U.S. patent application number 10/409953 was filed with the patent office on 2003-11-06 for fast-release extrudates and process for their production, and preparations obtainable therefrom.
This patent application is currently assigned to Bayer Aktiengesellschaft. Invention is credited to Kanikanti, Venkata-Rangarao, Sdebik, Jurgen.
Application Number | 20030206947 10/409953 |
Document ID | / |
Family ID | 7915826 |
Filed Date | 2003-11-06 |
United States Patent
Application |
20030206947 |
Kind Code |
A1 |
Kanikanti, Venkata-Rangarao ;
et al. |
November 6, 2003 |
Fast-release extrudates and process for their production, and
preparations obtainable therefrom
Abstract
The present invention relates to stable quick-release extrudates
that contain low-viscosity hydroxypropylcellulose and at least one
active ingredient. This invention also relates to a method for
preparing said extrudates without the use of solvents as well as to
the use of said extrudates in the production of quick-release
preparations.
Inventors: |
Kanikanti, Venkata-Rangarao;
(Leverkusen, DE) ; Sdebik, Jurgen; (Dusseldorf,
DE) |
Correspondence
Address: |
JEFFREY M. GREENMAN
BAYER PHARMACEUTICALS CORPORATION
400 MORGAN LANE
WEST HAVEN
CT
06516
US
|
Assignee: |
Bayer Aktiengesellschaft
Leverkusen
DE
|
Family ID: |
7915826 |
Appl. No.: |
10/409953 |
Filed: |
April 9, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10409953 |
Apr 9, 2003 |
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10031129 |
Jan 9, 2002 |
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6569455 |
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10031129 |
Jan 9, 2002 |
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PCT/EP00/06584 |
Jul 12, 2000 |
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Current U.S.
Class: |
424/452 ;
424/465; 514/57 |
Current CPC
Class: |
A61K 31/437 20130101;
A61K 9/2054 20130101 |
Class at
Publication: |
424/452 ;
424/465; 514/57 |
International
Class: |
A61K 009/48; A61K
009/20; A61K 031/717 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 23, 1999 |
DE |
199 34 610.0 |
Claims
1. Stable, fast-release extrudates comprising
hydroxypropylcellulose of low viscosity with an average molecular
weight of from 30 000 to 100 000 and with a molar degree of
substitution of at least 3 in an amount of at least 50% by weight
based on the active ingredient/polymer mixture and at least one
active pharmaceutical ingredient.
2. Extrudates as claimed in claim 1, characterized in that they
comprise hydroxypropylcellulose in an amount of least 66% by weight
based on the active ingredient/polymer mixture.
3. Extrudates as claimed in claim 1, characterized in that they
comprise hydroxypropylcellulose with an average molecular weight of
from 55 000 to 70 000.
4. The use of extrudates as claimed in any one of claims 1 to 3 for
producing pharmaceutical preparations.
5. A pharmaceutical preparation as set forth in claim 4.
6. A pharmaceutical preparation as claimed in claim 5,
characterized in that the preparation is a tablet which comprises
the disintegrant crosslinked polyvinylpyrrolidone (PVPP).
7. A pharmaceutical preparation as claimed in claim 5,
characterized in that the preparation is a sachet.
8. A pharmaceutical preparation as claimed in claim 5,
characterized in that the preparation is a capsule.
9. A solvent-free process for producing extrudates as claimed in
claim 1, characterized in that a mixture of at least one active
ingredient and hydroxypropylcellulose of low viscosity in an amount
of at least 50% by weight based on the active ingredient/polymer
mixture is passed through an extruder which has at the place where
the product enters a temperature of from 25 to 40.degree. C. and at
the exit die has a temperature of .ltoreq.225.degree. C., where the
exit die(s) has (have) a diameter of from 0.5 to 5 mm, and the
extruded strands are comminuted after their emergence.
10. The process as claimed in claim 9, characterized in that the
exit die(s) has (have) a diameter of from 1 to 3 mm.
Description
[0001] The present invention relates to stable, fast-release melt
extrudates comprising hydroxypropylcellulose of low viscosity and
at least one active pharmaceutical ingredient and to a solvent-free
process for their production, and to their use in the production of
fast-release preparations.
