Note: Descriptions are shown in the official language in which they were submitted.
CA 02876294 2014-12-10
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Our reference: HA0019P-WO
Pharmaceutical form for extended release of active substances
This invention relates to pharmaceutical forms for extended release of active
substances, in
particular of active substances with bad solubility at high pH values. A
special embodiment
relates to such a pharmaceutical form which does not only release a first
active substance with
bad solubility at high pH values in an extended manner, but does also release
a second active
substance in a retarded manner, in particular a second active substance with a
better solubility
at high pH values than the first active substance. For this purpose
embodiments of this
invention comprise several compartments which may contain one active substance
each. Such
a pharmaceutical form according to the present invention may for example have
the design of
a layer tablet.
A lot of pharmaceutically active substances are organic bases, i.e. they
comprise functional
groups with a pKB value of lower than 7, in particular lower than 5. Such
active substances
show bad solubility in the milieu of the intestine. The reason for that is
that the intestine is
characterized by an alkaline pH value. Thus, there the organic bases are not
protonated and so
= they are not charged. Then these molecules show bad solubility. But the
intestine, in particular
the small intestine, is the place at which typically the resorption of the
active substances takes
place and should take place.
So that an active substance can be resorbed, it has to be dissolved before.
When it does not
dissolve, then it is not released from its pharmaceutical form.
For the above mentioned organic bases it is true that they typically show
better solubility in
acidic milieu. The reason for that is that the basic group in the respective
molecule is
protonated in the acidic milieu so that the organic base is positively
charged. Such an acidic
milieu can typically be found in the fasting human stomach.
The above mentioned circumstances of a better solubility in the fasting
stomach on the one
hand and a worse solubility in the intestine on the other hand result in
problems, when
pharmaceutical forms are formulated, in particular in the case, when extended
release is
desired.
=
CA 02876294 2014-12-10
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It has to be considered that the pH value in the human stomach is not always
extremely acidic.
After the ingestion of a meal the pH value may also reach neutral values,
generally values of
between about pH 4 and 6. Only with time the pH value becomes lower and lower
again.
Generally, a pH value of < 2 is reached again only after 90 to 120 minutes.
This means that
the active substance with the above described properties at first shows bad
solubility in the
stomach, when it is taken after a meal, and that this bad solubility improves
only gradually,
when the pH value in the stomach becomes more acidic again.
It is particularly difficult to achieve an extended release of such active
substances with bad
solubility. One idea for solving the mentioned problem is the formulation of
pharmaceutical
forms with extended release. This is often achieved with a pharmaceutical form
having a
coating which releases the active substance only slowly, or in that the active
substance is
dispersed in a matrix which only slowly erodes.
But here again the problem arises that the active substance shows bad
solubility in the alkaline
milieu of the intestine. But for the extended, preferably linear release it is
required that the
active substance is continuously dissolved. In practice this results in
pharmaceutical forms
which should release a basic active substance with bad solubility in the
intestine in an
extended manner, and they are indeed successful in fulfilling this requirement
at first (in the
stomach), but when the pharmaceutical form reaches the intestine it results in
such a had
release that its use in total is not expedient.
A further problem arises, when two active substances with different solubility
behavior should
be released from one pharmaceutical form in the same kind. In the case of
better soluble
active substances, in particular such ones with permanent charge, the problem
arises that these
better soluble active substances are allowed only to be released in a retarded
manner. So with
respect to the first active substance a stimulation of the release has to be
achieved, at least in
the intestine, and with respect to the second active substance retardation has
to be achieved.
It is an object of the present invention to provide pharmaceutical forms
enabling an extended
release of an active substance with bad solubility at high pH values. Certain
embodiments in
addition solve the object of extendedly releasing an active substance with had
solubility at
=
high pH values and an active substance with higher solubility in an equal
manner. "Releasing"
in this connection means that the active substance is made available at the
site of resorption,
thus in the small intestine. The pharmaceutical forms according to the present
invention are
3
characterized by a long residence time in the stomach so that they are present
in the stomach
for such a long time that a significant proportion of the first active
substance can be dissolved.
The pharmaceutical form of this invention contains at least one first active
substance and at
least one emulsifier, wherein the emulsifier has a structural motif of the
following formula
R1-0-[CH2-CH2-01,-R2
wherein R1 and R2 independently from each other are selected from hydrogen,
alkyl, glyceride
and polyalkylcne oxide, and n is an integer of at least 4, wherein the mass
ratio of active
substance to emulsifier is at least 1 to 30 and at most 1 to I.
The pharmaceutical form according to the present invention may comprise either
only one
compartment with the first active substance or several compartments which may
contain
further active substances. In a preferable embodiment the pharmaceutical form
comprises at
least one first compartment and one second compartment. In exceptionally
preferable
embodiments the pharmaceutical form according to the present invention
consists of the first
compartment containing active substance and the second compartment containing
active
substance.
The pharmaceutical form of this invention is preferably a solid oral
pharmaceutical form. The
design of the pharmaceutical form according to the present invention is
preferably such that
its mass does not exceed a value of 1750 mg, preferably 1500 mg, further
preferably 1400 mg,
still further preferably 1200 mg and particularly preferably 1000 mg.
According to the
conditions of its formulation its mass is preferably at least 700 mg, further
preferably at least
800 mg. Here, the mass of the second compartment, if present, is preferably at
least 150 mg,
further preferably at least 200 mg and in particularly at most 500 mg,
preferably at most 400
mg and further preferably at most 350 mg.
The pharmaceutical form of this invention may have the design of a monolithic
pharmaceutical form, in particular the form of a tablet. A capsule is also
possible. Preferable
forms are tablets, in particular layer tablets. The pharmaceutical form
according to the present
invention is preferably a layer tablet comprising at least two layers, wherein
the first layer is
the above described first compartment and the second layer is the above
described second
compartment. Furthermore, such a layer tablet may also contain further layers.
Exceptionally
preferably, the pharmaceutical form according to the present invention is a
layer tablet
CA 2876294 2019-11-25
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consisting of two layers, wherein one layer is the first compartment and the
other layer is the
second compartment.
= The layer tablet may also be a shell-core tablet. In this case one layer
is disposed in the core
and a further layer forms the shell. In other words, the design of the layer
tablet may be such
that one layer completely surrounds the other layer. But preferable is an
embodiment in which
the layers are adjacent, wherein however the one layer does not completely
surround the other
layer. The one layer does "not completely" surround the other layer, when
preferably not
more than 70 %, further preferably at most 62 % and exceptionally preferably
at most 52 % of
the total outer surface of the one layer are covered with the other layer.
In particularly preferable embodiments the pharmaceutical form which is
described here is a
form with long residence time in the stomach. This means that the
pharmaceutical form is not
so strongly dissolved in the stomach that it can quickly leave the stomach
through the pylorus
sphincter. Preferably, the pharmaceutical form according to the present
invention resides in
the stomach of the patient for at least 2 hours, further preferably at least 3
hours, before it
enters the intestine. According to the present invention this is achieved by
designing the
pharmaceutical form such that it is dissolved very slowly. So over a longer
period of time the
=
size of it is such that it cannot leave the stomach.
The pharmaceutical form preferably at at least one site has a diameter of more
than 2 mm, in
particularly more than 4 mm and particularly preferably at least 5 mm. So it
is guaranteed that
the pharmaceutical form cannot leave the stomach through the pylorus
sphincter, but still
stays in the stomach for a period of time.
After the food intake the stomach is not emptied immediately, but it step by
step releases the
chyme into the small intestine. This physiological fact can be used with the
pharmaceutical
form according to the present invention. As described above, the first active
substance is
preferably an active substance with a solubility which is better at a low pH
value, thus in an
acidic milieu, than in an alkaline milieu.
Typically, in the stomach the pH value is low. But after a meal the pH
increases to higher
values, e.g. about pH 5. Only after a certain time the pH gradually decreases
to lower values
again. This means that the first active substance after food intake would at
first be dissolved
worse, because the pH value is too high. But the pharmaceutical form according
to the present
invention enables the dissolution of a part of the first active substance by
the measures which
are described here.
