United States Patent [19]
`Hauer et al.
`
`USOO5342625A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,342,625
`Aug. 30, 1994
`
`[54] PHARMACEUTICAL COMPOSITIONS
`COMPRISING CY CLOSPORINS
`[75] Inventors: Birgit Hauer, Lahr; Armin Meinzer,
`Freiburg/Munzingen; Ulrich
`Posanski, Freiburg, all of Fed. Rep.
`of Germany; Friedrich Richter,
`Schéinbiihl-Urtenen, Switzerland
`[73] Assignee:
`Sandoz Ltd., Basel, Switzerland
`[21] Appl. No.: 990,734
`[22] Filed:
`Dec. 15, 1992
`
`[63]
`
`Related US. Application Data
`Continuation of Ser. No. 680,211, Apr. 4, 1991, aban
`doned, which is a continuation of Ser. No. 406,656,
`Sep. 13, 1989, abandoned.
`Foreign Application Priority Data
`[30]
`Sep. 16, 1988 [GB] United Kingdom ............... .. 8821754
`Feb. 9, 1989 [GB] United Kingdom ..
`8902900
`Feb. 9, 1989 [GB] United Kingdom ..
`8902903
`
`[51] Int. Cl.5 ..................... .. A61K 9/66; A61K 9/107;
`A61K 37/02; C07K 7/64
`[52] US. Cl. .................................. .. 424/455; 424/456;
`424/457; 424/489; 514/11; 514/885; 514/937;
`514/938; 514/963; 514/964; 514/970; 514/974;
`514/975; 530/321
`[58] Field of Search ............. .. 424/455, 456, 457, 489;
`514/9, 11, 885, 937, 938, 970, 963, 964, 974,
`975; 530/317, 321, 322
`References Cited
`U.S. PATENT DOCUMENTS
`
`[56]
`
`4,108,985 8/ 1978 Riiegger et a1. .................... .. 514/11
`4,210,581 7/ 1980 Riiegger et a1. ..
`530/321
`4,220,641 9/1980 Traber et a1.
`514/11
`
`4,388,307 6/1983 Cavanak . . . . . . .
`
`. . . . . . . .. 514/11
`
`4,835,002 5/ 1989 Wolf et a1. ................ .. 426/590
`
`4,914,188 4/1990 Dumont et a1. . . . . . .
`
`. . . . . .. 530/317
`
`424/427
`4,990,337 2/1991 Kurihara et al.
`4,996,193 2/1991 Hewitt et al. ....................... .. 514/11
`
`FOREIGN PATENT DOCUMENTS
`
`2098865 12/1992 United Kingdom .
`
`OTHER PUBLICATIONS
`W. A. Ritschel, et al., Pharm. Res., 1988 (May 1910),
`Suppl. 108.
`Derwent No. 86/335072/51, (Apr. 26, 1985).
`Takada, et al., J. Pharmacobia-Dyn., vol. 11, pp. 80-87
`(1988).
`Bryan D. Tan, et al., Pharmaceutical Research, vol. 6,
`No. 1, pp. 40-43 (1989).
`Reymond, et al., Pharmaceutical Research, vol. 5, No.
`10, pp. 673-679 (1988).
`Remington’s Pharmaceutical Sciences, 17th Edition,
`pp. 298-299 (1985).
`Derwent No. 87-086213/ 12 (1985).
`Takada, et al., International Jour. of Pharmaceutics,
`vol. 44, Pp. 107-116 (1988).
`Derwent No. 89/088668/ 12 (Jul. 31, 1987).
`Derwent 87/024776/04 (Apr. 4, 1985).
`W. A. Ritschel, et al., Meth. Find. Exp. Clin. Phar
`macoL, vol. 11, pp. 281-285 (1989).
`Primary Examiner-Christina Y. Chan
`Attorney, Agent, or Firm-Robert S. Honor; Melvyn M.
`Kassenoff; Carl W. Battle
`[57]
`ABSTRACT
`Pharmaceutical compositions comprising a cyclosporin,
`e.g. Ciclosporin or [NvaP-Ciclosporin, in’ “microemul
`sion pare-concentrate” and microemulsion form. The
`compositions typically comprise (1.1) a C1.5a1ky1 or
`tetrahydrofurfuryl di- or partial-ether of a low molecu
`lar weight mono- or poly-oxy-alkane diol, e.g. Tran
`scutol or Glycofurol, as hydrophilic component. Com
`positions are also provided comprising a cyclosporin
`and (1.1) and, suitably, also a saccharide monoester, e.g.
