Indian Patents. 257323:PROLONGED-RELEASE COMPOSITIONS COMPRISING TORASEMIDE AND A MATRIX-FORMING POLYMER

Title of Invention	PROLONGED-RELEASE COMPOSITIONS COMPRISING TORASEMIDE AND A MATRIX-FORMING POLYMER
Abstract	The invention discloses a Prolonged-release composition comprising torasemide as active ingredient, a matrix-forming polymer, wherein the matrix forming polymer is guar gum and is present in a proportion of from 1 to 40% of said composition, and lactose as a diluent.

Full Text	Field of the invention This invention relates to prolonged-release diuretic compositions containing torasemide as active ingredient. Brief description of the accompanying drawings Figure 1 shows the curves of in-vitro release rate (cumulative values) of torasemide comparatively for immediate-release (IR) tablets and prolonged-release (PR) tablets according to Example 8. Figure 2 shows the curves of in-vitro release rate of torasemide comparatively for immediate-release (IR) tablets and prolonged-release (PR) tablets according to Example 8. Figure 3 shows the plasma concentration curves in man after administration of torasemide comparatively for immediate-release (IR) tablets and prolonged-release (PR) tablets according to Example 8. Figure 4 shows the versus-time curves of the number of urinary urgencies in man after administration of torasemide comparatively for immediate-release (IR) tablets and prolonged-release (PR) tablets according to Example 8. Figure 5 shows release profiles (with HC1 0.1N) of Torasemide from Meyprogat® 90 matrix tablets. Background of the invention Torasemide (US 4018929) is a potent diuretic with an extensive clinical use. Torasemide mainly acts by inhibiting sodium reabsorption in the ascending limb of Henle's loop (Puschett JB and Jordan LL. Mode of action of Torasemide in man. Progress in Pharmacology and Clinical Pharmacology. 1990;8(1):7-13). Torasemide interferes with Na+2C1-K+ pump in the luminal cell membrane and blocks the basolateral chloride conductance (Greger R. Inhibition of active NaCl reabsortion in the thick ascending limb of the loop of Henle by torasemide. Arzneim Forsch./Drug Res. 1988;38{1):151-155). The bioavailability for torasemide is 80-90% after oral administration, the kinetics is linear and the elimination half-life is 3-4 hours. The pharmacokinetic profile is characterized by a peak of maximum plasma concentration (Cmax) which is reached within a rather short period of time {tmax: approximately 1 hour) and by a rapid elimination (t4: approximately 3-4 hours) (Neugebauer G, Besenfelder E and Mollendorf E. Pharmacokinetics and metabolism of torasemide in man. Arzneim Forsch./Drug Res. 1988;38 (1):164-166). Torasemide shows a, linear dose-response relationship at doses, from 2.5 to 20 mg for urinary volume. The sodium excretion exerts a minimal effect on potassium. (Scheen AJ. Dose- response curve of torasemide in healthy volunteers. Arzneim Forsch./Drug Res. 1988/38 (1):156-159; Barr WH et al. Torasemide dose-proportionality of pharmacokinetics and pharmacodynamics. Progress in Pharmacology and Clinical Pharmacology. 1990;8(1):29-37). The maximal effects on urine and electrolytes excretions are observed at approximately 2 hours after oral administration (Lesne M. Comparison of the pharmacokinetics and pharmacodynamics of torasemide and furosemide in healthy volunteers. Arzneim Forsch./Drug Res. 1988;38(1):160- 163) . All these effects clinically become apparent as an acute diuresis and by episodes of urinary urgency and suprapubic discomfort (Lambe R, Kennedy 0, Kenny M and Darragh A. Study of tolerance and diuretic properties of torasemide following oral or intravenous administration to healthy volunteers. Eur J Clin Pharmacol 1986;31(Suppl):9-14). Therefore, the availability of torasemide compositions, which may avoid the troublesome urinary urgencies caused by conventional immediate-release compositions is of a great interest. Summary of the invention. An object of the present invention is to prepare diuretic compositions that may provide more stable plasma levels of torasemide in order to avoid the initial peak. This will provide a kinetic profile with fewer fluctuations and steadier levels. Thus, the frequency of urinary urgencies is reduced, which results in a greater comfort for patients who need treatment with torasemide. The compositions of the present invention comprise torasemide, as active ingredient, and an excipient chosen from matrix-forming polymers, for example, polymers of acrylic acid, cellulose, glycerol behenate, guar gum, xanthan gum, chitosan, gelatin, polyvinyl alcohol and the like. In each composition one only polymer or a mixture thereof may be used. Other components that complete the compositions of the present invention are the usual excipients in pharmaceutical technology comprising diluents, for example, lactose, cellulose, mannitol, calcium phosphate and the like, as well as the mixtures thereof; binding- and