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Through the motion of the stomach the released first active substance is mixed
with the
chyme and is then gradually released into the small intestine. Then the active
substance is
resorbed in the proximal small intestine, thus a short time after leaving the
stomach. So the
stomach serves as a retardation means for the first active substance. At the
same time also the
second active substance, if present, is dissolved, wherein this second active
substance
preferably shows a higher solubility than the first active substance. The
second active
substance preferably has higher solubility, when its solubility is at least
one decimal power
higher than the solubility of the first active substance.
When the pH value in the stomach has reached a lower value, e.g. about pH 3,
then the first
active substance is dissolved better. Lest the total residual content of the
first active substance
is released at once, the emulsifier is preferably selected such that it can
slow down the release
of the first active substance. For that optionally at least one surfactant, at
least one triglyceride
and/or at least one retarding agent are present for further support.
In the second compartment no emulsifier is required, so that preferably no
emulsifier is
present there. Instead of preferably at least one retarding agent is present
there which is
suitable for slowing down the release of the second active substance so that
here an extended
release can he achieved.
Since the pharmaceutical form is only dissolved very slowly, it preferably
stays in the
stomach until it is nearly emptied. Then a great proportion of the chyme has
entered the small
intestine via the pylorus sphincter. In such a moment the stomach is emptied
by means of so-
called housekeeper contractions. In this way also bodies which normally do not
enter the
small intestine via the pylorus sphincter are yet able to get there.
Then the pharmaceutical form will further release the active substances in the
small intestine.
So a nearly linear release of both active substances becomes possible.
The first active substance is preferably an active substance with bad
solubility in basic milieu.
This means in particular that the first active substance in an aqueous
solution with a pH value
of 7 has a solubility of lower than 0.5 mo1/1, in particular lower than 0.1
mo1/1 as well as
preferably lower than 0.01 mo1/1. Unless otherwise stated, the solubility is
determined at
standard conditions (DIN 1343), and this is also true for all other parameters
in this
description.
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This regularly applies to active substances with at least one functional group
having a pKB
value of at most 5, in particular at most 4, wherein the first active
substance of this invention
preferably comprises such a functional group. This preferably may be a
functional group
which is selected from amino groups, guanidine groups and nitrogen-containing
heterocyclic
groups. Amino groups are particularly preferable. Thus, the first active
substance comprises at
least one functional group being selected from amino group, guanidine group
and nitrogen-
containing heterocyclic group. Here according to the present invention the
term "amino
group" comprises primary, secondary and tertiary amines, including nitrogen
atoms in
saturated or partially unsaturated cyclic hydrocarbons. It is exceptionally
preferable, when the
first active substance comprises at least one amino group, further preferably
at least two
amino groups.
Nevertheless according to the present invention not the molecular structure of
the first active
substance is very important, but rather its solubility behavior. Therefore,
also active
substances which do not comprise an above mentioned functional group according
to the
present invention may be first active substances, when in the stomach at an
acidic pH value
they show good solubility and at an alkaline pH value they show had
solubility.
According to the present invention "good soluble" or "good solubility" means
that the such
characterized substance can be dissolved in the respective milieu and/or
solvent in an amount
of higher than 0.5 "Bad soluble"
or "bad solubility" means that the such characterized
substance can be dissolved in the respective milieu and/or solvent in an
amount of at most
0.5 11101/1, in particular at most 0.1 mo1/1 and preferably at most 0.01
mo1/1.
The first active substance being used according to the present invention has
preferably an
n-octanollwater distribution coefficient (logPow) at 20 C of higher than 1,
preferably higher
than 2, more preferably higher than 3 and particularly preferably higher than
4, in particular
higher than 5. This distribution coefficient is a measure for the lipophilic
property of a
substance. As already mentioned above, in particular lipophilic active
substances profit from
the active substance matrix of this invention. The advantage fur such active
substances is also
particularly great, because normally the resorption of lipophilic active
substances functions
very well, when these substances are dissolved. In other words, the
dissolution of these active
substances from a pharmaceutical form is the rate-determining step of the
assimilation of the
active substance into the body.
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But there are also active substances, the lipophilic property of which is so
strong that the
active substance matrix which is proposed here is not sufficient for
guaranteeing a sufficient
bioavailability. Therefore, the first active substances which are used
according to the present
invention have n-octanol/water distribution coefficients (logPow) at 20 C of
preferably at
most 100, further preferably at most 50, in particularly preferably at most
30, particularly
preferably at most 15 and in particularly at most 7.
For improving the solubility of the first active substance after application
it is preferable
according to the present invention to use the first active substance in small
particle size.
Therefore, the first active substance in the pharmaceutical form of this
invention has
preferably mean particle sizes of at most 1000 nm, further preferably at most
600 nm and
particularly preferably at most 300 nm. Preferably according to the present
invention the
mean particle size is determined by the analysis method of dynamic light
scattering.
The small particle size is especially important, when the active substance
does not or hardly
dissolve in the emulsifier. This is often true, when the emulsifier comprises
a particularly
large hydrophilic proportion, such as a lot of poloxamers, and/or the active
substance is
especially lipophilic. According to the present invention it is preferable
that the active
substance can nearly completely, preferably completely, be dissolved in the
emulsifier. So an
improved release is achieved.
This effect can simply be achieved, when the lipophilic proportion of the
emulsifier is
adjusted to the lipophilic property of the active substance. How this can be
achieved can be
followed from the explanations about the emulsifier and its molecular
structure which can be
found below.
The pharmaceutical form according to the present invention is particularly
well suitable for
the administration of active substances which at least comprise one amino
group. It is
advantageous, when these active substances do not comprise hydroxyl groups
and/or carboxyl
groups. In any case, such active substances especially profit from the design
of the
pharmaceutical form according to the present invention. So the first active
substance
preferably does not comprise any hydroxyl group and/or carboxyl group.
In a preferable embodiment the first active substance according to the present
invention is
selected from the following active substances and their salts:
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= antihistamines, in particular diphenhydramine, chlorphenoxamine,
doxylamine,
carbinoxamine, phenyltoloxamine, diphenylpyralin, clemastine, pheniramine,
brompheniramine, dexchlorpheniramine, triprolicline, dimetinden, promethazine,
mequitazine, oxatomid, meclozine, hydroxyzine, bamipin, cyproheptadine,
ketotifen.
pizotifen, emedastine, azelastine, ebastine, loratadine, desloratadine,
ranitidine,
nizatidine, roxatidine acetate, cimetidine;
= neuroleptics, in particular promazine, chlorpromazine, triflupromazine,
prothipendyl,
alimemazine, levomepromazine, thioridazine, periciazine, perazine,
trifluoperazine,
fluphenazine decanoate, chlorprothixene, haloperidol decanoate, melperone,
pipamperone, benperidol, pimozide, fluspirilene, clozapine, olanzapine,
zotepine,
quetiapine, sulpiride, amisulpiride, risperidone,, ziprasidone, aripiprazole;
= antidepressants, in particular imipramine, desipramine, clomipramine,
trimipramine,
lofepramine, amitriptyline, nortriptyline, doxepin, dosulepin, dibenzepin,
mianserin,
maprotiline, fluoxetine, paroxetine, citalopram, sertraline, fluvoxamine,
reboxetine,
viloxazine, atomoxetine, venlafaxine, duloxetine, mirtazapine, trazodone,
nefazo done,
tranylcypromine, moclobemide;
= triptans, in particular sumatriptan, zolmitriptan, almotriptan,
rizatriptan, naratriptane,
eletriptan, frovatriptan;
= antiemetics, in particular cinnarizine, betahisline, tropisetron,
granisetron, dolasetron,
ondansetron, aprepitant;
= tranquilizers, in particular chlordiazepoxide, nordazepam, diazepam,
prazepam,
flurazepam, nitrazepam, clonazepam, flu nitrazepam, tetrazepam, bromazepam,
clotiazepam, alprazolam, triazolam, midazolam, brotizolam, zopiclon, zaleplon,
zolpiclem;
= agents against Parkinson disease, in particular pergolide, cabergoline,
lisuride,
= ropinirole, pramipexole, se,legiline, rasagiline, amantadine, memantine,
budipine,
benzatropin, bornaprin, metixene;
= spasmolytic agents, in particular papaverine, ethaverine, moxaverine;
= antidementives, in particular tacrine, donepezil, rivastigmine,
nimodipine;
= sympatholytic agents, in particular prazosine, terazosine, doxazosine,
alfuzosinc,
bunazosine, tamsulosin, urapidil, dapiprazole, indoramine;
= diuretics, in particular hydrochlorothiazide, butizide,
trichlormethiazide, polythiazide,
hendroflumethiazide, bemetizide, metolazone, clopamid, indapamid, azosemid,
amiloride, triamteren, dorzolamicle, brinzolamide;
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= calcium canal blockers, in particular nitrendipine, nisoldipine,
nimodipine, isradipine,
felodipine, nicardipine, nilvadipine, barnidipine, amlodipine, lacidipine,
lercanidipine,
verapamil, gallopamil, diltiazem, flu narizine, bencyclan
= antiestrogens, in particular clomifene, tamoxifene, toremifene;
= antidiabetics, in particular pioglitazone, rosiglitazone.
