperature and optionally
defined atmospheric humidity are recommended in the prior art in
order to achieve a storage-stable release profile within days
rather than after several months' storage (EP-A-0 548 448, EP-A-0
630 646).
[0004] According to the teaching of U.S. Pat. No. 5,645,858, it has
also been proposed to provide a multiparticulate tramadol
preparation in the form of accretion pellets with two or more
controlled release coatings of ethylcellulose and to subject the
resultant coated accretion pellets of the active substance to a
heat treatment process for one day at elevated temperature in order
to achieve a stable release profile.
[0005] Known methods for producing controlled release coatings from
aqueous ethylcellulose dispersions thus have the disadvantage that
a storage-stable active substance release profile of tramadol or
tramadol hydrochloride is achieved only by elaborate heat treatment
processes or only by multilayer application in combination with a
heat treatment process.
SUMMARY OF THE INVENTION
[0006] The object of the present invention was accordingly to
provide oral tramadol preparations having a controlled release
ethylcellulose coating which, despite being applied from an aqueous
ethylcellulose dispersion, has a largely storage-stable active
substance release profile immediately after the production thereof,
and which may optionally, if desired, be still further increased
without affecting storage stability.
[0007] This is achieved according to the invention by the process
of the invention, in accordance with which a preferably
multiparticulate, oral, controlled release tramadol preparation or
a preparation of a physiologically compatible salt of tramadol
having a storage stable active substance release profile is
produced. To this end, the preferably multiparticulate active
substance preparation is coated with an aqueous ethylcellulose
dispersion which contains at least one physiologically compatible,
lipophilic diester of a C.sub.6-C.sub.40 aliphatic or aromatic
dicarboxylic acid and a C.sub.1-C.sub.8 aliphatic alcohol as
plasticizer, and the coating is dried at conventional
temperatures.
[0008] The controlled release tramadol preparations produced in
this manner surprisingly exhibit a storage stable active substance
release profile immediately after the production thereof, without
any heat treatment subsequent to the conventional drying being
necessary. The controlled release tramadol preparations produced
according to the invention exhibit a so-called coalesced
ethylcellulose coating, in which the discrete ethylcellulose
particles have coalesced to form a coating.
[0009] The controlled release active substance preparations
according to the invention furthermore have the unexpected
advantage that the active substance release profile may be
increased as desired without the storage stability of the increased
active substance release profile being impaired. This is achieved
by heat treating the controlled release active substance
preparations after production thereof at temperatures of
>35.degree. C. until the selected, increased release profile is
achieved.
[0010] Tramadol or preferably a physiologically compatible salt of
tramado, such as tramadol hydrochloride, is used for the process
according to the invention in the form of tablets, microtablets,
granules, crystals, pellets, such as extrusion or accretion pellets
preferably having a size of 0.3 to 2.5 mm. The production of such
multiparticulate substrates is known to persons skilled in the
art.
[0011] The controlled release coatings are produced by using
aqueous ethylcellulose dispersions having a concentration of
water-insoluble ethylcellulose of 3 to 35 wt. %, preferably of 10
to 25 wt. %. The aqueous ethylcellulose dispersions which are used
as the coating material contain at least one physiologically
compatible lipophilic diester of a C.sub.6-C.sub.40, preferably
C.sub.6-C.sub.30, particularly preferably C.sub.10-C.sub.16,
aliphatic or aromatic dicarboxylic acid and a C.sub.1-C.sub.8,
preferably C.sub.2-C.sub.6, particularly preferably C.sub.2-C.sub.5
aliphatic alcohol as a plasticizer. The plasticizers used are
preferably dibutyl phthalate, diethyl phthalate, dibutyl sebacate
or diethyl sebacate, particularly preferably dibutyl sebacate. The
quantity of plasticizer is from 5 to 50 wt. %, preferably 10 to 40
wt. %, particularly preferably 10 to 30 wt. %, relative to
ethylcellulose. Especially preferred controlled release coatings
are those prepared from ethylcellulose containing 10 to 30 wt. %
dibutyl sebacate, relative to the ethylcellulose.
[0012] The aqueous ethylcellulose dispersions used may be
commercial products such as, for example, Aquacoat.TM. or
Surelease.TM.. Such dispersions, such as for example Surelease, may
already contain the necessary plasticizer. It is, however, also
possible to incorporate the plasticizers into the aqueous
ethylcellulose dispersion, preferably with the assistance of
surfactants or emulsifiers, such as for example polysorbate 80
(Tween 80.TM.). It is particularly preferred to use an aqueous
ethylcellulose dispersion which already contains the plasticizer as
a component during the production of the ethylcellulose dispersion,
such as the commercial product Surelease E-7-7050.TM..
