U.S. patent application number 15/695334 was filed with the patent office on 2017-12-28 for pharmaceutical composition including pimobendan.
The applicant listed for this patent is Boehringer Ingelheim Vetmedica GmbH. Invention is credited to Martin A. Folger, Bernhard Hassel, Stefan Henke, Jens Lehmann.
Application Number | 20170368062 15/695334 |
Document ID | / |
Family ID | 34877563 |
Filed Date | 2017-12-28 |
United States Patent
Application |
20170368062 |
Kind Code |
A1 |
Folger; Martin A. ; et
al. |
December 28, 2017 |
PHARMACEUTICAL COMPOSITION INCLUDING PIMOBENDAN
Abstract
A solid formulation includes pimobendan or a pharmaceutically
acceptable salt thereof, which is homogenously dispersed with a
polyvalent acid and a flavor suitable to animals.
Inventors: |
Folger; Martin A.;
(Ingelheim, DE) ; Hassel; Bernhard; (Ockenheim,
DE) ; Henke; Stefan; (Kirchen, DE) ; Lehmann;
Jens; (Mandel, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim Vetmedica GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
34877563 |
Appl. No.: |
15/695334 |
Filed: |
September 5, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14465273 |
Aug 21, 2014 |
|
|
|
15695334 |
|
|
|
|
13802989 |
Mar 14, 2013 |
8859554 |
|
|
14465273 |
|
|
|
|
13402292 |
Feb 22, 2012 |
8846680 |
|
|
13802989 |
|
|
|
|
11072207 |
Mar 4, 2005 |
8846679 |
|
|
13402292 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/32 20130101;
A61K 47/38 20130101; A61K 47/12 20130101; A61P 9/04 20180101; A61K
9/14 20130101; A61K 9/2031 20130101; A61K 9/2059 20130101; A61K
47/46 20130101; A61K 9/2018 20130101; A61K 47/26 20130101; A61K
9/2095 20130101; A61K 31/501 20130101; A61K 9/2013 20130101; A61K
9/2009 20130101; A61K 9/2054 20130101 |
International
Class: |
A61K 31/501 20060101
A61K031/501; A61K 47/38 20060101 A61K047/38; A61K 9/14 20060101
A61K009/14; A61K 47/26 20060101 A61K047/26; A61K 47/12 20060101
A61K047/12; A61K 9/20 20060101 A61K009/20; A61K 47/46 20060101
A61K047/46; A61K 47/32 20060101 A61K047/32 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 8, 2004 |
DE |
102004011512 |
Claims
1. A solid formulation comprising a homogenous dispersion of:
pimobendan or a pharmaceutically acceptable salt thereof; a
polyvalent acid selected from the group consisting of citric acid,
acetic acid, maleic acid, tartaric acid or their anhydrides; and a
flavor acceptable to small animals; wherein: the content of
pimobendan in relation to polyvalent acid is 1:10 to 1:40; the
content of polyvalent acid within the solid formulation is 2.5 to
10% (w/w); and the flavor is homogenously dispersed within the
solid formulation.
2. The solid formulation according to claim 1, further comprising
one or more pharmaceutically acceptable carriers and/or
excipients.
3. The solid formulation according to claim 1, wherein the one or
several excipients are selected from the group consisting of
diluents, disintegrants, carriers, binders, flow regulators,
lubricants and solvents.
4. The solid formulation according to claim 2, wherein the binder
is selected from the group consisting of polyvidone/povidone,
methylcellulose, hydroxypropylmethylcellulose (HPMC),
hydroxymethylcellulose, starch and gelatine.
5. The solid formulation according to claim 2, wherein the
disintegrant/carrier is selected from the group consisting of
lactose, starch, cellulose, microcrystalline cellulose and
methylcellulose.
6. The solid formulation according to claim 5, wherein the lactose
consists of coarse particles greater than 200 .mu.m in size.
7. The solid formulation according to claim 2, wherein the starch
or various starches are selected from the group consisting of
native starch, gelatinized starch, partly gelatinized starch,
starch powder, starch granules, chemically modified starch and
swellable physically modified starch.
8. The solid formulation according to claim 2, wherein the
disintegrant is selected from the group consisting of
croscarmellose sodium, sodium starch glycolate, pregelatinised
starch and cross-linked polyvinylpyrrolidone.
9. The solid formulation according to claim 2, wherein the flow
regulator is selected from the group consisting of silica,
preferably colloidal anhydrous silica, calcium silicate, magnesium
silicate and talc.
10. The solid formulation according to claim 2, wherein the
lubricant is selected from the group consisting of magnesium
stearate, calcium stearate, glyceryl behenate, polyethylene glycol,
stearic acid and talc.
11. The solid formulation according to claim 2, wherein the flavor
is selected from the group consisting of artificial beef flavors,
artificial chicken flavors, pork liver extract, artificial meat
flavor and honey flavor.
12. The solid formulation according to claim 1, further comprising
0.5 to 20 mg of pimobendan.
13. The solid formulation according to claim 1, wherein the weight
of the whole solid formulation is in the range of 250 mg to 3000
mg.
14. The solid formulation according to claim 1, wherein the solid
formulation is a tablet or a granule.
15. The solid formulation according to claim 1, wherein the solid
formulation is a tablet and consists of 1.25 mg, 2.5 mg, 5 mg or 10
mg pimobendan, and further consists of lactose, corn starch,
croscarmellose-sodium, citric acid, artificial beef flavor,
polyvidone, colloidal anhydrous silica and magnesium stearate.
16. The solid formulation according to claim 1, wherein the solid
formulation is a tablet and consists of 1.25 mg, 2.5 mg, 5 mg or 10
mg pimobendan, and further consists of 35 to 50% (w/w) lactose, 25
to 50% (w/w) corn starch, 1 to 5% (w/w) croscarmellose-sodium, 2.5
to 10% (w/w) citric acid, 5 to 30% (w/w) artificial beef flavor, 1
to 5% (w/w) polyvidone, 0.1 to 1% (w/w) colloidal anhydrous silica
and 0.25 to 1.5% (w/w) magnesium stearate.
17. A tablet comprising granules compressed together, each granule
comprising the solid formulation of claim 1.
18. A solid formulation comprising a homogenous dispersion of:
pimobendan or a pharmaceutically acceptable salt thereof; a
polyvalent acid selected from the group consisting of citric acid,
acetic acid, maleic acid, tartaric acid or their anhydrides;
croscarmellose-sodium; and a flavor acceptable to small animals;
wherein the flavor is homogenously dispersed within the solid
formulation.
19. A method of prevention and/or treatment of congestive heart
failure in a mammal, the method comprising administering a solid
formulation to the mammal, the solid formulation comprising
pimobendan or a pharmaceutically acceptable salt thereof, a
polyvalent acid selected from the group consisting of citric acid,
acetic acid, maleic acid, tartaric acid or their anhydrides; and a
flavor acceptable to small animals, wherein the flavor is
homogenously dispersed within the solid formulation.
20. A fluid-bed granulation process to form tablets comprising the
solid formulation of claim 1, the process comprising: a) spraying
an aqueous dispersion of pimobendan and an aqueous solution of a
binder onto a solid support comprising one or several carriers
and/or excipients, flavor and citric acid anhydrous; b) drying the
mixture of a); c) sieving and de-agglomerating the mixture of b);
d) adding a flow regulator to the mixture of c); e) adding a
lubricant to the mixture of d); f) blending the mixture of e) for
uniformity of granules to obtain final granules; and g) compressing
the final granules of f) to tablets.
21. The fluid-bed granulation process according to claim 19,
wherein the binder of step a) is povidone, and the solid support of
step a) comprises lactose, starch, flavor and citric acid
anhydrous.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
Nonprovisional application Ser. No. 14/465,273, filed 21 Aug. 2014
and entitled "Pharmaceutical Composition Including Pimobendan",
which is a continuation of U.S. Nonprovisional application Ser. No.
13/802,989, filed 14 Mar. 2013 and entitled "Packaging Assembly for
Pharmaceutical Composition Including Pimobendan," which is a
continuation of U.S. Nonprovisional application Ser. No.
13/402,292, filed 22 Feb. 2012 and entitled "Pharmaceutical
Composition Comprising Pimobendan," which is a divisional of U.S.
Nonprovisional application Ser. No. 11/072,207, filed 4 Mar. 2005
and entitled "Pharmaceutical Composition Comprising Pimobendan,"
which claims priority to German Patent Application No.
102004011512, filed on 8 Mar. 2004. The disclosure of each
aforementioned application is incorporated herein by reference in
its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to the field of animal health. In
particular, the invention relates to novel oral pharmaceutical
compositions comprising, as part of the pharmaceutically active
compounds, pimobendan.
BACKGROUND OF THE INVENTION
[0003] Pimobendan,
(4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)--
pyridazone) is disclosed in U.S. Pat. No. 4,361,563, herein
incorporated by reference in its entirety. Pimobendan is a
cardiotonic, hypotensive and anti-thrombotic. Said substance is
useful in the treatment of congestive heart failure.
[0004] Pimobendan hardly dissolves in water. The resorption of
pimobendan when administered orally is prone to considerable inter-
and intra-individual fluctuations if the active substance is
incorporated in known or conventional pharmaceutical forms for oral
administration. The reason for this is that pimobendan is
characterized by a low solubility in aqueous media and a very
highly pH-dependent solubility. To overcome this, hard gelatine
capsules were used containing pimobendan formulated with citric
acid, in particular at a weight ratio of pimobendan to citric acid
of between 1:10 and 1:20 (U.S. Pat. No. 5,364,646, herein
incorporated by reference in its entirety). However, the high
quantity of citric acid and the acidic taste of citric acid is not
readily accepted by most animals--thus, such capsules have to be
force-fed to the animals or mixed with food prior to
application.
[0005] The problem underlying the present invention was to provide
a pimobendan solid formulation readily acceptable by mammalian
subjects, especially small animals.