The above mentioned active substances all comprise at least one amino group
which is
typically protonated in the milieu of the stomach and typically deprotonated
in the milieu of
the intestine so that the solubility of the active substances is substantially
characterized by this
functional group. Furthermore, these active substances do not comprise neither
hydroxyl nor
carboxyl groups.
In a particularly preferable embodiment the first active substance is
cinnarizinc, a salt of
cinnarizine and/or a cinnarizine derivative, in particular a pro-drug. It is
exceptionally
preferable, when the first active substance is cinnarizinc.
The first active substance is preferably used in an amount of at least 10 mg
and further
= preferably at least 20 mg or especially preferably at least 40 mg in the
pharmaceutical form.
The amount of the first active substance should preferably not exceed a value
of 200 mg,
further preferably 100 mg and especially preferably 80 mg.
The emulsifier supports the release of the first active substance. This is
especially important
so that at least a part of the first active substance is dissolved as quick as
possible and
uniformly already in the stomach. As described above, the pH value in the
stomach after the
intake of a meal is only lowered slowly. But it is required that the first
active substance is
already dissolved now in the stomach so that it is mixed with the chyme. The
mixing is
conducted by the motion of the stomach. The use of an emulsifier according to
the present
invention in the pharmaceutical forms according to the present invention in
particular enables
an improvement of the solubility of the first active substance at higher pH
values. The
emulsifier according to the present invention contributes to the release of
the first active
substance, ideally already in dissolved form, and subsequently to the
possibility of a
resorption thereof.
So that the improvement of the release is especially distinct, the emulsifier
should preferably
have an HLB value of at least 1 and at most 16, in particular at least 9 and
at most 14.
Preferably, the emulsifier is not an ionic one.
CA 02876294 2014-12-10
It has been shown that such emulsifiers having a certain structural motif
achieve particularly
advantageous results. This structural motif is a polyethylene glycol chain. It
was found that
emulsifiers with this structural motif are characterized by a double function.
On the one hand,
at high pH values starting at about pH 4 they result in an improvement of the
solubility of the
first active substance. On the other hand, at low pH values, namely when the
first active
substance shows better solubility, they result in retardation of the release.
This is a desired
behavior according to the present invention, because the release of the first
active substance
should happen as continuously as possible over a long period of time.
The polyethylene glycol chain is the hydrophilic part of the emulsifier and is
connected with a
lipophilic part. The lipophilic part may advantageously be a glyceride group
or another
polyalkylene oxide chain.
As glyceride groups mono- and diglyceride groups can be used, wherein
diglyceride groups
are preferable. According to the chain lengths of the used fatty acid groups
monoglyceride
groups may optionally be not lipophilic enough.
As polyalkylene oxide chains in particular polyalkylene oxides with
uninterrupted carbon
chains of at least 3 carbon atoms may be used. A preferable example of a
polyalkylene oxide
chain in the emulsifier of this invention is polypropylene oxide.
These emulsifiers can be obtained according to methods which are known by a
person skilled
in the art. Polyethylene glycol glycerides can for example be prepared by
reaction of
respective glycerides with polyethylene glycol. Commercially available
polyethylene glycol
glycerides are for example Gelucire 43/01 and Gelucire 50/13.
In other words: the emulsifiers which are used in the pharmaceutical form
according to the
present invention comprise the following structural element:
R1-0- [CI-H-CFL-0],-R2 (formula 1)
In this formula RI and R2 are the same or different. R1 and R2 independently
from each other
are hydrogen, alkyl, glyceride or polyalkylene oxide. Alkyl is preferably a
short-chain alkyl,
i.e. its chain length amounts to at most 6 carbon atoms. Preferably, R1 and R2
independently
from each other are hydrogen, glyceride or polyalkylene oxide.
When one group R1 or R2 is hydrogen, then the groups R.' and R2 are different,
i.e. the
respective other group is not hydrogen; and when R.' or R2 is alkyl, then the
groups R1 and R2
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11
are different, i.e. the respective other group is not alkyl. Otherwise, the
molecule would not
have the required emulsifying effect. Preferably, R` and R2 are neither
hydrogen nor alkyl,
when the respective other group is hydrogen or alkyl.
n is the number of the chain members in the polyethylene oxide chain.
Preferably, n is an
integer of at least 4, further preferably at least 10 and particularly
preferably at least 20. When
n is lower, then the desired effect according to the present invention is not
very strong,
because the lipophilic part of the emulsifier is too small. In preferable
embodiments n is not
higher than 100, in particular not higher than 50, further preferably not
higher than 40 or not
higher than 30. It has been shown that longer chains result in slower
degradation of the
emulsifier by pancreatin and lipases. With that the extended release can be
controlled. I3ut
when the chain is too long, then the pharmaceutical form does not release the
first active
substance fast enough.
When R and/or R2 are a polyalkylene oxide group, then the residue has the
following general
formula:
-0-[Y-0101-R3 (formula II)
In this formula R3 is hydrogen or alkyl, in particular short-chain alkyl (up
to C6). Y is an
alkylene group having a carbon chain length of at least C3 and preferably at
most C6, further
preferably at most C4.
1.11 is the number of the chain members in the polyalkylene oxide chain. m is
preferably an
integer of at least 3, in particular at least 5 and particularly preferably at
least 10. Preferably,
m should not exceed an integer of 50, in particular 40 and particularly
preferably 30 or 20. In
preferable embodiments R' and R2 are polyalkylene oxide groups.
When R' and/or R2 are glyceride groups, then the glyceride group has the
following general
form ula:
Fe
R4 Re
(formula III)
=
^
Here formula III at one of the positions R`-', R5 or R6 is connected with the
structural element
of formula I. According to the present invention it is irrelevant at which
position the structure
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12
of formula III is connected with the structure of formula I. So one of the
groups R4, R5 or R6
is the structure of formula I. For the remaining two groups the following is
true:
R4 is preferably hydrogen or a fatty acid group. The fatty acid group R4 has a
chain length of
preferably at least C6, further preferably at least Cs and particularly
preferably at least C10. A
minimum chain length should be satisfied, so that the lipophilic property of
the glyceride
group is sufficient. The number of the carbon atoms in the fatty acids is
preferably even.
Preferably, the chain length should not exceed a value of C22, further
preferably Cts and
particularly preferably C16, because otherwise the solubility of the
emulsifier may be
compromised.
R5 is preferably hydrogen or a fatty acid group. The fatty acid group R5 has a
chain length of
preferably at least C6, further preferably at least C8 and particularly
preferably at least C10. A
minimum chain length should be satisfied, so that the lipophilic property of
the glyceride
group is sufficient. The number of the carbon atoms in the fatty acids is
preferably even.
Preferably, the chain length should not exceed a value of C22, further
preferably C18 and
particularly preferably C16, because otherwise the solubility of the
emulsifier may be
compromised.
