Note: Descriptions are shown in the official language in which they were submitted.
2034569
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56224.701
Pimobendan Compositions
This invention relates to orally administrable
pharmaceutical compositions comprising pimobendan and
methods for their preparation. Pimobendan is 4,5-
dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-
methyl-3(2H)-pyridazinone and is a substance having
cardiotonic, hypotensive and antithrombotic activities.
Pimobendan and other structurally different
substances are described in European Patent No. 8391.
However, unlike other substances described in that
patent, the resorption of pimobendan when administered
orally is prone to considerable inter- and intra-
individual fluctuations when incorporated in known or
conventional oral pharmaceutical forms. The reason for
this is that pimobendan is characterised by a low and
very highly pH-dependent solubility in aqueous media.
Depending on the buffer system used, about 100 to
300 mg of pimobendan dissolve per litre at a pH between
1 and 3 (corresponding to a 0.01 to 0.03% solution), but
at pH 5 only about 1 mg/1 will dissolve in water
(corresponding to a 0.0001% solution or 1 ppm).
In in vivo tests on humans in which pimobendan was
packed into hard gelatin capsules, one test subject
showed no detectable blood level of pimobendan, a second
test subject showed a very low blood level and a third
showed higher blood levels. Overall, the blood levels
of pimobendan fluctuated very considerably from one
individual to another and the levels were generally too
low. These unsatisfactory resorption characteristics
can be explained primarily by the high pH-dependency of
the solubility of pimobendan in aqueous media and by the
fluctuating pH conditions in the gastrointestinal tracts
of the test subjects. It is known that the pH of the
gastric juices, particularly in patients who have been
fasting, can fluctuate between 1 and 6, whereas in
2Q34569
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patients who have not fasted it is more frequently
between 3 and 5 than 1 and 2.
It therefore appeared to be clear that the
solubility of pimobendan could be increased by the
simultaneous administration of an acid. In vitro tests
showed, however, that pimobendan in 0.1 N hydrochloric
acid (pH 1.1) dissolved in a quantity of only 100 mg/1
(corresponding to a 0.01% solution). In a fumaric acid
solution (pH 2.27) only 50 mg/1 dissolve (corresponding
to a 0.005% solution), in a 20% (by weight) tartaric
acid solution (pH 1.2) 960 mg/1 dissolve (corresponding
to a 0.096% solution), and in a 40% (by weight) tartaric
acid solution (pH 0.7) only 3.9 g/1 dissolve
(corresponding to a 0.39% solution). None of these
levels is sufficient, or the quantity of acid required
is no longer practicable for dissolving a sufficient
quantity of the active substance and thereby ensuring
reliable resorption, even if such quantities of these
acids are administered orally simultaneously with the
active substance.
Surprisingly, we have now succeeded in overcoming
the low solubility and high pH-dependency of the
solubility of pimobendan thereby ensuring a very
satisfactory and more constant resorption, even when
there are considerable pH fluctuations in the
gastrointestinal tracts. This is achieved by
formulating pimobendan together with citric acid in an
acid:pimobendan ratio by weight of at least 5:1.
Thus viewed from one aspect the invention provides
an orally administrable pimobendan-containing
pharmaceutial composition comprising an intimate mixture
of citric acid and pimobendan in a weight ratio of at
least 5:1, optionally together with one or more
pharmaceutical carriers or excipients.
The compositions of the invention may be produced
by intimately mixing pimobendan with citric acid in a
ratio of up to 1 part by weight of pimobendan per 5
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parts by weight of citric acid, and subsequently
processing it with conventional excipients to form a
powder, pellets or granules for oral administration.
The granules, powder or pellets may also be compressed
with suitable excipients to form tablets which may, if
desired, be covered with a flavour-masking coating.
Citric acid is a safe and well tolerated excipient
which increases the solubility of pimobendan by a factor
of 100, compared with artificial gastric juice (pH 1.2).
Thus, 7.6g of pimobendan will dissolve per litre in an
aqueous solution containing 20% by weight of citric acid
(pH 1.4), whilst in an aqueous solution containing 40%
by weight of citric acid (pH 1.0) as much as 12.1 g of
pimobendan will dissolve per litre. These quantities of
dissolved pimobendan are sufficient to ensure adequate
resorption of the active substance even in patients who,
when given conventional pimobendan preparations by oral
route, showed either no detectable blood level or a very
low and sharply fluctuating blood level of pimobendan.
