Note: Descriptions are shown in the official language in which they were submitted.
2170748
Pharmaceutical Preparations for the Targeted
Treatment of Crohn's Disease and Ulcerative Colitis
The invention relates to a pharmaceutical preparation for the enteral
treatment of
Crohn's disease and ulcerative colitis, which contains an immunosuppressive
active agent, which is administered in the form of a special galenic
formulation for
targeted local activity in the intestinal area, its use and a process for the
production thereof.
The therapies known today for the treatment of Crohn's disease and ulcerative
colitis are not very effective. At the end of drug treatment, the patient
usually
faces surgical intervention. There are numerous preparations for extending and
improving the therapeutical possibilities, but until now no preparation has
been
able to meet the medicinal requirements to a maximum degree.
One possibility of local, enteral therapy of inflammatory intestinal
infections was
opened up with the development and usage of special mesalazine-containing
(5-aminosalicyclic acid) preparations, which release the active agent in the
distal
part of the small intestine and in the large intestine. The preparations
concerned
are solid forms of administration, which contain the active agent in
crystalline form
despite its poor solubility.
US Patent 5,206,219 describes pharmaceutical preparations for oral
administration, comprising a dosage unit of a proteinase inhibitor and of a
protein-
like medicament, selected from the group consisting of erythropoietin,
insulin,
growth hormone, calcitonin, growth-colony-stimulating factor, cyclosporin,
vasopressin, vasopressin-agonist, vasopressin antagonist, t-PA, bat's
plasminogen, amplificator, urokinase, streptokinase, interferon and
interleukin, a
phospholipid, cholesterol, a hyrophilic or hydrophobic, surface-active agent
and an
essentially non-aqueous, non-alcoholic, pre-emulsified emulsifiable solution.
2170748
-2-
A new possibility is represented by the use of immunosuppressive active agents
which are more effective than the salicyclic acid derivatives, but when
applied
systemically in therapeutically effective dosages have considerable side
effects.
The present invention is based on the problem of making available a
pharmaceutical preparation for the targeted treatment of Crohn's disease and
ulcerative colitis, which contains an immunosuppressive active agent. The
activity
of the preparation should be targeted at the small and large intestines, and
the
preparation should ensure local, enteral application of the immunosuppressive
active agent at the site of occurrence of the inflammatory disorder.
Surprisingly, an improvement in the rate of effect over the side effects of
the
immunosuppressive active agent, i.e. a broadening of the therapeutical range,
is
achieved through the local application of the active agents in the form of a
new
pharmaceutical preparation, which transports the active agent to the site of
occurrence of the inflammatory disorder and allows optimum activity there.
The immunosuppressive active agents from the group of macrolides claimed here
are poorly soluble in aqueous media, e.g. in the lumen of the gastrointestinal
tract.
The dissolution conditions are extremely unfavourable for poorly soluble
active
agents owing to the small amount of fluid available, especially in the area
being
envisaged for activity of the preparation, the distal small intestine and the
large
intestine. As a consequence thereof, the active agent should advantageously be
transported to the site of the disorder in an already dissolved form. To this
end,
ideally, a solution of the active agent is filled into starch capsules, or
hard or soft
gelatin capsules. The unmodified gelatin capsule or starch capsule does not
survive transit through the stomach and the upper small intestine area.
Undesired dissolution of the capsule shell in the area of the stomach or upper
small intestine is prevented by coating the external capsule wall with a
polymer
film. The choice and usage of appropriate polymers, including additional
materials
CA 02170748 2007-02-08
-3-
such as softeners and pore-forming agents, control the site of dissolution of
the
capsule and the release of solution containing the active agent.
The object of the invention is a pharmaceutical preparation which contains one
or
several immunosuppressive active agent(s) in dissolved form in a starch
capsule,
or hard or soft gelatin capsule which is coated with one or several polymer
films,
as a single active substance.
