United States Patent [19]
`Fricker et al.
`
`US005932243A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,932,243
`Aug. 3, 1999
`
`[54] GALENICAL FORMULATIONS
`
`FOREIGN PATENT DOCUMENTS
`
`[75] Inventors: Gerd Fricker, Staufen, Germany;
`Barbara Haeberlin, Riehen,
`Switzerland; Armin Meinzer,
`Freiburg/Munzingen, Germany; Jacky
`Vonderscher, Fiedishheim, Germany
`
`[73] Assignee: Novartis AG, Basel, Switzerland
`
`[21] Appl. No.: 08/916,243
`[22]
`Filed:
`Aug. 22, 1997
`
`Related US. Application Data
`
`[63] Continuation of application No. 08/248,993, May 25, 1994,
`abandoned.
`Foreign Application Priority Data
`
`[30]
`
`May 27, 1993 [GB]
`Oct. 5, 1993 [GB]
`
`United Kingdom ................. .. 9310974
`United Kingdom ................. .. 9320463
`
`[51] Int. Cl.6 ......................... .. A61K 9/107; A61K 9/127
`[52] US. Cl.
`424/450; 424/400; 514/11;
`514/937; 514/938
`[58] Field of Search ................................... .. 624/450, 400;
`514/11, 937, 938—943
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,929,992 12/1975 Sehgal et a1. .
`4,388,307
`6/1983 Cavanak .
`4,719,239
`1/1988 Muller et a1. .
`4,831,018
`5/1989 Kirsh et a1. .
`4,987,139
`1/1991 Chen et a1. .
`5,104,871
`4/1992 Bell et a1. .
`5,169,851 12/1992 Hughes et al. .
`5,190,950
`3/1993 Beattie et a1. .
`5,206,018
`4/1993 Sehgal et a1. .
`5,215,995
`6/1993 Honbo et a1. .
`5,318,895
`6/1994 Kahn et a1. .
`5,342,625
`8/1994 Hauer et a1. .
`5,741,512
`4/1998 Hauer .................................... .. 424/450
`
`41795 12/1981
`European Pat. Off. .
`184162 6/1986
`European Pat. Off. .
`302370 2/1989
`European Pat. Off. .
`361928 4/1990
`European Pat. Off. .
`401747 12/1990
`European Pat. Off. .
`423 714 4/1991
`European Pat. Off. .
`427680 5/1991
`European Pat. Off. .
`428169 5/1991
`European Pat. Off. .
`444659 9/1991
`European Pat. Off. .
`483842 5/1992
`European Pat. Off. .
`532862 3/1993
`European Pat. Off. .
`533433 3/1993
`European Pat. Off. .
`679118 12/1991
`Switzerland .
`907430 10/1962
`United Kingdom .
`1322306 7/1973 United Kingdom .
`2222770 3/1990 United Kingdom .
`2247620 3/1992 United Kingdom .
`2248184 4/1992 United Kingdom .
`2249027 4/1992 United Kingdom .
`2257359
`1/1993 United Kingdom .
`2271121 4/1994 United Kingdom .
`90/14094 11/1990 WIPO .
`91/19495 12/1991 WIPO .
`92/21341 12/1992 WIPO .
`93/20833 10/1993 WIPO .
`
`OTHER PUBLICATIONS
`
`Charman et al., Pharm. Res., vol. 9, No. 1, 87—92 (1992).
`Chemical Abstract JP 85—133882 Jun. 1985.
`
`Primary Examiner—Gollamudi S. Kishore
`Attorney, Agent, or Firm—Gabriel Lopaz
`
`[57]
`
`ABSTRACT
`
`A pharmaceutical composition containing macrolide, e.g. a
`rapamycin compound in an emulsion preconcentrate or
`microemulsion preconcentrate for oral administration. The
`carrier medium for the rapamycin compound includes a
`hydrophilic phase, a lipophilic phase and a surfactant. The
`composition is stable and provides high absorption effi
`ciency.
`
`7 Claims, No Drawings
`
`Ex. 1123-0001
`
`

`

`1
`GALENICAL FORMULATIONS
`
`5,932,243
`
`This is a continuation of application Ser. No. 08/248,993,
`?led May 25, 1994 noW abandoned.