Citric acid is difficult to process into solid
preparations. To avoid the formation of salts of
pimobendan with citric acid, which would increase the
hygroscopicity of the formulation, it would appear that
one should process the active substance and acid in two
separate granulates. However, it has been found (see
Examples 1b to 1d and 2a below) that when separated in
this way the citric acid is unable to develop its full
solubilising activity. However, it has been found that
by intimately mixing pimobendan with citric acid to form
a powder mixture which may subsequently be processed
into granules, pellets or tablets, it is possible to
obtain preparations with small amounts of citric acid
which ensure adequate dissolution and sufficiently high
blood levels of pimobendan.
Thus viewed from a further aspect the invention
also provides a process for preparing compositions
according to the invention in which citric acid and
CA 02034569 2001-03-19
27169-1F37
_ ,1 _
pi_mobeadan i.n a wei_dht rat~:io of at lea~;i: 5:1. :rrr~ broudlai
lrlt0 all lrlti_mate.l.y mixed for-m by granm.lai iorr.
Tec)rn_ica_Lly, t~lW s can k>e aclri.evr~cl, I or- exnmpl_e~, lay
aqueou~~ or non-aqueous granulation, e.d. k>y dranulat: ion
with al_ccohol or by t:he use of suitab l c> rlt-anu_Lati ncl
methods which make i.t poss.i ble t:o add the dram.rl at.incl
fluid in <3ccurately metered amounts, w_i.t=.Ir sirnul.tanec~m;
dry.i_ng. Another p«;,sibi_7..it=y i s the f~i-~parat i on of
granules by dry granulation, t=hese dr_antr l.es conta.i.n i.ocl
the active st.rbstanr::e~ and c_itr_ is acjd irrt. i ma t-.e 1y m i xecl .
Owing to the hygro:~copi.c properties of tire cit:r_:ic ac:i.ci,
care must be taken t.o ensure that: the composit.i.ons
disintegrate rapid_l.y in the re 1. ease mecli_trm; in the c:a<~e
of tablets, this may be achieved Por example by the
addition of di_sintegrants, e.g. Amberl it~* IF2H F3 t3
(methacryl i_c res in with exchangeable protons ) ,
Crospovidone* (cros~~7_inked polyvinyl_pyrr_-ol. i.done) and
microcrystalline cellulose, which simult~aneotrsl.y improve
the compression properties oL c:itric acid.
A weight ratica of pimobendan to c:i t:.r:-ic aci.d of
between 1:10 and 1:20 is pr-eferred, the upper li.m:it
being defined by the abi_li_ty of the preparations to be
swallowed.
Viewed from a still. further aspect the invention
also provides a method of treatment of the human or_ non-
human animal. body to combat cardlotonlc, hypo tensi.vf=a and
anti-thrombotic conditions, said method cornpr:ising
orally administering to said body a pharrmaceutical
composition according to the invention.
The prevention of sharply fluct:uat.ing blood leve~l_s
(both inter- and int:ra-i.Ildiv_i_drrall.y) by t_he addition of:
citric acid can perhaps be explained as follows: when
the intimate mixture o1 active sub:~tance and citric acid
comes into contact with gastric juices, an acidic
. microsphere is formed around the particles due to the
high rate of dissolution of the citric acid. This
microsphere is a Lway:~ acidic, i rrespect i.ve of the pII of
*Trademark
A ~4 ~~~
27169-187
the gastrointestinal juices, and ensures that the finely divided
active substance reliably dissolves and is therefore freely
available for resorption.
Solubility tests have shown, for pH values between 1 and
6, that the active substance dissolves out of this intimate
mixture virtually irrespective of the pH. In addition, the active
substance also forms supersaturated solutions with the citric acid
which remain stable for hours. This ensures a high level of
resorption in any case, even in patients with gastrointestinal
juices of abnormally high pH. Of the many acids tested for this
purpose, citric acid has unexpectedly proved to be outstanding;
not only does it act as an acid, but it also serves as a
solubilizing agent and a stabilizer for the solution of active
substance obtained. An important prerequisite for the dissolving
of the active substance independently of the local physiological
pH value is the intimate mixing of the pimobendan with the citric
acid. For this, both substances should be present in powder form
or as very small crystals, thereby ensuring contact with each
other over a large surface area.