[0013] The release profiles obtained immediately after production
may be adjusted by methods known to persons skilled in the art,
such as for example by varying the particular thickness of the
coating or by addition of further auxiliary substances as coating
constituents. Pigments, such as iron oxides, titanium dioxide,
lubricants, such as talcum, Aerosil, glycerol monostearate,
hydrophilic pore-formers such as lactose, polyethylene glycol,
mannitol and/or water-soluble polymers, such as
hydroxypropylmethylcellulose, polyvidone, may be considered for
this purpose. It is also possible by blending with other coating
dispersions, such as for example Eudragit.TM. RS 30D, RL 30D, NE
30D, or dispersions of film-formers resistant to gastric juices,
such as for example Endragit L 30D, to control the release of the
active substance such that a delay on the order of at least 4 hours
up to 24 hours is achieved.
[0014] The controlled release coating of ethylcellulose is produced
by coating the active substance substrates, once produced, with the
aqueous dispersion by spraying, preferably using the fluidized bed
process, and simultaneously drying at conventional temperatures.
Desired product temperatures in this process are at least
35.degree. C., preferably 35.degree. C. to 80.degree. C.,
particularly preferably 40.degree. C. to 45.degree. C., which are
established using feed air at a temperature of at least 50.degree.
C., preferably of 55.degree. C. to 70.degree. C.
[0015] In the event that the storage stable release profile of the
active substance obtained immediately after production is
subsequently to be changed, it is possible after drying to expose
the controlled release active substance preparations to heat
treatment at temperatures of >35.degree. C. until the desired
increase in release of the active substance is achieved. By
measuring the particular active substance release profile as a
function of the duration of the heat treatment process at a
specific temperature, persons skilled in the art are able to
determine the correlation between release profile and heat
treatment conditions by means of simple tests. It is thus
straightforwardly possible to establish an appropriate active
substance release profile at any time.
[0016] The present invention accordingly also provides oral,
preferably multiparticulate, controlled release preparations of
tramadol or a physiologically compatible salt of tramadol having a
storage stable active substance release profile.
[0017] The controlled release tramadol or tramadol salt
preparations according to the invention are characterized by the
active substance preparation being provided with a coalesced
ethylcellulose coating, which has been obtained by coating the
preferably multiparticulate active substance preparation with an
aqueous ethylcellulose dispersion containing a plasticizer which is
comprised of a lipophilic diester of a C.sub.6-C.sub.40 aliphatic
or aromatic dicarboxylic acid and a C.sub.1-C.sub.8 aliphatic
alcohol, and which provides a storage stable active substance
release profile after only drying the coating at conventional
temperature. The active substance release profile may be increased
by subsequent heat treatment at temperatures of >35.degree. C.
without affecting storage stability.
[0018] In order to protect the very readily water-soluble tramadol
or tramadol salt, such as tramadol hydrochloride, during coating
with the aqueous ethylcellulose dispersion, it may be advantageous
to apply a protective coating to the active substance substrate
before application of the controlled release coating. The
protective coating is preferably applied for isolation purposes in
a quantity of 1 to 10 wt. %, preferably of 2.5 to 5 wt. %, relative
to the quantity of the active substance substrate to be coated.
This results in no substantial reduction in the application rate
required for controlled release purposes, but avoids dissolution of
the water-soluble active substance during coating with
ethylcellulose and prevents the active substance from penetrating
the controlled release film.
[0019] Aqueous solutions of water-soluble polymers, such as for
example hydroxypropylmethylcellulose or hydroxypropyl-cellulose,
poylvidone with or without further auxiliary substances, such as
for example talcum, or lipophilic substances applied by melt
coating or from organic solutions, such as for example fatty
alcohols, fatty acids, fats, waxes, glycerol monostearate, glycerol
behenate types may be used as a protective coating material.
[0020] External coatings over the controlled release substrates are
generally applied in order to prevent adhesion of the substrates
during storage. The external coatings may, however, also be
functional coatings which provide additional protection, for
example against elevated atmospheric humidity or against the
penetration of gastric acid into the substrate. The quantity of the
external coating is determined in accordance with its function and
ranges from .ltoreq.1 wt. % to provide protection against sticking
up to 30 wt. % to increase resistance to gastric juices.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a graph showing the storage stability of tramadol
release from pellets coated with 11% of a coating according to the
invention without adjustment of the release profile after
coating.
[0022] FIG. 2 is a graph showing the storage stability of tramadol
release from pellets coated with 11% of a coating according to the
invention after adjustment of the release profile for 24 hours at
60.degree. C.
