(12) UK Patent Application
`
`(19) GB (11) 2 222 770(13)A
`
`(43) Date of A publication 21.03.1990
`
`(51) INT Cl'
`A61K 9/10 37/02
`
`(52) UK Cl (Edition J)
`ASB BKA BlB B170 8180 8190 821Y B216 826Y
`830Y B303 831Y B317 834Y 8340 8343 835Y
`8351 B40Y 8403 8822
`U1S 52411
`
`(56) Documents cited
`None
`
`(58) Field of search
`UK Cl (Edition J) A5B BKA BKB
`INTCl' A61K
`Online databa.es : WPI
`
`(21) Application No 8920597.5
`
`(22) Date of filing 12.09.1989
`
`(30) Priority data
`(31) 8821754
`8802903
`8802900
`
`(71) Applicant
`Sandoz ltd
`
`(32) 16.09.1988
`09.02.1989
`09.02.1989
`
`(33) GB
`
`(Incorporated In Switzerland)
`
`35 Ucht.tra .... CHo4OO2 Ba.le. Switzerland
`
`(72) Inventors
`Birgit Hauer
`Armin Meinzer
`Ulrich Posan.k1
`Friedrich Richter
`
`(74) Agent and/or Address for Service
`BAYorke & Co
`Coomb Hou.e. 7 SI John', Rd. 1,leworth. Middlesex.
`TW7 8NH. United Kingdom
`
`(54) Cyclosporln emulsion compositions
`
`(57) Pharmaceutical compos~ions comprising a cyclosporin, e.g. Ciclosporin or [Nva]LCiclosporin, in "microemulsion
`pre-concentrate" and microemulsion form. The compositions typically comprise (1.1) a C1•5 alkyl or tetrahydrofurfuryl di- or
`partial-ether of a low molecular weight mono- or poly-oxy-alkane diol, as hydrophilic component. Compos~ions are also
`provided comprising a cyclosporin and (1.1) and, su~ably, also a saccharide monoester, e.g. raffinose or saccharose
`monolaurate. Dosage forms include topical formulations and, in particular, oral dosage forms.
`
`/
`
`At least one drawing originally filed was informal and the print reproduced here is taken from a later filed lormal copy.
`
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`oc-
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`222277'0
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`N
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`N
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`~
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`~
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`
`-1-
`
`2222770
`
`PBARHACEUTICAL COMPOSITIONS COMPRISING CYCLOSPORINS
`
`The present invention relates to novel galenic formulations comprising
`a cyclosporin as active ingredient.
`
`The cyclosporins comprise a class of structurally distinctive, cyclic,
`poly-N-methylated endecapeptides, commonly possessing pharmacological,
`in particular immunosuppressive, anti-inflammatory and/or
`anti-parasitic activity, The first of the cyclosporins to be isolated
`was the naturally occurring fungal metabolite Ciclosporin or
`Cyclosporine, also known as cyclosporin A and commercially available
`under the Registered Trade Mark SANDIMMUNR or SANDIMMUNER, Ciclosporin
`is the cyclosporin of formula A.
`
`MeBmt-aAbU_Sar_MeLeu_val_MeLeU_Ala_(D)Ala_MeLeu_MeLeu_Mevall
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11 _
`
`(A)
`
`r
`
`wherein -MeBmt- represents the N-methyl-(4R)-4-but-2E-en-l-yl-4-
`methyl-(L)threonyl residue of formula B
`
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`(B)
`
`in which -x-y- is -CH=CH- (trans).
`
`As the parent of the class Ciclosporin has so far received the most
`attention. The primary area of clinical investigation for Ciclosporin
`has been as an immunosuppressive agent, in particular in relation to
`its application 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 field Ciclosporin has achieved a remarkable success and
`reputation.
`
`At the same time, applicability of Ciclosporin to various autoimmune
`diseases and to inflammatory conditions, in particular inflammatory
`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. Specific
`
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`auto-immune diseases for which Ciclosporin therapy has been proposed
`or applied include, autoimmune hematological disorder (including e.g.