A further object of the invention is a process for the production of the
preparation
according to the invention, which is characterised in that the active agent is
dissolved in a solvent which is suitable for encapsulation into starch or
gelatin
capsules, or in a mixture of several solvents and optionally solubilizers
and/or
other excipients, the solution is then filled in a manner known per se into
starch
capsules, or hard or soft gelatin capsules in a measured dose, the capsules
are
sealed and the capsules are coated with a solution or dispersion of a polymer
or
polymer mixture and dried, whereby the coating procedure may be repeated once
or several times.
In one particular embodiment there is provided pharmaceutical preparation,
containing rapamycin, tacrolimus, cyclosporin A or combinations thereof as
immunosuppressive active ingredient in dissolved form in a starch capsule, or
hard
or soft gelatin capsule, which has been coated with one or several polymer
films,
whereby the capsule is coated with at least one polymer film which contains at
least
one pore-forming agent.
CA 02170748 2007-02-08
- 3a -
The preparation according to the invention is suitable for the local, enteral
treatment of Crohn's disease and ulcerative colitis. It contains an
immunosuppressive active agent which is poorly soluble in water. The
preparation
according to the invention contains as active agent rapamycin, tacrofimus,
cyclosporin A or combinations of these active agents. The solvents that are
appropriate for dissolving the active agent are those that are
pharmaceutically
acceptable and in which the active agent dissolves.
Examples of these are ethanol, 1,2-propylene glycol, glycerol, polyethylene
glycol
300/400, benzyl alcohol, medium-chained triglycerides and vegetable oils.
CA 02170748 2007-02-08
-4-
If required, the usual medicament excipients may be added to the solution of
active agent and solvent, for example surface-active agents and agents which
affect viscosity. Examples of such excipients are mono-/di-fatty acid
glycerides,
sorbitan fatty acid esters, polysorbates, Mirj 52, lecithin, sodium lauryl
sulphate,
sodium dioctylsulphosuccinate, Cremophor RH40/EL, AerosilTM and water-soluble
cellulose derivatives.
Mixtures of solvents and the above-mentioned excipients may also be used. The
concentration of active agent in the solvent or mixture is adjusted such that
it lies
between 0.2 and 20 % (weight/weight), preferably between 1 and 15 %
(weight/weight), particularly preferred between 2 and 10 % (weight/weight).
The
solution of the active agent is filled into a conventional starch capsule, or
soft or
hard gelatin capsule in an amount of 0.05 ml to 2 ml, preferably in an amount
of
0.1 to 1.4 ml. The gelatin capsules or starch capsules employed may be those
that are normally used in the pharmaceutical field and that are available
commercially. If desired, the capsule may be additionally provided with a
sealing
strip, in order to prevent the solution of active agent from escaping.
Production of
the soft gelatin capsules is effected for example analogously to the known
Scherer
processes. The starch capsules are available under the commercial name
Capill .
To enable local enteral application of the immunosuppressive active agents
deoxyspergualin, rapamycin, tacrolimus, and cyclosporin A to take place, after
swallowing the capsule, there must be passage of the intact capsule through
the
stomach and the upper small intestine region. To this end, the soft or hard
gelatin
capsule is coated with one or several polymer films, whereby the targeted
capsule
dissolution and release of active agent is achieved through the film
composition.
Two principles or a combination of these principles may be offered for this
purpose:
4a - 2170748
1. Premature dissolution of the capsule is prevented by coating the capsule
with a polymer film containing acid groups, whereby the type of acid and
the number of acid groups control dissolution of the film in dependence of
the Ph value of the surroundings.
2. Dissolution of the capsule is controlled by diffusion mechanisms, whereby
the polymer film is insoluble in water and the diffusion operations are
influenced by additional substances such as water-soluble pore forming
agents and softeners.
Within the sense of this invention, especially suitable polymers for principle
1 are:
Cellulose-acetate trimellitate, -acetate succinate, -acetate phthalate,
hydroxypropyl
CA 02170748 2007-02-08
-5-
methylcellulose phthalate, -acetate succinate, carboxymethylethyl cellulose
(Trade
mark e.g. Duodcell ), polyvinyl acetate phthalate (commercial products, e.g.
Coateric0, Opadry Entericft copolymerisates of vinyl acetate and crotonic acid
(commercial product, e.g. Coating CE 51420), polymethacrylates, e.g.
copolymerisates of methacrylic acid and methyl-methacrylate, copolymerisates
of
methacrylic acid and ethyl acrylate (commercial products are e.g. Eudragit
UL30D). Mixtures of these polymers may also be used.
