Title of Invention	PROCESS FOR THE PRODUCTION OF ACTIVE INGREDIENT COMPOSITIONS WITH CONTROLLED RELEASE FROM A MATRIX
Abstract	The present invention provides a controlled release composition and a process for preparing the same. The controlled release composition is with a controlled release matrix containing pharmaceutically active ingredient, which comprises granulating the active ingredient with a molten matrix material or with a matrix material while it is being melted and with optional additional inactive materials lat la first elevated temperature, then cooling and screening the granulate, forming a fluidized bed of the resulting material at a second elevated temperature, and recovering the resulting product; and the product formed by the process.

Title of Invention

PROCESS FOR THE PRODUCTION OF ACTIVE INGREDIENT COMPOSITIONS WITH CONTROLLED RELEASE FROM A MATRIX

Abstract

The present invention provides a controlled release composition and a process for preparing the same. The controlled release composition is with a controlled release matrix containing pharmaceutically active ingredient, which comprises granulating the active ingredient with a molten matrix material or with a matrix material while it is being melted and with optional additional inactive materials lat la first elevated temperature, then cooling and screening the granulate, forming a fluidized bed of the resulting material at a second elevated temperature, and recovering the resulting product; and the product formed by the process.

Full Text	Process for the production of active ingredient compositions with controlled release from a matrix The invention relates to a novel process for the production of compositions with controlled release, in which the active ingredient is released from a matrix. Pharmaceutical forms with controlled release are dosage forms which are substantially adapted to therapeutic requirements and from which the release of medicinal substance is controlled by mechanisms which are influenced to an insignificant extent or not at all by physiological conditions (pH, enzymes, nature and quality of the diet). According to the control principles applied, a distinction is made between diffusion-, matrix-, swelling-, membrane- or chemically controlled release. According to the more comprehensive definition of the American Food and Drug Administration, controlled release products mean formulations which are intended to release the active ingredient at rates which differ significantly from the corresponding compositions with immediate release. This definition includes all types of slow release (depot) pharmaceutical forms as well as those with release at fixed times, for example enteric-coated products. A large number of processes for the production of such formulations are known from the available literature. For example, EP 324 989 describes the production of a novel pharmaceutical formulation with controlled release by wet granulation, wherein the active ingredient is mixed with appropriate ancillary substances and granulated in 95% ethanol. After subsequent drying, the resulting granules are screened to the required size. Formulations with controlled release can also be produced by melt granulation as described, for example, in DE 24 26 812. In this case, the binding ingredient is present in a liquid state of aggregation because the temperature during the granulation process is higher than the melting point of the low-melting ingredient. Further processes known in the prior art for producing formulations with controlled release are granulation or extrusion as described, for example, in DE 44 08 326. The active ingredient compositions obtained by the known processes in some cases show incomplete delay of release or wide variations in the individual values for release of active ingredient. This may have particularly disadvantageous effects for the patient because maintenance of the required plasma concentration, and thus the bioavailability, cannot be ensured. The present invention is now based on the object of developing a novel, industrially straightforward process for the production of formulations with controlled release, which makes reproducible releases of active ingredient possible. The object is achieved according to the invention by the active ingredient or a combination of active ingredients being granulated, alone or mixed with ancillary substances, with the addition of binders or mixtures of binders, which are either molten on addition or first converted into the molten state of aggregation by heating during this process, and being screened after the cooling, and the resulting granules subsequently undergoing after-treatment with heating in a fluidized bed. This procedure entails the active ingredient, which may be insoluble in water or else soluble in water, being introduced