SUMMARY OF THE INVENTION
[0006] The invention relates to novel solid formulations comprising
as a pharmaceutically active compound pimobendan or a
pharmaceutically acceptable salt thereof which is homogenously
dispersed in a polyvalent acid and a flavor acceptable to small
animals. Preferably, such solid formulations are granules or
tablets. Most preferred is a tablet characterized in that the
tablet comprises, 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and
further comprises lactose, corn starch, croscarmellose-sodium,
citric acid, preferably at an amount of 50 mg/g of the solid
formulation, artificial beef flavor, polyvidone, colloidal
anhydrous silica and magnesium stearate.
[0007] The invention further relates to fluid-bed granulation
processes for production of the solid formulations comprising the
following steps: [0008] a) an aqueous solution of pimobendan and a
binder as defined above is sprayed onto a solid carrier bed
comprising one or more carriers and/or excipients, flavor and
citric acid anhydride and [0009] b) the resulting mixture is dried
and [0010] c) the dried mixture is sieved and de-agglomerated and
[0011] d) a flow regulator is added to the sieved and
de-agglomerated mixture and [0012] e) a lubricant is added to the
resulting mixture and [0013] f) the resulting mixture with
lubricant is blended for uniformity of granules to obtain final
granules and/or [0014] g) the final granules are compressed to
solid formulations.
[0015] Step g) is omitted if the solid formulation is a granule. If
the solid formulation is a tablet, step g) is carried out.
[0016] Furthermore, the invention relates to a method of prevention
and/or treatment of diseases wherein cardiotonic, hypotensive and
anti-thrombotic substances have a therapeutic benefit, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of a solid formulation prepared as
described above.
[0017] Preferred is a method of prevention and/or treatment of
congestive heart failure, comprising administering to a mammal in
need of such treatment a therapeutically effective amount of a
solid formulation according to the invention as disclosed above.
Most preferably, the method comprises administering a tablet
according to the invention, as defined above.
[0018] Furthermore, the invention relates to a method for
manufacturing a medicament for the prevention and/or treatment of
congestive heart failure, Additionally, the invention relates to a
method for manufacturing a medicament for the prevention and/or
treatment of congestive heart failure, characterized in that a
tablet comprising 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan and
further comprising lactose, corn starch, croscarmellose-sodium, 50
mg/g citric acid, artificial beef flavor, polyvidone, colloidal
anhydrous silica and magnesium stearate is made.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1: Illustration of the basic top spray fluid bed
process. Reference signs: 1 Exhaust air ventilator; 2 Filter; 3
Pump; 4 Stirrer; 5 Aqueous Suspension of micronized pimobendan and
binder solution (PVP, HPMC, starch, gelatin); 6 Heating device for
inlet air; 7 Sieve; 8 Nozzle, aqueous suspension is sprayed onto
powder bed (citric acid, lactose, starch, flavor); 9 Powder
bed.
[0020] FIG. 2: Flow Chart of Manufacturing Process.
[0021] FIG. 3: Dissolution Profiles, Pimobendan 1.25 mg tablets,
showing 95% confidence intervals of the mean; USP apparatus 2
(Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Comparison of
dissolution profiles of tablets which were stored 1 and 6 months at
40.degree. C./75% in HDPE bottles; batch no. PB020049.
[0022] FIG. 4: Dissolution Profiles, Pimobendan 1.25 mg tablets,
showing 95% confidence intervals of the mean; USP apparatus 2
(Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Comparison of
dissolution profiles of tablets which were stored 12 days at
25.degree. C./60% in open glass bottles; batch no. PB010080.
[0023] FIG. 5: Dissolution Profiles, Pimobendan 2.5 mg tablets,
showing 95% confidence intervals of the mean; USP apparatus 2
(Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Comparison of
dissolution profiles of tablets which were stored 3 and 6 months at
40.degree. C./75% in Alu-Alu Blister; batch no. PB010076
[0024] FIG. 6: Dissolution Profiles, Pimobendan 5.0 mg tablets,
showing 95% confidence intervals of the mean; USP apparatus 2
(Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Comparison of
dissolution profiles of tablets which were stored 6 months at
40.degree. C./75% in HDPE bottles; batch no. PB020059.
[0025] FIG. 7: Dissolution Profiles, Pimobendan 5.0 mg tablets,
showing 95% confidence intervals of the mean; USP apparatus 2
(Paddle), Rotation Speed 75 rpm, Buffer pH 4.0. Manufacturing
variable: Different compression forces; batch no. PB020205.
DETAILED DESCRIPTION OF THE INVENTION
[0026] Before the embodiments of the present invention it must be
noted that as used herein and in the appended claims, the singular
forms "a", "an", and "the" include plural reference unless the
context clearly dictates otherwise. Thus, for example, reference to
"a tablet" includes a plurality of such tablets, reference to the
"carrier" is a reference to one or more carriers and equivalents
thereof known to those skilled in the art, and so forth. Unless
defined otherwise, all technical and scientific terms used herein
have the same meanings as commonly understood by one of ordinary
skill in the art to which this invention belongs. All given ranges
and values may vary by 1 to 5% unless indicated otherwise or known
otherwise by the person skilled in the art. Accordingly, the term
"about" is not used in the description.
[0027] Although any methods and materials similar or equivalent to
those described herein can be used in the practice or testing of
the present invention, the preferred methods, devices, and
materials are described. All publications mentioned herein are
incorporated herein by reference for the purpose of describing and
disclosing the substances, excipients, carriers, and methodologies
as reported in the publications which might be used in connection
with the invention. Nothing herein is to be construed as an
admission that the invention is not entitled to antedate such
disclosure by virtue of prior invention.
[0028] The solution to the above technical problem is achieved by
the description and the embodiments characterized in the
claims.
[0029] To overcome the difficulties in the art, a process was
invented. Only the invention of this novel, fluid-bed granulation
process allowed the formulation of solid formulations according to
the invention. With the process according to the invention, it was
possible to formulate a long-term stable, capable of being produced
on a large scale, homogenously dispersed, fast-releasing solid
formulation. Despite the large size, pimobendan was homogenously
dispersed. Such solid formulations comprise a flavor suitable for
small animals, which surprisingly still allows a formulation having
a polyvalent acid and yet have a palatibility rate of more than
70%--in many cases more than 90%. Thus, the solid formulations
according to the invention are a major step forward in therapeutic
application as they do not have to be force-fed to the animal.
[0030] In a first important embodiment, the invention relates to a
solid formulation, comprising pimobendan or a pharmaceutically
acceptable salt thereof, see e.g. U.S. Pat. No. 4,361,563 or U.S.
Pat. No. 5,364,646 (both herein incorporated by reference in its
entirety), which is homogenously dispersed in a polyvalent acid
selected from the group consisting of citric acid, acetic acid,
maleic acid, tartaric acid and the anhydride of any of said
polyvalent acids and mixtures thereof, and a flavor acceptable to
small animals. Such flavors according to the invention preferably
are selected from artificial beef flavors, artificial chicken
flavors, pork liver extract, artificial meat flavor, honey flavor
and the like. Said flavors not only disguise the taste of the
polyvalent acid, but also the taste of pimobendan.
[0031] Preferably, the solid formulation according to the invention
is a tablet or granule formulation. The granule formulation
according to the invention is explained in more detail below. More
preferably, the solid formulation is chewable.
[0032] The invention preferably also relates to a solid formulation
according to the invention, further comprising one or several
pharmaceutically acceptable excipients. Excipients according to the
invention are preferably selected from the group consisting of
diluents, disintegrants, carriers, binders, flow regulators,
lubricants and solvents. Any other excipients known to the skilled
person and found suitable for the solid formulation according to
the invention may also be comprised in the solid formulation
according to the invention. See also Remington, J. P. The science
and Practice of Pharmacy (2000). 20th ed. Lippincott Williams &
Wilkins Publishers, Philadelphia, US. More preferably, said
excipients are carriers/disintegrants selected from the group
lactose, starch, cellulose, microcrystalline cellulose and
cellulose derivatives, e.g. methylcellulose, and the like. Any
other carrier known to the skilled person and found suitable for
the solid formulation according to the invention may also form part
of the solid formulation according to the invention. See also
Remington, J. P. The science and Practice of Pharmacy (2000). 20th
ed. Lippincott Williams & Wilkins Publishers, Philadelphia,
US.
[0033] One or several binders according to the invention are
preferably selected from the group consisting of polyvidone (used
synonymously for povidone), methylcellulose,
hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose,
starch, gelatin, and the like. Any other binder known to the
skilled person and found suitable for the solid formulation
according to the invention may also be comprised in the solid
formulation according to the invention. See also Remington, J. P.
The science and Practice of Pharmacy (loc. cit.).
[0034] The solid formulation according to the invention may also
comprise one or several flow regulators selected from the group
consisting of silica, preferably colloidal anhydrous silica,
calcium silicate, magnesium silicate, talc, and the like. Any other
flow regulator known to the skilled person and found suitable for
the solid formulation according to the invention may also be
incorporated into the solid formulation according to the invention.
See also Remington, J. P. The science and Practice of Pharmacy
(loc. cit.).
[0035] The solid formulation according to the invention may also
comprise one or several disintegrants selected from the group
consisting of croscarmellose sodium, sodium starch glycolate,
pregelatinised starch, cross-linked polyvinylpyrrolidone and the
like. Any other disintegrant known to the skilled person and found
suitable for the solid formulation according to the invention may
also form part of the solid formulation according to the invention.
See also Remington, J. P. The science and Practice of Pharmacy
(loc. cit.).
[0036] The solid formulation according to the invention may also
comprise one or several lubricants selected from the group
consisting of magnesium stearate, calcium stearate, glyceryl
behenate, polyethylene glycol, stearic acid, talc and the like. Any
other lubricant known to the skilled person and found suitable for
the solid formulation according to the invention may form part of
the solid formulation according to the invention. See also
Remington, J. P. The science and Practice of Pharmacy (loc.
cit.).
[0037] The invention preferably also relates to a solid formulation
according to the invention, characterized in that the carriers are
starch and lactose. The invention preferably also relates to a
solid formulation according to the invention, characterized in that
the lactose consists of coarse particles greater than 200 .mu.m in
size. The person skilled in the art knows other types of lactose
which are suitable as well as carrier according to the invention,
e.g. fine lactose equal or smaller than 200 .mu.m in size or
spray-dried lactose. Preferred is lactose consisting of coarse
particles greater than 200 .mu.m in size.
