Note: Descriptions are shown in the official language in which they were submitted.
15. DEZ ' 97 (MO) 13:08 BOETERS & BAUER +49 89 653962 B. . 3
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~-~.
~,----_ ', _ -, . . _ . . ~ ~ 1
~,2th ~Tu~xe 1995/St
Iiexal AC;, Industriestral3e 25, 8360'1 Holzkirchen
Pharmaceutical pxeparatibn ca~ntain~.z~g ayalosporia ~
1 _ Field of tha . ~.aventior,~
The invention relates to pharms.ceutiaal px~epara-
t~.ons which contain, an effective mount of cyclospor~.z~. A
in cambinat~.om. with emulsifying vitamin E deriv$tives and
a further emulsifier.
2. Prior art
Cyclosporin A is a clsclic, water-insolub7.e, non-
polar uxidecapeptide. 'fhe compound is a hir~hly effective
imm~u~.oauppressant, obtained front fungal aultureg (Carxe et
al. , Traxs,splant x~tCC. I3, - 349358 (1981) i gerguson et
al., Surgery 92, 175-182 (1982)). the medicament is
employed to prevent the rejection of transplanted
allogenic organs (Bennett & Norman, Arzn. Rev. Med. 37.
215-224 Ø986); Van. Basen, Surg. Clin. North Am. 66,
435449 (1985) ) . Its imtaunosuppred,sive effect is based on
a selective inhibition of ,ca~.l function. which allows a
survival of, for examp~.e. heart transp~.ants without
myelocyte aupprassion (Myers et al., New England Journal.
of Medicine 311, 699 (1984) ) . Add~.t~,onally to use in
traxaaplantations, mox'e recent clinical trials have shown
that ayclospoxin A is effective in the treatment of a
~.arge number of autaiamnune disorders. For example,
clinical trials were carried out on the treatment of
poly~ayositis, ayetemia lupus erythematoaus, rheumatoid
arthrit~.a or even of ~uvezzile insulin-dependerit diabetes
(sae the corresponding chapter in: Cyclosporine in
Autoimmune Di~.seages, Editor Schindlex. Springer Verlag.
Berlin 19985 Ls~.cl ) - t
Cyclosporin A is a ,l~.~poph3.l~:a molecule having a
maleculaac weight of 1,,202 daltons. On account of the poor
water solubi,~.ity and the high lipaph~.~.icity of cyclo-
spox~in A, its pharmaceutical composit~.o~s with customary
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sol3,d dr liquid pharmaceutical. excipients often have
disadvantages. Thus the cy~losporina are not adequately
absorbed fro~an such compositions (Cavanak & Suckex,
Fozmulation of nosage Foxms, Prog. Allergy 3B, 65-72
(1986)), or the compoe~.tions are not well tolerated, ox
they are not adequately stable on sstorage, for example
against the arystalla.zation of cyclosporin. Often the
dissolved aoncentrat~.on in relation to t~,e dose of up to
g daily is lava e.g. only 3%, which ateans the admiaia
trat3.on of 30 g of solul;ion. A h~.glaer eolub3.lityr is
mentioned in DE~Ia~2 907 460, in which a eo~.ution of
cyaZoe~ao~~iu in vegetable oi.l, such as o~.3.~re oil or ataize
0~.1, ethaaol sad an emulsifier consisting of a non~ion3.c
ester o~ a triglycerido with a polyalkylene glycol is
described. Examples o~ the preferred compo8itione g~.v'en
by this patent are drink~.ng solution, drinking emulsion,
injection ealution and solution in capau~.es.
The admin~,atration of the above composition Zs
preferably carried out intramuscuLa.rly or subcuGaneou~tly
or, ~.z~, particular, orally. Cycloepox~.n .A, administered
with the above pharmaceutical farms, is distinguished by'
a good bioava~.lability. h,fter absorption,, the substance
binds rapidly to plasma proteins and has a teravir~a~. half-
life of 2~k hours. It is metabolised to a high perce~r.tage
in the liver, biliary excretion being the main elimina-
tion route (Hevex~.ge, Cycloepor~.z~ A: in: Proceedings o~
Internat~.onal Symposium, Cambridge, editor white,
pages 35-44 (1982)).