`raf?nose or saccharose monolaurate. Dosage forms
`include topical formulations and, in particular, oral
`dosage forms.
`
`26 Claims, 4 Drawing Sheets
`
`Exhibit 1023
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`US. Patent
`
`Aug. 30, 1994
`
`Sheet 1 of 4
`
`5,342,625
`
`N
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`P .QE
`
`'r
`
`000002
`
`

`

`US. Patent
`
`Aug. 30, 1994
`
`Sheet 2 of 4
`
`5,342,625
`
`3 N2:
`
`000003
`
`

`

`US. Patent
`
`Aug. 30, 1994
`
`Sheet 3 of 4
`
`5,342,625
`
`m .OE
`
`NP
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`1 G00?
`
`I Own
`
`1
`
`1 com
`
`1 6mm
`
`000004
`
`

`

`US. Patent
`
`Aug. 30, 1994
`
`Sheet 4 of 4
`
`5,342,625
`
`on
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`m?
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`NF
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`I 000?
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`I omw
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`I com
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`I 0mm
`
`000005
`
`

`

`1
`
`PHARMACEUTICAL COMPOSITIONS
`COMPRISING CY CLOSPORINS
`
`5,342,625
`2
`sprue, autoimmune in?ammatory bowel disease (includ
`ing e. g. ulcerative colitis and Crohn’s disease) endocrine
`opthalmopathy, Graves disease, sarcoidosis, multiple
`sclerosis, primary billiary cirrhosis, juvenile diabetes
`This is a continuation of application Ser. No. 5 (diabetes mellitus type I), uveitis (anterior and poste
`rior), keratoconjunctivitis sicca and vernal keratocon
`07/680,211, filed Apr. 4, 1991 now abandoned which in
`junctivitis, interstitial lung ?brosis, psoriatic arthritis
`turn is a continuation of application Ser. No.
`and glomerulonephritis (with and without nephrotic
`07/406,656, ?led Sep. 13, 1989, now abandoned.
`syndrome, eg including idiopathic nephrotic syn
`The present invention relates to novel galenic formu
`10 drome or minimal change nephropathy).
`lations comprising a cyclosporin as active ingredient.
`The cyclosporins comprise a class of structurally
`Further areas of investigation have been potential
`distinctive, cyclic, poly-N-methylated endecapeptides,
`applicability as an anti-parasitic, in particular anti
`commonly possessing pharmacological, in particular
`protozoal agent, with possible uses suggested including
`immunosuppressive, anti-in?ammatory and/or anti
`treatment of malaria, coccidiomycosis and schistosomi
`parasitic activity. The ?rst of the cyclosporins to be
`15 asis and, yet more recently, use as an agent for reversing
`isolated was the naturally occurring fungal metabolite
`or abrogating anti-neoplastic agent resistance in tu
`Ciclosporin or Cyclosporine, also known as cyclosporin
`mours and the like.
`Since the original discovery of ciclosporin, a wide
`A and commercially available under the Registered
`variety of naturally occurring cyclosporins have been
`Trade Mark SANDIMMUN® or SANDIMMU
`NE ®. Ciclosporin is the cyclosporin of formula A.
`20 isolated and identi?ed and many further non-natural
`
`MeBmt-aAbu- Sar-MeLeu—Val—MeLeu—Ala-(D)A1a— MeLeu-MeLzau- MeVal
`9
`l0
`1 l
`
`5
`
`6
`
`7
`
`8
`
`l- l
`
`2
`
`3
`
`4
`
`(A)
`
`_l
`
`wherein ~MeBmt- represents the N-methyl-(4R)-4-but
`2E-en-1-yl-4-methyl-(L) threonyl residue of formula B
`
`CH3
`
`(B)
`
`(5)
`CH3
`
`in which -x-y- is --CH:CH— (trans).
`As the parent of the class Ciclosporin has so far re
`ceived the most attention. The primary area of clinical
`investigation for Ciclosporin has been as an immuno
`suppressive agent, in particular in relation to its applica
`tion to recipients of organ transplants, e.g. heart, lung,
`combined heart-lung, liver, kidney, pancreatic, bone
`marrow, skin and corneal transplants and, in particular,
`allogenic organ transplants. in this ?eld Ciclosporin has
`achieved a remarkable success and reputation.