R6 is preferably hydrogen or a fatty acid group. The fatty acid group R6 has a
chain length of
= preferably at least C6, further preferably at least C8 and particularly
preferably at least Clie A
minimum chain length should be satisfied, so that the lipophilic property of
the glyceride
group is sufficient. The number of the carbon atoms in the fatty acids is
preferably even.
Preferably, the chain length should not exceed a value of C22, further
preferably C18 and
particularly preferably C16, because otherwise the solubility of the
emulsifier may be
compromised.
Preferably, two of the groups R4, R5 and R6 are fatty acid groups. So then it
is a diglyceride
group.
It has to be considered that the correct chain length of the fatty acid groups
strongly
corresponds with the number of the chain members in the polyethylene oxide
chain (n). When
the polyethylene oxide chain is longer, then also the fatty acid chains may be
longer.
The emulsifiers described here can be produced by reaction of respective mono-
, di- and/or
triglycerides with respective polyalkylene oxides. These educts are
commercially available.
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The emulsifiers according to the present invention are preferably mixtures of
the mentioned
substances.
In preferable embodiments the emulsifier is selected from Gelucire 50/13,
Gelucire 43/01,
Poloxamer 407 and mixtures thereof.
Good solubilization is achieved, when the ratio of the masses of active
substance to
emulsifiers is at least 1 to 30, further preferably at least 1 to 20 and
particularly preferably at
least 1 to 10 and still further preferably at least 1 to 8. The mentioned
ratio is at most 1 to 1,
preferably lower than 1 to 1, further preferably at most 1 to 2, still further
preferably at most 1
to 3 and still further preferably at most 1 to 4 and particularly preferably
at most 1 to 6.
Basically it is true, that a higher amount of emulsifier enables better
solubilization. But it has
to be considered drat a pharmaceutical form should not exceed a certain
maximum volume, so
that the intake thereof is not unnecessarily unpleasant. In addition, a too
high amount of an
emulsifier may also result in hindrance of the release of the first active
substance. It has been
shown that a mass ratio of active substance to emulsifier of at least 1 to 10
and at most 1 to 2
is particularly suitable, wherein a mass ratio of at least 1 to 8 and at most
1 to 2 is an ideal
one. When these mass ratios were fulfilled, then this resulted in a
particularly advantageous
release acceleration together with an especially favorable size of the
pharmaceutical form.
The pharmaceutical form or the first compartment contains the emulsifier
preferably in a
proportion of at least 7 % by weight, preferably at least 10 % by weight,
further preferably at
least 15 % by weight and particularly preferably at least 20 % by weight. The
proportion of
the emulsifier should preferably not exceed a proportion of 50 % by weight,
further preferably
40 % by weight and particularly preferably 32 % by weight. In tests for
determining the
optimum ratio of solubilization and volume of the pharmaceutical form it has
been shown that
these amounts are advantageous.
In particularly preferable embodiments instead of the above mentioned
substances or in
addition to the above mentioned substances at least one phospholipid is used.
The
phospholipid is preferably selected from phosphatidylcholines (lecithins),
phosphatidylethanolamines (kephalins), phosphatidylserines, sphingomyclins and
mixtures
thereof. Especially preferable are phosphatidylcholines (lecithins). It has
surprisingly been
found that phospholipids also result in the above described advantageous
effects, like the
above mentioned emulsifiers.
CA 02876294 2014-12-10
14
Thus, the emulsifier may be a phospholipid. Preferably, the emulsifier
comprises the
phospholipid in addition to at least one of the above mentioned substances. In
such a case the
phospholipid strengthens the advantageous effects of the above mentioned
substances.
In preferable embodiments the pharmaceutical form in addition contains at
least one
surfactant. The purpose of the surfactant is the strengthening of the
solubilization imparted by
the emulsifier. Namely, when a mixture of emulsifier and surfactant is used,
then the effect of
these substances is a synergistic one. So the total mass of emulsifier and
surfactant in relation
to the active substance can be reduced. As mentioned above, for optimum
solubilization it
may be necessary to choose a very high amount of emulsifier in relation to the
active
substance. This high amount can be reduced by the use of a surfactant.
Preferable surfactants are ionic surfactants, in particular anionic
surfactants. Metal soaps have
shown to be particularly advantageous. Metal soaps preferably means substances
comprising
as anionic component an organic acid and as cationic component a metal cation.
The metal
cation is preferably selected from alkali and alkaline earth metal ions.
Especially preferable
are alkali metal ions and in particular sodium and potassium. Under the
alkaline earth metal
ions magnesium and calcium are especially preferable.
Preferable organic acids which can be used as anionic component in the
surfactants are acids
with at least 6 carbon atoms. It has been shown that organic acids with
shorter carbon chain
lengths have lower efficacy. But the organic acids should preferably not
exceed chain lengths
of 22 carbon atoms. In the case of longer carbon chains the synergistic effect
in connection
with the emulsifier is not very strong. It is particularly preferable, when
the organic acids in
the surfactants have chain lengths of at least 10 and at most 18, further
preferably at least 12
and at most 16 carbon atoms.
The organic acids may comprise branched or unbranched carbon chains, but
preferably the
carbon chains are unbranched. A particularly preferable surfactant is sodium
myristate.
A further purpose of the surfactants according to the present invention is the
slowing of the
stomach-intestine passage of the chyme and thus the resorption of the first
active substance. It
has interestingly been found that this can be achieved especially with the
metal soaps
described here and that they can have a direct effect onto the control of the
gastrointestinal
passage, with the result that in total a higher amount of the first active
substance can be
reso rb ed.
CA 02876294 2014-12-10
The proportion of the surfactant in the pharmaceutical form according to the
present invention
should preferably be at least 2 % by weight, preferably at least 7 % by
weight, further
preferably at least 12 % by weight and particularly preferably at least 17 %
by weight. It has
been shown that so the effects of the surfactant are especially more distinct.
But an amount of
preferably 35 % by weight, further preferably 25 % by weight and particularly
preferably 20
% by weight should not be exceeded. Because otherwise the release of the first
active
substance would be hindered too much. The absolute mass of the surfactant in
the
pharmaceutical form should not exceed a value of 300 mg, further preferably
250 mg and
particularly preferably 200 mg. The minimum amount of the surfactant should
preferably not
fall below a value of 10 mg, further preferably 50 mg and particularly
preferably 100 mg.
The content of the surfactant as a mass ratio to the first active substance
should not fall below
a proportion of 1 to 1, further preferably 1.5 to 1 and particularly
preferably 2 to 1. Preferably,
= this ratio should not exceed a value of 5 to 1, further preferably 4 to 1
and in particular 3 to 1.
When these values are fulfilled, then the above described advantageous effect
can be
optimally used.
In a preferable embodiment the pharmaceutical form of this invention comprises
at least one
triglyceride. The purpose of the triglyceride is the slowing of the stomach-
intestine passage of
the pharmaceutical form. The triglyceride can also be used in combination with
the surfactant
for additionally slowing down the release of the first active substance.
The triglyceride preferably comprises a fatty acid group with at least 10
carbon atoms, further
preferably at least 12 carbon atoms and particularly preferably at least 16
carbon atoms. This
minimum length of the chain is desired, because so the extension of the
residence time of the
pharmaceutical form in the stomach is especially distinct and the release of
the first active
substance can be supported in a particularly efficient manner. But the chain
length should
preferably not exceed a value of 22 carbon atoms, further preferably 20 carbon
atoms. In
particularly preferable embodiments at least two and exceptionally preferably
all fatty acid
groups in the triglyceride fulfill these prerequisites.
The triglyceride may preferably be used in the pharmaceutical form according
to the present
invention in a proportion of higher than 5 % by weight, preferably at least 7
% by weight,
further preferably at least 10 % by weight, still further preferably at least
15 % by weight and
particularly preferably at least 20 % by weight. But a maximum proportion of
preferably 40 %
= by weight, further preferably 30 % by weight and particularly preferably
25 % by weight
CA 02876294 2014-12-10
16
should not be exceeded, because otherwise the release of the first active
substance would be
restricted too much.