In spite of the. great value as an immuno
suppressant. the clinical use of cyclospor~.n A xa l~.xn~.ted
by the ma~.=z side effect ~.n chronic use, v~rhich ~.s the
nephrotox3.city of the active compoura.d itself (Yen Buren,
Surg. Cl~.a. North Am. 66, 435-449 (1986)). In about 80%
o~ the kidney traar~plantat~.on patients, xenal tox~.city
also occurs (Kahan, Dial. Transplant. l2, 620-30 0,983)),
mainly duo to this substance-inherent a3.de effect, ~rhich
is used for the protection of the transplant from re~ea-
tioz~.
Frequent side effects of ayaXosporin treatments
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in varivta,s auto3.mmur~e disorders include. in addition to
nephrotoxic~.ty: hypertension, hyperlcalae~aa~.a,
hyperuricoaemia [sxc7, hepatotoxicity, anaemia,
hypertrichiosis [sic), gingival hyperplas3.a,
gastrointest~.~aal side effects, trennor e.nd paresthesia
(''Von Qraffenried et al . , Cyclospvrine in Autoimanune
Diseases, Editor Schindler, Spa~inge~ Verlag, Her~.~.n,
pages 59-73 (2985) ) . O~ the' e~.de effects mentioned here.
the must fxequent is nepYirotoxicity. The acute
1o nephrotoxicity ~.nduced by cyclosporin is dose-dependent
and correlates with the cyclosporin blood leve~.s. It is
~rvveraible otter dose reduct~.an, or after completion of
cyclosporin therapy (Chapman et al., Lanaot I, 128
(1985)) .
Anute cyclosporin nephrotoxicity is accompgnied
mvrpho~.or~iCall~s by tubular lesions which are charac-
terized bar i.rlcXusion bodies, ~.sometriC vaeuolizatioz~ and
microcalcification (Mihatsch et al., Trs.nsplant. Proc.
15, 2821 (1983)). This leads to a decrease in the
gloanerular filtration rate, as can be detected on the
basis of the rapid rise of serum areatinine in
cyclosporin~treated patient,e. A reason for this Could be
the perturbation of the microciraulatfon by ~.atersction
of cyaloaporin with the local promtacyclin synthesis
(Neild et al.; in: Cyclosporine, editor ICahan, Gxuen &
Stratton., Orlando, ~'lorids, page 182 (1984)).
Although the mechanism o~ renal, dysfunction k~as
still not been completely clarified, ~.t was possible to
show that the rez~al synthesis of throxnbcaxane occurs
fluxing the progress of ~.mmune- and non-iaunune-mediated
models of renal damage (Lianos et. ~t~.., ~T. C~.i.zrs. Invest.
72, 1439-1448 (1983); Okegawa et al., ~'. Clin. Invest.
71, 81-90 (1983)). Thromboxane is a prvstanoid and thus
a metabo~.ite of arachidonic acid ~xam the cyclovxygeriase
cycle. xhe other prostanoids axe prostagland3.n.s anal
prostacyclins. Prostano~.ds are very efiectivo mediators
which are formed during immunologiaally generated ~.nflam-
mat~.oz~. processes. They can basi.ca~.~.y change the rer~al
haemodynamias (Morley; in: I~ymphokiaea, editor Pic,
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Acadeat~,c pa~ess, New York, 4, 377-391 (1981) ) .
~P-A-.0 30S 400 describes the conn.ect~.ons between
disordered prostanoid synthesis and nephrotoxicity.
According to ths,a the administration of cyclosporin is
accompanied by an increased ayr~thea~.s of throatboxane B2 ,
a mediator of inflammations. Cycloaperin shou~.d accvrd
ingly slap pxornote the formation of prostaglanditis of the
E seri~a, a,~.so inf~.ammat~.on mediators. rt was possible to
cozinect the re j ec tion of human kidney trazr~.aplanta with a
xapid rise in retially eli~nated throz~boxane B2.
~1?=A-0 305 400 ~urthernaore describes the use df
w3-unsaturated fatty acids Caic~ in combination with
cyclosporin A for the inhibition o~ prostagland~.n or
thromboxsne formation.