[0038] The invention preferably also relates to a solid formulation
according to the invention, characterized in that the starch or
various starches are selected from the group consisting of native
starch, gelatinized starch, partly gelatinized starch, starch
powder, starch granules, chemically modified starch and swellable,
physically modified starch.
[0039] The invention preferably also relates to a solid formulation
according to the invention, characterized in that the starch is
corn starch.
[0040] The invention preferably also relates to a solid formulation
according to the invention, comprising 0.5 mg to 20 mg of
pimobendan. The more preferred solid formulation contains 1 to 10
mg of pimobendan. The even more preferred solid formulation
contains 1.25 to 5 mg of pimobendan. Most preferred solid
formulations contain 1.25 mg, 2.5 mg, 5 mg or 10 mg of
pimobendan.
[0041] The invention preferably also relates to a solid formulation
according to the invention, comprising a content of 1:10-1:40 of
pimobendan in relation to citric acid anhydride. The preferred
ratio is 1:20.
[0042] The invention preferably also relates to a solid formulation
according to the invention, characterized in that the weight of the
whole solid formulation is in the range of 250 to 3000 mg, with a
more preferred weight range of 500 mg to 2000 mg, and most
preferred weight of 500 mg, 1000 mg or 2000 mg.
[0043] The invention preferably also relates to a solid formulation
according to the invention, characterized in that the solid
formulation is produced by a fluid-bed granulation process
comprising or consisting of the steps: [0044] a) an aqueous
solution of pimobendan and a binder as defined above is sprayed
onto a solid carrier bed comprising one or several carriers and/or
excipients as defined above, flavor and citric acid anhydride and
[0045] b) the mixture of a) is dried and [0046] c) the mixture of
b) is sieved and de-agglomerated and [0047] d) a flow regulator is
added to the mixture of c) and [0048] e) a lubricant is added to
the mixture of d) and [0049] f) the mixture of e) is blended for
uniformity of granules to obtain final granules and/or [0050] g)
the final granules of f) are compressed to solid formulations.
[0051] Step g) is omitted if the solid formulation is a granule. If
the solid formulation is a tablet, step g) is carried out.
[0052] The invention preferably also relates to a solid formulation
according to the invention, characterized in that the solid
formulation is produced by a fluid-bed granulation process
comprising or consisting of the steps: [0053] a) an aqueous
solution of pimobendan and povidone is sprayed onto a solid carrier
bed comprising lactose, starch, flavor and citric acid anhydride
and [0054] b) the mixture of a) is dried and [0055] c) the mixture
of b) is sieved and de-agglomerated and [0056] d) a flow regulator
is added to the mixture of c) and [0057] e) a lubricant is added to
the mixture of d) and [0058] f) the mixture of e) is blended for
uniformity of granules to obtain final granules and/or [0059] g)
the final granules of f) are compressed to solid formulations.
[0060] Step g) is omitted if the solid formulation is a granule. If
the solid formulation is a tablet, step g) is carried out.
[0061] The invention preferably relates to a granule formulation as
obtained by the process above that can either be administered in
the granular form or as tablets after compressing the final
granules to tablets. Therefore, the solid formulation according to
the invention preferably is a granule (or a plurality of such
granules) or a tablet. The administration of the granules can take
place by mixing with food or by offering the granules directly to
the animal, e.g. in a bowl. The application of the granular form
will allow an individual dosing of pimobendan according to the body
weight of the animal.
[0062] The tablets according to the invention have surprising
advantages. The dissolution profile ensures immediate release of
pimobendan. Surprisingly, it could be demonstrated that while
compressing the final granules as mentioned above, a decrease in
the dissolution characteristics is not observed. By ensuring an
immediate release profile of pimobendan, the amount of drug to be
administered can be kept as low as possible, thereby improving the
safety profile, which is especially important for long-term
treatment.
[0063] Furthermore, the dosing accuracy of the tablet is excellent.
This is due to the fact that in accordance with the manufacturing
process according to this invention, an excellent uniformity of
pimobendan content is achieved. Furthermore, the tablets can be
broken into two halves so that half the dose per tablet can be
administered. Compared with the existing gelatin capsule, the
dosing accuracy and compliance of both the animal and the animal
owner are assured. This is even more important since the drug is
administered for a chronic condition and long-term treatment.
[0064] Also, the palatability of the tablet is excellent. More than
90% of the dogs to whom the tablet according to this invention was
given accepted the tablet voluntarily with only the tablet offered
in a bowl. Compared with the existing gelatin capsule, the ease of
administration has increased compliance with the prescribed
treatment regime. This is important since the drug is administered
for a chronic condition.
[0065] The invention preferably also relates to a tablet according
to the invention, characterized in that the tablet is stable for at
least 18 months at 25.degree. C. and 60% relative humidity. In the
examples, testing parameter assays are disclosed for degradation of
pimobendan, dissolution, loss on drying, hardness and
disintegration of the tablet. The tablets according to the
invention are within the specification limits regarding degradation
of pimobendan, dissolution, loss on drying, hardness and
disintegration.
[0066] Suitable packaging materials for tablets according to the
invention are selected from, but not limited to: aluminum/aluminum
blisters, PVC/PVDC blisters, and HDPE (high density polyethylene
bottles).
[0067] The invention preferably also relates to a tablet according
to the invention, characterized in that the tablet is oblong in
shape. For such a tablet, characteristics like crushing strength,
disintegration, uniformity of weight and content uniformity fulfill
the requirements of the European Pharmacopoeia (ISBN/ISSN
92-871-5106-7 of 4.sup.th Edition 2004, Vol. 4.8, European
Directorate for the Quality of Medicines (EDQM), European
Pharmacopoeia, 226 avenue de Colmar, F-67029 Strasbourg, France,
http://www.pheur.org) and the United States Pharmacopoeia
(http://www.usp.org; in print: USP-NF, catalog No. 2270001).
[0068] The invention preferably relates to a solid formulation, and
most preferred a tablet according to the invention, characterized
in that the solid formulation or tablet comprising 0.5-20 mg
pimobendan, preferably of 1.25 mg, 2.5 mg, 5 mg or 10 mg
pimobendan, and further comprises lactose (35-50% by weight
relative to the dry mass of the solid formulation/tablet=(w/w)),
corn starch (25-50% w/w), croscarmellose-sodium (1-5%), citric acid
(2.5-10% w/w), artificial beef flavor (5-30% w/w), polyvidone (1-5%
w/w), colloidal anhydrous silica (0.1-1, preferably 0.1-0.5% w/w)
and magnesium stearate (0.25-1.5% w/w), wherein the percentage by
weight of pimobendan contains preferably about 0.25% (w/w) and the
sum of the percentages by weight of all ingredients of the solid
formulation including pimobendan is 100% (w/w). A skilled man is in
a position to prepare such solid formulations, preferably a tablet.
Thus, the skilled man knows that he can add to 0.25% (w/w)
pimobendan at most 32.625% (w/w) corn starch, 4% (w/w)
croscarmellose-sodium 5% (w/w) citric acid, 20% (w/w) artificial
beef flavor, 4% (w/w) polyvidone, colloidal, 0.5% (w/w) anhydrous
silica, 1% (w/w) magnesium stearate if the amount of lactose to be
32.625% (w/w). Moreover, the skilled man also knows that if he
decided to reduce the amount of the artificial beef flavor, for
example, to the minimum of 5% (w/w), he can increase the amount of
lactose, for example, to 47.625% (w/w). The invention also relates
to a solid formulation, preferably a tablet, comprising about 0.25%
(w/w) pimobendan and any of the above other ingredients of the
solid formulation, preferably the tablet, in the range given above
so that the sum of the amounts by weight of the individual
formulation ingredients is 100%.
[0069] The present invention is also directed to a solid
formulation, preferably to a tablet, which comprises 1 mg
pimobendan, 100-200 mg lactose, 100-200 mg corn starch, 4-20 mg
croscarmellose-sodium, 10-40 mg citric acid anhydrous, 20-120 mg
artificial beef flavor, 4-20 mg polyvidone, 0.4-4 mg colloidal
anhydrous silica, and 1-6 mg magnesium stearate for each 400 mg of
total weight of the solid formulation, preferably a tablet.
According to a further embodiment of the present invention, the
solid formulation, preferably the tablet, comprises 1 mg
pimobendan, 120-180 mg lactose, 120-180 mg corn starch, 8-18 mg
croscarmellose-sodium, 15-30 mg citric acid anhydrous, 40-100 mg
artificial beef flavor, 8-18 mg polyvidone, 0.5-2 mg colloidal
anhydrous silica, and 2-5 mg magnesium stearate for each 400 mg of
total weight of the solid formulation/tablet. For example, the
present invention relates to a solid formulation comprising for
each 400 mg of total weight: 1 mg pimobendan, 20 mg citric acid
anhydrous, 130.5 mg lactose, 130.5 mg corn starch, 16 mg
polyvidone, 16 mg croscarmellose-sodium, 80 mg artificial beef
flavor, 4 mg magnesium stearate, and 2 mg colloidal anhydrous
silica. A skilled man is in a position to prepare such solid
formulation/tablet. The skilled man also knows that he can vary the
amount of each ingredient of the solid formulation/tablet within
the ranges given above in that the total weight of the solid
formulation/tablet for each 1 mg pimobendan is 400 mg. For example,
the amount of lactose may be 100, 101, 102, . . . 108, 109, 110
etc.; 111, 112, . . . 118, 119, 120 etc.; 121, 122, . . . 128, 129,
120 etc.; 131, 132, . . . 138, 139, 140 etc.; 141, 142, . . . 148,
149, 150 etc.; 151, 152, . . . 158, 159, 160 etc.; 161, 162, . . .
168, 169, 170 etc.; 171, 172, . . . 178, 179, 180 etc.; 108, 182, .
