NOUVELLES PREPARATIONS PHARMACEUTIQUES RENFERMANT DE LA CYCLOSPORINE, POUR ADMINISTRATION ORALE

NEW PHARMACEUTICAL PREPARATIONS COMPRISING CYCLOSPORIN FOR ORAL ADMINISTRATION

Abrégé anglais

The invention relates to new cyclosporin-comprising oral
pharmaceutical preparations. The new pharmaceutical pre-
parations can be produced more easily and have a good bio-
availability. In addition to cyclosporin as active ingre-
dient the preparations contain an alkylene-polyether or
alkylene-polyester. Optionally, an alkylene-polyole, an
alkylene-glycole, a polyalkylene-glycole, an alkyldiether or
paxtial ether of a lower monooxyalkandiole or polyoxyal-
kandiole and/or a vegetable oil or its hydrated or
hydrolysed product may be contained.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Pharmaceutical preparation for oral administration
containing as the only component or consisting of
(a) a cyclosporin as active ingredient, and
(b) an alkylene-polyether or alkylene-polyester either
alone or in any mixture as vehicle, whereby the HLB of
the component (b) used being at least 10.
2. Pharmaceutical preparation according to claim 1,
further containing (c) an alkylene-polyole, alkylene-gly-
cole, a polyalkylene-glycole, an alkyldiether or partial
ether of a lower monooxyalkandiole or polyoxyalkandiole
and/or a vegetable oil or its hydrated or hydrolysed product
either alone or in any mixtures.
3. Preparation according to claim 1 or 2, in which the
respective components (a), (b) and/or (c) are available in
the following weight ratios: 1:1-50:0.5-20, preferably 1:5-
10:1-10, in particular 1:5:1.
4. Preparation according to one of claims 1 to 3, in
which the component (b) is chosen from among saturated poly-
glycolised glycerides.
5. Pharmaceutical preparation according to the previous
claim 4, in which the component (b) is chosen from among the
Gelucires GelucirR 35/10, 44/14, 42/12, 50/13, 53/10 and any
mixtures thereof.
6. Pharmaceutical preparation according to claim 2, in
which the additional component (c) is chosen from among gly-
cerine, propylene glycole, PEG with MG up to approx. 600,
transcutol and castor oil.
7. Pharmaceutical preparation according to one of the
previous claims in the form of hard-gelatin capsules or in
the form of a tablet.
8. Pharmaceutical preparation according to one of the
previous claims, characterized in that the active ingredient
concentration is 20 to 200 mg, preferably 50 to 100 mg per
dose unit.

Description

2161193
New Pharmac~uti~al Prepaxation5 Compri3ing Cy~lo~porin fox
Oral Admini~ration
The invention relates to new pharmaceutical preparations
comprising cycloRporin as active ingredien~ for oral admi-
nistration.
Cyclosporins are a class of peptides which are used as im-
m~no~uppres~ants, in particular. Moreover, cyclosporins are
known to have an~iphlogistic and antiparasitic effec~,
Therefore, the use of cyclosporins is not limlted to immuno-
suppre~sants only but relate~ to all phlogistic diseases in-
cluding various auto-immune diseases as well as other phlo-
gistic condition~, in partic~lar, phlogistic conditions ~n
~hich auto-;~ml1n~ processe~ play a xole. The above phlogis-
tic ~onditions also include, in particular, arthritic di-
sea~es such as rheumatoid arthritis as well as rheumatic
disea6es. Cyclosporin5 can be u~ed as antiparasitic agents
e.g. fox the ~reatment of protozoal infec~ions s~ch as ma-
laria.
Cyclosporins are highly hydrophobic subs~zn¢es, having the
consequence that it is difficult to easily process them into
pha~maceutical p~ep~ration~ e~suring furthe~ suf~icient bio-
~vailability. The latter aspec~ is particularl~ important,
~ecause th~ cycloRporins possess ~ephrotoxic side-effec~s of
essential impo~ance. Cyclosporin-cont~;nin~ pharmaceutical
prepar~ion~ proposed so far are based on the use of an ~1-
cohol and/ox oils or similar vehi~le~ i~ connection with a
surface-active agent. S~ch preparations are known from DE-OS
~9 07 460, for instance. The use of such liquid composi-
~ions, however, is accomp~n;ed by a num~er of disadv~ntages
and difficulties The use of oil~ or compar~ble vehicles on
oil basis leads to imp~ir~ent of the sen~e o~ taste, in par-
ticular, in the case Q~ long-time administr~tion as a con-
se~uence of lon~-term t~e~p~. Since for dissolving ~he ac-
ti~e ingredient a high amount of ~lcohol is ~equired, the
resul~ will b~ that in addition the patient is permanently
~min; stexed alcohol and in the oa~e of evapox~tion of the
alcohol during long-te~m use ~he active ingredient pre~i-
pitates. T~e ~ttempt to offer su~ preparations i~ ~he for~
o~ soft gelati~ c~psules did not yield ~ satisfactory so-
lution elthe~ due to the higher e~penditure conne~ted there-
with.
CHS