A diasdv$ntage of the lQr~gex..terni w3wfatty ac~,d
Csic1 adm4nistration i.s the fQrmat~.on of a vitam~.n E
deficiency state. Dcf~.ciency states are, for example,
haemolysis and a reduced lifetime of, the erytha~ocytes.
In animal experiments, vitamin E de.f~.c~.ency leads t~o
degenerative muscle changes, creatinuria, increased
haemolysis of the erythrocytes and ~to effects ot, certain
hormones and exizyuiee and also prote~.n and araahidonic
acid metabolism (xiachl~.n. Vitamin E; in: Machlin, hand-
book of Vitamins: Nutritional, Hiochemieal and Clinical
Aspects, pages 99-x,45, l~ara~1 Dekker, New York, 1984).
A further diaadvar~tage of th~.e combinat~.oz~ v~r~.th
w3-uaeaturated fatty acids Ceica (fiph oils) is the
obvioua~.y low active compound concentration to be
achieved ~,n this oil. Thus EP-A-0 305 400 describes only
3Q a concentration of 12.5 mg of cyclosporin A per gram of
fish oil. In the case of a customary da~,~.y dose of more
than 300 mg of cyclosporin A, this means a, total, adminis-
txativn amount of approximately 24 grates of the prepaxa-
tidn and in thca case of ~. g of cyclosporin A of a0 g of
preparation. For patients, this is an unreasonably high
amount of oil which would lead, for exa~p~.e encapsulated
in soft ge7.at~.n oapsu7.ea, to a daily administaration of
2~4 capsules containing 300 mg of tyclosporin A. Paren-
teral a,dm~,x~,3.s~tration by infusion would mean in an,
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optimistically calculated, 10 per cent oil-containing
infusion emulsion an amount of about 240 ml of emulsion
containing 300 mg of cyclosporin A, a volume which can
only be infused over a relatively long time. Both aspects
totally stand in the way of chronic administration, as is
necessary in the case of transplantation patients.
The formulations according to DE-B-2 907 460 are
indeed distinguished by a very high dissolving power for
cyclosporin A, but have the disadvantage that they only
include plant oils which contain no prostaglandin or
thromboxane synthesis-inhibiting substances whatsoever.
That means that the nephrotoxicity of cyclosporin A is
not inhibited by the preparations. The commercially
available parenteral solution of cyclosporin A
(SandimmunR) contains 50 mg of cyclosporin A, 32.9% of
ethanol and 650 mg of Cremophor EL*, an ethoxylated,
hydrogenated castor oil, in 1 ml of solution. In addition
to the amount of ethanol of 2 g per administration, which
is a burden to the liver, according to literature reports
Cremophor EL* is nephrotoxic similar to cyclosporin A
itself (Thiel et al., Clin. Nephrol. 25 (Suppl. 1),
540-542 (1986); Finn et al., Renal Failure 11, 3-15
(1989)). Thus Cremophor EL* in the isolated, perfused rat
kidney leads to a marked renal vasoconstriction with
reduced renal blood flow and tubular dysfunction (Besarab
et al., Transplantation 44, 195-201 (1987); Luke et al.,
Transplantation 43, 795-799 (1987)). In addition,
Cremophor EL* causes anaphylactic reactions up to shock
(Chapuis et al., Engl. J. Med. 312, 1259 (1985),
Leunissen et al., Lancet 1, 637 (1986); Magalini et al.,
Transplantation 42, 443-444 (1986)). The cause of the
anaphylactoid reaction was regarded as Cremophor EL*, as
it leads to histamine liberation (Ennis et al., Agents
Action 12, 64-80 (1982)). In some cases of therapy with
the i.v. solution, the allergic reaction was observed on
the first administration to humans (Friedmann et al., Am.
J. Med. 78, 343-345 (1985); Magalini et al., Transplanta-
tion 42, 443-444 (1986)). The disadvantage of the commer-
cially available parenteral preparation is accordingly
*Trademark
CA 02224792 2001-07-30
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the ingredient Cremophor EL*. A formulation is therefore
attempted which avoids the above side effects and
increases the safety of the medicament.
The favourable immunosuppressive properties of
S cyclosporin A are utilized in the treatment of psoriasis.
On account of its high molecular weight and its very high
lipophilicity, however, cyclosporin A is not able to
penetrate intact skin, especially the stratum corneum.