[0023] FIG. 3 is a graph showing the storage stability of tramadol
release from pellets coated with 11% of a coating according to the
invention after adjustment of the release profile for 2 hours at
60.degree. C.
[0024] FIG. 4 is a graph showing the adjustment of tramadol release
from pellets coated with a coating according to the invention by
subsequent adjustment treatment at 60.degree. C.
[0025] FIG. 5 is a graph showing the influence of the composition
of the dissolution medium on tramadol release from pellets coated
with a coating according to the invention.
[0026] FIG. 6 is a graph showing the influence of basket rotational
speed on tramadol release from pellets coated with a coating
according to the invention.
[0027] FIG. 7 is a graph showing tramadol release from pellets
provided with an 11% Surelease E-7-7050 coating and a 3%
subcoat.
[0028] FIG. 8 is a graph showing tramadol release from pellets
coated with an Aquacoat ECD 30, dibutyl sebacate (30%) and talcum
(20%) coating according to the invention.
[0029] FIG. 9 is a graph showing tramadol release from compression
molded tablets containing pellets coated with an Aquacoat ECD 30,
Opadry OY-29020 clear (9+1 parts), dibutyl sebacate (25%) and
talcum (25%) coating and a 0.6% subcoat.
[0030] FIG. 10 is a graph showing tramadol release from pellets
coated with an Aquacoat ECD 30 and dibutyl sebacate (20%) coating
according to the invention.
[0031] FIG. 11 is a graph showing tramadol release from tablets
coated with a 5% Surelease E-7-7050 coating and a 1% subcoat
according to the invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0032] As FIG. 1 to FIG. 3 show, all three release profiles for
tramadol HCl remain unchanged under conventional storage conditions
of 25.degree. C. to 30.degree. C. over the entire period of storage
and at both storage temperatures. Storage stability is measured
according to USP 23, pages 1959 et seq. "[1196]The stability
testing of new drug substances and products--The tripartite
guideline".
[0033] Despite having identical film thickness and film
composition, in the combined dissolution test comprising 2 hours in
gastric juice, pH 1.2, and 8 hours in intestinal juice, pH 7.2,
they exhibit completely different initial release rates. While the
film without additional treatment after production exhibits the
greatest delay with a release of approx. 75% in 8 hours, the same
film, once heat treated for 24 hours at 60.degree. C., releases
100% after only 5 hours. Heat treatment for 2 hours at 60.degree.
C. results in approx. 90% tramadol release in 8 hours. These
various release profiles show that appropriate, storage stable
tramadol release may be achieved with coatings of coalesced
ethylcellulose with the appropriate plasticizers, which release may
occur, as required, both immediately after production or also after
storage of the tramadol preparations coated with the coating
according to the invention. This provides the major advantage for
the large scale industrial production of the preparations that any
batches with an excessively slow release profile may be worked up
at any time. The release profile may also subsequently be adjusted
to the required release profile by purposeful post-treatment at,
for example, 60.degree. C., without impairing the storage stability
of the preparation.
[0034] FIG. 4 shows how the release profile of tramadol HCl pellets
with the coating according to the invention having a relatively
slow release immediately after production of less than 45% after
300 minutes may be modified in stages towards faster release up to
70% in 300 minutes. In addition to the standard dissolution test of
2 hours in gastric juice+6 hours in intestinal juice, the
controlled released tramadol HCl preparations according to the
invention were also tested for 8 hours with a pH gradient of pH 1.2
to pH 7.2, for 8 hours in artificial intestinal juice, pH 7.2, with
100 mM of NaCl (250 mM KH.sub.2PO.sub.4+100 mM NaCl), 8 hours in
artificial intestinal juice, pH 6.8 (220 mM KCl+30 mM
KH.sub.2PO.sub.4), 8 hours in artificial gastric juice, pH 1.2, 8
hours in buffer, pH 4.6 (100 mM NaC.sub.2H.sub.3O.sub.2+50 mM NaCl)
and 8 hours in artificial intestinal juice, pH 6.8 with 5 mM of Na
taurocholate (220 mM KCl+30 mM KH.sub.2PO.sub.4). Unless otherwise
stated, release was tested in baskets at a rotational speed of 100
m.sup.-1. Other rotational speeds were, however, also tested in
order to reveal the influence of mechanical stress on release.
[0035] As can be seen from FIG. 5 and FIG. 6, neither the
composition of the release medium with regard to molarity, pH value
or type of ion, nor the level of mechanical stress to which the
pellets were exposed had any great influence upon tramadol release
from pellets coated with the coating according to the invention.