into an intensive mixer or previously mixed with ancillary substances and granulated in an intensive mixer, with addition of binders or mixtures of binders, which are either molten on addition or first converted into the molten state of aggregation by heating during the process in the intensive mixer, at temperatures between 10 and 100°C. Intensive mixtures which can be employed are high-speed mixers with or without heatable or coolable jacket, such as Gral Collette or Diosna. The process according to the invention is particularly advantageous with mixers which have no jacket heating. After the cooling, the granules obtained in this way can be screened through a screen, for example of mesh width 3.0 mm, and heated in the fluidized bed of a fluidized bed granulator until the melting point of the fusible binder employed in the mixture is reached. The after-treatment is continued in the temperature range 30 - 100°C while feeding in heated air until the time when the fluidized bed almost collapses. It is subsequently cooled again. After this thermal after-treatment, the granules which have been screened again can be mixed with suitable tabletting ancillary substances, packed in capsules or compressed to tablets and, where appropriate, coated with a film layer or coated with sugar. Coatings can be, for example, those based on polymethacrylic acid derivatives or cellulose derivatives. The production of formulations with controlled release by the process according to the invention is particularly suitable for substances from the following classes of active ingredients: non-steroidal antiinflammatory drugs, bronchodilators, vasodilators, muscle relaxants, antirheumatics such as diclofenac, antiinflammatory agents, antiepileptics such as carbamazepine, antihypertensives, antihistamines, anticoagulants, intestinal therapeutic agents, cytostatics, calcium antagonists such as verapamil, and cardiac remedies. Substances which can be used as binders are those having a melting point between 35 and 90°C. Suitable binders are: water-soluble or swellable binders such as macrogol, polyvidone, polymethacrylic acid derivatives (Eudragit), lipophilic binders such as paraffin, cetyl palmiate, fatty alcohols such as cetyl alcohol, beeswax, carnauba wax, hydrogenated vegetable oils, triglycerides and stearic acid. These substances represent only a list of examples, so that formulations with controlled release can also be produced in this way with other active substances and binders. It was not to be foreseen that the formulations made from granules produced by the process according to the invention have reproducible controlled rates of release, with very narrow variations in individual values, even when the formulas are changed. It is possible, surprisingly, by the thermal after-treatment according to the invention to adjust specific release characteristics. This after-treatment, which takes place by heating in the fluidized bed after previously increasing the surface area by screening, achieves, irrespective of the contents of the formula, complete embedding or coating of the active ingredient in or by the binder in the matrix. This leads to delay of release complying with specification without disproportionate losses in the fluidized bed resulting in deviations in the active ingredient content. These facts are illustrated in/Figures 1-3: Figure 1: Effect of the after-treatment according to the invention on the release of the active ingredient diclofenac sodium compared with granules produced by conventional melt granulation in an intensive mixer according to the prior art without after-treatment Figure 2: Comparison of the variations in individual values of the release of active ingredient from the dosage forms from the two processes considered in Figure 1 Figure 3: Delay of release determined exclusively by the core and thus by the granulation conditions. The coating has no significant effect on the release of active ingredient. The process according to the invention can generally be applied to achieving specific rates of release, because the ensured optimal embedding or coating of the medicinal substance(s) makes it possible to achieve specific availabilities through the choice of a suitable binder in the process. The following examples are intended to illustrate the process according to the invention. Example 1: Tablet containing 100 mg of diclofenac sodium in mg/tablet consisting of: sucrose 105.0 diclofenac sodium 100.0 cetyl alcohol 55.20 silicon dioxide 0.52 magnesium stearate 1.30 polyvidone 1.28 Total 263.30 Sucrose and the active ingredient diclofenac sodium are mixed. The molten cetyl alcohol (temperature 65 ± 2°C) is subsequently added in an intensive mixer. After a granulation time of less than 10 minutes, an increase in power occurs and the granulation is stopped. The granules