[0002] Accurate control of release of active ingredients from
preparations is of great pharmaceutical importance. In use besides
slow-release preparations and those with controlled release are
fast-release preparations which ensure a rapid rise in the level of
the active ingredient in the circulation in an acute pathological
state.
[0003] Extrusion processes are frequently used to produce
corresponding preparations. The principle of melt extrusion has
been known for a long time (Beckmann 1964). In the extrusion
process, active ingredients and polymer are conveyed either
simultaneously, without previous mixing, or as mixture, after
previous mixing, in an extruder which has been heated so that the
mixture becomes extrudable and the active ingredient is not
degraded.
[0004] In contrast to conventional coprecipitate methods, the use
of solvents is unnecessary in this case: this is particularly
important because, besides the economic aspects, the use of
solvents leads to special technical problems such as prevention of
explosions in the premises and equipment.
[0005] The production of preparations with rapid release of active
ingredient by melt extrusion of hydroxypropylcellulose (HPC) with a
molecular weight of from 60 000 to 200 000 is described in the
application WO 96/25149. The content of hydroxypropylcellulose in
these preparations is from 10 to 30, preferably 20 to 30, % by
weight.
[0006] Such low contents of polymer are disadvantageous from the
pharmaceutical viewpoint because the resulting preparation is,
especially on use of high-potency active ingredients, very small
and thus difficult for the patient to handle, which considerably
reduces patient compliance. Extending the preparation with fillers
in turn increases the number of ingredients used and thus
complicates the process. This is disadvantageous inter alia in
relation to the compatibility of the fillers with the active
ingredient in particular at elevated temperature during the
extrusion.
[0007] A further disadvantage is the difficulty of maintaining
content uniformity, i.e. the uniformity of the preparations in
relation to the amounts of active ingredient.
[0008] One object of the present invention is to be regarded as
being to provide fast-release, stable extrudates with good content
uniformity and handleability for all types of active ingredients,
in particular for slightly soluble active ingredients.
[0009] It has now been found, surprisingly, that transparent melt
extrudates with the desired fast release and high stability can be
obtained in a simple manner with the specifically selected polymer
hydroxypropylcellulose of low viscosity with an average molecular
weight of from 30 000 to 100 000 and with a molar degree of
substitution of at least 3 in an amount of at least 50% by weight,
preferably 66% by weight, based on the active ingredient/polymer
mixture in conjunction with amorphous active ingredients.
[0010] The melt extrudates of the invention comprise
hydroxypropylcellulose of low viscosity with an average molecular
weight of from 30 000 to 100 000 and with a molar degree of
substitution of at least 3 in an amount of at least 50% by weight,
preferably 66% by weight, based on the active ingredient/polymer
mixture, one or more active ingredients and, where appropriate,
excipients.
[0011] Preferred melt extrudates comprise hydroxypropylcellulose in
an amount of at least 66% by weight based on the active
ingredient/polymer mixture.
[0012] The hydroxypropylcellulose preferably has an average
molecular weight of from 55 000 to 70 000,
[0013] The molar degree of substitution refers to the average
number of moles of propylene oxide reacted per glucose unit in the
cellulose.
[0014] The present application also relates to preparations
produced with use of the extrudates of the invention. Fast-release
extrudates or preparations mean for the purposes of the invention
those which release 80% of the active ingredient(s) within 60 min
in the USP XXII paddle method. The extrudates or preparations of
the invention display very rapid release and show a significant
supersaturation. They are therefore particularly well suited for
fast reaching of high plasma concentrations of active ingredient.
The fast release can be controlled as required by varying the
production parameters. The release of active ingredient is
influenced, for example, by the concentration of active ingredient
in the final product or by extrusion process parameters such as the
screw geometry, the extrusion rate, the extrusion temperature, the
diameter and surface area of the extrudate etc. The release rate is
influenced in particular by the particle size of the extrudate. In
single-unit dosage forms such as, for example, tablets, the release
is influenced in particular by the content of disintegrant in the
finished formulation.
[0015] Fast release, but at different times, of the active
ingredient on oral administration can be achieved by coating the
extrudates or preparations in such a way that they release the
active ingredient only in a particular region of the
gastrointestinal tract, for example with Eudragit L or S. Coatings
of this type are dissolved, for example, specifically at particular
pH values and make release possible at the optimal site. It is
possible in this way, for example, to protect acid-sensitive active
ingredients until the appropriate absorption window is reached (see
in this connection Chang, R., Pharmaceutical Technology, October
1990).