`hemolytic anaemia, aplastic anaemia, pure red cell anaemia and
`idiopathic thrombocytopaenia), systemic lupus erythematosus,
`polychondritis, sclerodoma, iegener granulamatosis, dermatomyositis,
`chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson
`syndrome, idiopathic sprue, autoimmune inflammatory bowel disease
`(including e.g. ulcerative colitis and Crohn's disease) endocrine
`opthalmopathy, Graves disease, sarcoidosis, multiple sclerosis,
`primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type
`I), uveitis (anterior and posterior), keratoconjunctivitis sicca and
`vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic
`arthritis and glomerulonephritis (with and without nephrotic syndrome,
`e.g. including idiopathic nephrotic syndrome or minimal change
`nephropathy).
`
`Further areas of investigation have been potential applicability as an
`anti-parasitic, in particular anti-protozoal agent, with possible uses
`suggested including treatment of malaria, coccidiomycosis and
`schistosomiasis and, yet more recently, use as an agent for reversing
`or abrogating anti-neoplastic agent resistance in tumours and the
`like.
`
`Since the original discovery of ciclosporin, a wide variety of natu(cid:173)
`rally occurring cyclosporins have been isolated and identified and
`many further non-natural cyclosporins have been prepared by total- or
`semi-synthetic means or by the application of modified culture techni(cid:173)
`ques. The class comprised by the cyclosporins is thus now substantial
`and includes, for example, the naturally occurring cyclosporins A
`through Z [c.f. Traber et al. 1, Helv. Chim. Acta. 60, 1247-1255
`(1977); Traber et al. 2, Helv. Chim. Acta. 65 no. 162, 1655-1667
`(1982); Kobel et al., Europ. J. Applied Microbiology and Biotechnology
`14, 273-240 (1982); and von iartburg et al., Progress in Allergy, 38,
`28-45 (1986)], as well as various non-natural cyclosporin derivatives
`and artificial or synthetic cyclosporins including the so called
`
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`dihydro-cyclosporins [in which the moiety -x-y- of the -MeBmt- residue
`(Formula B above) is saturated to give -x-y- ~ -CH2-CH2-; derivatised
`cyclosporins (e.g. in which a further substituent is introduced at the
`«-carbon atom of the sarcosyl residue at the 3-position of the
`cyclosporin molecule); cyclosporins in which the -MeBmt- residue is
`present in isomeric form (e.g. in which the configuration across
`positions 6' and 7' of the -MeBmt- residue is cis rather than trans);
`and cyclosporins wherein variant amino acids are incorporated at
`specific positions within the peptide sequence, employing e.g. the
`total synthetic method for the production of cyclosporins developed by
`R. Venger - see e.g. Traber 1, Traber 2 and Kobel loco cit.; U.S.
`Patents Nos. 4 108 985, 4 210 581 and 4 220 641; European Patent
`Publication Nos. 0 034 567 and 0 056 782; International Patent Publi(cid:173)
`cation No. VO 86/02080; Venger 1, Transp. Proc. 15, Supple 1:2230
`(1983); Venger 2, Angew. Chern. Int. Ed., 24, 77 (1985); and Venger 3,
`Progress in the Chemistry of Organic Natural Products 50, 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 [Nva]2-
`[Nva]S-Ciclosporin (also known as cyclosporins C,D, G and M respecti(cid:173)
`vely), [3-0-acyl-MeBmt]1-Ciclosporin (also known as cyclosporin A
`acetate), [Dihydro-MeBmt]1-[Val]2-Ciclosporin (also known as dihydro(cid:173)
`cyclosporin D), [(D)Fluoromethyl-Sar]3-Ciclosporin,
`[(D)Ser]8-Ciclosporin, [MeIle]ll-Ciclosporin, [(D)MeVal]ll-Ciclosporin
`(also known as cyclosporin H), [MeAla]6-Ciclosporin,
`[(D)Pro]3-Ciclosporin and so on.