The absolute mass of the triglyceride in the pharmaceutical form should not
exceed a value of
500 mg, further preferably 400 mg and particularly preferably 300 mg. The
minimum amount
of the triglyceride should preferably not fall below a value of 50 mg, further
preferably
100 mg and particularly preferably 150 mg.
The content of the triglyceride as a mass ratio to the first active substance
is preferably higher
than 1 to 1. The content of the triglyceride as a mass ratio to the first
active substance should
further preferably not fall below a proportion of 2 to 1, still further
preferably 3 to 1 and
particularly preferably 3.5 to 1. Preferably, this ratio should not exceed a
value of 20 to 1,
further preferably 10 to 1, still further preferably 7 to 1 and in particular
6 to 1. When these
values are fulfilled, then the above mentioned advantageous effect can be
optimally used.
The first compartment may comprise a compression aid. The compression aid is
preferably
selected from lactose and corn starch. Further preferably, the compression aid
is corn starch.
In another embodiment lactose is used as a compression aid. The purpose of the
compression
aid is inter alia the increase of the melting point of a mixture of active
substance and
emulsifier during the production so that a further processing of this mixture
is possible.
The proportion of this compression aid in the pharmaceutical form or, when the
pharmaceutical form comprises several compartments, in the first compartment
should
preferably be at least 10 % by weight, further preferably at least 20 % by
weight and
particularly preferably at least 30 % by weight. When the amount of the
compression aid used
is too low, then the desired effect cannot be achieved. An amount of the
compression aid
which is too high increases the size of the pharmaceutical form and is thus
not desired.
Therefore the proportion of the compression aid in the pharmaceutical form or,
when the
pharmaceutical form comprises several compartments, in the first compartment
should not
exceed a value of 65 % by weight, preferably 60 % by weight, further
preferably 50 % by
weight and particularly preferably 40 % by weight.
The pharmaceutical form of this invention may also contain a retarding agent.
The retarding
agent is preferably selected from polymeric organic substances, in particular
such ones which
are swellable. Preferable retarding agents are acrylate polymers, methacrylate
polymers and
their copolymers as well as mixtures thereof. Other preferable retarding
agents are celluloses,
in particular highly viscous celluloses. The retarding agent of the
pharmaceutical form of this
CA 02876294 2014-12-10
17
invention is preferably a polymer, in particular a polysaccharide. Preferred
are cellulose,
cellulose derivatives, alginates and mixtures thereof as well as their
hydrates, but also
polyacrylates, polymethylacrylates and their copolymers and mixtures can be
used. Especially
preferable cellulose derivatives are methylcellulose and
hydroxypropylmethylcellulose.
Preferably a retarding agent is used which in an aqueous solution in a
proportion of 2 7o by
weight at a temperature of 20 C and a pressure of 101.325 kPa results in a
viscosity of at least
1500 mPas. The viscosity is measured with a falling sphere viscosimeter (DIN
53015).
According to the desired extension of the release of the first active
substance is may be
desired, also to choose higher viscosities. The higher the viscosity of the
retarding agent, the
higher is the extension of the release. In especially preferable embodiments
the viscosity of
the retarding agent is even at least 2500 mPas and particularly preferably at
least 3500 mPas.
But when the viscosity is too high, then the release of the first active
substance is too slow.
This would have the result that the first active substance during its passage
through the
gastrointestinal tract may possibly not be completely released. Therefore, the
viscosity should
be restricted to a value of at most 200.000 mPas, further preferably at most
120.000 mPas.
The proportion of this retarding agent in the pharmaceutical form or, when the
pharmaceutical
form comprises several compartments, in the first compartment should
preferably be at least
% by weight, further preferably at least 20 % by weight and particularly
preferably at least
30 Vo by weight. When the amount of the retarding agent used is too low, then
the desired
effect is not achieved. When the amounts are too high, then the release of the
first active
substance is too slow. Therefore, the proportion of the retarding agent in the
pharmaceutical
form or, when the pharmaceutical form comprises several compartments, in the
first
compartment should not exceed a value of 60 % by weight, further preferably 50
% by weight
and particularly preferably 40 % by weight. The content of the retarding agent
as the mass
ratio to the first active substance should preferably be at least 3 to 1,
further preferably at least
5 to 1 and particularly preferably at least 7 to 1. But this ratio should not
exceed a value of 20
to 1, further preferably 15 to 1 and particularly preferably 10 to 1.
Furthermore, to the first and/or the second compartment a fatty alcohol can be
added. In this
case the fatty alcohol is preferably an alcohol with a chain length of at
least 10 carbon atoms,
further preferably at least 12 carbon atoms and particularly preferably at
least 14 carbon
atoms. But the chain length should preferably not exceed a value of 20 carbon
atoms, further
preferably 18 carbon atoms and in particular 16 carbon atoms. It has been
shown that the
=
CA 02876294 2014-12-10
18
addition of a fatty alcohol is suitable for retarding the release of the
active substances, in
particular the second active substance.
The weight proportion of the fatty alcohol in the pharmaceutical form or the
first
compartment (when the pharmaceutical form comprises several compartments) is
preferably
at least 5 % by weight, further preferably at least 10 % by weight and
particularly preferably
at least 18 % by weight. When the proportion of the fatty alcohol in the
pharmaceutical form
or the first compartment (when the pharmaceutical form comprises several
compartments) is
too low, then the effect according to the present invention may be
compromised. In the case
of a content which is too high, the structural identity of the pharmaceutical
form may be
compromised. Therefore, the content of the fatty alcohol in the pharmaceutical
form or the
first compartment (when the pharmaceutical form comprises several
compartments) is
preferably at most 40 % by weight, further preferably at most 35 % by weight
and particularly
preferably at most 30 % by weight.
The pharmaceutical form of this invention may comprise further pharmaceutical
adjuvants.
These adjuvants may preferably be selected from anti-blocking agents,
lubricants, binders,
disintegrants, antioxidants, complex-forming agents, coating agents, flow
promoters,
preservatives, fillers, plasticizers, pigments and mixtures of such
substances.
A preferred adjuvant in the pharmaceutical form is a pharmaceutically
acceptable carrier.
Preferred carriers are polysaccharides, in particular cellulose and/or
lactose. The carrier
results in sufficient stability of the pharmaceutical form. Because, the
pharmaceutical form
contains a high proportion of emulsifier. The emulsifier supports the
structural integrity of the
pharmaceutical form only in a very limited extent. Preferably, the
pharmaceutical form
contains the carrier in a weight proportion of at least 10 % by weight,
further preferably at
least 20 % by weight and particularly preferably at least 30 % by weight.
In summary, the pharmaceutical form or the first compartment, when the
pharmaceutical form
comprises several compartments, may inter alia contain:
a. a first active substance,
b. an emulsifier for improving the solubility of the first active substance at
high pH
values and for slowing down the dissolution of the first active substance at
low pH
values;
CA 02876294 2014-12-10
19
c. optionally a surfactant for improving the solubility of the first active
substance and for
slowing down the transport of the first active substance from the stomach into
the
intestine;
d. optionally a triglyceride, also for improving the solubility of the first
active substance
and for slowing clown the transport of the first active substance from the
stomach into
the intestine;
e. optionally a retarding agent for slowing down the dissolution of the first
active
substance at low pH values;
f. optionally a compression aid for supporting the processing of a mixture of
the first
active substance and the emulsifier during the production;
g. optionally a fatty alcohol for slowing down the dissolution of the first
active substance
at low pH values;
h. optionally further adjuvants.
In a preferable embodiment of this invention the pharmaceutical form comprises
at least two
compartments which preferably contain different active substances. In this
case the first
compartment comprises the above mentioned substances, namely the first active
substance
and the emulsifier and also optionally the surfactant, triglycericle,
retarding agent,
compression aid, fatty alcohol and optionally further adjuvants. It is
exceptionally preferable,
when the pharmaceutical form consists of two compartments containing active
substances,
wherein these active substances are different active substances and wherein
the first
compartment comprises the above mentioned substances. According to the present
invention
"different active substances" means that the active substances of the
compartments are
different, thus one and the same active substance is not contained in
different compartments.