. . 188, 189, 190 etc.; 191, 192, . . . 198, 199, 200 mg for each
400 mg of total weight of the solid formulation, preferably a
tablet, comprising about 1 mg pimobendan. In the same manner the
amount of corn starch may be 100, 101, 102, . . . 108, 109, 110
etc.; 111, 112, . . . 118, 119, 120 etc.; 121, 122, . . . 128, 129,
120 etc.; 131, 132, . . . 138, 139, 140 etc.; 141, 142, . . . 148,
149, 150 etc.; 151, 152, . . . 158, 159, 160 etc.; 161, 162, . . .
168, 169, 170 etc.; 171, 172, . . . 178, 179, 180 etc.; 108, 182, .
. . 188, 189, 190 etc.; 191, 192, . . . 198, 199, 200 mg for each
400 mg of total weight of the solid formulation, preferably a
tablet, comprising about 1 mg pimobendan. Furthermore, the amount
of citric acid anhydrous may be 10, 11, 12, . . . 18, 19, 20 etc.;
21, 22, . . . 28, 29, 30 etc.; 31, 32, . . . 38, 39, 40 mg for each
400 mg of total weight of the solid formulation, preferably a
tablet comprising about 1 mg pimobendan. Furthermore, the amount of
artificial beef flavor may be 20, 21, 22, . . . 28, 29, 30 etc.;
31, 32, . . . 38, 39, 40 etc.; 41, 42, . . . 48, 49, 50 etc.; 50,
51, 52, . . . 58, 59, 60 etc.; 61, 62, . . . 68, 69, 70 etc.; 71,
72, . . . 78, 79, 80 etc., 81, 82, 83, . . . 88, 89, 90 etc.; 91,
92, . . . 98, 99, 100 etc.; 101, 102, . . . 108, 109, 110 etc.;
111, 112, . . . 118, 119, 120 mg for each 400 mg of total weight of
the solid formulation, preferably a tablet, comprising about 1 mg
pimobendan. Furthermore, the amount of polyyidone may be 4, 5, 6, .
. . 8, 9, 10 etc.; 11, 12, . . . 18, 19, 20 mg for each 400 mg of
total weight of the solid formulation, preferably a tablet,
comprising about 1 mg pimobendan. Furthermore, the amount of
croscarmellose-sodium may be 4, 5, 6, . . . 8, 9, 10 etc.; 11, 12,
. . . 18, 19, 20 mg for each 400 mg of total weight of the solid
formulation, preferably a tablet, comprising 1 mg pimobendan.
Furthermore, the amount of magnesium stearate may be 1.0, 1.1, 1.2,
. . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, . . . 2.8, 2.9, 3.0 etc.; 3.1,
3.2, . . . 3.8, 3.9, 40 etc.; 4.0, 4.1, 4.2, . . . 4.8, 4.9, 5.0
etc.; 5.1, 5.2, . . . 5.8, 5.9, 6.0 mg for each 400 mg of total
weight of the solid formulation, preferably a tablet, comprising
about 1 mg pimobendan. Furthermore, the amount of colloidal
anhydrous silica may be 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 1.0, 1.1, 1.2,
. . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, . . . 2.8, 2.9, 3.0 etc.; 3.1,
3.2, . . . 3.8, 3.9, 4.0 mg for each 400 mg of total weight of the
solid formulation, preferably a tablet, comprising about 1 mg
pimobendan. A skilled man is in a position to prepare any of such
inventive solid formulation, preferably as a tablet.
[0070] In another important embodiment, the invention relates to a
fluid-bed granulation process comprising the following steps:
[0071] a) an aqueous solution of pimobendan and a binder as defined
above is sprayed onto a solid carrier bed comprising one or several
carriers and/or excipients as defined above, flavor and citric acid
anhydride and [0072] b) the mixture of a) is dried and [0073] c)
the mixture of b) is sieved and de-agglomerated and [0074] d) a
flow regulator is added to the mixture of c) and [0075] e) a
lubricant is added to the mixture of d) and [0076] f) the mixture
of e) is blended for uniformity of granules to obtain final
granules and/or [0077] g) the final granules of f) are compressed
to solid formulations.
[0078] Step g) is omitted if the solid formulation is a granule. If
the solid formulation is a tablet, step g) is carried out.
[0079] The invention preferably relates to a fluid-bed granulation
process comprising the following steps: [0080] a) an aqueous
solution of pimobendan and polyvidone is sprayed onto a solid
support comprising lactose, starch, flavor and citric acid
anhydride and [0081] b) the mixture of a) is dried and [0082] c)
the mixture of b) is sieved and de-agglomerated and [0083] d) a
flow regulator is added to the mixture of c) and [0084] e) a
lubricant is added to the mixture of d) and [0085] f) the mixture
of e) is blended for uniformity of granules to obtain final
granules and/or [0086] g) the final granules of f) are
tableted.
[0087] Step g) is omitted if the solid formulation is a granule. If
the solid formulation is a tablet, step g) is carried out.
[0088] Another embodiment is a method of prevention and/or
treatment of diseases wherein cardiotonic, hypotensive and
anti-thrombotic substances have a therapeutic benefit, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of a solid formulation according
to the invention as disclosed above. Preferred is a method of
prevention and/or treatment of congestive heart failure, comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of a solid formulation according
to the invention as disclosed above. Most preferably, the method
comprises administering a tablet according to the invention,
characterized in that the tablet comprises 1.25 mg, 2.5 mg, 5 mg or
10 mg pimobendan, and further comprises lactose, corn starch,
croscarmellose-sodium, citric acid preferably at an amount of 50
mg/g, artificial beef flavor, polyvidone, colloidal anhydrous
silica and magnesium stearate. Preferably also, such treatment is
by orally administering the solid formulation according to the
invention.
[0089] The mammal according to the invention is preferably a mammal
selected from the group consisting of dogs, cats and rodents such
as rabbits.
[0090] Furthermore, the invention relates to a method for
manufacturing a medicament for the prevention and/or treatment of
congestive heart failure, characterized in that a solid formulation
according to the invention is used. Preferably, the invention
relates to a method for manufacturing a medicament for the
prevention and/or treatment of congestive heart failure,
characterized in that a tablet consisting of 1.25 mg, 2.5 mg, 5 mg
or 10 mg pimobendan and further consisting of lactose, corn starch,
croscarmellose-sodium, 50 mg/g citric acid, artificial beef flavor,
polyvidone, colloidal anhydrous silica and magnesium stearate is
used.
[0091] The present invention furthermore relates to a kit, which
comprises a solid formulation, preferably a tablet according to the
present invention described herein, and a package leaflet or user
instruction including the information concerning how the solid
formulation, preferably the tablet, is to used via the oral route
for the prevention and/or treatment of congestive heart failure in
a mammal in need of such prevention or treatment, preferably in a
dog, cat or rodent.
EXAMPLES
[0092] The following examples serve to further illustrate the
present invention; but the same should not be construed as limiting
the scope of the invention disclosed herein.
Example 1
Compositions
[0093] Composition A
TABLE-US-00001 Composition A mg/tablet mg/tablet mg/tablet 1.25 mg
2.5 mg 5.0 mg Volatile Ingredients chewable chewable chewable
ingredient kg/batch (01) Pimobendan 1.250 2.500 5.000 0.175 (02)
Citric acid 25.000 50.000 100.00 3.500 anhydrous <200 .mu.m (03)
Starch 163.125 326.250 652.500 22.8375 (04) Lactose, coarse 163.125
326.250 652.500 22.8375 (05) Polyvidone 20.000 40.000 80.000 2.800
(06) Croscarmellose 20.000 40.000 80.000 2.800 Sodium (07)
Artificial Powered 100.000 200.00 400.000 14.000 Beef Flavour (08)
Silica, colloidal 2.500 5.00 10.000 0.350 anhydrous (09) Magnesium
stearate 5.000 10.00 20.000 0.700 (10) Purified water + 500.000
1000.000 2000.000 - 70.000
[0094] Composition B
TABLE-US-00002 Composition B mg/tablet mg/tablet mg/tablet 1.25 mg
2.5 mg 5.0 mg Volatile Ingredients chewable chewable chewable
ingredient kg/batch Pimobendan 1.250 2.500 5.000 0.175 Citric acid
25.000 50.000 100.000 3.500 anhydrous <200 .mu.m Starch 163.125
326.250 652.500 22.8375 Lactose, coarse 238.125 476.250 952.500
22.8375 Polyvidon 20.000 40.000 80.000 2.800 Croscarmellose 20.000
40.000 80.000 2.800 Sodium Meat Flavour 25.000 50.000 100.000
14.000 Silica, colloidal 2.500 5.000 10.000 0.350 anhydrous
Magnesium stearate 5.000 10.000 20.000 0.700 Purified water +
500.000 1000.000 2000.000 - 70.000
Example 2
Raw Materials
[0095] (01) Pimobendan
[0096] Function: Active ingredient
[0097] (02) Citric acid anhydrous <200 .mu.m
[0098] Function: Diluent, Disintegrant
[0099] (03) Starch
[0100] Function: Carrier, Disintegrant
[0101] (04) Lactose coarse
[0102] Function: Carrier, Disintegrant
[0103] (05) Povidone
[0104] Function: Binder
[0105] (06) Croscarmellose Sodium
[0106] Function: Disintegrant
[0107] (07) Artificial Powdered Beef Flavor
[0108] Function: Flavor
[0109] (08) Silica, colloidal anhydrous
[0110] Function: Flow regulator, Disintegrant
[0111] (09) Magnesium stearate
[0112] Function: Lubricant
[0113] (10) Purified water
[0114] Function: Solvent
Example 3
Product Description
[0115] Appearance: brownish, oblong tablets, with break line.