disintegrating-action agents, for example, Aerosil® 200, starch, and the like, as well as the mixtures thereof; lubricants, for example, magnesium stearate, talc, and the like, as well as the mixtures thereof. Generally, the compositions of the present invention contain the active ingredient in a proportion from 0.5 to 20%, and the matrix-forming polymer in a proportion from 1 to 40%. The compositions of the present invention are tablets for oral administration. The compositions of the present invention maintain diuresis over a maximal period of 24 hours, preferably within the first 12 hours; thus, the possible disturbance of nocturnal enuresis is avoided. As the Cmax of plasma levels attained after administration is minimal, the troublesome urinary urgency induced by immediate-release compositions is prevented. Detailed description of the invention The tablets of the present invention contain the active ingredient, torasemide, in an amount of 0.5 to 20 mg. In practice, doses of 5, 10 and 20 mg per tablet are preferred. The matrix-forming polymers are chosen from the following groups: 1) acrylic polymers, for example, Carbopol® (a carbomer -a polymer of acrylic acid polymer), Kollicoat® (a copolymer of methacrylic acid), and their analogues and derivatives; 2) cellulose polymers, for example Methocel® (hydroxypropylmethylcellulose), methylcellulose, sodium carboxymethylcellulose, Natrosol® (hydroxyethylcellulose) and their analogues and derivatives; 3) Compritol® (glyceryl behenate); 4) Meyprogat® (guar gum) and its analogues and derivatives; 5) xanthan gum; 6) chitosan; 7) gelatin; and 8) polyvinyl alcohol and its derivatives. The compositions of the present invention contain the active ingredient, torasemide, in a proportion from 0.5 to 20% and the matrix-forming polymer in a proportion from 1 to 40%. The most convenient matrix-forming polymer was found to be guar gum, preferably in a proportion of 4%. However, other matrix-forming polymers may be employed in the compositions; their proportions may be varied within a relatively wide range. Thus, Carbopol® is formulated at concentrations from 1 to 20%, preferably 10%, Methocel® at concentrations from 1 to 50%, preferably 40%, Natrosol® and Compritol® at concentrations from 1 to 40%, preferably 20%, Kolllcoat* at concentrations from 1 to 40%, preferably 15% and Meyprogat® at concentrations from 1 to 40%, preferably 4%. The tablets of the present invention are manufactured according to standard procedures of pharmaceutical technology by direct compression or by wet granulation in such a way that moisture of the resulting dry granulate is lower than 10 %. An in vitro dissolution test is performed on the tablets of the present invention using apparatus 2/paddle stirring element (according to U.S. Pharmacopeia) at 50 rpm. In order to obtain a dissolution profile that fully models the physiological conditions, the test is performed within the first 2 hours at pH 1 and thereafter at pH 6.8. The results obtained are presented in Figures 1 and 2. Fig. 1 shows torasemide release (cumulative values) and Fig. 2 shows torasemide release. The present invention is further illustrated by - but not limited to - the following examples. Example 1: 5 mg tablets of torasemide with Carbopol® and a total weight of 85 mg Torasemide 5.0 mg Carbopol 940® 10.0 mg Lactose 48.0 mg Magnesium stearate 0.3 mg Aerosil® 200 0.5 mg Mannitol q.s. 85 mg Example 2: 5 mg tablets of torasemide with Methocel® and a total weight of 100 mg Torasemide 5.0 mg Methocel K 15 M* 40.0 mg Lactose 18.0 mg Corn starch 36.2 mg Pregelatinized starch 0.3 mg Aerosil® 200 0.5 mg Example 3: 5 mg tablets of torasemide with Natrosol® and a total weight of 85 mg Torasemide 5.0 mg Natrosol HX® 20.0 mg Magnesium stearate 0.3 mg Aerosil® 200 0.5 mg Microcrystalline cellulose q.s. 85 mg Example 4: 5 mg tablets of torasemide with Compritol® and a total weight of 100 mg Torasemide 5.0 mg Compritol 888® 20.0 mg Lactose 38.0 mg Corn starch 36.2 mg Magnesium stearate 0.3 mg Talc 0.5 mg Example 5: 10 mg tablets of torasemide with Kollicoat® and a total weight of 85 mg Torasemide 10.0 mg Kollicoat® SR 30 D 30.0 mg Magnesium stearate 0.6 mg Talc 1.0 mg Calcium phosphate q.s. 85 mg Example 6: 5 mg tablets of torasemide with Meyprogat® and a total weight of 100 mg Torasemide 5.0 mg Meyprogat® 90 4 .0 mg Lactose 54.0 mg Corn starch 36.2 mg Magnesium stearate 0.3 mg Aerosil® 200 0.5 mg Example 7: 5 mg tablets of torasemide with Meyprogat® and a total weight of 85 mg Torasemide 5.0 mg Meyprogat® 90 3.4 mg Corn starch 30.77 mg Aerosil® 200 0.42 mg Magnesium stearate 0.25 mg Lactose 45.16 mg Example 8: 10 mg tablets of torasemide with Meyprogat® and a total weight of 170 mg Torasemide 10.0 mg Meyprogat® 90 6.8 mg Corn starch 61.54 mg Aerosil® 200 0.85 mg Magnesium stearate 0.51 mg Lactose 90.30 mg Example 9: 20 mg tablets of torasemide with Meyprogat® and a total weight of 340 mg Torasemide 20.0 mg Meyprogat® 90 13.6 mg