`
`[In accordance with now conventional nomenclature for cyclosporins,
`these are defined by reference to the structure of Ciclosporin (i.e.
`Cyclosporin A). This is done by first indicating the amino acid
`residues present which differ from those present in Ciclosporin (e.g.
`"[(D)Pro]3 11
`to indicate that the cyclosporin in question has a
`-(D)Pro- rather than -Sar- residue at the 3-position) and then
`applying the term "Ciclosporin" to characterise remaining residues
`
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`which are identical to those present in Ciclosporin. Individual
`residues are numbered starting with the residue -MeBmt- or
`-dihydroMeBmt- in position 1.]
`
`Very many of these further cyclosporins exhibit comparable
`pharmaceutical utility to Ciclosporin or more specific utility, for
`example activity particularly in reversing tumor resistance to
`cytostatic therapy, and proposals for their application as therapeutic
`agents abound in the literature.
`
`Despite the very major contribution which Ciclosporin has made, in
`particular to the areas of organ transplant and the therapy of
`autoimmune diseases, difficulties encountered in providing more
`effective and convenient means of administration as well as the
`reported occurrence of undesirable side reactions, in particular
`nephrotoxic reaction, have been obvious serious impediments to its
`wider use or application. The cyclosporins are characteristically
`highly hydrophobic. Proposed liquid formulations, e.g. for oral
`administration of cyclosporins, have hitherto been based primarily on
`the use of ethanol and oils or similar excipients as carrier media.
`Thus the commercially available Ciclosporin drink-solution employs
`ethanol and olive oil as carrier medium in conjunction with labrafil
`as a surfactant - see e.g. US patent no. 4,388,307. Use of the
`drink-solution and similar compositions as proposed in the art is
`however accompanied by a variety of difficulties.
`
`First, the necessity to use oils or oil based carriers may lend the
`preparations an unpleasant taste or otherwise reduce palatability, in
`particular for the purposes of long-term therapy.' These effects can be
`masked by presentation in gelatin capsule form. However, in order to
`maintain the cyclosporin in solution, the ethanol content has to be
`kept high. Evaporation of the ethanol, e.g. from capsules or from
`other forms, e.g. when opened, results in the development of a
`cyclosporin precipitate. ~here such compositions are presented in e.g.
`
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`soft gelatin encapsulated form, this particular difficulty
`necessitates packaging of the encapsulated product in an air-tight
`compartment, for example an air-tight blister or aluminium-foil
`blister-package. This in turn renders the product both bulky and more
`expensive to produce. The storage characteristics of formulations as
`aforesaid are far from ideal.
`
`Bioavailability levels achieved using existing oral cyclosporin dosage
`systems are also low and exhibit wide variation between individuals,
`individual patient types and even for single individuals at different
`times during the course of therapy. Thus reports in the literature
`indicate that currently available therapy employing the commercially
`available Ciclosporin drink solution provides an average absolute
`bioavailability of ca. 30% only, with marked variation between
`individual groups, e.g. between liver (relatively low bioavailability)
`and bone-marrow (relatively high bioavailability) transplant
`recipients. Reported variation in bioavailability between subjects has
`varied from anything between one or a few percent for some patients to
`as much as 90% or more for others. And as already noted, marked change
`in bioavailability for individuals with time is frequently observed.
`
`To achieve effective immunosuppressive therapy, cyclosporin blood or
`blood serum levels have to be maintained within in a specified range.
`The required range can in turn vary, depending on the particular
`condition being treated, e.g. whether therapy is to prevent transplant
`rejection or for the control of an autoimmune disease, and on whether
`or not alternative immunosuppressive therapy is employed concomitantly
`with cyclosporin therapy. Because of the wide variations in
`bioavailability levels achieved with conventional dosage forms, daily
`dosages needed to achieve required blood serum levels will also vary
`considerably from individual to individual and even for a single
`individual. For this reason it is necessary to monitor
`blood/blood-serum levels of patients receiving cyclosporin therapy at
`regular and frequent intervals. Monitoring of blood/blood-serum
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`levels, vhich is generally performed by RIA or equivalent immunoassay
`technique, e.g. employing monoclonal antibody based technology, has to
`be carried out on a regular basis. This is inevitably time consuming
`and inconvenient and adds substantially to the overall cost of
`therapy.