In the following description of the invention reference
is made to the accompanying drawings, of which:
Figure 1 is a graph showing the pimobendan plasma level
with time, after oral administration of pimobendan in the absence
of citric acid to dogs;
Figure 2 is a graph showing the pimobendan plasma level
with time, after oral administration of pimobendan and citric acid
to dogs;
5
,,
A4a~9
27169-187
Figures 3 and 4 are graphs showing the pimobendan plasma
level with time, after oral administration of pimobendan and
citric acid to humans; and
Figures 5a, 5b and 5c are graphs showing the pimobendan
plasma levels with time, after oral administration of pimobendan
in the absence of citric acid to humans.
A comparison of the results from tests on dogs after
oral administration of a composition according to Example 1a
containing 5 mg of pimobendan, with those from a composition
according to Example 1b containing 5 mg of pimobendan and 50 mg of
citric acid, showed that the pimobendan plasma level was
approximately trebled by the form containing the citric acid
compared with the form containing no citric acid. Each test was
carried out on 5 experimental animals. The mean curves for the
plasma levels of pimobendan found are shown in Figures 1 and 2, in
which the plasma level values are given in nanograms per
millilitre as a function of time.
Human trials using oral pimobendan compositions
according to Examples 3b and 3c (capsules) on 11 test subjects
gave the mean curves for the plasma levels of pimobendan shown in
Figure 3. The maxima occurred at 1
5a
CA 02034569 2001-03-19
27169-187
to 1. 5 hours after uc:lministrat.i.on. In add.i ti_Orl to the
capsule for-mtrlat.iorm> according to F;xmmpl.~s 11:~ m~cl rtc;,
the plasma level curves of pi.mobendan for the tW.~let
according to Example 2b and the capsule according t:.o
Example 4 were each tested on 11 t=est subjects. It: was
found that the tab:.l_ei~ containing only 50 mg of ci.tr-.ic
acid according to l~x.ample 2b :i s bi.oec uival.ent to t.t-m
capsule formulat1011 contalni ng ?.09 and of c.i.tr is nc ic.l
according t;o Example 4. The plasma levels of pimobemlao
were obtained by h.i_cltr pressure 1 i_quid chromatogra~luiw
methods, resu:Lung i.n the mean curves shown i.n Fi.guro ~1
(mean values ~ standard deviati.ons).
By way of a comparison, a tablet formulation
according to Examp:l_c~ 3a, i.e. a formulation with no
citric acid, was ac.lministered o.ral_ly. '1'hi.:~ re~~ul_tecl in
the curves for_ the plasma 1. evel.s of. pimober~dan i.11 thr-ce
test subjects as shown in Figures 5a to 5c. I1: Figures
5a to 5c are compared with Figure 4, the superiority of
the citric acid containing composition over a
composition without. c:i_tric acid becomes very clear.
This is made apparent by the reduced fluctuations in
plasma levels of pi.mobendan.
It goes withor:rt. saying, that instead of using
pimobendan, one of it:s pas..>ible enanti.omer_s can also lie
used with equal suwc:ess.
The following n.on-limiting Examples are provided to
illustrate the preparation of some oral pharmaceutical
compositions of pimobendan. All percentages given are
by weight. In the~~e Examples
Amber:lite I:RP 88 = methacryl_ic resin with exchangeable IlF
Collidone 25 - polyvinylpyrrol.idone, aver_ age
molecular weight ?9,000
Avicel - microcrystalline cellulose
Polyplasdone XL - crosslinked polyvinylpyrroli.done
* polyvinylpolypyrrolic~one
Comprit.ol t'.88 - qlyceryl. monobehenate
*Trademark
CA 02034569 2001-03-19
27169-187
Tween F30 _. ~c~l.yoxyethylen~e-(2c>)-sorb.i.ton mf»~o-_
~oleate
Explotah* --- sodium carboxymethyl. starch
Aer_osil 130 V - lhighly dispersed, X-.ray amorphou~~
ailicon di_oxic3e.
All measurements of rates of dissolution of
pi_mobendan were carried out according t.o iJSP XX:11-I ,
paddle method, 7_50 rpm, in Mcl:lva:ine buffer, pIt ~: . ~-> ~~toc3
in each case mean v~al_ues were ca:lcul ated from 3
individual measurements.