`At the same time, applicability of Ciclosporin to vari
`ous autoimmune diseases and to in?ammatory condi
`tions, in particular in?ammatory conditions with an
`aetiology including an autoimmune component such as
`arthritis (for example rheumatoid arthritis, arthritis
`chronica progrediente and arthritis deformans) and
`rheumatic diseases, has been intensive and reports and
`results in vitro, in animal models and in clinical trials are
`wide-spread in the literature. Speci?c auto-immune
`diseases for which Ciclosporin therapy has been pro
`posed or applied include, autoimmune hematological
`disorder (including e.g. hemolytic anaemia, aplastic
`anaemia, pure red cell anaemia and idiopathic throm
`bocytopaenia), systemic lupus erythematosus, poly
`chondritis, sclerodoma, Wegener granulamatosis, der
`matomyositis, chronic active hepatitis, myasthenia gra
`vis, psoriasis, Steven-Johnson syndrome, idiopathic
`
`cyclosporins have been prepared by total- or semi-syn
`thetic means or by the application of modi?ed culture
`30 techniques. The class comprised by the cyclosporins is
`thus now substantial and includes, for example, the
`naturally occurring cyclosporins A through Z [c.f. Tra
`ber et al. 1, Helv. Chim. Acta. 60, 1247-1255 (1977);
`Traber et al. 2, Helv. Chim. Acta. 65 no. 162, 1655-1667
`35 (1982); Kobel et al., Europ. J. Applied Microbiology
`and Biotechnology 14, 273-240 (1982); and von Wart
`burg et al., Progress in Allergy, 38, 28-45 (1986)], as
`well as various non-natural cyclosporin derivatives and
`arti?cial or synthetic cyclosporins including the so
`40 called dihydro-cyclosporins (in which the moiety —x-y
`of the -MeBmt- residue (Formula B above) is saturated
`to give -x-y-=-CH2—CH2—; derivatised cyclospo
`rins (eg in which a further substituent is introduced at
`the a-c'arbon atom of the sarcosyl residue at the 3-posi
`45 tion of the cyclosporin molecule); cyclosporins in
`which the -MeBmt- residue is present in isomeric form
`(e.g. in which the con?guration across positions 6’ and
`7’ of the -MeBmt- residue is cis rather than trans); and
`cyclosporins wherein variant amino acids are incorpo
`50 rated at speci?c positions within the peptide sequence,
`employing eg the total synthetic method for the pro
`duction of cyclosporins developed by R. Wenger-see
`e.g. Traber l, Traber 2 and Kobel loc. cit.; US. Pat.
`Nos. 4,108,985, 4,210,581 and 4,220,641; European Pa
`55 tent Publication Nos. 0 034 567 and 0 056 782; Interna
`tional Patent Publication No. W0 86/ 02080; Wenger 1,
`Transp. Proc. 15, Suppl. 12230 (1983); Wenger 2, An
`gew. Chem. Int. Ed., 24, 77 (1985); and Wenger 3,
`Progress in the Chemistry of Organic Natural Products
`60 so, 123 (1986).
`The class comprised by the cyclosporins is thus now
`very large indeed and includes, for example, [Thr]2-,
`[Val]2-, [Nva]2- and [NvaP-[NvaP-Ciclosporin (also
`known as cyclosporins C,D, G and M respectively),
`65 [3-0-acyl-MeBmt]l-Ciclosporin (also known as cyclos
`porin A acetate), [Dihydro-MeBmt]l-[ValP-Ciclospo
`rin
`(also known as
`dihydrocyclosporin D),
`[(D)Fluoromethyl-Sar]3-Ciclosporin, [(D)Ser]3-Ciclos
`
`000006
`
`

`

`15
`
`25
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`35
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`4
`3
`porin, [MellePl-ciclosporin, [(D)MeVal]11-Ciclosporin
`tween subjects has varied from anything between one
`(also known as cyclosporin H), [MeAlaP-Ciclosporin,
`or a few percent for some patients to as much as 90% or
`[(D)Pro]3-Ciclosporin and so on.
`more for others. And as already noted, marked change
`in bioavailability for individuals with time is frequently
`(In accordance with now conventional nomenclature
`for cyclosporins, these are de?ned by reference to the
`observed.
`structure of Ciclosporin (i.e. Cyclosporin A). This is
`To achieve effective immunosuppressive therapy,
`done by ?rst indicating the amino acid residues present
`cyclosporin blood or blood serum levels have to be
`which differ from those present in Ciclosporin (e.g.