The first compartment at least comprises the first active substance, the
second compartment at
least comprises one second active substance. Besides the first and second
active substances in
the pharmaceutical form also further active substances may be contained. Thus,
besides the
first and/or second active substances the first and at least the second
compartment may
contain further active substances. However, exceptionally preferably the
active substance
proportion of the pharmaceutical form consists of the first and the second
active substances.
The weight proportion of the first compartment in the pharmaceutical form
according to the
present invention is preferably 45 to 100 % by weight, further preferably 55
to 87.5 % by
weight. The reason for that is that the first compartment is not only
responsible for the
CA 02876294 2014-12-10
extended release, but also for the solubilization of the first active
substance which normally
can be formulated only with difficulties.
A second compartment of the pharmaceutical form comprises at least the second
active
substance. The second active substance is preferably an active substance with
higher water-
solubility than the first active substance which thus dissolves better in the
stomach and also in
the intestine than the first active substance. So the second active substance
preferably has a
higher solubility than the first active substance, at least in an extent of
one decimal power, in
particular at pH 7.
The second compartment may in particular contain:
a. a second active substance,
b. optionally a retarding agent for slowing down the release of the second
active
substance,
c. optionally a long-chain alcohol for slowing down the release of the second
active
substance,
d. optionally a surfactant as described above for slowing down the transport
of the active
substance from the stomach into the intestine;
e. optionally a triglyceride as described above for slowing down the transport
of the
active substance from the stomach into the intestine;
f. optionally further adjuvants.
In prior art no satisfying pharmaceutical form is proposed which enables in
one
pharmaceutical form a retarded release of an active substance with bad
solubility (here: first
active substance) and also of a second active substance each, in particular
when the second
active substance shows higher solubility than the first active substance.
Because the release of
the active substance with bad solubility has to be supported and in the case
of a second active
substance with better solubility at the same time the release of the second
active substance has
to be suppressed. This invention provides a solution for this problem by
providing a
pharmaceutical form according to the present invention which preferably
comprises two
compartments, wherein the first compartment contains the first active
substance and the
second compartment contains the second active substance.
In the context of the pharmaceutical form described here it is a challenge to
retard the release
of the second active substance. One reason for that is that for the
solubilization of the first
active substance a relatively high amount of emulsifier is necessary. This
results in the fact
CA 02876294 2014-12-10
21
that due to the necessary solubility-enhancing measure with respect to the
first active
substance the volume of the pharmaceutical form is already nearly completely
exhausted. So
the release-retarding measure with respect to the second active substance must
be possible in
a minimum volume.
Thus, a simple coating of the whole pharmaceutical form is not preferred,
because this coating
would suppress the release of both active substances. So according to the
present invention it
is preferable, that the pharmaceutical form comprises two compartments,
wherein the first
compartment at least comprises the first active substance and at least one
emulsifier. The
second compartment comprises the second active substance. So that the second
active
substance is extendedly released, the second compartment preferably contains a
retarding
agent.
In a preferred embodiment of this invention the pharmaceutical form comprises
at least two
compartments in the form of layers. Here preferably one of the layers is the
first compartment
and another one of the layers is the second compartment. The pharmaceutical
form may also
comprise further layers, in particular a third layer.
In an embodiment of this invention the pharmaceutical form of this invention
comprises a
shell and a core. In this case the core may be a compartment of this
invention, in particular the
first compartment. The shell may be another compartment, in particular the
second
compartment. In this case the shell preferably completely surrounds the core.
In other words,
the core is completely embedded within the shell.
Basically each active substance can profit from the presentation form of the
pharmaceutical
form according to the present invention which should be administered over a
longer period of
time in an extended manner. Examples of such active substances and classes of
active
substances which can advantageously be used as a second active substance in
the context of
the present invention are:
Pharmaceutical products for the treatment of pain and for pain therapy with
peripherally
acting analgesics, centrally acting analgesics and adjuvant non-analgesics.
Preferably, those
= concerned here are the following analgesics and adjuvant substances:
acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, naproxen,
piroxicam, paracetamol,
metamizole, celecoxib, parecoxib, tramadol, pethidine, codeine,
dihydrocodeine, piritramide,
tilidinc, morphine. hydromorphone, oxycodone, levomethadone, fentanyl,
sufentanil,
CA 02876294 2014-12-10
22
buprenorphine, pentazocine, naloxone, flupirtine, carbamazepine, metoprolol,
metoclopramide, amitriptyline, doxepin, clomipramine, mianserin, maprotiline,
triptans such
as e.g. naratriptan, rizatriptan, sumatriptan, zolmitriptan, calcium
antagonists such as:
flunarizine, topiramate, valproic acid, phenytoin, baelofen, other agents such
as: botulinum
toxin, ergotamine, lisuride, methysergide, pizotifen, oxcarbazepine,
gabapentin and
lamotrigine, dexamethasone, methylprednisolone, prednisolone, triamcinolone,
diazepam,
tetrazepam, tizanidine, butylscopolamine and/or combination of tilidine and
naloxone.
Drugs for the treatment of the nervous system, alone or in combination, e.g.
seizure disorders
(in particular clonazepam, diazepam, lorazepam, midazolam, clobazam,
phenytoin,
clomethiazole, valproic acid, phenobarbital, gahapentin, lamotrigine,
oxcarbazepine,
pregabalin, topiramate, ethosuximide, levetracetam, mesuximide, primidone,
nitrazepam
and/or vigabitrine), Parkinson syndrome (in particular levodopa, with
benserazidelearbidopa,
bromocriptine, cabergoline, dihydroergocriptine, lisuride, pergolide mesylate,
pramipexole,
ropinirole, apomorphine, biperidene, metixene hydrochloride, trihexphenidyl,
entacaponc,
amantadine, budidine, selegiline and/or apomorphine), stroke (in particular
acetylsalicylic
acid, clopidogrel, dipyridamole, tficlopicline, heparin, phenprocoumon,
warfarin, protamine,
phytomenadione, nimodipine, paracetamol, tramadol and/or buprenorphine),
intracranial
pressure (in particular furosemide and/or mannitol), tremor (in particular
propranolol,
clozapine, alprazolam and/or primidone).
Drugs for the treatment of psychiatric diseases such as anxiety disorders (in
particular
alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene,
levomepromazine,
thioridazine, flupentixol and/or fluspirilene), depressions (in particular
imipramine,
amitriptyline, desipramine, maprotiline, minaserine, citalopram, fluoxetine,
paroxetine,
trazodone, moclobemide and/or miratazepam), psychoses and schizophrenias (in
particular
sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine,
pimozide,
fluphenazine, olanzapine and/or risperidone), sleep disorders (in particular
triazolam,
brotizolam, oxazepam, flu razepam, nitrazepam, temazepam, zolpidem tartrate,
zopiclon,
promethazine, chlorprothixene, pipamperone, thioridazine and/or chloral
hydrate), conditions
of restlessness and disorientation/confusion (in particular alprazolam,
oxazepam, doxepin,
clornipramine, imipramine, thioridazine and/or perazine), dementia of the
Alzheimer type (in
particular donepezil, rivastigmine, tacrine, mernantine, nimodipine and/or
selegininc).