[0016] It is also possible during the melt extrusion or during
further processing, for example tableting, to use other
conventional excipients which are conventional in pharmacy in the
production of preparations and are known from the literature, such
as, for example, magnesium stearate or masking flavors. None of
these excipients is, however, necessary in order to achieve
essentially the desired fast release of the drug.
[0017] In a preferred embodiment, the extrudate or the preparation
is administered orally. For this purpose, in one embodiment, the
extrudate of the invention is comminuted, for example ground to an
average particle diameter of less than 0.5 mm, and packed into
gelatin capsules or as sachets.
[0018] In a further embodiment, the extrudate of the invention is,
where appropriate in comminuted form, mixed with a disintegrant
and, where appropriate, further excipients and processed to a
single-unit dosage form. Disintegrants are substances which ensure
rapid disintegration of the single-unit dosage form in aqueous
solution, such as, for example, crosslinked polyvinylpyrrolidone
(PVPP). In this case it is preferred to use large amounts of
disintegrant, that is to say more than 0.1 part by weight of
disintegrant per 1 part of extrudate (active ingredient and
HPC).
[0019] Single-unit dosage forms mean preparations which are
administered as a single dose, for example tablets, coated tablets
or capsules.
[0020] It is further possible in this way to produce combination
products which comprise in a single-unit dosage form contents of
different active ingredient-containing extrudates: thus, it is
possible to use different active ingredients but also different
extrudates differing in release profile in order to control
accurately active ingredient contents in the circulation over
time.
[0021] The active ingredient to be used may be any drugs such as,
for example, anti-infectives, cardiovascular agents, antimycotics,
antidepressants, antidementia agents, antiepileptics,
antiinflammatory agents, analgesics, antiasthmatics,
antithrombotics, antitumor agents, antimalarials, non-steroidal
antiinflammatory drugs (NSAID), diuretics, antiarrhythmics,
hypoglycemic agents, ACE inhibitors, sedatives, decongestants,
antihistamines or lipid-lowering agents. Also suitable as active
ingredients are crop protection agents or veterinary agents. For
the purposes of the present invention, only those drugs which do
not decompose under the temperature and processing conditions are
incorporated. The amount of active ingredient to be administered
per dosage unit may be varied within wide limits depending on the
nature of the drug and the release rate. Slightly soluble active
ingredients are preferred, that is to say those which have a
solubility of less than 1 g/100-1 000 g of solvent. A further
possibility is to employ mixtures of drugs.
[0022] The present invention further relates to a process for
manufacturing the extrudates and preparations of the invention.
This simple process requires only a conventional extruder and makes
do without complicated manufacturing methods or solvents and
plasticizers.
[0023] In the present process, a mixture of at least one active
ingredient and hydroxypropylcellulose of low viscosity in an amount
of at least 50% by weight, in particular at least 66% by weight,
based on the active ingredient/polymer mixture and, where
appropriate, further conventional pharmaceutical excipients is
produced, and the mixture is passed through an extruder which has
at the place where the product enters a temperature of from 20 to
40.degree. C. and at the exit die or dies has a temperature of
.ltoreq.225.degree. C., where the exit dies have a diameter of from
0.5 to 5 mm, preferably from 1 to 3 mm, and the extruded strands
are comminuted after their emergence. The residence time of the
mixture in the extruder depends on technical aspects of the process
and may vary to a large degree. It is generally less than 3 min,
preferably less than 1 min.
[0024] The ingredients can be mixed before entry into the extruder
or inside the latter. Premixing, that is to say mixing before
entry, is preferred inter alia for reasons of the abovementioned
content uniformity. Continuous operation of the extruder is
likewise preferred.
[0025] It has been found, surprisingly, that extrusion is possible
in the process of the invention even with large contents of
hydroxypropylcellulose without the use of plasticizers or solvents.
This was not to be expected by the skilled worker because in
general an increasing content of hydroxypropylcellulose is
associated with less good extrudability in a conventional
extruder.
[0026] The viscosity is determined using a rotational viscometer in
a known manner at 20.degree. C. on a 2% strength aqueous solution;
the low-viscosity celluloses of the present invention have
viscosities of less than 400 cP.