`maintained within in a speci?ed range. The required
`“[(D)Pro]3” to indicate that the cyclosporin in question
`range can in turn vary, depending on the particular
`has a -(D)Pro- rather than -Sar- residue at the 3-posi
`condition being treated, e.g. whether therapy is to pre
`tion) and then applying the term “Ciclosporin” to cha
`vent transplant rejection or for the control of an autoim
`racterise remaining residues which are identical to those
`mune disease, and on whether or not alternative immu
`present in Ciclosporin. Individual residues are num
`nosuppressive therapy is employed concomitantly with
`bered starting with the residue -MeBmt- or -dihy
`cyclosporin therapy. Because of the wide variations in
`droMeBmt- in position 1.)
`bioavailability levels achieved with conventional dos
`Very many of these further cyclosporins exhibit com
`age forms, daily dosages needed to achieve required
`parable pharmaceutical utility to Ciclosporin or more
`blood serum levels will also vary considerably from
`speci?c utility, for example activity particularly in re
`individual to individual and even for a single individual.
`versing tumor resistance to cytostatic therapy, and pro
`For this reason it is necessary to monitor blood/blood
`posals for their application as therapeutic agents abound
`serum levels of patients receiving cyclosporin therapy
`in the literature.
`at regular and frequent intervals. Monitoring of
`Despite the very major contribution which Ciclospo
`blood/blood-serum levels, which is generally per
`rin has made, in particular to the areas of organ trans
`formed by RIA or equivalent immunoassay technique,
`plant and the therapy of autoimmune diseases, dif?cul
`e.g. employing monoclonal antibody based technology,
`ties encountered in providing more effective and conve
`has to be carried out on a regular basis. This is inevita
`nient means of administration as well as the reported
`bly time consuming and inconvenient and adds substan
`occurrence of undesirable side reactions, in particular
`tially to the overall cost of therapy.
`nephrotoxic reaction, have been obvious serious imped
`Beyond all these very evident practical dif?culties
`iments to its wider use or application. The cyclosporins
`lies the occurrence of undesirable side reactions already
`are characteristically highly hydrophobic. Proposed
`alluded to, observed employing available oral dosage
`liquid formulations, e.g. for oral administration of cy
`forms.
`closporins, have hitherto been based primarily on the
`Several proposals to meet these various problems
`use of ethanol and oils or similar excipients as carrier
`have been suggested in the art, including both solid and
`media. Thus the commercially available Ciclosporin
`liquid oral dosage forms. An overriding dif?culty
`drink-solution employs ethanol and olive oil as carrier
`which has however remained is the inherent insolubility
`medium in conjunction with labra?l as a surfactant——see
`of the cyclosporins, e.g. Ciclosporin, in aqueous media
`e.g. US. Pat. No. 4,388,307. Use of the drink-solution
`and hence provision of a dosage from which can con
`and similar compositions as proposed in the art is how
`tain cyclosporins in suf?ciently high concentration to
`ever accompanied by a variety of dif?culties.
`permit convenient use and yet meet the required criteria
`First, the necessity to use oils or oil based carriers
`in terms of bioavailability, e.g. enabling effective re
`may lend the preparations an unpleasant taste or other
`sorption from the stomach or gut lumen and achieve
`wise reduce palatability, in particular for the purposes
`ment of consistent and appropriately high blood/blood
`of long-term therapy. These effects can be masked by
`serum levels.
`presentation in gelatin capsule form. However, in order
`The particular dif?culties encountered in relation to
`to maintain the cyclosporin in solution, the ethanol
`45
`oral dosaging with cyclosporins have inevitably led to
`content has to be kept high. Evaporation of the ethanol,
`restrictions in the use of cyclosporin therapy for the
`e.g. from capsules or from other forms, e.g. when
`treatment of relatively less severe or endangering dis
`opened, results in the development of a cyclosporin
`ease conditions. A particular area of difficulty in this
`precipitate. Where such compositions are presented in
`respect has been the adoption of cyclosporin therapy in
`e. g. soft gelatin encapsulated form, this particular dif?
`the treatment of autoimmune diseases and other condi
`culty necessitates packaging of the encapsulated prod
`tions affecting the skin, for example for the treatment of
`uct in an air-tight compartment, for example an air-tight
`atopic dermatitis and psoriasis and, as also widely pro
`blister or aluminium-foil blister-package. This in turn
`posed in the art, for hair growth stimulation, e.g. in the
`renders the product both bulky and more expensive to
`treatment of alopecia due to ageing or disease.