For this reason, severe cases of psoriasis are treated by
oral and parenteral cyclosporin administration. The
disadvantage [sic] of this use are the systemic side
effects on the circulation (hypertension) and the kidney
function. Topical preparations for the treatment of
psoriasis, with which the systemic side effects would be
reduced, need absorption promoters, such as, for example,
propylene glycol and azone (Duncan et al., British
Journal of Dermatology 123, 631-640 (1990)). However, it
is now especially known of azone that its permeation-
promoting properties are to be attributed to a perturba-
tion or even destruction of the protective function of
the stratum corneum. Propylene glycol leads to a drying-
out of the skin. Both substances would thus be more of a
hindrance than a help in the healing of psoriasis. For
this reason, a topical preparation having a thera-
peutically adequate cyclosporin A content in combination
with substances promoting the healing process would be
desirable. Moreover, the combination should promote the
permeation of cyclosporin A through intact skin.
3_ Object of the invention
The object of the present invention, then, is
to find an advantageous solvent system which dissolves
cyclosporin A in adequate amount, so that it can be taken
orally in the therapeutically customary daily dose, can
reduce the nephrotoxic effect and on topical application
can promote both skin permeation and the healing process
in the treatment of psoriasis.
4. Description of the invention
*Trademark
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The obJect on which the ~.~avention 1e based has
now been achieved by a pharmsaeutica~, pareparati.oa which
consists of or aonta~.ne cycloeporin A, an ennuleifying
a-tocopherol derivative. an ethoxylat~.on product of
vegetable oils, fatty ac~,da or fats as a further
emulsifier and a phax'maceu>rically customary alcohol.
This phaxuwaeutioa~, preparation can be charac-
terized by 1~-ct-tocophe~rol polyethylene glycol 1000
auccinate (vitama.n L-TPGS) as a-tortopherol derivative.
The pharmaceutical preparation can fuxthmrznore be
character~.~ed by a coxxtent of a-tocopherol der~.vat~.ve of
up to a 9-fold amount on the basis of cyclospor3.ra A-
The pharmaceutical preparation can furthermore be
characterized by a content of cyclosporin A of a 10% on
the basis of the cou~ao~sftion.
The pharmaceutical pxgparation can furthermore be
characterized by Sts content of ethanol or ~.aopropanol ae
pharmaceutical7.y customary a7~cohol, in particular ~.n
amountrt~ of up to 30~.
The pht~~rmaceutiaal preparation can ~rxrthexmore be
chaxs.cterized by a aox~tent of ethoxy~,ated castor oil as
g further emu~.sifier.
The pharmaceutical preparat~,oz~, can furthermore be
characterized by a coxxtent of thickener.
According to the invention, it was thus surpris-
~.ng7.y found that emulsifying a-tocophexol derivatives,
such as D-cx-tocopherol po~.yethylene glycol, 1000 suc-
cinate, have an excellent emulsifying os solvent power
for cyclospor~.n A, and at the sage time iahibit the
synthesis of prostanoids such as prostaglaz~.dirss and
thromboxanes, wh~,ch ~aan be utilized to reduce nephrotox~.-
c~.ty and to cause ~.nflanmtatory xeactiona in the skin to
die down and at the same time promotes the absorption of
GycZosporin A through the intact sk3.n. The particu~.ar
advantage of the solutions acco~-da.ng to the invent3.on
consists. in addition to the achievement of high concen-
t~cations of dissolved cyclosporin A of at least 10$, in
that tho ri-a-tocophero~. derivatives; as derivative of
natural vitamin E, have ~.r~trinsia effects wh~.eh on the
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one hand counteract tox~.c effects of cyoloeporin A at the
customary high dosee on oral admi.nietration and on the
other hand by means of the absorption-promoting action
~.narease the intexrded immunosuppressive effect ~.n the
topica,~, treatma~.t of psoriasis
Thus vitamin E and its dex~.~at,ives affect arach~.-
donic acid metabolism ixx the sense of as inhlbit~.on of
pxoetaglandin, thromboxane and leucotriene biosynthesis
and an ~.x~,creage is prostaayclin fornnation. These pro-
~.0, potties are connected with a biological inh~.bit~.on of
inflammation and with thrombotic disorders (Machlin,
Vitamin E. = 1x1: Mach~.in, Handbook of Vitam~.ns : Ntritional
[sica, Biochemical and Clinical Aspects. pages 99-145,
Marvel Dekkar, New Ydrk, 1984). After oral admin~,a-
tration, vitaatin E aaa also promote the activity of nozs-
steroidal anti.-3nflama~tory drugs (Bertolini et al.,
Rivista d1 Phax-makolog3,a et Therapies 8. pages 27-34
(1982); Klein .& Bl,ankenhoxn, Vergleich der kllnischen
Wirksamkeit von vitamin F and Diclof~nac Natrium beg.