[0027] The invention is explained further by means of the following
examples.
EXEMPLARY EMBODIMENTS
[0028] Measurement of the Active Ingredient Release by the USP XXII
Paddle Method
[0029] The release of the abovementioned active ingredients from
the tablets or gelatin capsules is measured by the USP XXII paddle
method. Stirrer speed 75 rpm, release medium 0.1 N HCl (0.9 l) with
small amounts of solubilizers (for example: .ltoreq.0.5 (w/v)
sodium lauryl sulfate), temperature 37.degree. C. All the examples
of the invention apart from comparative example A release about 80%
of active ingredient within 60 min.
Example 1
[0030] 1 part by weight of nifedipine is mixed with 2 parts by
weight of low-viscosity HPC (average MW 55 000-70 000). The mixture
is processed in a twin screw extruder with an exit die having a
diameter of 2 mm. The material is extruded at a die temperature of
170.degree. C. The transparent extrudates are comminuted, and the
fraction (<125 .mu.m; 90 parts by weight) is mixed with 119
parts by weight of crosslinked polyvinylpyrrolidones (PVPP) and
then with magnesium stearate (1 part by weight) and tableted (30 mg
of nifedipine per tablet).
Example 2
[0031] 1 part by weight of nifedipine is mixed with 2.5 parts by
weight of low-viscosity HPC (average MW 55 000-70 000). The mixture
is processed in a twin screw extruder with an exit die having a
diameter of 2 mm. The material is extruded at a die temperature of
170.degree. C. The transparent extrudates are comminuted, and the
fraction (<125 .mu.m; 105 parts by weight) is mixed with 135
parts by weight of crosslinked polyvinylpyrrolidones (PVPP) and
then with magnesium stearate (1.2 parts by weight) and tableted (30
mg of nifedipine per tablet).
Example 3
[0032] Analogous to example 1 but the die temperature is
160.degree. C.
Example 4
[0033] Analogous to example 1 but nimodipine is used as drug; the
die temperature is 120.degree. C.
Example 5
[0034] 1 part by weight of
2-cyclopentyl-2-[4-(2,4-dimethylpyrido[2,3-b]in-
dol-9-ylmethyl)phenyl]-N-(2-hydroxy-1-phenylethyl)acetamide is
mixed with 2 parts by weight of low-viscosity HPC (average MW 55
000-70 000). The mixture is processed in a twin screw extruder with
an exit die having a diameter of 2 mm. The material is extruded at
a die temperature of 220.degree. C. The transparent extrudates are
comminuted, and the fraction (<125 .mu.m; 240 parts by weight)
is mixed with 118.8 parts by weight of crosslinked
polyvinylpyrrolidones (PVPP) and then with magnesium stearate (1.2
parts by weight) and tableted (80 mg of
(2S)-2-cyclopentyl-2-[4-(2,4-dimethylpyrido[2,3-b]indol-9-ylmethyl)phenyl-
]-N-(1R)-2-hydroxy-1-phenylethyl)acetamide per tablet).
Example 6
[0035] Analogous to example 1 but the mixture is packed into
gelatin capsules.
Example 7
[0036] Analogous to example 4 but the mixture is packed into
gelatin capsules.
Comparative Example A
[0037] Analogous to example 5 but 2 parts by weight of the drug
2-cyclopentyl-2-[4-(2,4-dimethylpyrido[2,3-b]indol-9-ylmethyl)phenyl]-N-(-
2-hydroxy-1-phenylethyl)acetamide are mixed with 1 part by weight
of low-viscosity HPC (average MW 55 000-70 000). The mixture is
processed in a twin screw extruder with an exit die having a
diameter of 2 mm. The material is extruded at a die temperature of
220.degree. C. The transparent extrudates are comminuted, and the
fraction (<125 .mu.m; 240 parts by weight) is mixed with 118.8
parts by weight of crosslinked polyvinylpyrrolidones (PVPP) and
then with magnesium stearate (1.2 parts by weight) and tableted (80
mg of (2S)-2-cyclopentyl-2-[4-(2,4-dimethylpy-
rido[2,3-b]indol-9-ylmethyl)phenyl]-N-(1R)-2-hydroxy-1-phenylethyl)acetami-
de per tablet).
* * * * *