Corn starch 123.08 mg Aerosil® 200 1.70 mg Magnesium stearate 1.02 mg Lactose 180.6 mg Example 10: Pharmacokinetics of torasemide in man A randomized clinical trial was performed in a group of 10 healthy volunteers who were cross-administered with a 10 mg prolonged-release tablet of torasemide and a 10 mg immediate-release commercial tablet of torasemide (Sutril®, Novag, Spain). There was 1-week interval between the administration of each tablet. The prolonged-release torasemide composition exhibited a lower peak of plasma levels (Cmax) attained less acutely (tmax) with steadier levels and fewer fluctuations (Fig. 3) . The prolonged- release composition produced a lesser frequency of acute diuresis episodes than the immediate-release composition (Fig. 4). These data show that the compositions of torasemide in the present invention produce a lower peak of plasma levels and fewer fluctuations than the immediate-release composition. In addition, there is a shorter number of urinary urgency episodes after the prolonged-release torasemide composition. Experimental Data on kinetic profiles of torasemide formulations (tablets) of the invention Meyprogat® 90 (i.e. guar gum) at 10%, 5% and 3% of the total tablet weight was tested as shown in Table below for the 5 mg tablet dose (5 mg torasemide). The following dissolution tests were performed with hydrochloric acid 0.1 N. In comparison with Sutril® (Immediate release formulation) experimental tablets showed a prolonged release behaviour starting from 3% of guar gum (batch T1804). The total release of the active in this batch (T1804) was produced in 5 hours. Batches with 5% and 10% of the excipient (T1704 and T1604) presented a 75% active release within 5 hours with a similar kinetic profile. The following table and figure show the results of the kinetic profile of these formulations. Table. Release values (with HC1 0.1N) for tablets manufactured with Meyprogat® 90. Figure.5 - Release profiles (with HC1 0.1N) of Torasemide from Meyprogat® 90 matrix tablets. The percentage of lactose in the experiments is above 45% with respect of the blend. The amount of guar gum is in the range of 1 to 20%. Clearly, the specific combination of elements in the formulations, and their concentrations provide a surprising effect on release rate compared to an immediate release composition (Sutril®). WE CLAIM : 1) Prolonged-release compositions containing torasemide as active ingredient, a matrix-forming polymer, and lactose as diluent, wherein: a) the torasemide is present in a proportion of from 0.5 to 20% by weight; and b) the matrix-forming polymer is guar gum in a proportion of from 1% to 40% by weight. 2) Prolonged-release compositions as claimed in claim 1, wherein said compositions are tablets for oral administration. 3) Prolonged-release compositions as claimed in claim 1 or 2, wherein the matrix-forming polymer further comprises one or more of the group of polymers consisting of acrylic acid, cellulose, glycerol behenate, xanthan gum, chitosan, gelatin, polyvinyl alcohol, and mixtures thereof. 4) Prolonged-release compositions as claimed in claim 3, wherein the acrylic matrix-forming polymer is an acrylic acid polymer. 5) Prolonged-release compositions as claimed in claim 3, wherein the cellulose matrix-forming polymer is selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, and their pharmaceutically acceptable salts, and mixtures thereof. 6) Prolonged-release compositions according to any one of claims 1-5, wherein torasemide is present in a proportion from 4 to 10%. 7) Prolonged-release compositions as claimed in any one of claims 1-6, wherein the matrix-forming polymers are present in a proportion from 2 to 40%. 8) Prolonged-release compositions as claimed in any one of preceding claims comprising in addition one or more excipients selected from the group consisting of diluents, binders, disintegrants, and lubricants. 9) Prolonged-release compositions as claimed in claim 8, wherein, the diluents are selected from the group consisting of celluloses, mannitol, calcium phosphate, and the mixtures thereof. 10)Prolonged-release compositions as claimed in claim 8, wherein, the binders are selected from the group consisting of Aerosil® 200, starch, and mixtures thereof. 11)Prolonged-release compositions as claimed in claim 8, wherein, the disintegrants are selected from the group consisting of Aerosil© 200, starch, and mixtures thereof. 12) Prolonged-release compositions as claimed in claim 8, wherein, the lubricants are selected from the group consisting of magnesium stearate, talc, and mixtures thereof. ABSTRACT PROLONGED-RELEASE COMPOSITIONS COMPRISING TORASEMIDE AND A MATRIX-FORMING POLYMER The invention discloses a Prolonged-release composition comprising torasemide as active ingredient, a matrix-forming polymer, wherein the matrix forming polymer is guar gum and is present in a proportion of from 1 to 40% of said composition, and lactose as a diluent.