are passed through a suitable screen. The after-treatment then takes place in a fluidized bed granulator, with the inlet air at a temperature of 60 - 75°C. At a product temperature of about 43°C, the binder starts to melt, and further granule formation starts. The endpoint of the granulation is reached before the fluidized bed collapses, and it is cooled. Screening is subsequently carried out once again. After the addition of silicon dioxide, magnesium stearate and polyvidone and mixing, the resulting tabletting mixture is compressed to tablets with an active ingredient content of 100 mg. Example 2: Tablet containing 120 mg of verapamil hydrochloride in mg/tablet, consisting of: verapamil hydrochloride 120 cetyl alcohol 183 cellulose 101 silicon dioxide 2 magnesium stearate__________________4_ Total 410 Molten cetyl alcohol is added to the active ingredient verapamil hydrochloride while stirring in an intensive mixer. After a short granulation time, the granules are removed, screened and then heated in a fluidized bed. The required melting process starts at a product temperature of about 43°C and is continued up to an endpoint before the fluidized bed collapses. It is then immediately cooled, screened and mixed with silicon dioxide and magnesium stearate. Tablets with a content of 120 mg of verapamil hydrochloride are produced. Example 3: verapamil hydrochloride 120 cetyl alcohol 66 cellulose 101 sucrose 117 silicon dioxide 2 magnesium stearate__________________4_ Total 410 Production takes place in analogy to Examples 1 and 2. WE CLAIM: 1. A process for the preparation of pharemaceutical active ingredient compositions with a controlled release matrix comprising the steps of : • granulating said active ingredients with a molten matrix material or with a matrix material while it Is being melted and with optional additional inactive materials by heating; • cooling and screening the granulate; - forming a fiuidized bed of the resulting material by thermal after treatment; and • recovering the resulting product. 2. The process according to claim 1, wherein said recovering step comprises cooling the resultant product 3. The process according to claim 2, wherein said step of recovering comprises screening the cooled resulting product 4. The process according to claim 3, comprising finishing the screened resulting product by filling it into capsules, or compressing it into tablets. 5. The process according to claim 4, comprising sugar coating or film coating said tablets. 6. The process according to claim 1, wherein said pharmaceutlcally active ingredient is a nonsteroldal antiinflammatory, broncholytic, vasodilator, muscle relaxant, antlrheumatic, antiphiogistelc, antiepilepti, antihistamine, anticoagulant, Intestinal drug, cytostatic, calcium antagonist, or cardiac drug. 7. The process according to claim 6, wherein said antirtieumatic is diclofenac, said antiepileptic Is carbamazeplne, and said calcium antagonist Is verapamll. 8. The process according to claim 1, wherein said matrix material has a melting point from 35° to 90°C. 9. The process according to claim 8, wherein said matrix material is a water soluble or water swdlable material, or a lipophylic binder. 10. The process according to claim 9, wherein said material is one or more of macrogol, polyvidone, a polymethacrylic acid derivatives one or more lipophylic binder. 11. The process according to claim 10, wherein said lipophylic binder Is one or more of paraffin, cetyl palmltate, a fatty alcohol beeswax, camauba wax, hydrogenated vegetable oil, triglyceride, and stearic acid. 12. The process according to claim 11, wherein said fatty alcohol Is cetyl alcohol. 13. The process according to claim 1, wherein said heating in the granulating step Is at a temperature between 10°C to 100°C. 14. The process according to claim 1, wherein said second elevated temperature is higher than the melting temperature of said matrix material. 15. The process according to claim 1, wherein said step of granulating is carried out in an intensive mixer without a heating jacket 16. The process according to claim i, wherein said step of forming the fluidized bed is carried out in a fluidzed bed granulator or in a Wuster. The present invention provides a controlled release composition and a process for preparing the same. The controlled release composition is with a controlled release matrix containing pharmaceutically active ingredient, which comprises granulating the active ingredient with a molten matrix material or with a matrix material while it is being melted and with optional additional inactive materials at a first elevated temperature, then cooling and screening the granulate, forming a fluidized bed of the resulting material at a second elevated temperature, and recovering the resulting product; and the product formed by the process.