`This invention relates to galenic formulations containing
`macrolides, e.g. compounds of the rapamycin class. In
`particular this invention relates to galenic formulations
`Which are in the form of micro-emulsions, micro-emulsion
`preconcentrates, emulsion or emulsion-preconcentrate.
`The macrolide may contain eg 1, 2 or 3 ring oxygen or
`nitrogen or other atoms besides carbon atoms. It may have
`side chains, eg in the form of fused rings, or substituents,
`e.g. oxy groups. It may contain double bonds. It may contain
`eg from 15 to 35 ring atoms eg of carbon.
`Rapamycin is a macrolide antibiotic produced by Strep
`tomyces hygroscopicus. It has been found to be pharmaceu
`tically useful in a variety of applications, particularly as an
`immunosuppressant for use in the treatment and prevention
`of organ transplant rejection and autoimmune diseases.
`Rapamycin has the folloWing structure:
`
`CH3
`
`10
`
`15
`
`20
`
`25
`
`30
`
`EH3 0on3 CH3 EH3
`
`(40)
`
`(Kesseler, H., et al., Helv. Chim. Acta (1993) 76: 117;
`US. Pat. No. 3,929,992). Large numbers of derivatives of
`rapamycin have been synthesiZed, including for example
`those disclosed in US. Pat. Nos. 5,221,670 and 5,221,740,
`certain acyl and aminoacyl-rapamycins (see for example
`US. Pat. No. 4,316,885, US. Pat. No. 4,650,803, and US.
`Pat. No. 5,151,413), and carbonates and amide esters (see
`for example EP 509795 and 515140) 27-desmethyl
`rapamycin (see for example WO 92/14737), 26-dihydro
`rapamycin (see for example US. Pat. No. 5,138,051), alkox
`yester derivatives (see for example U.S. Pat. No. 5,233,036),
`and certain pyraZole derivatives (US. Pat. No. 5,164,399).
`Rapamycin and its structurally similar analogs and deriva
`tives are termed collectively as “compounds of the rapamy
`cin class” in this speci?cation.
`Compounds of the rapamycin class are extremely potent
`immunosuppressants and have also been shoWn to have
`antitumor and antifungal activity. HoWever their utility as
`pharmaceuticals especially on oral administration has been
`restricted by their very loW solubility, loW and variable
`bioavailability and their high toxicity. Little is knoWn con
`cerning the causes of these properties and the site of absorp
`tion. Thus loW bioavailability may be thought to due to due
`to extensive metabolism of the macrolide ring and not
`solvable by a galenical formluation.
`Therefore there is a need for an acceptable pharmaceu
`tical composition that contains compounds of the rapamycin
`class.
`FK506 is a macrolide immunosuppressant that is pro
`duced by Streptomyces tsukubaensis No 9993. The structure
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`of FK506 is given in the appendix to the Merck Index, as
`item A5. Also a large number of related compounds Which
`retrain the basic structure and immunological properties of
`FK506 are also knoWn. These compounds are described in
`a large number of publications, for example EP 184162, EP
`315973, EP 323042, EP 423714, EP 427680, EP 465426, EP
`474126, WO 91/13889, WO 91/19495, EP 484936, EP
`532088, EP 532089, WO 93/5059 and the like. Little is
`knoWn concerning the biopharmaceutical properties of such
`compounds. These compounds are termed collectively
`“FK506 compounds” in this speci?cation.
`It has noW been surprisingly found that stable composi
`tions containing macrolides that offer high absorption
`ef?ciency, can be obtained by formulating the macrolide
`With certain carrier media.
`Accordingly, this invention provides a pharmaceutical
`composition comprising a macrolide and a carrier medium
`comprising a hydrophilic phase, a lipophilic phase and a
`surfactant.
`In another aspect the invention provides a pharmaceuti
`cal composition Which comprises an orally administrable
`active agent Which is other than a cyclosporin and a micro
`emulsion preconcentrate carrier medium therefor Which
`comprises
`i) a reaction product of castor oil and ethylene oxide,
`ii) a transesteri?cation product of a vegetable oil and
`glycerol comprising predominantly linoleic acid or
`oleic acid mono-, di- and tri-glycerides, or a polyoxy
`alkylated vegetable oil,
`iii) 1,2 propylene glycol and
`iv) ethanol.
