CA2224792C - Pharmaceutical preparation containing cyclosporin a - Google Patents

Abstract

The invention relates to a pharmaceutical pre- paration which consists of or contains cyclosporin A, an emulsifying .alpha.-tocopherol derivative, an ethoxylation product of vegetable oils, fatty acids or fats as a further emulsifier and a pharmaceutically customary alcohol.

Description

15. DEZ ' 97 (MO) 13:08 BOETERS & BAUER +49 89 653962 B. . 3 ~-~.
~,----_ ', _ -, . . _ . . ~ ~ 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 15. DEZ ' 97 (MO) 13:08 BoETEAS & BAUER +49 89 653962 8. . 4 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 15.DEZ '97 (MO) 13:09 BOETERS & BAUEA +49 89 653962 s..5

3 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, 1 5. DEZ ' 97 (MOB 1 3 = 09 BOETERS & BALTER +49 89 653962 s. . 6 _ 4 _ 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, 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 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 15. DEZ ' 97 (MO) 13: 11 BOETERB & BAtIER +49 89 653962 ~. - 9 7 _ 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 1 5. DEZ ' 97 (MO) 1 3 : 1 2 BOETERB & HALTER +49 89 653962 s- - 1 0 - g -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 - 9 ..
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-15. DEZ ' 97 (MO) 19: 13 BOETER6 & BAL1ER +49 89 653962 ~. - 12 lent to the commercially avai~.able product with respect to blood levels.

Claims (8)

1. Pharmaceutical preparation, consisting of cyclosporin A, an emulsifying .alpha.-tocopherol derivative, an ethoxylation product of vegetable oils, fatty acids or fats as a further emulsifier and a pharmaceutically customary alcohol.

2. Pharmaceutical preparation according to Claim 1, characterized by D-.alpha.-tocopherol polyethylene glycol 1000 succinate as .alpha.-tocopherol derivative.

3. Pharmaceutical preparation according to any of Claims 1 or 2, characterized in that it contains up to a 9-fold amount of an .alpha.-tocopherol. derivative on the basis of cyclosporin A.

4. Pharmaceutical preparation according to any of Claims 1 to 3, characterized in that it contains >= 10 WT%
of cyclosporin A on the basis of: the total weight of the preparation.

5. Pharmaceutical preparation according to any of Claims 1 to 4, characterized in that it contains ethanol or isopropanol as pharmaceutically customary alcohol.

6. Pharmaceutical preparation according to any of claims 1 to 5 wherein said pharmaceutically customary alcohol is present in the preparation in amounts of up to 30 wt% on the basis of the total weight of the preparation.

7. Pharmaceutical preparation according to any of claims 1 to 6, in a form characterized in that it contains an ethoxylated castor oil as a further emulsifier.

8. Pharmaceutical preparation according to any of claims 1 to 7, in a form characterized in that it contains a suitable thickener.