Full Text

Process for the production of active ingredient
compositions with controlled release from a matrix
The invention relates to a novel process for the
production of compositions with controlled release, in
which the active ingredient is released from a matrix.
Pharmaceutical forms with controlled release are dosage
forms which are substantially adapted to therapeutic
requirements and from which the release of medicinal
substance is controlled by mechanisms which are
influenced to an insignificant extent or not at all by
physiological conditions (pH, enzymes, nature and
quality of the diet). According to the control
principles applied, a distinction is made between
diffusion-, matrix-, swelling-, membrane- or chemically
controlled release. According to the more comprehensive
definition of the American Food and Drug
Administration, controlled release products mean
formulations which are intended to release the active
ingredient at rates which differ significantly from the
corresponding compositions with immediate release. This
definition includes all types of slow release (depot)
pharmaceutical forms as well as those with release at
fixed times, for example enteric-coated products.
A large number of processes for the production of such
formulations are known from the available literature.
For example, EP 324 989 describes the production of a
novel pharmaceutical formulation with controlled
release by wet granulation, wherein the active
ingredient is mixed with appropriate ancillary
substances and granulated in 95% ethanol. After
subsequent drying, the resulting granules are screened
to the required size.
Formulations with controlled release can also be
produced by melt granulation as described, for example,
in DE 24 26 812. In this case, the binding ingredient is
present in a liquid state of aggregation because the
temperature during the granulation process is higher than
the melting point of the low-melting ingredient.
Further processes known in the prior art for producing
formulations with controlled release are granulation or
extrusion as described, for example, in DE 44 08 326.
The active ingredient compositions obtained by the known
processes in some cases show incomplete delay of release or
wide variations in the individual values for release of
active ingredient. This may have particularly
disadvantageous effects for the patient because maintenance
of the required plasma concentration, and thus the
bioavailability, cannot be ensured.
The present invention is now based on the object of
developing a novel, industrially straightforward process for
the production of formulations with controlled release,
which makes reproducible releases of active ingredient
possible.
The object is achieved according to the invention by the
active ingredient or a combination of active ingredients
being granulated, alone or mixed with ancillary substances,
with the addition of binders or mixtures of binders, which
are either molten on addition or first converted into the
molten state of aggregation by heating during this process,
and being screened after the cooling, and the resulting
granules subsequently undergoing after-treatment with
heating in a fluidized bed.
This procedure entails the active ingredient, which may be
insoluble in water or else soluble in water, being
introduced into an intensive mixer or previously mixed with
ancillary substances and granulated in an intensive mixer,
with addition of binders or mixtures of binders, which are
either molten on addition or first converted into the molten
state of aggregation by heating during the process in the
intensive mixer, at temperatures between 10 and 100°C.
Intensive mixtures which can be employed are high-speed
mixers with or without heatable or coolable jacket, such as
Gral Collette or Diosna. The process according to the
invention is particularly advantageous with mixers which
have no jacket heating.
After the cooling, the granules obtained in this way can be
screened through a screen, for example of mesh width 3.0 mm,
and heated in the fluidized bed of a fluidized bed
granulator until the melting point of the fusible binder
employed in the mixture is reached. The after-treatment is
continued in the temperature range 30 - 100°C while feeding
in heated air until the time when the fluidized bed almost
collapses. It is subsequently cooled again.
After this thermal after-treatment, the granules which have
been screened again can be mixed with suitable tabletting
ancillary substances, packed in capsules or compressed to
tablets and, where appropriate, coated with a film layer or