`produce. The storage characteristics of formulations as
`Thus While oral Ciclosporin therapy has shown that
`aforesaid are far from ideal.
`the drug is of considerable potential bene?t to patients
`Bioavailability levels achieved using existing oral
`suffering e.g. from psoriasis, the risk of side-reaction
`cyclosporin dosage systems are also low and exhibit
`following oral therapy has prevented common use.
`wide variation between individuals, individual patient
`Various proposals have been made in the art for applica
`types and even for single individuals at different times
`tion of cyclosporins, e.g. Ciclosporin, in topical form
`during the course of therapy. Thus reports in the litera
`and a number of topical delivery systems have been
`ture indicate that currently available therapy employing
`described. Attempts at topical application have how
`the commercially available Ciclosporin drink solution
`ever failed to provide any demonstrably effective ther
`provides an average absolute bioavailability of ca. 30%
`apy. A means of topical application providing effective
`only, with marked variation between individual groups,
`65
`e.g. between liver (relatively low bioavailability) and
`dermal delivery and useful, e.g. for the treatment of
`psoriasis, would effectively make cyclosporin therapy
`bone-marrow (relatively high bioavailability) transplant
`recipients. Reported variation in bioavailability be
`available to, what is, a major patient population at need.
`
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`By the present invention there are provided novel
`brought into contact, that is without substantial energy
`cyclosporin galenic formulations in the form of a micro
`supply, e.g. in the absence of heating or the use of high
`shear equipment or other substantial agitation. They
`emulsion pre-concentrate and/or based on the use of
`exhibit thermodynamic stability. They are monophasic.
`particular solvent media as hereinafter de?ned, which
`meet or substantially reduce dif?culties in cyclosporin,
`They are substantially non-opaque, i.e. are transparent
`or opalescent when viewed by optical microscopic
`e.g. Ciclosporin, therapy hitherto encountered in the
`art. In particular it has been found that the compositions
`means. In their undisturbed state they are optically
`of the invention permit the preparation of solid, semi
`isotropic, though an anisotropic structure may be ob
`solid and liquid compositions containing a cyclosporin
`servable using e. g. x-ray technique.
`Microemulsions comprise a dispersed or particulate
`in suf?ciently high concentration to permit, e. g. conve
`(droplet) phase, the particles of which are of a size less
`nient oral administration, while at the same time achiev
`ing improved efficacy, e.g. in terms of bioavailability
`than 2,000 A, hence their optical transparency. The
`particles of a microemulsion may be spherical, though
`characteristics.
`More particularly it has been found that compositions
`other structures are feasible, e.g. liquid crystals with
`lamellar, hexagonal or isotropic symmetries. Generally,
`in accordance with the present invention enable effec
`tive cyclosporin dosaging with concomitant enhance
`micro-emulsions comprise droplets or particles having a
`maximum dimension (e.g. diameter) of less than 1,500
`ment of resorption/bioavailability levels, as well as
`reduced variability in resorption/bioavailability levels
`A, e.g. typically from 100 to 1,000 A.
`achieved both for individual patients receiving cyclos
`(For further discussion of the characteristics of mi
`porin therapy as well as between individuals. By appli
`croemulsions see, e.g. Rosof, Progress in Surface and
`cation of the teachings of the present invention cyclos
`Membrane Science, 12, 405 et seq. Academic Press
`(1975); Friberg, Dispersion Science and Technology, 6
`porin dosage forms are obtainable providing reduced
`variablility in achieved cyclosporin blood/blood serum
`(3), 317 et seq. (1985); and Miiller et a1. Pharm. Ind., 50
`levels between dosages for individual patients as well as
`(3), 370 et seq. (1988)).
`between individuals/individual patient groups. The
`From the foregoing it will be understood that the
`25
`invention thus enables reduction of cyclosporin dosage
`“microemulsion pre-concentrates” of the invention are
`galenic systems comprising a cyclosporin as active in
`levels required to achieve effective therapy. In addition
`gredient capable of forming a microemulsion, spontane
`it permits closer standardisation as well as optimisation
`of on-going daily dosage requirements for individual
`ously or substantially spontaneously on contact with
`subjects receiving cyclosporin therapy as well as for
`water alone.
`groups of patients undergoing equivalent therapy.