~16I143
DE-OS 40 03 844 proposes a preparation syste~ which i~ addi-
~ion to the active ing~edient contains a fatty acid sa~char-
ide monoester and ~ diluent or vehicle by ~e~s of which it
i~ said to be po~si~le to provide ~olid, semi-solid and li-
quid prepa~tions having a content of cyclo~porin in a suf-
fi~iently hi~h conce~tration, so that ~hus o~a~ adm~nis-
~ration is comfortably possible ~nd an improved efficiency,
for in~tance, with respect to the bio-availability prop-
e~ies will be achieved. Accordingly, these forms of adm~-
ni~tra~ion contain at least two ~omponents in additio~ to
the active in~redient.
The applicant now has surprisingly found a preparation sys-
tem for oral ~i ni stration by means of which it is possible
to provide a cyclosporin-~omprising pharma~eu~ical prepara-
tion for oral administration, which in addition to~the ac-
tive in~redient cyclo~porin contains onl~ one vehicle com-
ponent. Said component is ~n alkylene-polyether ox alkylene-
polyester or any mixtu~ thereof, in which ~he vehicle sys-
te~ must have an HLB of at leas~ 10. The preparations ac-
cording to the invention yield a bio-avail~bili~y of the
active ingredient whi~h at least is comparable with the
best, known cyclosporin-containing preparations.
Ha~ing a comparably good bio-availability the pharmaceutical
preparaticns according to the invention can be produced in a
more economical way, ~void additives impairing the sense of
taste as well as the disadvantageous alcohol contained and,
in addition, lead to a ~etter patien~ compliance within the
~ense that the total weight of the formulation to ~e admi-
nistered is reduced as ~o~pared ~ith known preparation~,
with the active ingred.ient concen~ration staying ~he same.
Therefore, the inve~tion rela~es to pharmaceutical p~epara-
tions for oral administra~ion, containing cyclosporin as ac-
~i~e ing~edient and bein~ compo~ed as follo~s
a) a cyclorporin as active inyr~dient,
b) an alkylene-polyether or alkylene-polyester ~s vehicle
or an~ mixture thereof, with ~he HLB ~eing at least 10.
Optionally, the p~eparations according to the invention may
contain as further component (~) an alkylene polyole, an al-
kylene glycole, a polyalkylene glycole, a C~s-al~yldie~her
or partial ether of a lower ~onoo~yalkandiole or polyoxyal-
kandiole having 2 ~o 15 carbon atoms and/o~ a vegetable oil
or its hy~ ed or hyd~olysed produ~t.
Moreover, the preparation~ according to the inven~ion can
con~ain furthe~ known, com~on and pha~maceutically accept-