Suitable polymers for principle 2 are:
Methylcellulose (Trade mark e.g. Methocel), ethylcellulose (commercial product
e.g. Ethocel0, Aquacoat(D ECD30), cellulose acetate, cellulose acetate
propionate,
cellulose acetate butyrate, polyvinyl derivatives, e.g. polyvinyl alcohol,
polyvinyl
acetate, vinyl acetate/vinyl pyrrolidone copolymers (commercial products are
e.g.
PVP-VA types of GAF), copolymerisates of methacrylic acid and ethyl acrylate
(commercial products are e.g. EudragitO RURS/NE30D/RL30D/RS30D),
copolymerisates of polymethyl vinyl ether and malonic acid anhydride,
copolymerisates of polymethyl vinyl ether and malonic acid or the ethyl-,
isopropyl-,
n-butylesters thereof (commercial products are e.g. the Gantrez polymers of
the
series ES/AN/S), or mixtures of these polymers.
Moreover, for both principles, the thickness of the polymer film on the
capsule
surface is significant for the progress of capsule dissolution and the release
of
active agent. The required film thickness may differ individually for each
polymer. In
addition, it depends on other excipients, e.g. softeners, the solvent or
dispersing
agent used during the film-coating process, the film application technique,
and the
capsule shape. In practice, the amounts applied lie between 1 mg/cm2 and 100
mg
dry film substance / cm2 capsule surface. The proportion by weight of the
dried film
coating on the whole medicinal substance is normally less than 10% (by
weight).
If both principles are used in combination and the polymers are applied
separately,
2170748
-6-
then one film serves as an external film corresponding to principle 1. This
external
film must have a dissolution time of more than 2 hours in the gastric juices.
The properties of the polymer films may be further influenced by additions of
pore-
forming agents and softeners. Suitable pore-forming agents to form open pores
and
thus to increase the diffusion rate through the polymer coating are water-
soluble
substances, e.g. lactose, saccharose, sorbitol, mannitol, glycerol,
polyethylene
glycol consisting of less than 6000 ethylene oxide units, 1,2-propylene
glycol,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, as
well as
mixtures thereof. The proportion by weight of the pore-forming agents on the
dried
film coating is less than 20% (weight/weight).
Suitable softeners are the alkyl esters of citric acid, tartaric acid and 1,8-
octanedi-
carboxylic acid, e.g. triethyl citrate, tributyl citrate, acetyl triethyl
citrate, dibutyl
tartrate, diethyl sebacate, or resp. esters of phthalic acid, e.g. dimethyl
phthalate,
diethyl phthalate, dioctyl phthalate, or resp. glycerol esters, e.g. castor
oil, sesame
oil, acetylated fatty acid glycerides, glycerol triacetate, glycerol
diacetate, or resp.
higher alcohols, e.g. glycerol, 1,2-propylene glycol, or resp. polyethers,
e.g. poly-
ethylene glycols and polyoxyethylene-polypropylene block copolymers, or resp.
wetting agents, e.g. PEG-400 stearate, sorbitan monooleate, PEG-sorbitan mono-
oleate.
For application, the polymer or a mixture of polymers is dissolved or
dispersed in
an organic solvent or in a solvent mixture. Suitable solvents are for example
ethanol, isopropanol, n-propanol, acetone, ethyl acetate, methyl ethyl ketone,
methanol, methylene chloride, tert.-butanol, propylene glycol monomethyl ether
and
water.
Solvent mixtures or mixtures of these solvents with water may also be used.
For
better processing of the film coatings, the usual excipients may be added to
them,
for example colloidal silicon dioxide, talcum and magnesium stearate. In order
to
CA 02170748 2007-02-08
-7-
apply and dry the polymer film, all known processes for applying films to
tablet or
pellets are suitable, e.g. dip-sword, immersion tube, coating, fluidised bed,
Wurster
column, Accela-CotaT"", Hi-CoaterTM, DriacoaterTM or ball-coater processes.