Full Text

Field of the invention
This invention relates to prolonged-release diuretic
compositions containing torasemide as active ingredient.
Brief description of the accompanying drawings
Figure 1 shows the curves of in-vitro release rate
(cumulative values) of torasemide comparatively for
immediate-release (IR) tablets and prolonged-release (PR)
tablets according to Example 8.
Figure 2 shows the curves of in-vitro release rate of
torasemide comparatively for immediate-release (IR)
tablets and prolonged-release (PR) tablets according to
Example 8.
Figure 3 shows the plasma concentration curves in man
after administration of torasemide comparatively for
immediate-release (IR) tablets and prolonged-release (PR)
tablets according to Example 8.
Figure 4 shows the versus-time curves of the number of
urinary urgencies in man after administration of
torasemide comparatively for immediate-release (IR)
tablets and prolonged-release (PR) tablets according to
Example 8.
Figure 5 shows release profiles (with HC1 0.1N) of
Torasemide from Meyprogat® 90 matrix tablets.
Background of the invention
Torasemide (US 4018929) is a potent diuretic with an
extensive clinical use. Torasemide mainly acts by
inhibiting sodium reabsorption in the ascending limb of

Henle's loop (Puschett JB and Jordan LL. Mode of action
of Torasemide in man. Progress in Pharmacology and
Clinical Pharmacology. 1990;8(1):7-13). Torasemide
interferes with Na+2C1-K+ pump in the luminal cell
membrane and blocks the basolateral chloride conductance
(Greger R. Inhibition of active NaCl reabsortion in the
thick ascending limb of the loop of Henle by torasemide.
Arzneim Forsch./Drug Res. 1988;38{1):151-155).
The bioavailability for torasemide is 80-90% after oral
administration, the kinetics is linear and the
elimination half-life is 3-4 hours. The pharmacokinetic
profile is characterized by a peak of maximum plasma
concentration (Cmax) which is reached within a rather
short period of time {tmax: approximately 1 hour) and by a
rapid elimination (t4: approximately 3-4 hours)
(Neugebauer G, Besenfelder E and Mollendorf E.
Pharmacokinetics and metabolism of torasemide in man.
Arzneim Forsch./Drug Res. 1988;38 (1):164-166). Torasemide
shows a, linear dose-response relationship at doses, from
2.5 to 20 mg for urinary volume. The sodium excretion
exerts a minimal effect on potassium. (Scheen AJ. Dose-
response curve of torasemide in healthy volunteers.
Arzneim Forsch./Drug Res. 1988/38 (1):156-159; Barr WH et
al. Torasemide dose-proportionality of pharmacokinetics
and pharmacodynamics. Progress in Pharmacology and
Clinical Pharmacology. 1990;8(1):29-37). The maximal
effects on urine and electrolytes excretions are observed
at approximately 2 hours after oral administration (Lesne
M. Comparison of the pharmacokinetics and
pharmacodynamics of torasemide and furosemide in healthy
volunteers. Arzneim Forsch./Drug Res. 1988;38(1):160-
163) . All these effects clinically become apparent as an
acute diuresis and by episodes of urinary urgency and
suprapubic discomfort (Lambe R, Kennedy 0, Kenny M and