~1611~3
--3
able additives (d) ~uch as are known i~ the field of theproduction of oral fox~ulations.
In pa~ts by weigh~ the prep~rations according to the in~en-
tion contai~ 1 to 50 pa~ by weight of (b) and/or 0.5 to ~0
parts by weight o~ (c) per par~ by weight active in~redient,
preferably S to 10 part5 by weight (b) and/or 1 to 10 parts
b~ weigh~ (c) per 1 ~art acti~e ingredient and, in particu-.
lar 5 part~ by ~eigh~ (b~ and/or 1 pa~ ~y weight (c) pe~ 1
part by weight active ingredie~t
In the case of component (b) it suitably pertains to C3 to
C5 alkylene-triolether or C3 to Cs ~lk~lene-trioester, in
particular glycerine. These also include e.g. ~ranses~erifi-
c~ion product~ of the ~lkylene-triolesters with other mono-
oles, dioles or polyoles as well as those subst~ces de-
sc~ibed under "~omponent Csl' in DE-OS 4~ 03 84~. Saturated
polyglycolised glyceride having an HL~ of at least lO are
paxticularly adv~ntageous. Preferably, the satura~ed, poly- ~'
glycolised glycerides known under the mark tenm Gelucire
(the term Gelucire i~ a tr~e~rk of the company Gattefoss~)
are u8ed and, in particular, the Gelucixe~ 35/10, 44/14,
4~/12, 50/13, 53/10 and any mixtuxes ~hereof, in which
connection the ELB of the vehicle components used is at
least lO.
The option~l component (c) comprise, for instance, di-ethers
or partial ethers of lower (Cz.l~) mono- or polyoxyalkandi-
ole~ æuch as are described in D~-OS 39 30 ~2~ in the sec~ion
relating to the co~ponent 1.1. ~he optional component (c)
fur~her comprises C3 s alkylene polyole~, C24 alkylene gly- -
~oles, poly-(C2,-alkylene~-glycoles, and vegetable oils as
well as their hydration a~d/or hydrolysis products such ~s
ca~tor oil, olive oil, palm oil, coconut oil, corn oil, se-
sa~e oil. The componen~ (c) may be contai~ed as single sub-
stance or in any mixture~ Preferred examples of the compo-
nent (c) are glycerine, p~opylene glycole and polyalkylene
glycole having ~ molecular weight of up to 600, in p~rticu-
lar transcutol and cas~or oil and the hydrated and hydrolys-
ed products thereof.
The fu~her u~able ~dditives pertain to pharmaceutically ac-
ceptable additive6 common in the field o~ oral form~ of ad-
ministration. Examples thereof are the relea8e of control-
ling ~u~stances, thickening agents, prese~vati~es, stabili-
zers, flavorings, ~inding agents, lub~icant~ and the like.
These additi~es may amount ~o up to SO~ of t~e total co~po-
sition, however, pre~erably does not exceed 25~ and, in par-
ticula~, not 10~ of the total composition.

21611~3
All of the known natural and ~yn~hetic cyclo~po~ins includ-
i~g their analogs and derivatives are suitable for ~he u~e
in p~eparations ~ccording to the invention. Exa~ples of such
cyclospo~ins are found e.g. in DE~OS 40 03 ~44 and DE-OS 40
05 190, Preferably cyclo~porin A i~ used.
The oral forms of administ~a~on include e.g. liquids, g~a-
nula~es and solid forms suc~ as ta~lets and capsule~ which
can be produced according to the common methods known to the
per~on ~killed in ~he art.
The oral forms of adminis~ration according to the invention
usually are available in ~t~n~rd dose form and contain
a~out 20 ~o 200 mg, preferabl~ 50 to 100 mg acti~e ingre-
dient per ~tand~d dose.
~he following example~ serve the fur~her illu~ration of the
invention.
Example~
1. Co~onent~ Amount ~m~
Cyclosporin A 50.0
Gelucix 53/10 300.0
Total 350.0
2. ~yclosporin A 50.0
Gelucir 44/14 250.0
Pxopylene glycole 50 0
Total 350-0
3. ~yclo~porin A ~0.0
Gelucir 50/13 250.0
Trans~utol 75.0
Total 375 0
4. Cyclospo~in A 50.0
Gelucix 44Jl4 250.0
Total 300 0