`The pharmaceutical composition is stable and results in
`surprisingly high and consistent absorption ef?ciency When
`administered orally. Therefore the macrolide may be admin
`istered in loWer doses, Which alleviates toxicity problems.
`For example, in animal trials in Which the pharmaceutical
`compositions are administered orally, the pharmaceutical
`compositions resulted in high bioavailabilities. Hence the
`pharmaceutical compositions have very surprising proper
`ties Which offer great advantages.
`Preferably the composition is in the form of a “micro
`emulsion preconcentrate” or “emulsion preconcentrate”, in
`particular of the type providing o/W (oil-in-Water) micro
`emulsions or emulsions. HoWever the composition may be
`in the form of a microemulsion or an emulsion Which
`additionally contains an aqueous phase; preferably Water.
`A “microemulsion preconcentrate” is de?ned in this
`speci?cation as being a formulation Which spontaneously
`forms a microemulsion in an aqueous medium, for example,
`in Water or in the gastric juices after oral application.
`A “microemulsion” is a non-opaque or substantially non
`opaque colloidal dispersion that is formed spontaneously or
`substantially spontaneously When its components are
`brought into contact. A microemulsion is thermodynami
`cally stable and contains dispersed particles of a siZe less
`than about 2000
`Generally microemulsions comprise
`droplets or particles having a diameter of less than about
`1500 A; typically from 30 to 1000
`Further characteristic
`can be found in British patent application 2 222 770 A; the
`disclosure of Which is incorporated herein by reference.
`An “emulsion preconcentrate” is de?ned in this speci?
`cation as being as being a formulation Which spontaneously
`forms an emulsion in an aqueous medium, for example, in
`Water or in the gastric juices after oral application. The
`emulsion formed is opaque, thermodynamically stable and
`contains dispersed droplets of a siZe greater than about 100
`nm, more usually greater than about 200 nm. Often bimodal
`
`Ex. 1123-0002
`
`

`

`3
`size range distributions are obtained. The emulsion precon
`centrates are preferably of the type providing o/W (oil-in
`Water) emulsions.
`A “pharmaceutical composition” means a composition in
`Which the individual components or ingredients are them
`selves pharmaceutically acceptable and, When a particular
`form of administration is foreseen, are suitable or acceptable
`for that form of administration.
`The lipophilic phase may comprise 10 to 85% by Weight
`of the carrier medium; preferably 15 to 70% by Weight, more
`preferably 20 to 60% by Weight and even more preferably
`about 25% by Weight.
`The surfactant may comprise 5 to 80% by Weight of the
`carrier medium; preferably 10 to 70% by Weight, more
`preferably 20 to 60% by Weight and even more preferably
`about 40% by Weight.
`The hydrophilic phase may comprise 10 to 50% by Weight
`of the carrier medium; preferably 15 to 40% by Weight, more
`preferably 20 to 35% by Weight and even more preferably
`about 30% by Weight.
`The macrolide is preferably present in an amount of 1 to
`15% by Weight of the composition; more preferably about 2
`to 10%.
`The macrolide may be rapamycin or an O-substituted
`derivative in Which the hydroxy in position 40 of the formula
`illustrated above is replaced by —OR1 in Which R1 is
`hydroxyalkyl, hydroalkoxyalkyl, acylaminoalkyl and ami
`noalkyl; for example 40-O-(2-hydroxy)ethyl-rapamycin,
`40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)
`ethoxy]ethyl-rapamycin and 40-O-(2-acetaminoethyl)
`rapamycin. These O-substituted derivatives may be pro
`duced by reacting Rapamycin (or dihydro or
`deoxorapamycin) With an organic radical attached to a
`leaving group (for example RX Where R is the organic
`radical Which is desired as the O-substituent, such as an
`alkyl, allyl, or benZyl moiety, and X is a leaving group such
`as CCl3C(NH)O or CF3SO3) under suitable reaction condi
`tions. The conditions may be acidic or neutral conditions, for
`example in the presence of an acid like tri?uoromethane
`sulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid
`or their respective pyridinium or substituted pyridinium salts
`When X is CCl3C(NH)O or in the presence of a base like
`pyridine, a substituted pyridine, diisopropylethylamine or
`pentamethylpiperidine When X is CF3SO3.