`Pharmaceutical “microemulsion pre-concentrate”
`compositions comprising cyclosporins as active ingredi
`By closer standardisation of individual patient dosag
`ent are novel. Accordingly in one aspect the present
`ing rate and blood/blood-serum level response, as well
`invention provides:
`as dosaging and response parameters for patient groups,
`A) A pharmaceutical composition comprising a cy
`monitoring requirements may be reduced, thus substan
`tially reducing the cost of therapy.
`closporin as active ingredient, which composition is a
`By reduction of required cyclosporin dosaging/stan
`“microemulsion pre-concentrate”.
`dardisation of achieved bio-availability characteristics,
`(The term “pharmaceutical composition” as used
`herein and in the accompanying claims is to be under
`the present invention also offers a means permitting
`stood as defining compositions of which the individual
`reduction in the occurrence of undesirable side-effects,
`in particular nephrotoxic reaction, in patients undergo
`components or ingredients are themselves pharmaceuti
`ing cyclosporin therapy.
`cally acceptable, e.g. where oral administration is fore
`In relation to topical application, the present inven
`seen, acceptable for oral use and, where topical adminis
`tration is foreseen, topically acceptable.)
`tion further enables the preparation of novel galenical
`formulations comprising a cyclosporin, e.g. Ciclospo
`In addition to the cyclosporin active ingredient, the
`“microemulsion pre-concentrate” compositions of the
`rin, as active ingredient and permitting improved treat
`invention will appropriately comprise:
`ment for autoimmune diseases affecting the skin, in
`1) a hydrophilic phase;
`particular, of dermatological disease involving morbid
`2) a lipophilic phase; and
`proliferation and/ or keratinisation of the epidermis,
`especially of psoriasis and atopic dermatosis. Topically
`3) a surfactant.
`The cyclosporin is carried in the lipophilic phase.
`applicable compositions in accordance with the inven
`Suitably both the hydrophilic and lipophilic phases will
`tion are also of use in the treatment of alopecia, e. g. for
`use in the promotion of hair growth.
`serve as carrier medium.
`“Microemulsion pre-concentrates” of the invention
`In a ?rst aspect, the present invention speci?cally
`provides pharmaceutical compositions comprising a
`are of a type providing o/w (oil-in-water) microemul
`cyclosporin as active ingredient, which compositions
`sions. As will be appreciated however, compositions in
`accordance with (A) may contain minor quantities of
`are in the form of a “microemulsion pre-concentrate”.
`water or otherwise exhibit ?ne structural features char
`By the term “microemulsion pre-concentrate” as ‘
`used herein is meant a system capable on contacting
`acteristic of microemulsions, e.g. of o/ W or w/o (water
`in-oil) type. The term “microemulsion pre-concentrate”
`with, e.g. addition to, water of providing a microemul
`sion. The term microemulsion as used herein is used in
`as used herein is accordingly to be understood as em
`bracing such possibilities.
`its conventionally accepted sense as a non-opaque or
`substantially non-opaque colloidal dispersion compris
`Microemulsions obtained on contacting the “micro
`ing water and organic components including hydropho
`emulsion pre-concentrate” compositions of the inven
`bic (lipophilic) organic components. Microemulsions
`tion with water or other aqueous medium exhibit ther
`modynamic stability, that is they will remain stable at
`are identi?able as possessing one or more of the follow
`ambient temperatures, e.g. without clouding or regular
`ing characteristics. They are formed spontaneously or
`substantially spontaneously when their components are
`emulsion size droplet formation or precipitation, over
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`5,342,625
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`prolonged periods of time. (It will of course be under
`stood that, to obtain a microemulsion, adequate water
`will be required. While the upper limit of dilution is not
`critical, a dilution of 1:1, preferably 1:5 parts per
`"weight (“microemulsion pre-concentrate”: H2O) or
`more will generally be appropriate.) Preferably, on
`contacting with water, the “microemulsion pre-concen
`trate” compositions of the invention are capable of
`providing microemulsions which remain stable at ambi
`ent temperatures, e.g. as evidenced by absence of any
`optically observable clouding or precipitation, over
`periods of at least 2 hours, more preferably at least 4
`hours, most preferably at least 12 to 24 hours. Micro
`emulsions obtainable from “microemulsion pre-concen
`trates” of the invention, e.g. at dilutions as indicated
`above, will preferably have an average particle size of
`less than about 1,500 A, more preferably of less than
`about 1,000 or 1,100 A, e.g. down to about 150 or 200 A.