coated with sugar.
Coatings can be, for example, those based on polymethacrylic
acid derivatives or cellulose derivatives.
The production of formulations with controlled release by
the process according to the invention is particularly
suitable for substances from the following classes of active
ingredients:
non-steroidal antiinflammatory drugs, bronchodilators,
vasodilators, muscle relaxants, antirheumatics such as
diclofenac, antiinflammatory agents, antiepileptics such as
carbamazepine, antihypertensives, antihistamines,
anticoagulants, intestinal therapeutic agents, cytostatics,
calcium antagonists such as verapamil, and cardiac remedies.
Substances which can be used as binders are those having a
melting point between 35 and 90°C. Suitable binders are:
water-soluble or swellable binders such as macrogol,
polyvidone, polymethacrylic acid derivatives (Eudragit),
lipophilic binders such as paraffin, cetyl palmiate, fatty
alcohols such as cetyl alcohol, beeswax, carnauba wax,
hydrogenated vegetable oils, triglycerides and stearic acid.
These substances represent only a list of examples, so that
formulations with controlled release can also be produced in
this way with other active substances and binders.
It was not to be foreseen that the formulations made from
granules produced by the process according to the invention
have reproducible controlled rates of release, with very
narrow variations in individual values, even when the
formulas are changed.
It is possible, surprisingly, by the thermal after-treatment
according to the invention to adjust specific release
characteristics.
This after-treatment, which takes place by heating in the
fluidized bed after previously increasing the surface area
by screening, achieves, irrespective of the contents of the
formula, complete embedding or coating of the active
ingredient in or by the binder in the matrix. This leads to
delay of release complying with specification without
disproportionate losses in the fluidized bed resulting in
deviations in the active ingredient content.
These facts are illustrated in/Figures 1-3:
Figure 1: Effect of the after-treatment according to
the invention on the release of the active
ingredient diclofenac sodium compared with
granules produced by conventional melt
granulation in an intensive mixer according to
the prior art without after-treatment
Figure 2: Comparison of the variations in individual
values of the release of active ingredient from
the dosage forms from the two processes
considered in Figure 1
Figure 3: Delay of release determined exclusively by
the core and thus by the granulation conditions.
The coating has no significant effect on the
release of active ingredient.
The process according to the invention can generally be
applied to achieving specific rates of release, because the
ensured optimal embedding or coating of the medicinal
substance(s) makes it possible to achieve specific
availabilities through the choice of a suitable binder in
the process.
The following examples are intended to illustrate the
process according to the invention.
Example 1:
Tablet containing 100 mg of diclofenac sodium in mg/tablet
consisting of:
sucrose 105.0
diclofenac sodium 100.0
cetyl alcohol 55.20
silicon dioxide 0.52
magnesium stearate 1.30
polyvidone 1.28
Total 263.30
Sucrose and the active ingredient diclofenac sodium are
mixed. The molten cetyl alcohol (temperature 65 ± 2°C)
is subsequently added in an intensive mixer. After a
granulation time of less than 10 minutes, an increase
in power occurs and the granulation is stopped. The
granules are passed through a suitable screen. The
after-treatment then takes place in a fluidized bed
granulator, with the inlet air at a temperature of 60 -
75°C. At a product temperature of about 43°C, the
binder starts to melt, and further granule formation
starts. The endpoint of the granulation is reached
before the fluidized bed collapses, and it is cooled.
Screening is subsequently carried out once again. After
the addition of silicon dioxide, magnesium stearate and
polyvidone and mixing, the resulting tabletting mixture
is compressed to tablets with an active ingredient
content of 100 mg.
Example 2:
Tablet containing 120 mg of verapamil hydrochloride in
mg/tablet, consisting of:
verapamil hydrochloride 120
cetyl alcohol 183
cellulose 101
silicon dioxide 2
magnesium stearate__________________4_
Total 410
Molten cetyl alcohol is added to the active ingredient
verapamil hydrochloride while stirring in an intensive
mixer. After a short granulation time, the granules are