Drugs for the treatment of cardiovascular diseases, such as coronary heart
disease/angina
= pectoris (in particular acetylsalicylic acid, clopidogrel, ticlopidine,
isosorbide dinitrate,
CA 02876294 2014-12-10
23
isosorbide mononitrate, nitroglycerin, molsidomine, trapidil, metoprolol,
bisoprolol, atenolol,
acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem, verapamil,
benazepril, lisinopril,
ramipril, fosinopril and/or enalapril), cardiac infarction and cardiac
insufficiency (in particular
isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captoprol, ramipril,
lisinopril,
candesartan, eprosartan, irbesatan, losartan, chlortaliclone, xipamide,
hydrochlorothiazide,
furosemide, piretanide, triameterene, digitalis glycosides, carvedilol,
metoprolol and/or
prazosine), cardiac arrhythmia (in particular ajmaline, quinidine,
disopyramide, flecainkle,
propafenone, propranolol, carvedilol, amiodarone, verapamil and/or diltiazem),
hypertension
(in particular metoprolol, atenolol, urapidil, clonidine, dihydralazine,
chlortalidone,
hydrochlorothiazide, furosemicle, felodipine, israpicline, laciclipine,
diltiazem, captopril,
enalapril, fosinopril, lisinopril, ramnipril, vcrapamil, candesartan,
eprosartan, irbesatan,
=
losartan, doxazosine, bunazosine, prazosine, terazosine, moxonidine,
dihydralazine and/or
minoxidil).
Drugs, alone or in combination, for the treatment of the respiratory tract and
the lung (in
particular theophylline, methylprednisolone, flucortone, dexamethasone,
montekulast,
roxithromycin, erythromycin, azithromycin, ciprofloxacin, clarithromycin,
levofloxacin,
ofloxacin, doxycycline, ampicillin and sulbactam, amoxicillin, cefuroxime,
clindamycin,
cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin and/or
moxifloxacin).
Drugs for the treatment of the gastrointestinal tract and the pancreas (in
particular
fluconazole, mesalazine, sulfasalazine, budenoside, azathioprine, prednisone,
metronidazole,
infliximab, loperamide, co trimo xazole,, ciprofloxacin, metro nidazo le,
vancom ycin,
esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine,
ranitidine,
nizatidine, sucralfate, misoprostol, metocloprarnide, pirenzepine, bisacodyl,
clomperidone,
sulpiride, alizapride, dimenhydrinate, cinnarizine, flunarizine,
levomeprazine, ondansetron,
betahistine and/or aprepitant).
Drugs for infection defense with antibiotics or antivirally active substances
(in particular
acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazoline,
cefixime, cefprozil,
ceftriaxone, chloroquirk,s, ciprofloxacin, clotrimazole, dicloxacillin,
doxycyclline, econazole,
erythromycin, ethambutol, fosfomycin, flucloxacillin, fluconazole, fusidic
acid, gramicidin,
idoxuridine, indinavir, interferon, itraconazole, isoniazide, josamycin,
ketoconazole,
lamivudine, lomefioxacin, mafenide, mebendazole, mesalazine, mezlozillin,
mupirocine,
miconazole, naftifine, nalidixic acid, norfioxacin, ofloxacin, oxacillin,
oxytetracyclinc,
piperacillin, praziquantel, primaquim, proguanil, ribavirine, rifabutine,
rimantadine,
CA 02876294 2014-12-10
24
roxothromycin, saquinavir, spectinomycin, spriramycin, stavudine, sulbactam,
teiucoplanin,
terbinafin, tetracycline, tetroxoprim, ticarcillin, tinidazole, tromantadine,
to lna fla te,
vancomycin, zidovudine and/or zalcitabine).
Drugs for the treatment of erectile dysfunction (in particular sildenafil,
tadalafil, vardenafil,
theobromine, caffeine and/or theophylline).
In preferable embodiments the pharmaceutical form according to the present
invention does
not comprise antibiotics in pharmaceutically active amounts, in particular no
representative of
the class of active substances of tetracyclines. Antibiotics compromise the
flora of the
intestine by killing important bacteria in the intestine. In the case of the
pharmaceutical form
of this invention this effect would result in strong adverse effects, since
partially the
pharmaceutical form is dissolved only very late.
In preferable embodiments the pharmaceutical form according to the present
invention does
not comprise proton pump inhibitors. Proton pump inhibitors increase the pH
value in the
stomach and thus disturb the dissolution of many drugs from the first unit
containing active
substance, in particular the weakly basic active substances.
Preferably, the second active substance is contained in the second compartment
in the form of
small particles. This means that the mean particle size of the second active
substance
preferably does not exceed 1000 nm. Further preferably, the mean particle size
of the second
active substance is not higher than 300 nm. The particle size of the active
substance will be
= determined by means of laser diffraction.
The second active substance may be an active substance with good water-
solubility. The
second active substance is in particular an active substance which comprises
at least one
hydroxyl group, at least one carboxyl group and/or at least one permanent
charge. A
preferable active substance is dimenhydrinate.
The second active substance is preferably used in the pharmaceutical form in
an amount of at
= least 50 mg and further preferably at least 80 mg or particularly
preferably at least 100 mg.
The amount of the second active substance should preferably not exceed a value
of 400 mg,
further preferably 300 mg and particularly preferably 200 mg.
The retarding agent in the second compartment of the pharmaceutical form of
this invention is
preferably a polymer, in particular a polysaccharide. Preferred are
celluloses, cellulose
derivatives, alginates or mixtures thereof, but also polyacrylates,
polymethacrylates and their
CA 02876294 2014-12-10
copolymers and mixtures can be used. Especially preferable cellulose
derivatives are
methylcellulose and hydroxypropylmethylcellulose. Such cellulose derivatives
enable a
particularly preferable release of the second active substance and do not show
an
unfavourable pH dependent behavior.
Preferably a retarding agent is used which in aqueous solution in a proportion
of 2 % by
weight at a temperature of 20 C and a pressure of 101.325 kPa results in a
viscosity of at least
1500 mPas. The viscosity is measured with a falling sphere viscosimeter (DIN
53015).
According to the desired retardation of the release of the second active
substance it may be
desired, also to choose higher viscosities. The higher the viscosity of the
retarding agent, the
stronger is the retardation of the release. In especially preferable
embodiments the viscosity of
the retarding agent is even at least 2500 mPas and particularly preferably at
least 3500 mPas.
But when the viscosity is too high, then the release of the second active
substance is too slow.
This would have the result that the second active substance during its passage
through the
gastrointestinal tract may possibly not be completely released. Therefore, the
viscosity should
be restricted to a value of at most 200.000 mPas, further preferably at most
120.000 mPas.
The proportion of this retarding agent in the second compartment should
preferably be at least
10 % by weight, further preferably at least 20 % by weight and particularly
preferably at least
% by weight. When the amount of the retarding agent used is too low, then the
effect
according to the present invention is not achieved. When the amount is too
high, then the
release of the second active substance is too slow. Therefore, the proportion
of the retarding
agent in the second compartment should not exceed a value of 60 % by weight,
further
preferably 50 % by weight and particularly preferably 40 % by weight.
Furthermore, to the first andjor the second compartment a long-chain alcohol
can be added.
Here "long-chain" alcohol means an alcohol with a chain length of at least 10
carbon atoms,
further preferably at least 12 carbon atoms and particularly preferably at
least 14 carbon
atoms. But the chain length should preferably not exceed a value of 20 carbon
atoms, further
preferably 18 and in particularly 16 carbon atoms. It has been shown that the
addition of a
long-chain alcohol is suitable for retarding the release of the active
substances, in particular of
the second active substance.
The weight proportion of the long-chain alcohol in the second compartment of
the invention
is preferably at least 5 % by weight, further preferably at least 10 % by
weight and
particularly preferably at least 18 % by weight. When the proportion of the
long-chain alcohol
CA 02876294 2014-12-10
26
in the second compartment is too low, then the desired effect is not achieved.
When the
content is too high, then the structural integrity of the pharmaceutical form
may be
compromised. Therefore, the content of the long-chain alcohol in the second
compartment is
preferably at most 40 % by weight, further preferably at most 35 % by weight
and particularly
preferably at most 30 % by weight.
Furthermore, the second compartment in the pharmaceutical form according to
the present
invention may contain further adjuvants. These adjuvants may preferably be
selected from
anti-blocking agents, lubricants, binders, disintegrants, antioxidants,
complex-forming agents,
coating agents, flow promoters, preservatives, fillers, plasticizers, pigments
and mixtures of
such substances.