`Especially preferred in accordance with the present
`invention are compositions as de?ned under (A) in
`which the hydrophilic phase comprises:
`1.1. A pharmaceutically acceptable C1_5alkyl or tetra
`hydrofurfuryl di- or partial-ether of a low molecular
`weight mono- or poly-oxy-alkanediol; or
`1.2. 1,2-propyleneglycol.
`Suitable components (1.1.) are, e.g. di- or- partial-,
`especially partial-, -ethers of mono- or poly-, especially
`mono- or di-, -oxy-alkanediols comprising from 2 to 12,
`especially 4 carbon atoms. Preferably the mono- or
`poly-oxy-alkanediol moiety is straight-chained. Espe
`cially suitable for use in accordance with the invention
`are di- or partial-ethers of formula I
`
`20
`
`25
`
`8
`refractive index of ca. 1.4545 (sodium D line, 589 mm)
`(at 40° C.); and a viscosity of ca. 8-18 mN s/m2 (at 20°
`). (c.f. “Handbook of Pharmaceutical Excipients, pub
`lished by American Pharmaceutical Association/ The
`Pharmaceutical Society of Great Briatin (1986), p. 127
`and Fiedler, “Lexikon der Hilfstoffe”, 3rd edition
`(1989), p. 577.)
`The precise properties of COLYCOFUROL vary
`according to relative purity. Thus lower quality grades
`contain signi?cant amounts of tetrahydrofurfuryl alco
`hol and other impurities. For the purposes of the pres
`ent invention COLYCOFUROL 75, designating a
`product meeting the above physical data and for which
`the fraction having the formula I above in which x=1-2
`amounts to a minimum of 95%, is preferred.
`Use of components de?ned under (1.1.) and (1.2.)
`above has in particular been found to provide composi
`tions in accordance with (A) in which the hydrophilic
`phase is especially well suited as cyclosporin carrier
`medium, e.g. in which the hydrophilic phase enables
`cyclosporin-loading of the composition, adequate for
`convenient therapeutic dosaging, e.g. for oral adminis
`tration.
`Compositions in accordance with (A) comprising
`components as de?ned under (1.1.) and /or (1.2.) as
`hydrophilic phase may of course additionally include
`one or more further ingredients as hydrophilic phase
`component. Preferably however any additional compo
`nents will comprise materials in which the cyclosporin
`active ingredient is suf?ciently soluble, such that the
`ef?cacy of the hydrophilic phase as cyclosporin carrier
`medium is not materially impaired. Examples of possi
`ble additional hydrophilic phase components are lower
`(e.g. C1-5) alkanols, in particular ethanol.
`In an especially preferred embodiment the hydro
`philic phase of compositions de?ned under (A) will
`consist or consist essentially of components as de?ned
`under (1.1.) or (1.2.) above, in particular TRAN
`SCUTOL, COLYCOFUROL and/or 1,2-propylene
`glycol. Most suitably they will consist or consist essen
`tially of either components (1.1.) or component (1.2.).
`Compositions in accordance with (A) comprising a
`component (1.1), especially COLYCOFUROL, are of
`particular interest in that they are well adapted for
`presentation in soft gelatin encapsulated form. Such
`compositions have, in accordance with the invention,
`also been found to exhibit surprisingly advantageous
`stability, e.g. as evidenced in long-term stability tests at
`normal and elevated temperatures. Such compositions
`are thus particularly well suited to meet dif?culties
`commonly encountered in transport and storage of drug
`products, including long term storage at the user end,
`e.g. in hospitals, clinics and like facilities.
`Compositions de?ned under (A) additionally com
`prise a lipophilic phase (2).
`Suitable components for use as lipophilic phase in
`clude any pharmaceutically acceptable solvent which is
`non-miscible with the selected hydrophilic phase, e. g. as
`de?ned under (1.1.) or (1.2.). Such solvents will appro
`priately be devoid or substantially devoid of surfactant
`function. Especially suitable components for use as
`lipophilic phase components (2) are, e.g.:
`Fatty acid triglycerides, preferably medium chain
`fatty acid triglycerides. Especially suitable are neutral
`oils, e.g. neutral plant oils, in particular fractionated
`coconut oils such as known and commercially available
`
`10
`
`35
`
`45
`
`R1 is C1-5 alkyl or tetrahydrofurfuryl,
`R2 is hydrogen, C1_5alkyl or tetrahydrofurfuryl, and
`x is an integer of from 1 to 6, especially from 1 to 4,
`most especially about 2.