Spondylitis Aacylosans (Morbus Bechterew) LCampaxiaon of
the Clixiiaal Act~.vity of Vitamin E and n~.clofenac Sodium
in Ankylosing Spondylitis (Bechterew's . disease)).
Vitamix~.apyar 2, pages 137-142 (1987) ) . After topical
administration, vitamin E permeates the stratum cornetl'!11
very tell. Quantitative absorption studies were carried
out ox~ the skta of expcaximental axl,ir:tals . In th~.e way,
1~ hours after application of 300 E,cg of a a per cent
vitamin E so3,ution ixa. ethanol per cm2, 10.7% of v~.tamin E
was fc~utad irx the horny layer and about 40.9% in undex-
ly~.ng akin 3.syers (D7eragsi, et al., Vitamin E:
Biochemical function and its ro~.e in cosmetics, Drug &
Cosmetic Industry 13, No. 1, pages 29-31, 34, 78 (198fi)).
Applied loaa~.xy. vitaa:in E acts as a membrane-stabila.~ing
antioxidaz~.t and inhibits the release of h~.etam~.ne and
hydrolytic enzymes, for example from the mast cells and
the lysosomas,.by stabilization of their membranes. It
also inhibits the synthesis of, certain pxoataglanding.
deactivates oxygen radicals and detoxi.f~.ae corresponding
secondary products (Saes. $~.ldung von Superoxidradikalen
15. DE2 ' 97 (MO) 13: 12 BOETERB & BAUER +49 89 653962 6. . 11
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and Peroxiden [Formation of Superaxide Radicals az~d
Peroxides]; in: superox~.ddiemutase ~ Biochemis and
therapeutJ.scher Einsatz IBuperoxide Dismutase - Bio-
chemistxy and Therapeutic ZTseJ; editors Puhl t~ Ries,
Perimed Varlag. Erlangen, 1982). Vitamin E moreover
increases the moistness o~ tha skin and-acts virtually as
an occluding agent. 111 these described properties are
advantageous in the tree,tment of psoriasis.
Gyeloeporin A now dissolves completely uziex~
pectedly in such a high coneeutrat~.oss o~ a 10% in pxe
parations accordi~(a.g to the invention that the combination
can be therapeutically usefully eanployed aA a solution
both in soft gelatin capsules and izi to~aieal foxmuls
tiong.
~.S In addition, the formulations can contain
thickenexa, such as colloidal s~.~.~.a3c acid or polyacrylic
acid or palyacrylic aG~.d derivatives or ae~.lulose dQ~'irra-
tives~ as well as antioxidgnts and f~.avouringe.
S _ E~ca~~.os
8xample 1 (soft gelatin capsule)
The aompoaition of the formulation was as
Follows:
Cya~.ospoxin A ~.0 o mg
Ethyl aZcoho~, 96~ 200 mg
2'S Vitamizi . E-TPGS 300 mg
Poiyethoxylated castor ail. 200 mg as ethoxylation
produtty of a fgt
Polyethylene glycol ~QO X00 mg
The mixture was filled ~.nta hard gelatin capsuJ.es
[s~.eJ and tested in a cross-over expaximent in dogs in
comparison with a con~mexGfally available product
(sandirunun OptivalR) . The b~.ood level analysis was
caxrfed.out by means of flrxorescanee 3mmuno-essay Isle].
It can be seen clearly ~rcam Fig. 1 that the
capsule preparation according to the invention is ec~uiva-
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lent to the commercially avai~.able product with respect
to blood levels.