TABLE-US-00003 Tablet Tablet Tablet Weight 500 mg 1000 mg 2000 mg
Length About 19.0 mm About 24.0 mm About 25.0 mm Width About 7.0 mm
About 7.5 mm About 15.0 mm Thick- About 4.2 mm About 5.6 mm About
6.0 mm ness
Example 4
Manufacturing Process
[0116] 1 batch=140000 tablets (1.25 mg Dosage)
[0117] 1 batch=70000 tablets (2.50 mg Dosage)
[0118] 1 batch=35000 tablets (5.00 mg Dosage)
[0119] 1. 1. Granulating
TABLE-US-00004 Transfer in a suitable Granulator after
presereening: (01) Starch (e.g. 18 mesh sieve) 22.8375 kg (02)
Lactose (e.g. 18 mesh sieve) 22.8375 kg (03) Citric acid anhydrous
(e.g. 18 mesh sieve) 3.500 kg (04) Croscarmellose sodium (e.g. 18
mesh sieve) 2.800 kg (05) Artificial Beef Flavour (e.g. 45 mesh
sieve) 14.000 kg (05) Povidone (Spray solution) 2.800 kg (06) UDCG
115 BS (Spray liquid) 0.175 kg Premix in the granulator and
granulate 68.950 kg
Purified water (e.g. 16.8 kg, range; 12.0-18.0 kg) is used as a
solvent for the spray solution povidone and dispersion of
pimobendan.
[0120] 2. Screening
TABLE-US-00005 Screen the premixture 1. 68.950 kg 68.950 kg
[0121] 3. Final Mixing
TABLE-US-00006 Add (07) Sillica, colloidal anhydrous (e.g. 25 mesh
sieve) 0.350 kg (08) Magnesium stearate (e.g. 25 mesh sieve) 0.700
kg In a tumbling mixer, mix the screened premixture (2.) 70.000 kg
and the two ingredients 70.000 kg
[0122] 4. Compression
TABLE-US-00007 Using a rotary press, compress the final mixture
(3.) 70.000 kg into tablets of 500 mg, 1000 mg, 2000 mg. 70.000
kg
[0123] 5. Packaging
[0124] Transfer the tablets in a suitable container.
[0125] The tablets can be packed e.g. by blistering of the tablets
in a suitable machine.
Example 5
In Process Controls
[0126] 1. Granules
[0127] 1.1 Appearance: Brownish, white-speckled granules
[0128] 1.2 Loss on Drying: Determine the loss on drying
[0129] e.g.: HR73; 3 g/105.degree. C./5 min
[0130] Target: approx. 3.0%
[0131] Tolerance limits: below 5.0%
[0132] 2. Tablets
[0133] 2.1 Appearance: Brownish, white-speckled, oblong tablets
with breakline
[0134] 2.2 Weight uniformity:
TABLE-US-00008 1) 1.25 mg chewable Average weight: 475-525 mg 2)
2.5 mg chewable Average weight: 950-1050 mg 3) 5 mg chewable
Average weight: 1900-2100 mg
[0135] 2.3 Hardness: Determine the hardness
TABLE-US-00009 1) 1.25 mg Target: 140 N Tolerance: 60-250 N 2) 2.5
mg Target: 160 N Tolerance: 60-250 N 3) 5.0 mg Target 190 N
Tolerance: 60-300 N
[0136] 2.4 Disintegration time: Determine the disintegration time
according to USP/EP
[0137] Tolerance limits: .ltoreq.15 minutes with water at
37.degree. C., with disks
Example 6
Palatability Study
[0138] A study to investigate the palatability of
pimobendan-containing tablets was carried out. For a period of four
days, two products were given to twenty or ten dogs, respectively,
for voluntary uptake. For example, the following formulations with
a content of 5 mg/500 mg active ingredient were examined:
TABLE-US-00010 Ch. 010122 (tablets with 10% Ch. 010123 (tablets
with 10% content of artificial beef flavor) content of artificial
beef flavor) Pimobendan 5 mg Pimobendan 5 mg (UD-CG 115 BS) (UD-CG
115 BS) Lactose 85.5 mg Lactose 55.5 mg Corn starch 199.5 mg Corn
starch 129.5 mg Croscarmellose- 20 mg Croscarmellose- 20 mg Sodium
Sodium Citric acid 100 mg Citric acid 100 mg Artificial Beef 50 mg
Artificial Beef 150 mg Flavor Flavor Polyvidone 25 mg Polyvidone 25
mg Macrogol 6000 15 mg Macrogol 6000 15 mg Total: 500 mg Total: 500
mg
[0139] In case of Ch. 010123 in competition with the identical
formulation in granulated format, a voluntary uptake was observed
in 36 out of 40 possible opportunities (i.e. when offered to 10
dogs for 10 days). This compares to an acceptance rate of
90.0%.
[0140] In case of Ch. 010222 in competition with a formulation in
granulated format of equal quantity with 30% flavor, a voluntary
uptake was observed in 31 out of 40 possible opportunities. This
compares to an acceptance rate of 77.5%.
Example 7
Dissolution Profiles
[0141] Examples for representative dissolution profiles of the
tablet according to this invention are as disclosed in FIG. 3.
Dissolution Profiles, Pimobendan 1.25 mg Tablets
Showing 95% Confidence Intervals of the Mean
USP Apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer PH 4.0
Comparison of Dissolution Profiles of Tablets Which Were Stored 1
and 6 Months at 40.degree. C./75% in HDPE Bottles
Batch No. PB020049
[0142] Examples for representative dissolution profiles of the
tablet according to this invention are as disclosed in FIG. 4.
Dissolution Profiles, Pimobendan 1.25 mg Tablets
Showing 95% Confidence Intervals of the Mean
USP Apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer pH 4.0
Comparison of Dissolution Profiles of Tablets Which Were Stored 12
Days at 25.degree. C./60% in Open Glass Bottles
Batch No. PB010080
Dissolution Profiles, Pimobendan 1.25 mg Tablets
Manufacturing Variable: Different Compression Forces
TABLE-US-00011 [0143] % Dissolved, mean (n = 6) Time Tablet
hardness Batch No. (min) 70 N 105 N 135 N 157 N 020102 10 82 82 81
84 20 98 97 97 98 30 101 99 100 100 45 101 101 102 102
[0144] Examples for representative dissolution profiles of the
tablet according to this invention are as disclosed in FIG. 5.
Dissolution Profiles, Pimobendan 2.5 mg Tablets
Showing 95% Confidence Intervals of the Mean
USP Apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer pH 4.0
Comparison of Dissolution Profiles of Tablets Which Were Stored 3
and 6 Months at 40.degree. C./175% in Alu-Alu Blister
Batch No. PB010076
[0145] Examples for representative dissolution profiles of the
tablet according to this invention are as disclosed in FIG. 6.
Dissolution Profiles, Pimobendan 5.0 mg Tablets
Showing 95% Confidence Intervals of the Mean
USP Apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer pH 4.0
Comparison of Dissolution Profiles of Tablets Which Were Stored 6
Months at 40.Degree. C./75%/ in HDPE Bottles
Batch No. PB020059
[0146] Examples for representative dissolution profiles of the
tablet according to this invention are as disclosed in FIG. 7.
Dissolution Profiles, Pimobendan 5.0 mg Tablets
Showing 95% Confidence Intervals of the Mean
USP Apparatus 2 (Paddle), Rotation Speed 75 rpm, Buffer pH 4.0
Manufacturing Variable: Different Compression Forces
Batch No. 020205
TABLE-US-00012 [0147] % Dissolved, mean (n = 6) Tablet hardness
Time Batch No. (min) 117 N 150 N 186 N 222 N 020205 10 56 56 56 56
20 76 75 76 76 30 79 79 80 80 45 80 80 81 81
TABLE-US-00013 Analytical Results for Pimobendan Chewable Tablet
Batches Used in Stability Study % dissolved in t = 30 minutes, mean
(n = 6) Tablet Initial 6 Months 6 Months 6 Months strength Batch
No. Packaging value 25.degree. C./60% 30.degree. C./70% 40.degree.
C./75% 1.25 mg PB020049 HDPE bottle 97 95 94 93 PB020049 Alu-Alu
blister 95 93 94 PB020049 PVC/PVDC blister 94 93 93 PB020050 HDPE
bottle 94 92 93 91 PB020050 Alu-Alu blister 92 92 91 PB020050
PVC/PVDC blister 93 93 92 PB020051 HDPE bottle 94 93 92 92 PB020051
Alu-Alu blister 94 93 92 PB020051 PVC/PVDC blister 93 93 91 2.5 mg
PB020052 HDPE bottle 98 n.d. n.d. 93 PB020052 Alu-Alu blister n.d.
n.d. 94 PB020052 PVC/PVDC blister n.d. n.d. 92 PB020053 HDPE bottle
97 n.d. n.d. 91 PB020053 Alu-Alu blister n.d. n.d. 91 PB020053
PVC/PVDC blister n.d. n.d. 91 PB020054 HDPE bottle 97 n.d. n.d. 91
PB020054 Alu-Alu blister n.d. n.d. 92 PB020054 PVC/PVDC blister
n.d. n.d. 91 5.0 mg PB020059 HDPE bottle 95 93 92 92 PB020059
Alu-Alu blister 93 92 92 PB020059 PVC/PVDC blister 92 92 91
PB020060 HDPE bottle 92 91 90 89 PB020060 Alu-Alu blister 91 91 90
PB020060 PVC/PVDC blister 91 91 89 PB020061 HDPE bottle 94 91 91 89
PB020061 Alu-Alu blister 92 92 90 PB020061 PVC/PVDC blister 91 91
89 n.d. = not determined
Example 8
Content Uniformity
[0148] Samples were taken from both the final blend before
tableting and from the tableting process. The following results
demonstrate the uniformity of pimobendan content.