`
`Beyond all these very evident practical difficulties lies the
`occurrence of undesirable side reactions already alluded to, observed
`employing available oral dosage forms.
`
`Several proposals to meet these various problems have been suggested
`in the art, including both solid and liquid oral dosage forms. An
`overriding difficulty which has hovever remained is the inherent
`insolubility of the cyclosporins, e.g. Ciclosporin, in aqueous media
`and hence provision of a dosage from which can contain cyclosporins in
`sufficiently high concentration to permit convenient use and yet meet
`the required criteria in terms of bioavailability, e.g. enabling
`effective resorption from the stomach or gut lumen and achievement of
`consistent and appropriately high blood/blood-serum levels.
`
`The particular difficulties encountered in relation to oral dosaging
`vith cyclosporins have inevitably led to restrictions in the use of
`cyclosporin therapy for the treatment of relatively less severe or
`endangering disease conditions. A particular area of difficulty in
`this respect has been the adoption of cyclosporin therapy in the
`treatment of autoimmune diseases and other conditions affecting the
`skin, for example for the treatment of atopic dermatitis and psoriasis
`and, as also widely proposed in the art, for hair grovth stimulation,
`e.g. in the treatment of alopecia due to ageing or disease.
`
`Thus vhile oral Ciclosporin therapy has shovn that the drug is of
`considerable potential benefit to patients suffering e.g. from
`psoriasis, the risk of side-reaction folloving oral therapy has
`prevented common use. Various proposals have been made in the art for
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`application of cyclosporins, e.g. Ciclosporin, in topical form and a
`number of topical delivery systems have been described. Attempts at
`topical application have however failed to provide any demonstrably
`effective therapy. A means of topical application providing effective
`dermal delivery and useful, e.g. for the treatment of psoriasis, would
`effectively make cyclosporin therapy available to, what is, a major
`patient population at need.
`
`By the present invention there are provided novel cyclosporin galenic
`formulations in the form of a micro-emulsion pre-concentrate and/or
`based on the use of particular solvent media as hereinafter defined,
`which meet or substantially reduce difficulties in cyclosporin, e.g
`Ciclosporin, therapy hitherto encountered in the art. In particular it
`has been found that the compositions of the invention permit the
`preparation of solid, semi-solid and liquid compositions containing a
`cyclosporin in sufficiently high concentration to permit, e.g.
`convenient oral administration, while at the same time achieving
`improved efficacy, e.g. in terms of bioavailability characteristics.
`
`More particularly it has been found that compositons in accordance
`with the present invention enable effective cyclosporin dosaging with
`concomitant enhancement of resorption/bioavailability levels, as well
`as reduced variability in resorption/bioavailability levels achieved
`both for individual patients receiving cyclosporin therapy as well as
`between individuals. By application of the teachings of the present
`invention cyclosporin dosage forms are obtainable providing reduced
`variablility in achieved cyclosporin blood/blood serum levels between
`dosages for individual patients as well as between individuals/
`individual patient groups. The invention thus enables reduction of
`cyclosporin dosage levels required to achieve effective therapy. In
`addition it permits closer standardisation as well as optimisation of
`on-going daily dosage requirements for individual subjects receiving
`cyclosporin therapy as well as for groups of patients undergoing
`equivalent therapy.
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`By closer standardisation of individual patient dosaging rate and
`blood/blood-serum level response, as well as dosaging and response
`parameters for patient groups, monitoring requirements may be reduced,
`thus substantially reducing the cost of therapy.