This accordingly confirms robust release behavior of the
preparations according to the invention with regard to in vitro
testing, such that reliable release may also be expected in
vivo.
EXAMPLES
[0036] In vitro release of tramadol was determined by the
dissolution test to Ph. Eur. using the basket method at a
rotational speed of 100 m.sup.-1. Unless otherwise stated, the
preparation was initially tested for 2 hours in artificial gastric
juice, pH 1.2, and then for a further 6 hours in artificial
intestinal juice, pH 7.2. The quantity of tramadol in solution at
each particular measurement time was determined
spectrophotometrically and stated as a percentage of the total dose
of tramadol hydrochloride. The stated release values and curves are
the mean from n=3 tests.
Example 1
[0037] Tramadol HCl pellets having an active substance content of
70 wt. % were produced by aqueous granulation with microcrystalline
cellulose and hydroxypropylcellulose with a low degree of
substitution, extrusion and subsequent spheronisation. The dried
pellets having a screened size of 800-1250 .mu.m were then coated
by the fluidized bed method at a feed air temperature of 60.degree.
C. initially with 3 wt. % of protective coating of
hydroxypropylmethylcellulose, PEG 400 and talcum and then provided
with a controlled release coating of 11 wt. %, relative to the
weight of the pellets.
[0038] The composition of the aqueous dispersion for producing a
protective coating on 5 kg of pellets was:
1 Hydroxypropylmethylcellulose (Pharmacoat 104.0 g 603/ShinEtsu)
PEG 400 12.0 g Micronized talcum 35.0 g Purified water 2160.0 g
Total: 2311.0 g
[0039] The composition of the aqueous coating composition for
coating 5 kg of pellets provided with protective coating was:
2 Surelease E-7-7050 (aqueous ethylcellulose 2115.0 g dispersion;
Colorcon) Purified water 1323.0 g Total: 3438.0 g
[0040] The solids content of the dispersion was 16 wt. %. Once the
pellets had been coated, they were either not heat treated, or the
active substance release was adjusted for 2 hours at 60.degree. C.
163 mg of pellets, corresponding to a dose of 100 mg of tramadol
hydrochloride, were packaged in size 1 capsules and active
substance release determined as stated above. The stated release
values are the mean from n=6 tests (FIG. 7).
3 Propor- tion re- Propor- Propor- Propor- Propor- leased tion tion
tion tion in % released released released released Propor- after 6
in % in % in % in % tion months' after 6 after after 6 after 6 Time
re- storage months' treatment months months' in leased at storage
for 2 h storage storage min in % 25.degree. C. at 30.degree. C. at
60.degree. C. at 25.degree. C. at 30.degree. C. 120 1 1 1 5 4 5 240
29 26 27 46 45 48 360 61 61 60 75 70 74 480 80 79 78 91 86 90 600
94 95 94 99 98 100
Example 2
[0041] Tramadol HCl pellets having an active substance content of
55 wt. % were produced by aqueous granulation with microcrystalline
cellulose and hydroxypropylcellulose with a low degree of
substitution, extrusion and subsequent spheronisation. The dried
pellets having a screened size of 800-1250 .mu.m were then coated
by the fluidized bed method at a feed air temperature of 60.degree.
C. with a total coating weight of 8 wt. %, relative to the starting
weight of the pellets.
[0042] The composition of the aqueous dispersion for coating 300 g
of pellets was:
4 Aquacoat ECD 30 (aqueous ethylcellulose 53.0 g dispersion)
Dibutyl sebacate 4.8 g Talcum (micronized) 3.2 g Polysorbate 80
0.02 g Silicon emulsion 0.02 g Purified water 65.0 g Total: 126.0
g
[0043] The solids content of the dispersion was 19 wt. %. Once the
pellets had been coated, active substance release was adjusted for
2 or 27 hours at 60.degree. C. 196 mg of pellets, corresponding to
a dose of 100 mg of tramadol hydrochloride, were packaged in size 1
capsules and active substance release determined as stated above.
The stated release values are the mean from n=3 tests (FIG. 8).
5 Proportion released Proportion released in % after treatment in %
after treatment Time in min for 2 hours at 60.degree. C. for 27
hours at 60.degree. C. 120 26 38 240 63 91 360 82 101 480 92
101
Example 3
[0044] Tramadol HCl pellets having an active substance content of
55 wt. % were produced by aqueous granulation with microcrystalline
cellulose and hydroxypropylcellulose with a low degree of
substitution, extrusion and subsequent spheronization. The dried
pellets having a screened size of 800-1250 .mu.m were then coated
by the fluidized bed method at a feed air temperature of 60.degree.