TABLE-US-00014 Blend Uniformity Batch Assay [mg/g] % Target
0007LP-A 2.37 94.8 0007LP-B 2.48 99.2 0007LP-C 2.43 97.2 0007LP-D
2.44 97.6 0007LP-E 2.47 98.8 0007LP-F 2.50 100.0 0007LP-G 2.49 99.6
0007LP-H 2.49 99.6 0007LP-I 2.50 100.0 0007LP-J 2.43 97.2 Average
2.46 98.4 0008LP-A 2.41 96.4 0008LP-B 2.48 99.2 0008LP-C 2.45 98.0
0008LP-D 2.45 98.0 0008LP-E 2.46 98.4 0008LP-F 2.43 97.2 0008LP-G
2.46 98.4 0008LP-H 2.44 97.6 0008LP-I 2.47 98.8 0008LP-J 2.50 100.0
Average 2.46 98.2
TABLE-US-00015 Uniformity of Process Batch Assay [mg/g] % Target
PM020080-1 2.48 99.2 PM020080-2 2.52 100.8 PM020080-3 2.50 100.0
PM020080-4 2.52 100.8 PM020080-5 2.49 99.6 PM020080-6 2.52 100.8
Average 2.51 100.2 PM020081-1 2.45 98.0 PM020081-2 2.51 100.4
PM020081-3 2.48 99.2 PM020081-4 2.45 98.0 PM020081-5 2.47 98.8
PM020081-6 2.45 98.0 Average 2.47 98.7
Example 9
Accuracy of Broken Tablets
[0149] The tablets according to this invention were part of an
content uniformity test for the broken tablets. 10 tablets were
taken from the beginning, middle and end of the tabletting process
and broken into two halves. The pimobendan content was
determined.
TABLE-US-00016 Pimobendan 5 mg tablet, batch no. 0000251607
Specification Start Middle End CU min. (mg) .gtoreq.2.13 2.44 2.43
2.41 CU max. (mg) .ltoreq.2.87 2.61 2.57 2.57 CU average (mg
2.25-2.62 2.52 2.51 2.50 RSD (%) .ltoreq.6.0 2.3 1.9 2.0
TABLE-US-00017 Pimobendan 1.25 mg tablet, batch no. 0000251604
Specification Start Middle End CU min. (mg) .gtoreq.0.532 0.577
0.590 0.582 CU max. (mg) .ltoreq.0.718 0.664 0.650 0.645 CU average
(mg 0.563-0.656 0.621 0.621 0.616 RSD (%) .ltoreq.6.0 5.4 3.4
3.6
Example 10
Stability Data After 24 Months (Dissolution/Assay of
Pimobendan/Degradation of Pimobendan)
TABLE-US-00018 [0150] Product: Pimobendan chewable tablets 1.25 mg
HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) Batch No.:
PB020049 Dissolution 25.degree. C./60.degree. C. 0 months 95
(min)-102 0 months 95 (min)-102 0 months 95 (min)-102 (max)/97
(avg); 24 (max)/97 (avg); 24 (max)/97 (avg); 24 months 96-99/97
months 96-99/97 months 92-96/94 30.degree. C./70.degree. C. 0
months 95 (min)-102 0 months 95 (min)-102 0 months 95 (min)-102
(max)/97 (avg); 24 (max)/97 (avg); 24 (max)/97 (avg); 24 months
96-97/97 months 96-98/97 months 95-99/97 40.degree. C./75.degree.
C. 0 months 95 (min)-102 0 months 95 (min)-102 0 months 95
(min)-102 (max)/97 (avg); 6 (max)/97 (avg); 6 (max)/97 (avg); 6
months 92-94/93 months 91-94/93 months 92-95/94 Batch No.: PB020049
HDPE bottle (m) PVC/PVDC (m) Aluminium blister (m) Assay of
25.degree. C./60.degree. C. 0 months 1.251; 24 0 months 1.251; 24 0
months 1.251; 24 Pimobendan months 1.233 months 1.236 months 1.237
30.degree. C./70.degree. C. 0 months 1.251; 24 0 months 1.251; 24 0
months 1.251; 24 months 1.229 months 1.242 months 1.236 40.degree.
C./75.degree. C. 0 months 1.251; 6 0 months 1.251; 6 months 0
months 1.251; 6 months 1.221 1.214 months 1.231 Degradation of
25.degree. C./60.degree. C. 0 months 1) <0.10 (K2006a); 0 months
1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); Pimobendan 2)
<0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS);
3) <0.10 (any 134 BS); 3) <0.10 (any BS); 3) <0.10 (any
unspecified); 4) <0.10 (total); unspecified); 4) <0.10
(total; unspecified); 4) <0.10 (total; 24 months 1) <0.10; 24
months 1) <0.10; 24 months 2) <0.10; 3) <0.10; 4) <0.10
2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 4) <0.10 3)
<0.10; 4) <0.10 30.degree. C./7.degree. C. 0 months 1)
<0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0 months 1)
<0.10 (K2006a); 2) <0.10 (DU- 2) <0.10 (DU-CG 2) <0.10
(DU-CG CG 134 134 BS); 3) <0.10 (any 134 BS); 3) <0.10 (any
BS); 3) <0.10 (any unspecified); 4) <0.10 (total);
unspecified); 4) <0.10 (total); unspecified); 4) <0.10
(total); 24 months 1) 0.35; 24 months 1) <0.10; 24 months 2)
<0.10; 3) <0.10; 4) 0.35 2) <0.10; 3) <0.10; 1)
<0.10; 2) 0.10; 4) <0.10 3) <0.10; 4) 0.10 40.degree.
C./75.degree. C. 0 months 1) <0.10 (K2006a); 0 months 1)
<0.10 (K2006a); 0 months 1) <0.10 (K2006a); 2) <0.10 (DU-
2) <0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS); 3) <0.10
(any 134 BS); 3) <0.10 (any BS); 3) <0.10 (any unspecified);
4) <0.10 (total); unspecified); 4) <0.10 (total);
unspecified); 4) <0.10 (total); 6 months 1) 0.55; 6 months 1)
<0.10; 6 months 1) 0.10; 2) <0.10; 3) <0.10; 4) 0.55 2)
<0.10; 3) <0.10; 2) 0.11; 3) <0.10; 4) 0.21 4) <0.10
Batch No.: PB020050 Dissolution 25.degree. C./60.degree. C. 0
months 91 (min)-96 0 months 91 (min)-96 0 months 91 (min)-96
(max)/94 (avg); 24 (max)/94 (avg); 24 (max)/94 (avg); 24 months
96-104/99 months 84-101/95 months 92-96/94 30.degree. C./70.degree.
C. 0 months 91 (min)-96 0 months 91 (min)-96 0 months 91 (min)-96
(max)/94 (avg); 24 (max)/94 (avg); 24 (max)/94 (avg); 24 months
94-102/97 months 93-102/97 months 97-105/99 40.degree.
C./75.degree. C. 0 months 91 (min)-96 0 months 91 (min)-96 0 months
91 (min)-96 (max)/94 (avg); 6 (max)/94 (avg); 6 (max)/94 (avg); 6
months 91-92/91 months 91-93/92 months 91-92/91 Assay of 25.degree.
C./60.degree. C. 0 months 1.231; 24 0 months 1.231; 24 0 months
1.231; 24 Pimobendan months 1.224 months 1.201 months 1.228
30.degree. C./70.degree. C. 0 months 1.231; 24 0 months 1.231; 24 0
months 1.231; 24 months 1.213 months 1.217 months 1.230 40.degree.
C./75.degree. C. 0 months 1.231; 6 0 months 1.231; 6 months 0
months 1.231; 6 months 1.205 1.202 months 1.215 Degradation of
25.degree. C./60.degree. C. 0 months 1) <0.10 (K2006a); 0 months
1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); Pimobendan 2)
<0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS);
3) <0.10 (any 134 BS); 3) <0.10 (any BS); 3) <0.10 (any
unspecified); 4) <0.10 (total); unspecified); 4) <0.10
(total); unspecified); 4) <0.10 (total); 24 months 1) <0.10;
24 months 1) <0.10; 24 months 2) <0.10; 3) <0.10; 4)
<0.10 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 4)
<0.10 3) <0.10; 4) <0.10 30.degree. C./7.degree. C. 0
months 1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0
months 1) <0.10 (K2006a); 2) <0.10 (DU- 2) <0.10 (DU-CG 2)
<0.10 (DU-CG CG 134 134 BS); 3) <0.10 (any 134 BS); 3)
<0.10 (any BS); 3) <0.10 (any unspecified); 4) <0.10
(total); unspecified); 4) <0.10 (total); unspecified); 4)
<0.10 (total); 24 months 1) <0.37; 24 months 1) <0.10; 24
months1) <0.10; 2) <0.10; 3) <0.10; 4) <0.37 2)
<0.10; 3) <0.10; 2) <0.10; 3) <0.10; 4) <0.10 4)
<0.10 40.degree. C./75.degree. C. 0 months 1) <0.10 (K2006a);
0 months 1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 2)
<0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS);
3) <0.10 (any 134 BS); 3) <0.10 (any BS); 3) <0.10 (any
unspecified); 4) <0.10 (total); unspecified); 4) <0.10
(total); unspecified); 4) <0.10 (total); 6 months 1) 0.58; 6
months 1) <0.10; 6 months 1) <0.10; 2) <0.10; 3) <0.10;
4) 0.58 2) <0.10; 3) <0.10; 2) <0.10; 3) <0.10; 4)
<0.10 4) <0.10 Batch No.: PB020051 Dissolution 25.degree.
C./60.degree. C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months
92 (min)-95 (max)/94 (avg); 24 (max)/94 (avg); 24 (max)/94 (avg);
24 months 92-100/96 months 94-101/97 months 91-100/95 30.degree.
C./70.degree. C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months
92 (min)-95 (max)/94 (avg); 24 (max)/94 (avg); 24 (max)/94 (avg);
24 months 92-99/96 months 95-98/97 months 92-100/97 40.degree.
C./75.degree. C. 0 months 92 (min)-95 0 months 92 (min)-95 0 months
92 (min)-95 (max)/94 (avg); 6 (max)/94 (avg); 6 (max)/94 (avg); 6
months 91-93/92 months 90-92/91 months 91-94/92 Assay of 25.degree.
C./60.degree. C. 0 months 1.230; 24 0 months 1.230; 24 0 months
1.230; 24 Pimobendan months 1.222 months 1.225 months 1.228
30.degree. C./70.degree. C. 0 months 1.230; 24 0 months 1.230; 24 0
months 1.230; 24 months 1.214 months 1.221 months 1.230 40.degree.