removed, screened and then heated in a fluidized bed.
The required melting process starts at a product
temperature of about 43°C and is continued up to an
endpoint before the fluidized bed collapses. It is then
immediately cooled, screened and mixed with silicon
dioxide and magnesium stearate. Tablets with a content
of 120 mg of verapamil hydrochloride are produced.
Example 3:
verapamil hydrochloride 120
cetyl alcohol 66
cellulose 101
sucrose 117
silicon dioxide 2
magnesium stearate__________________4_
Total 410
Production takes place in analogy to Examples 1 and 2.
WE CLAIM:
1. A process for the preparation of pharemaceutical active
ingredient compositions with a controlled release matrix
comprising the steps of :
• granulating said active ingredients with a molten
matrix material or with a matrix material while it Is
being melted and with optional additional inactive
materials by heating;
• cooling and screening the granulate;
- forming a fiuidized bed of the resulting material by
thermal after treatment; and
• recovering the resulting product.
2. The process according to claim 1, wherein said
recovering step comprises cooling the resultant product
3. The process according to claim 2, wherein said step of
recovering comprises screening the cooled resulting
product
4. The process according to claim 3, comprising finishing
the screened resulting product by filling it into capsules,
or compressing it into tablets.
5. The process according to claim 4, comprising sugar
coating or film coating said tablets.
6. The process according to claim 1, wherein said
pharmaceutlcally active ingredient is a nonsteroldal
antiinflammatory, broncholytic, vasodilator, muscle
relaxant, antlrheumatic, antiphiogistelc, antiepilepti,
antihistamine, anticoagulant, Intestinal drug, cytostatic,
calcium antagonist, or cardiac drug.
7. The process according to claim 6, wherein said
antirtieumatic is diclofenac, said antiepileptic Is
carbamazeplne, and said calcium antagonist Is verapamll.
8. The process according to claim 1, wherein said matrix
material has a melting point from 35° to 90°C.
9. The process according to claim 8, wherein said matrix
material is a water soluble or water swdlable material, or
a lipophylic binder.
10. The process according to claim 9, wherein said material is
one or more of macrogol, polyvidone, a polymethacrylic
acid derivatives one or more lipophylic binder.
11. The process according to claim 10, wherein said
lipophylic binder Is one or more of paraffin, cetyl
palmltate, a fatty alcohol beeswax, camauba wax,
hydrogenated vegetable oil, triglyceride, and stearic acid.
12. The process according to claim 11, wherein said fatty
alcohol Is cetyl alcohol.
13. The process according to claim 1, wherein said heating in
the granulating step Is at a temperature between 10°C to
100°C.
14. The process according to claim 1, wherein said second
elevated temperature is higher than the melting
temperature of said matrix material.
15. The process according to claim 1, wherein said step of
granulating is carried out in an intensive mixer without a
heating jacket
16. The process according to claim i, wherein said step of
forming the fluidized bed is carried out in a fluidzed bed
granulator or in a Wuster.
The present invention provides a controlled release composition
and a process for preparing the same. The controlled release
composition is with a controlled release matrix containing
pharmaceutically active ingredient, which comprises granulating
the active ingredient with a molten matrix material or with a
matrix material while it is being melted and with optional
additional inactive materials at a first elevated temperature, then
cooling and screening the granulate, forming a fluidized bed of the
resulting material at a second elevated temperature, and
recovering the resulting product; and the product formed by the
process.

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Patent Number

216313

Indian Patent Application Number

1172/CAL/1998

PG Journal Number

11/2008

Publication Date

14-Mar-2008

Grant Date

12-Mar-2008

Date of Filing

06-Jul-1998

Name of Patentee

AWD, PHARMA GMBH & CO. KG.

Applicant Address

LEIPZIGER STRASSE 7-13, 01097 DRESDEN

Inventors:

#	Inventor's Name	Inventor's Address
1	KLAUS LIEBOLD	ELSASSER STR. 17, 01307 DRESDEN
2	HEIKO SCHUMACHER	PALMENWEG 8, 63741 ASCHAFFENBURG
3	TORSTEN HOFFMANN	GUTENBERGSTR. 10, 01445 RADEBEUL
4	JOACHIM WOLF	HOHE STR. 4, 01445 RADEBEUL

PCT International Classification Number

A 61 K 9/16

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	19729487.1	1997-07-10	Germany