Darragh A. Study of tolerance and diuretic properties of
torasemide following oral or intravenous administration
to healthy volunteers. Eur J Clin Pharmacol
1986;31(Suppl):9-14).
Therefore, the availability of torasemide compositions,
which may avoid the troublesome urinary urgencies caused
by conventional immediate-release compositions is of a
great interest.
Summary of the invention.
An object of the present invention is to prepare diuretic
compositions that may provide more stable plasma levels
of torasemide in order to avoid the initial peak. This
will provide a kinetic profile with fewer fluctuations
and steadier levels. Thus, the frequency of urinary
urgencies is reduced, which results in a greater comfort
for patients who need treatment with torasemide.
The compositions of the present invention comprise
torasemide, as active ingredient, and an excipient chosen
from matrix-forming polymers, for example, polymers of
acrylic acid, cellulose, glycerol behenate, guar gum,
xanthan gum, chitosan, gelatin, polyvinyl alcohol and the
like. In each composition one only polymer or a mixture
thereof may be used. Other components that complete the
compositions of the present invention are the usual
excipients in pharmaceutical technology comprising
diluents, for example, lactose, cellulose, mannitol,
calcium phosphate and the like, as well as the mixtures
thereof; binding- and disintegrating-action agents, for
example, Aerosil® 200, starch, and the like, as well as
the mixtures thereof; lubricants, for example, magnesium
stearate, talc, and the like, as well as the mixtures

thereof. Generally, the compositions of the present
invention contain the active ingredient in a proportion
from 0.5 to 20%, and the matrix-forming polymer in a
proportion from 1 to 40%.
The compositions of the present invention are tablets for
oral administration.
The compositions of the present invention maintain
diuresis over a maximal period of 24 hours, preferably
within the first 12 hours; thus, the possible disturbance
of nocturnal enuresis is avoided. As the Cmax of plasma
levels attained after administration is minimal, the
troublesome urinary urgency induced by immediate-release
compositions is prevented.
Detailed description of the invention
The tablets of the present invention contain the active
ingredient, torasemide, in an amount of 0.5 to 20 mg. In
practice, doses of 5, 10 and 20 mg per tablet are
preferred. The matrix-forming polymers are chosen from
the following groups: 1) acrylic polymers, for example,
Carbopol® (a carbomer -a polymer of acrylic acid polymer),
Kollicoat® (a copolymer of methacrylic acid), and their
analogues and derivatives; 2) cellulose polymers, for
example Methocel® (hydroxypropylmethylcellulose),
methylcellulose, sodium carboxymethylcellulose, Natrosol®
(hydroxyethylcellulose) and their analogues and
derivatives; 3) Compritol® (glyceryl behenate); 4)
Meyprogat® (guar gum) and its analogues and derivatives;
5) xanthan gum; 6) chitosan; 7) gelatin; and 8) polyvinyl
alcohol and its derivatives.