`Apreferred compound is 40-O-(2-hydroxy)ethyl rapamy
`cin (hereinafter compound A) as disclosed in PCT/EP/93/
`02604.
`Examples of compounds of the FK506 class are those
`mentioned above. They include for example FK506, asco
`mycin and other naturally occuring compounds. They
`include also synthetic analogues.
`Apreferred compound of the FK506 class is disclosed in
`EP 427 680, eg Example 66a. Other preferred compounds
`are disclosed in EP 465 426.
`The hydrophilic phase may be selected from Transcutol
`(Which has the formula C2H5—[O—(CH2)2]2—OH), Gly
`cofurol (also knoWn as tetrahydrofurfuryl alcohol polyeth
`ylene glycol ether) and 1,2-propylene glycol, or mixtures
`thereof, and is preferably 1,2-propylene glycol. The hydro
`philic phase may include further hydrophilic
`co-components, for example loWer alkanols such as ethanol.
`These co-components Will generally be present in partial
`replacement of other components of the hydrophilic phase.
`While the use of ethanol in the compositions is not essential,
`it has been found to be of particular advantage When the
`compositions are to be manufactured in soft gelatine, encap
`sulated form. This is because storage characteristics are
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`5,932,243
`
`4
`improved, in particular the risk of rapamycin precipitation
`folloWing encapsulation procedures is reduced. Thus the
`shelf life stability may be extended by employing ethanol or
`some other such co-component as an additional ingredient of
`the hydrophilic phase. The ethanol may comprise 0 to 60%
`by Weight of the hydrophilic phase; preferably 20 to 55% by
`Weight and more preferably about 40 to 50% by Weight.
`Small quantities of liquid polyethylene glycols may also be
`included in the hydrophilic phase.
`Preferred lipophilic phase components are medium chain
`fatty acid triglycerides, mixed mono-, di-, tri-glycerides, and
`transesteri?ed ethoxylated vegetable oils. Suitable medium
`chain fatty acid triglycerides are those knoWn and commer
`cially available under the trade names Miglyol, Captex,
`Myritol, Capmul, Captex, Neobee and MaZol; Miglyol 812
`being the most preferred. These triglycerides are described
`in Fiedler, H. P. “Lexikon der Hilfsstoffe fiir PharmaZie,
`Kosmetik und angrenZende Gebiete”, Editio Cantor, D-7960
`Aulendorf, 3rd revised and expanded edition (1989), the
`contents of Which are hereby incorporated by reference.
`The mixed mono-, di-, tri-glycerides preferably comprise
`mixtures of C122O fatty acid mono-, di- and tri-glycerides,
`especially mixed C16_18 fatty acid mono-, di- and triglycer
`ides. The fatty acid component of the mixed mono-, di- and
`tri-glycerides may comprise both saturated and unsaturated
`fatty acid residues. Preferably hoWever they are predomi
`nantly comprised of unsaturated fatty acid residues; in
`particular C18 unsaturated fatty acid residues. Suitably the
`mixed mono-, di-, tri-glycerides comprise at least 60%,
`preferably at least 75%, more preferably at least 85% by
`Weight of a C18 unsaturated fatty acid (for example linolenic,
`linoleic and oleic acid) mono-, di- and tri-glycerides. Suit
`ably the mixed mono-, di-, tri-glycerides comprise less than
`20%, for example about 15% or 10% by Weight or less,
`saturated fatty acid (for example palmitic and stearic acid)
`mono-, di- and tri-glycerides.
`The mixed mono-, di-, tri-glycerides are preferably pre
`dominantly comprised of mono- and di-glycerides; for
`example mono- and di-glycerides comprise at least 50%,
`more preferably at least 70% based on the total Weight of the
`lipophilic phase. More preferably, the mono- and
`di-glycerides comprise at least 75% (for example about 80%
`or 85% by Weight of the lipophilic phase.
`Preferably the monoglycerides comprise from about 25 to
`about 50%, based on the total Weight of the lipophilic phase,
`of the mixed mono-, di-, tri-glycerides. More preferably
`from about 30 to about 40% (for example 35 to 40%)
`monoglycerides are present.