C./75.degree. C. 0 months 1.230; 6 0 months 1.230; 6 months 0
months 1.230; 6 months 1.210 1.202 months 1.218 Degradation of
25.degree. C./60.degree. C. 0 months 1) <0.10 (K2006a); 0 months
1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); Pimobendan 2)
<0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-GG CG 134 134 BS);
3) <0.10 (any 134 BS); 3) <0.10 (any BS); 3) <0.10 (any
unspecified); 4) <0.10 (total); unspecified); 4) <0.10
(total); unspecified); 4) <0.10 (total); 24 months 1) <0.10;
24 months 2) <0.10; 3) <0.10; 4) <0.10 1) <0.10; 2)
<0.10; 3) <0.10; 4) <0.10 30.degree. C./7.degree. C. 0
months 1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0
months 1) <0.10 (K2006a); 2) <0.10 (DU- 2) <0.10 (DU-CG 2)
<0.10 (DU-CG CG 134 134 BS); 3) <0.10 (any 134 BS); 3)
<0.10 (any BS); 3) <0.10 (any unspecified); 4) <0.10
(total); unspecified); 4) <0.10 (total); unspecified); 4)
<0.10 (total); 24 months 1) <0.33; 24 months 2) <0.10; 3)
<0.10; 4) 0.33 1) <0.10; 2) <0.10; 3) <0.10; 4)
<0.10 40.degree. C./75.degree. C. 0 months 1) <0.10 (K2006a);
0 months 1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 2)
<0.10 (DU- 2) <0.10 (DU-CG 2) <0.10 (DU-CG CG 134 134 BS);
3) <0.10 (any 134 BS); 3) <0.10 (any BS); 3) <0.10 (any
unspecified); 4) <0.10 (total); unspecified); 4) <0.10
(total); unspecified); 4) <0.10 (total); 6 months 1) <0.54; 6
months 1) <0.10; 2) <0.10; 3) <0.10; 4) <0.54 2) 0.10;
3) <0.10; 4) 0.10
TABLE-US-00019 Product: Pimobendan chewable tablets 2.5 mg HDPE
bottle (m) PVC/PVDC (m) Aluminium blister (m) Batch No.: PB020052
Dissolution 30.degree. C./70.degree. C. 0 months 97 (min)-99 0
months 97 (min)-99 0 months 97 (min)-99 (max)/98 (avg); 12 (max)/98
(avg); 12 (max)/98 (avg); 12 Months 93-95/94 months 93-94/94 months
94-97/96 40.degree. C./75.degree. C. 0 months 97 (min)-99 0 months
97 (min)-99 0 months 97 (min)-99 (max)/98 (avg); 6 (max)/98 (avg);
6 (max)/98 (avg); 6 months 93-94/93 months 91-93/92 months 93-95/94
Assay of 30.degree. C./70.degree. C. 0 months 2.49; 12 0 months
2.49; 12 months 0 months 2.49; 12 Pimobendan months 2.49 2.47
months 2.50 40.degree. C./75.degree. C. 0 months 2.49; 6 0 months
2.49; 6 months 0 months 2.49; 6 months months 2.41 2.41 2.45
Degradation of 30.degree. C./7.degree. C. 0 months 0 months 0
months Pimobendan 1) <0.10 (K2006a); 1) <0.10 (K2006a); 1)
<0.10 (K2006a); 2) <0.10 (UDCG 134 2) <0.10 (UDCG 134 BS);
2) <0.10 (UDCG 134 BS); 3) <0.10 (any 3) <0.10 (any BS);
3) <0.10 (any unspecified); unspecified); unspecified); 4)
<0.10 (total); 12 4) <0.10 (total); 12 months 4) <0.10
(total); 12 months 1) <0.10; 1) <0.10; 2) <0.10; months 1)
<0.10; 2) <0.10; 3) <0.10; 3) <0.10; 4) <0.10 2)
<0.10; 3) <0.10; 4) <0.10 4) <0.10 40.degree.
C./75.degree. C. 0 months 0 months 0 months 1) <0.10 (K2006a);
1) <0.10 (K2006a); 1) <0.10 (K2006a); 2) <0.10 (UDCG 134
2) <0.10 (UDCG 134 BS); 2) <0.10 (UDCG 134 BS); 3) <0.10
(any 3) <0.10 (any BS); 3) <0.10 (any unspecified);
unspecified); unspecified); 4) <0.10 (total); 6 4) <0.10
(total); 6 months 4) <0.10 (total); 6 months months 1) <0.10;
1) 0.43; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 2)
<0.10; 3) <0.10; 4) 0.43 3) <0.10; 4) <0.10 4) <0.10
Batch No.: PB020053 Dissolution 30.degree. C./70.degree. C. 0
months 96 (min)-98 0 months 96 (min)-98 0 months 96 (min)-98
(max)/97 (avg); 12 (max)/97 (avg); 12 (max)/97 (avg); 12 months
92-94/93 months 90-93/92 months 91-95/93 40.degree. C./75.degree.
C. 0 months 96 (min)-98 0 months 96 (min)-98 0 months 96 (min)-98
(max)/97 (avg); 6 (max)/97 (avg); 6 (max)/97 (avg); 6 months
89-93/91 months 91-91/91 months 90-92/91 Assay of 30.degree.
C./70.degree. C. 0 months 2.44; 12 0 months 2.44; 12 months 0
months 2.44; 12 Pimobendan months 2.44 2.41 months 2.46 40.degree.
C./75.degree. C. 0 months 2.44; 6 0 months 2.44; 6 months 0 months
2.44; 6 months months 2.41 2.40 2.40 Degradation of 30.degree.
C./7.degree. C. 0 months 0 months 0 months Pimobendan 1) <0.10
(K2006a); 1) <0.10 (K2006a); 1) <0.10 (K2006a); 2) <0.10
(UDCG 134 2) <0.10 (UDCG 134 BS); 2) <0.10 (UDCG 134 BS); 3)
<0.10 (any 3) <0.10 (any BS); 3) <0.10 (any unspecified);
unspecified); unspecified); 4) <0.10 (total); 12 4) <0.10
(total); 12 months 4) <0.10 (total); 12 months 1) <0.10; 1)
<0.10; 2) <0.10; months 1) <0.10; 2) <0.10; 3)
<0.10; 3) <0.10; 4) <0.10 2) <0.10; 3) <0.10; 4)
<0.10 4) <0.10 40.degree. C./75.degree. C. 0 months 0 months
0 months 1) <0.10 (K2006a); 1) <0.10 (K2006a); 1) <0.10
(K2006a); 2) <0.10 (UDCG 134 2) <0.10 (UDCG 134 BS); 2)
<0.10 (UDCG 134 BS); 3) <0.10 (any 3) <0.10 (any BS); 3)
<0.10 (any unspecified); unspecified); unspecified); 4) <0.10
(total); 6 4) <0.10 (total); 6 months 4) <0.10 (total); 6
months months 1) <0.10; 1) 0.39; 2) <0.10; 3) <0.10; 1)
<0.10; 2) <0.10; 2) <0.10; 3) <0.10; 4) 0.39 3)
<0.10; 4) <0.10 4) <0.10 Batch No.: PB020054 Dissolution
30.degree. C./70.degree. C. 0 months 96 (min)-98 0 months 96
(min)-98 0 months 96 (min)-98 (max)/97 (avg); 12 (max)/97 (avg); 12
(max)/97 (avg); 12 months 93-95/94 months 90-93/91 months 93-94/94
40.degree. C./75.degree. C. 0 months 96 (min)-98 0 months 96
(min)-98 0 months 96 (min)-98 (max)/97 (avg); 6 (max)/97 (avg); 6
(max)/97 (avg); 6 months 90-92/91 months 90-92/91 months 91-93/92
Assay of 30.degree. C./70.degree. C. 0 months 2.45; 12 0 months
2.45; 12 months 0 months 2.45; 12 Pimobendan months 2.47 2.45
months 2.44 40.degree. C./75.degree. C. 0 months 2.45; 6 0 months;
6 months 2.39 0 months 2.45; 6 months months 2.40 2.41 Degradation
of 30.degree. C./7.degree. C. 0 months 0 months 0 months Pimobendan
1) <0.10 (K2006a); 1) <0.10 (K2006a); 1) <0.10 (K2006a);
2) <0.10 (UDCG 134 2) <0.10 (UDCG 134 BS); 2) <0.10 (UDCG
134 BS); 3) <0.10 (any 3) <0.10 (any BS); 3) <0.10 (any
unspecified); unspecified); unspecified); 4) <0.10 (total); 12
4) <0.10 (total); 12 months 4) <0.10 (total); 12 months 1)
<0.10; 1) <0.10; 2) <0.10; months 1) <0.10; 2)
<0.10; 3) <0.10; 3) <0.10; 4) <0.10 2) <0.10; 3)
<0.10; 4) <0.10 4) <0.10 40.degree. C./75.degree. C. 0
months 0 months 0 months 1) <0.10 (K2006a); 1) <0.10
(K2006a); 1) <0.10 (K2006a); 2) <0.10 (UDCG 134 2) <0.10
(UDCG 134 BS); 2) <0.10 (UDCG 134 BS); 3) <0.10 (any 3)
<0.10 (any BS); 3) <0.10 (any unspecified); unspecified);
unspecified); 4) <0.10 (total); 6 4) <0.10 (total); 6 months
4) <0.10 (total); 6 months months 1) <0.10; 1) 0.36; 2)
<0.10; 3) <0.10; 1) <0.10; 2) <0.10; 2) <0.10; 3)
<0.10; 4) 0.36 3) <0.10; 4) <0.10 4) <0.10
TABLE-US-00020 Product: Pimobendan chewable tablets 5 mg HDPE
bottle (m) PVC/PVDC (m) Aluminium blister (m) Batch No.: PB020059
Dissolution 25.degree. C./60% 0 months 94 (min)-96 0 months 94
(min)-96 0 months 94 (min)-96 (max)/95 (avg); (max)/95 (avg); 24
(max)/95 (avg); 24 24 months 83-90/88 months 83-92/88 months
85-89/87 30.degree. C./70.degree. C. 0 months 94 (min)-96 0 months
94 (min)-96 0 months 94 (min)-96 (max)/95 (avg); (max)/95 (avg); 24
(max)/95 (avg); 24 24 months 83-95/89 months 82-97/88 months
83-91/87 40.degree. C./75.degree. C. 0 months 94 (min)-96 0 months
94 (min)-96 0 months 94 (min)-96 (max)/95 (avg); 6 (max)/95 (avg);
6 months (max)/95 (avg); 6 months 91-92/91 90-92/91 months 81-93/92
Assay of 25.degree. C./60% 0 month 4.95; 24 0 month 4.95; 24 month
0 month 4.95; 24 month Pimobendan month 4.94 4.92 4.92 30.degree.