*Trademark
2034509
_8_
Example 1
Tablets containing 5 mg of pimobendan
a) Tablets without citric acid
Each tablet comprises
(1)Pimobendan 5.0 mg
(2)Microcrystalline cellulose 58.0 mg
(3)Sec. calcium phosphate 72.0 mg
(4)Corn starch 54.0 mg
(5)Amberlite IRP 88 10.0 mg
(6)Magnesium stearate 1.0 mg
Total weight 200.0 mg
Some of the corn starch is dissolved in water with
heating and the mixture of ingredients (1) to (4) is
granulated therewith. (5) and (6) are added to the
dried granules. Tablets 8 mm in diameter and weighing
200 mg are compressed from the finished mixture.
Results:
Time (min) % pimobendan dissolved
8.5
10.2
10.7
10.8
10.8
b) Tablets containing 50 mg of citric acid
Each tablet comprises
(1) Pimobendan 5.0 mg
(2) Citric acid 50.0 mg
(3) Microcrystalline cellulose 42.0 mg
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_ g _
(4)Collidone 25 0.5 mg
(5)Sec. calcium phosphate 52.0 mg
(6)Corn starch 39.5 mg
(7)Amberlite IRP 88 10.0 mg
(8)Magnesium stearate 1.0 mg
Total Weight 200.0 mg
Some of the corn starch is dissolved in water with
heating and ingredient (1), some of (3), (5) and some of
(6) are granulated therewith. (2) and the remainder of
(3) and (6) are granulated with the aqueous solution of
(4). The granules are dried and mixed together. (7)
and (8) are added to the mixture of dried granules to
form the final mixture. This is then compressed to form
tablets 8 mm in diameter and weighing 200 mg.
The active substance and acid are present in
separate granulates for ease of manufacture but are
subsequently mixed together.
Results:
Time (min) % pimobendan dissolved
7.7
19.2
34.0
40.6
43.0
c) Tablets containing 103 mg of citric acid
Each tablet comprises
(1) Pimobendan 5.0 mg
(2) Citric acid 103.0 mg
(3) Microcrystalline cellulose 35.0 mg
(4) Collidone 25 1.0 mg
(5) Sec. calcium phosphate 31.5 mg
(6) Corn starch 81.5 mg
~(1~4569
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(7) Amberlite IRP 88 10.0 mg
(8) Magnesium stearate 3.0 mg
Total Weight 270.0 mg
The tablets are produced analogously to those of
Example 1b.
The resulting tablets are 9 mm in diameter, and
weigh 270 mg.
The active substance and acid are present in
separate granulates for ease of manufacture but are
subsequently mixed together.
d) Tablets containing 206 mg of citric acid
Each tablet comprises
(1)Pimobendan 5.0 mg
(2)Citric acid 206.0 mg
(3)Avicel 50.0 mg
(4)Collidone 25 2.0 mg
(5)Sec. calcium phosphate 63.0 mg
(6)Corn starch 46.0 mg
(7)Amberlite IRP 88 20.0 mg
(8)Magnesium stearate 3.0 mg
Total Weight 395.0 mg
The tablets are produced analogously to those of
Example lb.
The resulting tablets are 11 mm in diameter, and
weigh 395 mg.
The active substance and acid are present in
separate granulates for ease of manufacture but are
subsequently mixed together.
Results:
Time (min) % pimobendan dissolved
23.8
~o34ss~
- 11 -
59.0
67.0
30 69.0
Example 2
Tablets containing 2.5 mq-of pimobendan
a) Tablets containing 103 mq of citric acid
Each tablet comprises
(1) Pimobendan 2.5 mg
(2) Corn starch 23.0 mg
(3) Microcrystalline cellulose 26.0 mg
(4) Anhydrous calcium phosphate 31.5 mg
(5) Polyplasdone XL 59.0 mg
- (6) Citric acid, fine particles (anhydrous) 103.0 mg
(7) Compritol 888 5.0 mg
Total weight 250.0 mg
(1) to (4) are granulated with aqueous starch
solution. The other ingredients are added to the dry
granules to make the final mixture. This is then
compressed to form tablets measuring 9 mm in diameter
and weighing 250 mg.
The active substance and acid initially are present
separately, for ease of manufacture, but are
subsequently mixed together.