`Preferably the diglycerides comprise from about 30 to
`about 60%, based on the total Weight of the lipophilic phase,
`of the mixed mono-, di-, tri-glycerides. More preferably
`from about 40 to about 55% (for example 48 to 50%)
`diglycerides are present.
`The triglycerides suitably comprise at least 5% but less
`than about 25%, based on the total Weight of the lipophilic
`phase, of the mixed mono-, di-, tri-glycerides. More pref
`erably from about 7.5 to about 15% (for example from about
`9 to 12%) triglycerides are present.
`The mixed mono-, di-, tri-glycerides may be prepared by
`admixture of individual mono-, di- or tri-glycerides in
`appropriate relative proportion. Conveniently hoWever they
`comprise transesteri?cation products of vegetable oils, for
`example almond oil, ground nut oil, olive oil, peach oil,
`palm oil or, preferably, corn oil, sunflower oil or safflower
`oil and most preferably corn oil, With glycerol.
`Such transesteri?cation products are generally obtained
`by heating the selected vegetable oil With glycerol, at high
`
`Ex. 1123-0003
`
`

`

`5,932,243
`
`6
`A suitable example of a mixed mono-, di-, tri-glyceride
`product containing lesser quantities of saturated fatty acids
`contains : 32 to 36% mono-glycerides, 45 to 55%
`di-glycerides and 12 to 20% tri-glycerides, by Weight based
`on the total Weight of the lipophilic phase. Further charac
`teristics include the folloWing:
`
`Fatty acid content
`(as determined as the methyl ester by
`chromatography)
`
`10
`
`Relative Density
`Hydroxyl Value
`Iodine Value
`Peroxide Value
`Free Glycerol
`Saponi?cation no
`Acid value
`
`5
`temperature in the presence of an appropriate catalyst under
`an inert atmosphere With continuous agitation (for example
`in a stainless steel reactor) to effect trans-esteri?cation or
`glycerolysis. In addition to their mono-, di- and tri-glyceride
`components, the transesteri?cation products also generally
`comprise minor amounts of free glycerol. The amount of
`free glycerol present is preferably less than 10%, more
`preferably less than 5%, most preferably about 1 or 2% by
`Weight based on the total Weight of free glycerol plus mono-,
`di- and tri-glycerides.
`Preferably some of the glycerol is ?rst removed to give a
`“substantially glycerol free batch” When soft gelatine cap
`sules are to be made.
`Trans-esteri?cation products of corn oil and glycerol
`provide particularly suitable mixed mono-, di-, and tri
`glycerides. An example of a suitable mixed glyceride prod
`uct is the trans-esteri?cation product commercially available
`under the trade name MAISINE. This product is comprised
`predominantly of linoleic and oleic acid mono-, di- and
`tri-glycerides together With minor amounts of palmitic and
`stearic acid mono-, di- and tri-glycerides (corn oil itself
`being comprised of about 56% by Weight linoleic acid, 30%
`oleic acid, about 10% palmitic and about 3% stearic acid
`constituents). The physical characteristics of MAISINE
`[available from the company Etablissements Gattefossé, of
`36, Chemin de Genas, PO. Box 603, 69804 Saint-Priest,
`Cedex (France)] are: up to 10% (typically 3.9 to 4.9% or, in
`“substantially glycerol free” batches, about 0.2%) free glyc
`erol; about 35% (typically 30 to 40% or, in “substantially
`glycerol free” batches, about 32 to 36%, for example about
`36%) mono-glycerides; about 50% (or, in “substantially
`glycerol free” batches about 46 to 48%) di-glycerides; about
`10% (or, in “substantially glycerol free” batches, about 12 to
`15%) tri-glycerides; and about 1% free oleic acid.
`Further physical characteristics for MAISINE are: an acid
`value of maximum about 2, an iodine no. of about 85 to 105,
`a saponi?cation no. of about 150 to 175 (Fiedler “Lexikon
`der Hilfsstoffe”, 3rd revised and expanded edition (1989)
`Vol. 2, p.768). The fatty acid content for MAISINE is
`typically: about 11% palmitic acid; about 2.5% stearic acid;
`about 29% oleic acid; about 56% linoleic acid; and 1.5%
`other acids.