C./70.degree. C. 0 month 4.95; 24 0 month 4.95; 24 month 0 month
4.95; 24 month month 4.90 4.92 4.96 40.degree. C./75.degree. C. 0
month 4.95; 6 0 month 4.95; 6 month 0 month 4.95; 6 month month
4.88 4.91 4.95 Degradation of 25.degree. C./60% 0 months 1)
<0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0 months 1)
<0.10 (K2006a); Pimobendan 2) <0.10 2) <0.10 (UD-CG 2)
<0.10 (UD- (UD-CG 134 BS); 3) 134 BS); 3) <0.10 (any CG 134
BS); 3) <0.10 <0.10 (any unspecified); 4) <0.10 (any
unspecified); 4) unspecified); 4) (total); 24 months 1) <0.10
(total); 24 months <0.10 (total); 24 <0.10; 2) <0.10; 3)
<0.10; 1) <0.10; 2) <0.10; 3) months 1) <0.10; 2) 4)
<0.10 <0.10; 4) <0.10 <0.10; 3) <0.10; 4) <0.10
30.degree. C./7.degree. C. 0 months 1) <0.10 (K2006a); 0 months
1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 2) <0.10 2)
<0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS); 3) 134 BS); 3)
<0.10 (any CG 134 BS); 3) <0.10 <0.10 (any unspecified);
4) <0.10 (any unspecified); 4) unspecified); 4) (total); 24
months 1) <0.10 (total); 24 months <0.10 (total); 24
<0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
months 1) <0.10; 2) 4) <0.10 <0.10; 4) <0.10 <0.10;
3) <0.10; 4) <0.10 40.degree. C./75.degree. C. 0 months 1)
<0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0 months 1)
<0.10 (K2006a); 2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
(UD-CG 134 BS); 3) 134 BS); 3) <0.10 (any CG 134 BS); 3)
<0.10 <0.10 (any unspecified); 4) <0.10 (any unspecified);
4) unspecified); 4) (total); 6 months 1) 0.23; <0.10 (total); 6
months <0.10 (total); 6 2) <0.10; 3) <0.10; 4) 1)
<0.10; 2) <0.10; 3) months 1) <0.10; 2) 0.23 <0.10; 4)
<0.10 <0.10; 3) <0.10; 4) <0.10 Batch No.: PB020060
Dissolution 25.degree. C./60% 0 months 91 (min)-94 0 months 91
(min)-94 0 months 91 (min)-94 (max)/92 (avg); (max)/92 (avg); 24
(max)/92 (avg); 24 24 months 85-90/87 months 84-90/86 months
82-88/86 30.degree. C./70.degree. C. 0 months 91 (min)-94 0 months
91 (min)-94 0 months 91 (min)-94 (max)/92 (avg); (max)/92 (avg); 24
(max)/92 (avg); 24 24 months 85-90/87 months 82-90/87 months
86-90/88 40.degree. C./75.degree. C. 0 months 94 (min)-96 0 months
91 (min)-94 0 months 91 (min)-94 (max)/95 (avg); 6 (max)/92 (avg);
6 months (max)/92 (avg); 6 months 88-89/89 88-90/89 months 89-92/90
Assay of 25.degree. C./60% 0 month 4.87; 24 0 month 4.87; 24 month
0 month 4.87; 24 month Pimobendan month 4.88 4.86 4.90 30.degree.
C./70.degree. C. 0 month 4.87; 24 0 month 4.87; 24 month 0 month
4.84; 24 month month 4.83 4.86 4.89 40.degree. C./75.degree. C. 0
month 4.87; 6 0 month 4.87; 6 month 0 month 4.87; 6 month month
4.86 4.87 4.86 Degradation of 25.degree. C./60% 0 months 1)
<0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0 months 1)
<0.10 (K2006a); Pimobendan 2) <0.10 2) <0.10 (UD-CG 2)
<0.10 (UD- (UD-CG 134 BS); 3) 134 BS); 3) <0.10 (any CG 134
BS); 3) <0.10 <0.10 (any unspecified); 4) <0.10 (any
unspecified); 4) unspecified); 4) (total); 24 months 1) <0.10
(total); 24 months <0.10 (total); 24 <0.10; 2) <0.10; 3)
<0.10; 1) <0.10; 2) <0.10; 3) months 1) <0.10; 2) 4)
<0.10; <0.10; 4) <0.10; <0.10; 3) <0.10; 4)
<0.10; 30.degree. C./7.degree. C. 0 months 1) <0.10 (K2006a);
0 months 1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 2)
<0.10 2) <0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS); 3) 134
BS); 3) <0.10 (any CG 134 BS); 3) <0.10 <0.10 (any
unspecified); 4) <0.10 (any unspecified); 4) unspecified); 4)
(total); 24 months 1) <0.10 (total); 24 months <0.10 (total);
24 <0.10; 2) <0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3)
months 1) <0.10; 2) 4) <0.10; <0.10; 4) <0.10;
<0.10; 3) <0.10; 4) <0.10; 40.degree. C./75.degree. C. 0
months 1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0
months 1) <0.10 (K2006a); 2) <0.10 2) <0.10 (UD-CG 2)
<0.10 (UD- (UD-CG 134 BS); 3) 134 BS); 3) <0.10 (any CG 134
BS); 3) <0.10 <0.10 (any unspecified); 4) <0.10 (any
unspecified); 4) unspecified); 4) (total); 24 months 1) <0.10
(total); 6 months <0.10 (total); 6 <0.10; 2) <0.10; 3)
<0.10; 1) <0.10; 2) <0.10; 3) months 1) <0.10; 2) 4)
<0.10; 6 months 1) <0.10; 4) <0.10 <0.10; 3) <0.10;
4) 0.22; 2) <0.10; 3) <0.10; <0.10 4) 0.22 Batch No.:
PB020061 Dissolution 25.degree. C./60% 0 months 92 (min)-95 0
months 92 (min)-95 0 months 92 (min)-95 (max)/94 (avg); (max)/94
(avg); 24 (max)/94 (avg); 24 24 months 83-90/87 months 86-91/88
months 65-92/84 30.degree. C./70.degree. C. 0 months 92 (min)-95 0
months 92 (min)-95 0 months 92 (min)-95 (max)/94 (avg); (max)/94
(avg); 24 (max)/94 (avg); 24 24 months 84-88/87 months 81-87/85
months 88-91/90 40.degree. C./75.degree. C. 0 months 92 (min)-95 0
months 92 (min)-95 0 months 92 (min)-95 (max)/94 (avg); 6 (max)/94
(avg); 6 months (max)/94 (avg); 6 months 88-90/89 88-90/89 months
88-91/90 Assay of 25.degree. C./60% 0 month 4.87; 24 0 month 4.87;
24 month 0 month 4.87; 24 month Pimobendan month 4.83 4.85 4.88
30.degree. C./70.degree. C. 0 month 4.87; 24 0 month 4.87; 24 month
0 month 4.87; 24 month month 4.82 4.80 4.90 40.degree.
C./75.degree. C. 0 month 4.87; 6 0 month 4.87; 6 month 0 month
4.87; 6 month month 4.83 4.82 4.88 Degradation of 25.degree. C./60%
0 months 1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0
months 1) <0.10 (K2006a); Pimobendan 2) <0.10 2) <0.10
(UD-CG 2) <0.10 (UD- (UD-CG 134 BS); 3) 134 BS); 3) <0.10
(any CG 134 BS); 3) <0.10 <0.10 (any unspecified); 4)
<0.10 (any unspecified); 4) unspecified); 4) (total); 24 months
1) <0.10 (total); 24 months <0.10 (total); 24 <0.10; 2)
<0.10; 3) <0.10; 1) <0.10; 2) <0.10; 3) months 1)
<0.10; 2) 4) <0.10; <0.10; 4) <0.10 <0.10; 3)
<0.10; 4) <0.10; 30.degree. C./7.degree. C. 0 months 1)
<0.10 (K2006a); 0 months 1) <0.10 (K2006a); 0 months 1)
<0.10 (K2006a); 2) <0.10 2) <0.10 (UD-CG 2) <0.10 (UD-
(UD-CG 134 BS); 3) 134 BS); 3) <0.10 (any CG 134 BS); 3)
<0.10 <0.10 (any unspecified); 4) <0.10 (any unspecified);
4) unspecified); 4) (total); 24 months 1) <0.10 (total); 24
months <0.10 (total); 24 <0.10; 2) <0.10; 3) <0.10; 1)
<0.10; 2) <0.10; 3) months 1) <0.10; 2) 4) <0.10;
<0.10; 4) <0.10; <0.10; 3) <0.10; 4) <0.10;
40.degree. C./75.degree. C. 0 months 1) <0.10 (K2006a); 0 months
1) <0.10 (K2006a); 0 months 1) <0.10 (K2006a); 2) <0.10 2)
<0.10 (UD-CG 2) <0.10 (UD- (UD-CG 134 BS); 3) 134 BS); 3)
<0.10 (any CG 134 BS); 3) <0.10 <0.10 (any unspecified);
4) <0.10 (any unspecified); 4) unspecified); 4) (total); 6
months 1) 0.22; <0.10 (total); 6 months <0.10 (total); 6 2)
<0.10; 3) <0.10; 4) 1) <0.10; 2) <0.10; 3) months 1)
<0.10; 2) 0.22 <0.10; 4) <0.10 <0.10; 3) <0.10; 4)
<0.10
* * * * *
References