`
`By reduction of required cyclosporin dosaging/standardisation of
`achieved bio-availability characteristics, the present invention also
`offers a means permitting reduction in the occurrence of undesirable
`side-effects, in particular nephrotoxic reaction, in patients
`undergoing cyclosporin therapy.
`
`In addition, the present invention enables the preparation of
`compositions which are non-alkanol based, e.g. which may be free or
`substantially free of ethanol. Such compositions avoid stability and
`related processing difficulties as hereinbefore discussed, inherent to
`known alkanolic compositions. The invention thus provides inter al.
`compositions which are better adapted, e.g. for presentation in
`capsule, e.g. hard or soft gelatin capsule form and/or which eliminate
`or substantially reduce packaging difficulties, for example as
`hereinbefore discussed, e.g. for soft gelatin encapsulated forms.
`
`In relation to topical application, the present invention further
`enables the preparation of novel galenical formulations comprising a
`cyclosporin, e.g. Ciclosporin, as active ingredient and permitting
`improved treatment for autoimmune diseases affecting the skin, in
`particular, of dermatological disease involving morbid proliferation
`and/or keratinisation of the epidermis, especially of psoriasis and
`atopic dermatosis. Topically applicable compositions in accordance
`with the invention are also of use in the treatment of alopecia, e.g.
`for use in the promotion of hair growth.
`
`In a first aspect, the present invention specifically provides
`pharmaceutical compositions comprising a cyclosporin as active
`ingredient, which compositions are in the form of a "microemulsion
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`pre-concentrate".
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`By the term "microemulsion pre-concentrate" as used herein is meant a
`system capable on contacting with, e.g. addition to, water of
`providing a microemulsion. The term microemulsion as used herein is
`used in its conventionally accepted sense as a non-opaque or
`substantially non-opaque ,colloidal dispersion comprising water and
`organic components including hydrophobic (lipophilic) organic
`components. Microemulsions are identifiable as possessing one or more
`of the following characteristics. They are formed spontaneously or
`substantially spontaneously when their components are brought into
`contact, that is without substantial energy supply, e.g. in the
`absence of heating or the use of high shear equipment or other
`substantial agitation. They exhibit thermodynamic stability. They are
`monophasic. They are substantially non-opaque, i.e. are transparent or
`opalescent when viewed by optical microscopic means. In their
`undisturbed state they are optically isotropic, though an anisotropic
`structure may be observable using e.g. x-ray technique.
`
`Microemulsions comprise a dispersed or particulate (droplet) phase,
`the particles of which are of a size less than 2,000 !, hence their
`optical transparency. The particles of a microemulsion may be
`spherical, though other structures are feasible, e.g. liquid crystals
`with lamellar, hexagonal or isotropic symmetries. Generally,
`micro-emulsions comprise droplets or particles having a maximum
`dimension (e.g. diameter) of less than 1,500 1, e.g. typically from
`100 to 1,000 1.
`
`[For further discussion of the characteristics of microemulsions see,
`e.g. Rosof, Progress in Surface and Membrane Science, 12, 405 et seq.
`Academic Press (1975); Friberg, Dispersion Science and Technology, ~
`(3), 317 et seq. (1985); and Milller et al, Pharm. Ind., 50 (3), 370 et
`seq. (1988)].
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`From the foregoing it will be understood that the "microemulsion
`pre-concentrates" of the invention are galenic systems comprising a
`cyclosporin as active ingredient capable of forming a microemulsion,
`spontaneously or substantially spontaneously on contact with water
`alone.
`
`Pharmaceutical "microemulsion pre-concentrate" compositions comprising
`cyclosporins as active ingredient are novel. Accordingly in one aspect
`the present invention provides:
`
`A) A pharmaceutical composition comprising a cyclosporin as active
`ingredient, which composition is a "microemulsion
`pre-concentrate".
`
`(The term "pharmaceutical composition" as used herein and in the
`accompanying claims is to be understood as defining compositions of
`which the individual components or ingredients are themselves
`pharmaceutically acceptable, e.g. where oral administration is
`foreseen, acceptable for oral use and, where topical administration is
`foreseen, topically acceptable.)