~1611g3
s
5. Cyclosporin A 50 0
Gelucir ~0/13 250.0
Propylene glycole 50.0
~otal
. Cyclosporin A 50 0
Gelucsr 35/10 250.0
Propylene glycole ~5 0
Total 325.0
7. Cyclo3porin ~ 50.0
Gelucir 53/10, ~2/12 27S.0
~ranscutol 50 0
Total 375,0
8. Cy~losporin A 50.0
Gelucir 42/~2 ~o~ o
Glyce~ine ~5.0
Total 375-0
9. C~closporin ~ S0.0
Gelucir 50/1~ 250.0
Castor oil 75.0
Total 375-0
Production: The composition~ of examples 1 to 9 are prod~ced
in that the component ~b~ is melted ~y heati~g preferably to
at lea~ 60~C and the ~tive ing~edient (a) is dissol~ed
the~ein by s~irring. If desired, optio~al component (c) i~
added to the mel~ed mass.
Subseque~tly, the preparations obtained are filled, ~or in-
stance, in liquid f~rm into hard-gelatin c~psules of the de-
sired ~i~e in the concen~ration~ de~ired. The compositions
can also be f~rther proce6~ed to tablet~ in ~he known man-
ner. ~or this pu~poe, the ~elted masses are produced a~
desc~i~ed in the above~ The liquid mel~ed masses are poured
out and after ~olidification diminuited by me~ns of a siev-
ing ~achine. The ~ranulates produced such are mixed with ~he
usual adjuvants such a~ slip agents ~nd lubricants, ~lastin~
age~ts, fillers, flavor corrige~t~ e~c. The finished mix-
tures are pressed to tablets ha~ing the desired content of
cyclosporin. The tablets may also be coated with a protec-
tive co~er.

2161143
~io-A~allability:
R~Am~n~tion~ as to the ~io-availability of ~he ~omposi~ions
accordin~ ~o the invention on dogs.
A group o~ six Be~gle dogs was used fo~ the bio-availability
e~Am;nAtiorls. The test drugs were orally ap~lied to the ani-
mal with an em~ty stomach ~y means of oesophayeal sounds. At
defined time~ blood is taken from ~he ~ena saphena of ~he
An;~?l 8 and collected in correspo~in~ plastic tubes with
E~TA additive. The blood samples are sto~ed until assayin~
at -18C. Assay of the cyclosporin take~ place in ~he whole
blood by means of fluorescence-polarisation ;~llnoassay
(FPIA).
The areas under the cur~es (AUC~ in which the ~loo~ d~u~
concentration is applied relative ~o time were calculated
accor~ing ~o the trapezoid ~ule. The aver~ge AUC values o~
compo~itioIls according to the invention are ~hown in the
followin~ table in comparison to ~he commercially available
sub~tances of cyclo~poxin drinking solution and cy~losporin
capsules (s~ndimmllnR) which ~ere ascertained in the same
in the same dosage with the same dogs.
~3xa~les AUC ( 0 -12 h) ng/rlll
Exa~ple 2 gO35 + 2~34
Example 3 785~ 1 1512
Example 4 755~ ~ 1lg4
Example 5 8228 ~ 8S7
Cyclo~porin Drinking Solution 7sao 1 13ZO
C~closporin Capsules 8098 + 1$04
As the above tests on ~he bio-a~ailability show, the phar-
maceutical prepa~ations according to ~he invention make it
possible ~o pro~ide the ac~ive ingr~dient cyclosporin in
such ~n oral form that its bio-availability at least ~o~re~-
ponds to ~he preparations ~own ~o far.