An especially preferable embodiment of the pharmaceutical form according to
the present
invention comprises as the first active substance cinnarizine, wherein it is
exceptionally
preferable that the first active substance is cinnarizine and the second
active substance is
dimenhydrinate. The pharmaceutical form is suitable for use in therapy of
dizziness of any
origin. Therefore, also the use of this pharmaceutical form for the treatment
of dizziness of
any origin is according to the present invention.
A great advantage of the pharmaceutical form according to the present
invention is that it can
be produced in a cost-effective way.
Preferably, the method for the production of the pharmaceutical form comprises
the steps:
a. mixing the constituents of the pharmaceutical form,
b. granulating the mixture and
c. preparing a monolithic pharmaceutical form from the granules.
The mixing of the constituents of the pharmaceutical form is conducted in
embodiments in
which the pharmaceutical form comprises at least two compartments, preferably
by mixing
the constituents of each single compartment so that at least two compartment
mixtures are
obtained. The granulation of the mixture comprises in embodiments in which the
pharmaceutical form comprises at least two compartments preferably the
granulation of the at
least two compartment mixtures, so that at least two compartment granulates
are obtained.
The production of a monolithic pharmaceutical form from the granules comprises
in
embodiments in which the pharmaceutical form comprises at least two
compartments
preferably the compression of the at least two compartment granulates.
CA 02876294 2014-12-10
27
The ingredients of the compartment each are preferably mixed and subjected to
melting
granulation. Preferably, the pharmaceutical form according to the present
invention does not
comprise a coating. In alternative embodiments the pharmaceutical form
comprises a coating
with good solubility.
When two compartments have to be produced, then preferably the constituents of
the first
compartment are mixed together and melting granules are produced thereof. The
same is
preferably conducted with the constituents of the second compartment. But also
with the help
of a spray method granules may be produced.
Then from the granulates a pharmaceutical form is produced. In the case of a
layer tablet the
granules are compressed in a tablet-compressing machine.
=
In preferred embodiments of the production method the first active substance
is mixed with
the emulsifier for the production of the first compartment. Preferably, the
active substance is
dissolved in the emulsifier. Optionally, a solvent can be used. Then active
substance,
emulsifier and solvent are mixed. According to the exact nature of active
substance and
emulsifier different solvents may be considered. Preferably, in the
pharmaceutical technology
common adjuvants are used, in particular alcohols, esters and/or ketones, in
particular
acetone.
This mixture is then preferably sprayed onto a carrier. The carrier may be the
above
mentioned compression aid and/or the retarding agent. The spraying operation
may preferably
be conducted in a fluidized bed facility.
In an alternative embodiment the active substance is mixed with the
emulsifier, in particular
in a compulsory mixer, and melted. Then this mixture is applied onto the
carrier which may
be the compression aid and/or the retarding agent.
Before compression, to the granulates being prepared by the melting method or
the alternative
spray method adjuvants such as lubricants and flow promoters can be added and
then they can
directly be compressed to the desired compartments.
If required, the active substance can be comminuted before, in particular in a
nano mill. The
powder thus obtained is preferably incorporated into the emulsifier. For the
incorporation a
solvent is used in which the active substance is not soluble, in particular
water. The
incorporation prevents the reagglomeration of the active substance particles.
28
The second compartment can be prepared in the same way. Preferably, granules
of active
substance and retarding agent arc prepared, for example by way of wet
granulation, wherein
these granules are then compressed to the second compartment, optionally
together with
adjuvants.
Examples
Example 1
Pharmaceutical forms with the following compositions were prepared (quantities
in mg each):
First compartment Ex. 1 Ex. 2 Ex. 3 Purpose
Cinnarizine 60 60 60 first active substance
Gelucire 50/13 120 240 480 emulsifier
Pharmatoserm 480 480 480 compression aid
Here the mentioned ingredients were mixed and then processed into granules by
way of a
common melting granulation method and subsequently compressed to tablets. The
release was
measured at a pH of 5.5 with a paddle apparatus.
Figure 1 shows the influence of the relative amount of the emulsifier in the
pharmaceutical
form onto the dissolution behavior. The ordinate shows the released amount of
active
substance in percent, the abscissa shows the elapsed minutes. It can be seen
that the amount of
emulsifier also increases the amount of released active substance.
Example 2
A pharmaceutical form with the following composition was prepared:
CA 2876294 2019-11-25
29
First compartment Amount in mg Purpose
C in nari7i ne 60 first active substance
Cielucire 50/13 240 emulsifier
Dynasan' 118 240 triglyceride
Pharmatose 480 compression aid
Sum 1020
Second compartment
Di m en hydrinate 120 second active substance
Nacolim 16-98 80 long-chain alcohol
Met h oce I mE4M (4000 cP) 120 retarding agent
Sum 320
Here at first the ingredients of the first compartment were mixed together and
processed into
granules by means of melting granulation. Thereafter also the ingredients of
the second
compartment were processed in the same way into melting granules. Thereafter
both
granulates together were compressed in a tablet-compressing machine to a
pharmaceutical
fbrrn with two compartments.
Example 3
The following example shows the influence of a triglyceride onto the release
of the active
substance with bad solubility. The test was conducted at a pH value of 5.5 in
a paddle
apparatus. The quantities of the constituents are given in mg.
First compartment Ex. 4 Ex. 5 Purpose
Cinnarizine 60 60 first active substance
Gelucirew 50/13 240 240 emulsifier
Dynasan 1 I 8 0 240 triglyceride
Pharmatose 480 480 compression aid
Figure 2 shows the influence of the triglyceride in the pharmaceutical form
onto the
dissolution behavior of the first active substance. It can be seen that the
triglyceride enhances
the release of cinnarizine. So according to Ex. 5 after 480 min already 23.6
mg of cinnarizine
were dissolved. This is a surprising and advantageous fact, because
cinnarizine at a pH value
CA 2876294 2019-11-25
CA 02876294 2014-12-10
of 5.5 (aqueous buffer) only dissolves in a maximum amount of 1 to 2 mg. The
ordinate
shows the amount of the released active substance in percent, the abscissa
shows the elapsed
minutes.
Example 4
The following example shows further tests for determining the influence of the
emulsifier
onto the amount of dissolved active substance with bad solubility. For that
the following
compositions were compressed to tablets (quantities are in mg each). The test
was conducted
at pH 5.5 in a Bio-Dis facility (30 minutes with 15 dip/minute). After 30
minutes each the
vessel was exchanged. The solutions were analyzed in a photometric manner.
First compartment Ex. 6 Ex. 7 Purpose
Cinnarizine 20 60 first active substance
Gelucire- 50/13 160 480 emulsifier
Pharmatose, anhydrous 160 480 compression aid
For the amount of dissolved cinnarizine the following values were obtained:
= t [minutes] Ex. 6
1! Ex. 7
30 2.14 I 3.92
60 1.12 2.15
90 1.27 2.26
120 0.85 2.36
150 2.07
180 0.45 1.57
Total: 5.83 14.33
It is a surprising fact that with the increase of the total amount of active
substance also the
absolute amount of substance which dissolves is increased. So it becomes clear
that the
amount of released cinnarizine is influenced by the emulsifier and is not
restricted by a
limiting concentration.
Example 5
CA 02876294 2014-12-10
31
The following example shows tests for the formation of an optional second
compartment of
the pharmaceutical form according to the present invention. For that with the
following
compositions (quantities in mg each) using the production method according to
the present.
invention layer tablets with dimensions of 18x8 mm were prepared, wherein for
the first
compartment a placebo mixture was used.
Second compartment Ex. 8 Purpose
Dimenh ydrinate 120 second active substance
Nacol 16-98 80 long-chain alcohol
Methocel E4M 120 retarding agent
Figure 3 shows the release of dimenhydrinate from thc pharmaceutical form. The
ordinate
shows the amount of released active substance in percent, the abscissa shows
the elapsed
minutes. It can be seen that at first within 60 minutes dimenhydrinate is
quickly released from
the second compartment, wherein subsequently the active substance is released
slower and
nearly linear. A retardation of the active substance in the second compartment
over 10 hours
was achieved.