`
`In addition to the cyclosporin active ingredient, the "microemulsion
`pre-concentrate" compositions of the invention will appropriately
`comprise:
`
`1) a hydrophilic phase;
`2) a lipophilic phase; and
`3) a surfactant.
`
`The cyclosporin is carried in the lipophilic phase. Suitably both the
`hydrophilic and lipophilic phases will serve as carrier medium.
`
`"Microemulsion pre-concentrates" of the invention are of a type
`providing o/w (oil-in-water) microemulsions. As will be appreciated
`
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`however, compositions in accordance with (A) may contain minor
`quantities of water or otherwise exhibit fine structural features
`characteristic of microemulsions, e.g. of o/w or w/o (water-in-oil)
`type. The term "microemulsion pre-concentrate" as used herein is
`accordingly to be understood as embracing such possibilities.
`
`Microemulsions obtained on contacting the "microemulsion
`pre-concentrate" compositions of the invention with water or other
`aqueous medium exhibit thermodynamic stability, that is they will
`remain stable at ambient temperatures, e.g. without clouding or
`regular emulsion size droplet formation or precipitation, over
`prolonged periods of time. [It will of course be understood that, to
`obtain a microemulsion, adequate water will be required. Yhile the
`upper limit of dilution is not critical, a dilution of 1:1, e.g. 1:5
`"p.p.w. ("microemulsion pre-concentrate": H20) or more will generally
`be appropriate. 1 Preferably, on contacting with water, the
`"microemulsion pre-concentrate" compositions of the invention are
`capable of providing microemulsions which remain stable at ambient
`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.
`Microemulsions obtainable from "microemulsion pre-concentrates" of the
`invention, e.g. at dilutions as indicated above, will preferably have
`an average particle size of less than about 1,500K, more preferably of
`less than about 1,000 or 1,100A, e.g. down to about 150 or 200K.
`
`Especially preferred in accordance with the present invention are
`compositions as defined under (A) in which the hydrophilic phase
`comprises:
`
`1.1. A pharmaceutically acceptable Cl_salkyl or tetrahydrofurfuryl
`di- or partial-ether of a low molecular weight mono- or
`poly-oxy-alkanediol; or
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`1.2.
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`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. Especially suitable for use in accordance with the
`invention are di- or partial-ethers of formula I
`
`wherein Rl is C1- S alkyl or tetrahydrofurfuryl,
`R2 is hydrogen, C1-salkyl 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 defined above, e.g. products of formula I, wherein
`R2 is hydrogen.
`
`C1-salkyl moieties in the above defined 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 Glycofurol.
`
`Transcutol is the compound diethyleneglycol monoethyl ether of formula
`I, wherein Rl = C2HS, R2 = H and x = 2.
`
`G1ycofurol, also known as tetrahydrofurfuryl alcohol polyethylene
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`Page 18 of 80
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`glycol ether or ~-(tetrahydrofurany1)-w-hydroxypo1y(oxy-l,2-ethanediy1)
`has the
`~
`formula I wherein Rl ~ CH 2--- , 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. 80-100 DC (at 40N/m2 ), a density of ca. 1.070 - 1.090
`g/cml (at 20 DC); a hydroxy value of ca. 300-400; a refractive index of
`ca. 1.4545 (sodium 0 line, 589mm) (at 40 0C); and a viscosity of ca.
`8-18 mN s/m2 (at 20 0 ). [c.f. "Handbook of Pharmaceutical Excipients,
`published by American Pharmaceutical Association/ The Pharmaceutical
`Society of Great Briatin (1986), p. 127 and Fiedler, "Lex~kon der
`Hilfstoffe", 3rd edition (1989), p. 577.1
`
`The precise properties of Glycofuro1 vary according "to relative purity.