The compositions of the present invention contain the
active ingredient, torasemide, in a proportion from 0.5
to 20% and the matrix-forming polymer in a proportion
from 1 to 40%. The most convenient matrix-forming polymer
was found to be guar gum, preferably in a proportion of
4%. However, other matrix-forming polymers may be
employed in the compositions; their proportions may be
varied within a relatively wide range. Thus, Carbopol® is
formulated at concentrations from 1 to 20%, preferably
10%, Methocel® at concentrations from 1 to 50%, preferably
40%, Natrosol® and Compritol® at concentrations from 1 to
40%, preferably 20%, Kolllcoat* at concentrations from 1
to 40%, preferably 15% and Meyprogat® at concentrations
from 1 to 40%, preferably 4%.
The tablets of the present invention are manufactured
according to standard procedures of pharmaceutical
technology by direct compression or by wet granulation in
such a way that moisture of the resulting dry granulate
is lower than 10 %.
An in vitro dissolution test is performed on the tablets
of the present invention using apparatus 2/paddle
stirring element (according to U.S. Pharmacopeia) at 50
rpm.
In order to obtain a dissolution profile that fully
models the physiological conditions, the test is
performed within the first 2 hours at pH 1 and thereafter
at pH 6.8. The results obtained are presented in Figures
1 and 2. Fig. 1 shows torasemide release (cumulative
values) and Fig. 2 shows torasemide release.
The present invention is further illustrated by - but not
limited to - the following examples.

Example 1: 5 mg tablets of torasemide with Carbopol® and a
total weight of 85 mg
Torasemide 5.0 mg
Carbopol 940® 10.0 mg
Lactose 48.0 mg
Magnesium stearate 0.3 mg
Aerosil® 200 0.5 mg
Mannitol q.s. 85 mg
Example 2: 5 mg tablets of torasemide with Methocel® and a
total weight of 100 mg
Torasemide 5.0 mg
Methocel K 15 M* 40.0 mg
Lactose 18.0 mg
Corn starch 36.2 mg
Pregelatinized starch 0.3 mg
Aerosil® 200 0.5 mg
Example 3: 5 mg tablets of torasemide with Natrosol® and a
total weight of 85 mg
Torasemide 5.0 mg
Natrosol HX® 20.0 mg
Magnesium stearate 0.3 mg
Aerosil® 200 0.5 mg
Microcrystalline cellulose q.s. 85 mg
Example 4: 5 mg tablets of torasemide with Compritol® and
a total weight of 100 mg
Torasemide 5.0 mg

Compritol 888® 20.0 mg
Lactose 38.0 mg
Corn starch 36.2 mg
Magnesium stearate 0.3 mg
Talc 0.5 mg
Example 5: 10 mg tablets of torasemide with Kollicoat® and
a total weight of 85 mg
Torasemide 10.0 mg
Kollicoat® SR 30 D 30.0 mg
Magnesium stearate 0.6 mg
Talc 1.0 mg
Calcium phosphate q.s. 85 mg
Example 6: 5 mg tablets of torasemide with Meyprogat® and
a total weight of 100 mg
Torasemide 5.0 mg
Meyprogat® 90 4 .0 mg
Lactose 54.0 mg
Corn starch 36.2 mg
Magnesium stearate 0.3 mg
Aerosil® 200 0.5 mg
Example 7: 5 mg tablets of torasemide with Meyprogat® and
a total weight of 85 mg
Torasemide 5.0 mg
Meyprogat® 90 3.4 mg
Corn starch 30.77 mg
Aerosil® 200 0.42 mg
Magnesium stearate 0.25 mg
Lactose 45.16 mg

Example 8: 10 mg tablets of torasemide with Meyprogat® and
a total weight of 170 mg
Torasemide 10.0 mg
Meyprogat® 90 6.8 mg
Corn starch 61.54 mg
Aerosil® 200 0.85 mg
Magnesium stearate 0.51 mg
Lactose 90.30 mg
Example 9: 20 mg tablets of torasemide with Meyprogat® and
a total weight of 340 mg
Torasemide 20.0 mg
Meyprogat® 90 13.6 mg
Corn starch 123.08 mg
Aerosil® 200 1.70 mg
Magnesium stearate 1.02 mg
Lactose 180.6 mg
Example 10: Pharmacokinetics of torasemide in man
A randomized clinical trial was performed in a group of
10 healthy volunteers who were cross-administered with a
10 mg prolonged-release tablet of torasemide and a 10 mg
immediate-release commercial tablet of torasemide
(Sutril®, Novag, Spain). There was 1-week interval between
the administration of each tablet. The prolonged-release
torasemide composition exhibited a lower peak of plasma
levels (Cmax) attained less acutely (tmax) with steadier
levels and fewer fluctuations (Fig. 3) . The prolonged-
release composition produced a lesser frequency of acute
diuresis episodes than the immediate-release composition
(Fig. 4).