Results:
Time (min) % pimobendan dissolved
5 18.7
10 20.5
21.8
22.2
60 22.7
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b) Tablets containing 50 mg' of citric acid
Each tablet comprises
(1)Pimobendan 2.5 mg
(2)Anhydrous powdered citric acid 50.0 mg
(3)Avicel PH 101 13.0 mg
(4)Anhydrous calcium hydrogen phosphate 15.0 mg
(5)Undried corn starch 6.0 mg
(6)Collidone 25 0.5 mg
(7)Insoluble polyvinylpyrrolidone 59.0 mg
(8)Compritol 888 3.0 mg
(9)Magnesium stearate 1.0 mg
Total Weight 150.0 mg
(6) is dissolved in ethanol and the mixture of
ingredients (1) to (5) is granulated therewith. (7) to
(9) are added to the dry granules to form the final
mixture. This mixture is compressed to form tablets
measuring 8 mm in diameter and weighing 150 mg.
The active substance and acid are present together
in the same granulate.
Results:
Time (min) % pimobendan dissolved
15 71.1
30 85.0
Example 3
Capsules containing 5 mg of pimobendan
a) Capsules without citric acid
Each capsule contains
(1) Pimobendan 5.0 mg
- 13 - 2034569
(2)Lactose 90.25 mg
(3}Corn starch 36.0 mg
(4}Tween 80 0.5 mg
(5)Explotab 8.0 mg
(6)Magnesium stearate 0.25 mg
Total weight 140.0 mg
The individual powders are intensively mixed
together and packed into size 4 hard gelatin capsules,
the contents of each weighing 140 mg.
b) Capsules containing 230 mg~ of citric acid
Each capsule contains
(1)Pimobendan 5.0 mg
(2)Citric acid 230.45 mg
(3)Collidone 25 3.78 mg
(4)Magnesium stearate 0.77 mg
Total Weight 240.00 mg
(1) and (2) are intensively mixed together and
granulated with an alcoholic solution of (3). (4) is
added to the dried granulate. The final mixture thus
obtained is packed into size 1 hard gelatin capsules,
the contents of each weighing 240 mg.
The active substance and acid are present together
in the same granulate.
Results:
Time (min) % pimobendan dissolved
100
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c) Capsules containing 207 mq of citric acid
Each capsule contains
(1)Pimobendan, finely ground 5.0 mg
(2)Citric acid 206.5 mg
(3)Microcrystalline cellulose 40.0 mg
(4)Aerosil 130 V 11.0 mg
(5)Collidone 25 4.0 mg
(6)Magnesium stearate 1.5 mg
Total Weight 268.0 mg
(1) is triturated with (2). (3) and (4) are added
to the triturated material. The mixture is granulated
with an alcoholic solution of (5). (6) is mixed into
the dry granulate. The finished mixture is packed into
size 1 capsules, the contents of each weighing 268 mg.
The active substance and acid are present in one
and the same granulate.
Results:
Time (min) % pimobendan dissolved
84.1
90.2
91.7
30 92.5
Exampl a 4
Capsules containing 2.5 mq of pimobendan and 209 mg of
citric acid
Each capsule contains
(1) Pimobendan 2.5 mg
(2) Powdered citric acid 209.0 mg
(3) Microcrystalline cellulose 40.0 mg
2U34 i69
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(4) Silicon dioxide 11.0 mg
(5) Polyvinylpyrrolidone 4.0 mg
(6) Magnesium stearate 1.5 mg
Total Weight 268.0 mg
The tablets are produced analogously to those of
Example 3c.
The active substance and acid are present in the
same granulate.
Results:
Time (min) % pimobendan dissolved
15 96.5
30 99.1
Example 5
Film coated tablet containing 2.5 m~~imobendan and
50 ma of citric acid
Each tablet comprises
(1)Pimobendan 2.5 mg
(2)Powdered anhydrous citric acid 50.0 mg
(3)Avicel PH 101 13.0 mg
(4)Anhydrous calcium hydrogen phosphate 15.0 mg
(5)Undried corn starch 6.0 mg
(6)Collidone 25 0.5 mg
(7)Insoluble polyvinylpyrrolidone 59.0 mg
(8)Compritol 888 3.0 mg
(9)Magnesium stearate 1.0 mg
Total weight 150.0 mg
The preparation procedure is as described in
Example 2b, but the finished mixture is compressed into
biconvex tablets, which are each coated with 5 mg of
hydroxypropyl-methylcellulose.
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The active substance and acid are together in the
same granulate.
Results:
Time (min) % pimobendan dissolved
76.8
30 86.1