`Thus lower quality grades contain significant amounts of
`tetrahydrofurfuryl alcohol and other impurities. For the purposes of
`the present invention Glycofurol 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 defined under (1.1.) and (1.2.) above has in
`particular been found to provide compositions in accordance with (A)
`in which the hydrophilic phase is especially well suited as
`cyc1osporin carrier medium, e.g. in which the hydrophilic phase
`enables cyclosporin-loading of the composition, adequate for
`convenient therapeutic dosaging, e.g. for oral administration.
`
`Compositions in accordance with (A) comprising components as defined
`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 components will
`comprise materials in which the cyclosporin active ingredient is
`sufficiently soluble, such that the efficacy of the hydrophilic phase
`as cyclosporin carrier medium is not materially impaired. Examples of
`possible additional hydrophilic phase components are lower (e.g. C1- S )
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`Page 19 of 80
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`alkanols, in particular ethanol.
`
`Yhile, however, use of alkanols, e.g. ethanol, as hydrophilic phase
`component is contemplated by the present invention, for reasons
`hereinbefore discussed, this will be generally less preferred.
`Preferably, compositions as defined under (A) will be non-alkanol(cid:173)
`based, i.e. will not comprise an alkanol as a predominant hydrophilic
`phase component. Suitably the hydrophilic phase comprises less than
`50%, more preferably less than 25%, most preferably less than 10% by
`weight alkanolic components. Most suitably, the hydrophilic phase will
`be free or substantially free of alkanolic components, i.e. comprise
`less than 5%, preferably less than 2%, e.g. from 0 to 1% alkanolic
`components. By "alkanol" is meant, in particular, Cl_salkanols,
`especially ethanol.
`
`In an especially preferred embodiment the hydrophilic phase of
`compositions defined under (A) will consist or consist essentially of
`components as defined under (1.1.) or (1.2.) above, in particular
`Transcutol, Glycofurol and/or 1,2-propylene glycol. Most suitably they
`will consist or consist essentially of either components (1.1.) or
`component (1.2.).
`
`Compositions in accordance with (A) comprlslng a component (1.1),
`especially Glycofurol, 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 difficulties
`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.
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`Compositions defined under (A) additionally comprise a lipophilic
`phase (2).
`
`Suitable components for use as lipophilic phase include any
`pharmaceutically acceptable solvent which is non-miscible with the
`selected hydrophilic phase, e.g. as defined under (1.1.) or (1.2.).
`Such solvents will appropriately 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 under the trade name Miglyol (c.f. Fiedler,
`loco cit. pp. 808-809), including the products:
`
`Miglyol 810: a fractionated coconut oil comprising caprylic-capric
`acid triglycerides and having a molecular weight : ca. 520. Fatty acid
`composition = C6 max. 2%, Cs ca. 65-75%, C10 ca. 25-35%, C12 max. 2%;
`acid no. = ca. 0.1; saponification no. = ca. 340-360; iodine no. =
`max. 1;
`
`Miglyol 812: a fractionated coconut oil comprising caprylic-capric
`acid triglycerides and having a molecular weight. ca. 520. Fatty acid
`composition = C6 max. ca. 3%, Cs ca. 50-65%, C10 ca. 30-45%, C12 max.
`5%; acid no. = ca. 0.1; saponification no. = ca. 330-345; iodine no. =
`max. 1;
`
`Miglyol 818: a caprylic-capric-linoleic acid triglyceride having a
`molecular weight = ca. 510. Fatty acid composition = C6 max. 3, Cs ca.
`45-60, C10 ca. 25-40, C12 ca. 2-5, C1S :2 ca. 4-6; acid no. = max. 0.2;
`saponification no. = ca. 315-335, iodine no. = max. 10; and
`
`Captex 355(1) a caprylic-capric acid triglyceride. Fatty acid content
`
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`caproic ca. 2%, caprylic ca. 55%, capric ca. 42%. Acid no. = max.
`0.1; saponification no. = ca. 325-340; iodine no. = max. 0.5.
`
`Also suitable are caprylic-capric acid triglycerides such as known and
`commercially available under th