`Particularly preferred for use in accordance with the
`invention are partial ethers as de?ned above, e.g. prod
`ucts of formula I, wherein R2 is hydrogen.
`C1_5alkyl moieties in the above de?ned ethers may be
`branched or straight chain, e.g. including methyl, ethyl,
`n-propyl, i-propyl, n-butyl and t-butyl groups.
`Such ethers are known products and commercially
`available or may be produced analogously to the known
`products. Especially preferred products of formula I for
`use in relation to the present invention are those known
`and commercially available under the trade names_
`TRANSCUTOL and COLYCOFUROL.
`Transcutol is the compound diethyleneglycol mono
`ethyl ether of formula I, wherein R1: C2H5, R2=H and
`x=2.
`COLYCOFUROL, also known as tetrahydrofurfuryl
`alcohol polyethylene glycol ether or a-(tetrahy
`drofuranyl)-w-hydroxypoly(oxy-1,2-ethanediyl) has the
`formula I wherein R1 =
`
`55
`
`R2=H and x has an average value of from 1 to 2. It has
`an average molecular weight of ca. 190; a b.p. of from
`ca. 80°—l00° C. (at 40N/m2), a density of ca. l.070—l.090
`g/cm3 (at 20° C.); a hydroxy value of ca. 300-400; a
`
`65
`
`000009
`
`

`

`20
`
`25
`
`9
`under the trade name MIGLYOL (c.f. Fiedler, loc. cit.
`pp. 808-809), including the products:
`MIGLYOL 810: a fractionated coconut oil compris
`ing caprylic-capric acid triglycerides and having a mo
`lecular weight : ca. 520. Fatty acid composition=C6
`max. 2%, C3 ca. 65-75%, C10 ca. 25-35%, C12 max. 2%;
`acid no.=ca. 0.1; saponi?cation no.=ca. 340-360; io
`dine no.=max. 1;
`MIGLYOL 812: a fractionated coconut oil compris
`ing caprylic-capric acid triglycerides and having a mo
`lecular weight=ca. 520. Fatty acid composition=C6
`max. ca. 3%, C3 ca. 50-65%, C10 ca. 30-45%, C12 max.
`5%; acid no.=ca. 0.1; saponi?cation no.=ca. 330-345;
`iodine no.=max. l;
`MIGLYOL 818: a caprylic-capric-linoleic acid tri
`glyceride having a molecular weight=ca. 510. Fatty
`acid composition=C6 max. 3, C8 ca. 45-60, C10 ca.
`25-40, C12 ca. 2-5, C13,; ca. 4-6; acid no.=max. 0.2;
`saponi?cation no.=ca. 315-335, iodine no.=max. 10;
`and
`CAPTEX 355(1) a caprylic-capric acid triglyceride.
`Fatty acid content=caproic ca. 2%, caprylic ca. 55%,
`capric ca. 42%. Acid no.=max. 0.1; saponi?cation no.
`=ca. 325-340; iodine no.=max. 0.5.
`Also suitable are caprylic-capric acid triglycerides
`such as known and commercially available under the
`trade name MYRITOL (c.f. Fiedler loc. cit., p. 834)
`including the product MYRITOL 813 which has an
`acid no.=max. l, a saponi?cation no. =ca. 340-350 and
`an iodine no.=ca. 0.5.
`Further suitable products of this class are CAPMUL
`MCT(1), CAPTEX 300(1) and CAPTEX 800(1), NEO
`BEE M5(2) and MAZOL 1400(3).
`((1)=Capital City Products, PO. Box 569, Columbus,
`Ohio, USA. (2)=Stepan, PVO Dept., 100 West Hunter
`Ave., Maywood, NJ. 07607, USA. (3)=Mazer Chemi
`cals, 3938 Porett Drive, Gurnee, Ill., USA).)
`Especially preferred as lipophilic phase component is
`the product MIGLYOL 812.
`Compositions in accordance with the invention de
`?ned under (A) further comprise a pharmaceutically
`acceptable surfactant (3). The surfactant component
`may comprise -‘ (3.1.) hydrophilic or (3.2..) lipophilic
`surfactants, or mixtures thereof. Especially preferred
`are non-ionic hydrophilic and non-ionic lipophilic sur
`factants. Examples of suitable hydrophilic surfactants