The person skilled in the art may determine the properties of the polymer
films by
means of simple preliminary tests. It is especially important here that, after
swallowing the preparation, the intact capsule is allowed to pass through the
stomach and the upper small intestine.
For example, the coated capsules undergo a test of the release of active agent
according to USP in a "dissolution rate" testing apparatus having a small
rotating
basket. To this end, the capsules are first of all exposed to artificial
gastric juice for
two hours. Afterwards, the medium is changed over to artificial intestinal
juice
pH 6.8. After a further four hours, it is adjusted to artificial intestinal
juice pH 7.2.
During the whole duration of the test, the concentration of active agent in
the
medium is determined continuously e.g. using a suitable HPLC method. During
the
testing periods, the active agent should not be detectable in the artificial
gastric
juice nor in the artificial intestinal juice pH 6.8, since otherwise the
intact capsule
would not be allowed to pass to the site of action.
The following examples illustrate the invention without restricting it.
2170748
-8-
Exam I
The following solution of active agent is filled into oval soft gelatin
capsules of size
minims:
Amounts in mg/capsule content after production:
cyclosporin A 25.0
ethanol 96% 25.0
polyoxyethylene-(40)-hydrogenated castor oil 87.5
neutral oil 50.0
di/tri/tetraglycerol fatty acid ester 62.5
Two polymer films are subsequently applied to the dried soft gelatin capsules.
To
this end, 250,000 soft gelatin capsules are filled into an Accela-Cota (AC48).
15.0 kg of the first polymer solution are sprayed on, and the solvent is
continuously
removed during the process. The temperature of the air supply for drying the
capsules is 35 C.
The first polymer solution consists of (amounts in % by weight):
ethyl cellulose 5.0
triacetine 1.0
polyethylene glycol 1500 0.6
ethanol 96% 93.4
The second polymer solution consists of (amounts in % by weight):
hydroxypropyl methylcellulose phthalate (HP-55) 8.0
dist. acetylated glycerides 0.8
acetone 46.0
ethanol 95% 45.2
2170748
13.5 kg of the second solution are applied in the same apparatus. The air
supply
temperature is lowered to 30 C. After ending the film application, the
temperature is
raised to 40 C to remove residual solvents.
Example 2
The following solution of tacrolimus is filled into soft gelatin capsules of
size
8 minims:
Amount of capsule content in mg per capsule after production:
tacrolimus 10.0
polysorbate 80 270.0
neutral oil 135.0
sorbitan monolaurate 45.0
A cellulose acetate film is applied to the dried capsules. To this end,
150,000 capsules are filled into a driacoater (DR 1200) having a solvent
recovery
system. The air supply temperature during film coating is set at 30 C. The
sprayed
polymer solution has the following composition:
cellulose acetate 5.0
polyethylene glycol 4000 0.3
acetone 80.0
water 14.7
Example 3
A solution containing the active agent rapamycin is filled into hard gelatin
capsules
of size 1 ". The amounts correspond to the capsule content in mg.
2170748
-10-
rapamycin 5.0
polysorbate 60 230.0
polyethylene glycol 400 190.0
glycerol 5.0
1,2-propylene glycol 20.0
total content 450.0
In addition to this, there is the weight of the empty capsule at 77 mg. Three
polymer solutions are applied in succession to these filled hard gelatin
capsules
(amounts respectively given in % by weight).
The composition of the first solution:
hydroxypropyl cellulose 7.5
polyethylene glycol 1500 0.5
ethanol 96% 92.0
This polymer film is applied to seal the capsules and assists the remaining
processing stages (undercoat).
The composition of the second solution:
Eudragit RS 30D 27.0
Eudragit RL 30D 6.0
triethyl citrate 2.0
talcum 2.5
water 62.5
2170748
-11-
The composition of the third solution:
hydroxypropyl methylcellulose acetate succinate 10.0
triethyl citrate 3.0
talcum 3.0
wate r 84.0
Film coating is effected in a fluidised bed apparatus. The air supply
temperature
during film application is 48 C. The spray rate and air diffusion are set such
that
the outgoing air temperature remains at 21 C.