C. initially with 0.6 wt. % of a protective coating and with a
total coating weight of 15 wt. %, relative to the weight of the
pellets provided with protective coating.
[0045] The composition of the aqueous coating dispersion for
producing a protective coating on 350 g of pellets was:
6 Opadry OY-29020 clear (= hydroxypropyl- 1.60 g methylcellulose
and PEG 400; Colorcon) Micronized talcum 0.50 g Purified water 27.9
g Total: 30.0 g
[0046] The composition of the aqueous coating composition for
coating 300 g of pellets provided with protective coating was:
7 Aquacoat ECD 30 (aqueous ethylcellulose 89.0 g dispersion;
Colorcon FMC) Opadry OY-29020 clear 3.0 g Dibutyl sebacate 7.6 g
Talcum (micronized) 7.7 g Polysorbate 80 0.03 g Silicon emulsion
0.03 g Purified water 129.6 g Total: 237.0 g
[0047] The solids content of the aqueous dispersion was 19 wt. %.
Once the pellets provided with a controlled release coating had
been produced, the release profile was adjusted by heat treatment
for 2 hours at 60.degree. C. 210 mg of pellets, corresponding to a
dose of 100 mg of tramadol hydrochloride were compression molded
with 192.1 mg of Cellactose, 16.8 mg of Kollidon CL.TM.
(=Crospovidone) and 1.1 mg of magnesium stearate to form tablets
having a diameter of 12 mm and a weight of 420 mg. In water, these
broke back down into the individual pellets within 1-2 minutes.
Active substance release was determined as stated above. The stated
release values are the mean from n=3 tests (FIG. 9).
8 Proportion released in % Time in min (treatment at 60.degree. C.,
2 h) 120 14 240 70 360 94 480 101
Example 4
[0048] Tramadol hydrochloride pellets having an active substance
content of 33 wt. % were produced by aqueous granulation with
microcrystalline cellulose and hydroxypropylcellulose with a low
degree of substitution, extrusion and subsequent spheronization.
The dried pellets having a screened size of 800-1250 .mu.m were
then coated by the fluidized bed method at a feed air temperature
of 60.degree. C. with a total coating film weight of 6 wt. %,
relative to the starting weight of the uncoated pellets.
[0049] The composition of the aqueous dispersion for coating 350 g
of pellets was:
9 Aquacoat ECD 30 (aqueous ethylcellulose 58.3 g dispersion;
Colorcon) Dibutyl sebacate 3.5 g Polysorbate 80 (Tween 80) 0.01 g
Aqueous silicone emulsion 0.01 g Purified water 78.2 g Total: 140.0
g
[0050] An aqueous silicone emulsion was used as an antifoam
controller in all the Examples.
[0051] The solids content of the dispersion was 15 wt. %. Once the
pellets had been coated and dried, they were kept at 120.degree. C.
for 60 minutes. 321 mg of pellets, corresponding to a dose of 100
mg of tramadol hydrochloride, were packaged in size 0 capsules, and
the active substance release was determined therefrom. (FIG.
10).
10 Time in min Proportion released in % 120 23 360 36 600 55 990 72
1440 83
Example 5
[0052] Tablets having a diameter of 10 mm and the following
composition were produced on a tabletting press:
11 Tramadol hydrochloride 100.0 mg Microcrystalline cellulose
(Avicel PH 101) 180.0 mg Polyvidone K30 16.0 mg Magnesium stearate
4.0 mg Total: 300.0 mg
[0053] Tramadol hydrochloride and microcrystalline cellulose were
granulated with an aqueous solution of polyvidone K30, dried,
screened and, once mixed with magnesium stearate, compression
molded into tablets of a weight of 300 mg. The tablets were coated
in a drum coater at a feed air temperature of 60.degree. C. with 5
wt. % of ethylcellulose controlled release film (relative to the
weight of the tablets) to yield a tablet weight of 315 mg.
[0054] The composition of the coating composition for coating 600 g
of tablets was:
12 Surelease E-7-7050 (aqueous 115.4 g ethylcellulose dispersion;
Colorcon) Purified water 72.1 g Total: 187.5 g
[0055] The solids content of the dispersion was 16 wt. %. No heat
treatment was performed after the tablets were coated. The active
substance release was determined as stated above. The stated
release values are the mean from n=2 tests (FIG. 11).
13 Time in min Proportion released in % 120 40 240 76 360 91 480
97
[0056] 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 disclosed embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations falling within the scope of the
appended claims and equivalents thereof.
* * * * *