These data show that the compositions of torasemide in
the present invention produce a lower peak of plasma
levels and fewer fluctuations than the immediate-release
composition. In addition, there is a shorter number of
urinary urgency episodes after the prolonged-release
torasemide composition.

Experimental Data on kinetic profiles of torasemide formulations (tablets) of the
invention
Meyprogat® 90 (i.e. guar gum) at 10%, 5% and 3% of the total tablet weight was tested as
shown in Table below for the 5 mg tablet dose (5 mg torasemide).

The following dissolution tests were performed with hydrochloric acid 0.1 N.
In comparison with Sutril® (Immediate release formulation) experimental tablets showed
a prolonged release behaviour starting from 3% of guar gum (batch T1804). The total
release of the active in this batch (T1804) was produced in 5 hours. Batches with 5% and
10% of the excipient (T1704 and T1604) presented a 75% active release within 5 hours
with a similar kinetic profile. The following table and figure show the results of the
kinetic profile of these formulations.

Table. Release values (with HC1 0.1N) for tablets manufactured with Meyprogat® 90.

Figure.5 - Release profiles (with HC1 0.1N) of Torasemide from Meyprogat® 90 matrix
tablets.
The percentage of lactose in the experiments is above 45% with respect of the blend. The
amount of guar gum is in the range of 1 to 20%.
Clearly, the specific combination of elements in the formulations, and their
concentrations provide a surprising effect on release rate compared to an immediate
release composition (Sutril®).

WE CLAIM :
1) Prolonged-release compositions containing torasemide as active
ingredient, a matrix-forming polymer, and lactose as diluent,
wherein:
a) the torasemide is present in a proportion of from 0.5 to 20% by
weight; and
b) the matrix-forming polymer is guar gum in a proportion of from 1%
to 40% by weight.

2) Prolonged-release compositions as claimed in claim 1, wherein said
compositions are tablets for oral administration.
3) Prolonged-release compositions as claimed in claim 1 or 2, wherein
the matrix-forming polymer further comprises one or more of the
group of polymers consisting of acrylic acid, cellulose, glycerol
behenate, xanthan gum, chitosan, gelatin, polyvinyl alcohol, and
mixtures thereof.
4) Prolonged-release compositions as claimed in claim 3, wherein the
acrylic matrix-forming polymer is an acrylic acid polymer.
5) Prolonged-release compositions as claimed in claim 3, wherein the
cellulose matrix-forming polymer is selected from the group
consisting of hydroxypropylmethylcellulose, methylcellulose,
carboxymethylcellulose, hydroxyethylcellulose, and their
pharmaceutically acceptable salts, and mixtures thereof.
6) Prolonged-release compositions according to any one of claims 1-5,
wherein torasemide is present in a proportion from 4 to 10%.
7) Prolonged-release compositions as claimed in any one of claims 1-6,
wherein the matrix-forming polymers are present in a proportion from
2 to 40%.

8) Prolonged-release compositions as claimed in any one of preceding
claims comprising in addition one or more excipients selected from
the group consisting of diluents, binders, disintegrants, and
lubricants.
9) Prolonged-release compositions as claimed in claim 8, wherein, the
diluents are selected from the group consisting of celluloses,
mannitol, calcium phosphate, and the mixtures thereof.
10)Prolonged-release compositions as claimed in claim 8, wherein, the
binders are selected from the group consisting of Aerosil® 200,
starch, and mixtures thereof.
11)Prolonged-release compositions as claimed in claim 8, wherein, the
disintegrants are selected from the group consisting of Aerosil©
200, starch, and mixtures thereof.
12) Prolonged-release compositions as claimed in claim 8, wherein,
the lubricants are selected from the group consisting of magnesium
stearate, talc, and mixtures thereof.

ABSTRACT

PROLONGED-RELEASE COMPOSITIONS COMPRISING
TORASEMIDE AND A MATRIX-FORMING POLYMER
The invention discloses a Prolonged-release composition comprising torasemide as
active ingredient, a matrix-forming polymer, wherein the matrix forming polymer is
guar gum and is present in a proportion of from 1 to 40% of said composition, and
lactose as a diluent.

PROLONGED-RELEASE COMPOSITIONS COMPRISING TORASEMIDE AND A MATRIX-FORMING POLYMER

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