`It is especially preferred that the mixed mono-, di-, and
`tri-glycerides are clear and remain clear for more than 20
`days upon storage at temperatures of 20° C. to 25° C. Also,
`a sample of the mixed mono-, di-, and tri-glycerides, Which
`has been kept in a refrigerator at about betWeen 2 and 80° C.
`for 24 hours and then held at room temperature for 1 hour,
`should be clear.
`Preferably the mono-, di-, tri-glycerides have a loW satu
`rated fatty acid content. Mixed mono-, di-, tri-glycerides
`meeting these requirements may be obtained from commer
`cially available products by separation techniques as knoWn
`in the art (for example freeZing procedures coupled With
`separation techniques such as centrifugation) to remove the
`saturated fatty acid components and enhance the unsaturated
`fatty acid component content. Typically the total saturated
`fatty acid component content Will be less than 15%, (for
`example <10%, or <5%) by Weight based on the total Weight
`of the lipophilic phase. A reduction of the content of
`saturated fatty acid component in the mono-glyceride frac
`tion may be observed after being subjected to the separation
`technique. A suitable process is described in WO 93/09211.
`The mixed mono-, di-, tri-glycerides thus preferably contain
`lesser quantities of saturated fatty acids (eg palmitic and
`stearic acids) and relatively greater quantities of unsaturated
`fatty acids (eg oleic and linoleic acids) than the starting
`material.
`
`15
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`20
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`30
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`35
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`40
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`45
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`50
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`55
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`60
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`65
`
`Methyl linoleate 53 to 63%,
`Methyl oleate 24 to 34%,
`Methyl linoleate 0 to 3%
`Methyl arachate 0 to 3%,
`Methyl palmitate 6 to 12%,
`Methyl stearate 1 to 3%
`0.94 to 0.96
`140 to 210
`110 to 20
`<4.0
`<1.0
`about 150 to 185
`max. about 2
`
`Mixed mono-, di-, tri-glycerides complying With these char
`acteristics are referred to in this speci?cation as “re?ned
`glycerol-transesteri?ed corn oils”. The “re?ned glycerol
`transesteri?ed corn oils” have the advantage of remaining
`stable for a long time.
`The lipophilic phase may alternatively comprise suitable
`transesteri?ed ethoxylated vegetable oils such as those
`obtained by reacting various natural vegetable oils (for
`example, maiZe oil, kernel oil, almond oil, ground nut oil,
`olive oil, soybean oil, sun?oWer oil, safflower oil and palm
`oil, or mixtures thereof) With polyethylene glycols that have
`an average molecular Weight of from 200 to 800, in the
`presence of an appropriate catalyst. These procedures are
`knoWn and an example is described in US. Pat. No. 3,288,
`824. Transesteri?ed ethoxylated corn oil is particularly
`preferred.
`Transesteri?ed ethoxylated vegetable oils are knoWn and
`are commercially available under the trade name LABRA
`FIL
`Fiedler, l0c cit, vol 2, page 707). Examples are
`LABRAFIL M 2125 CS (obtained from corn oil and having
`an acid number of less than about 2, a saponi?cation number
`of 155 to 175, an HLB value of 3 to 4, and an iodine number
`of 90 to 110), and LABRAFIL M 1944 CS (obtained from
`kernel oil and having an acid number of about 2, a saponi
`?cation number of 145 to 175 and an iodine number of 60
`to 90). LABRAFIL M 2130 CS (Which is a transesteri?ca
`tion product of a C12_18 glyceride and polyethylene glycol
`and Which has a melting point of about 35 to 40° C., an acid
`number of less than about 2, a saponi?cation number of 185
`to 200 and an iodine number of less than about 3) may also
`be used. The preferred transesteri?ed ethoxylated vegetable
`oil is LABRAFIL M 2125 CS Which can be obtained, for
`example, from Gattefossé, Saint-Priest Cedex, France.
`Examples of suitable surfactants are:
`i) reaction products of a natural or hydrogenated castor oil
`and ethylene oxide. The natural or hydrogenated castor
`oil may be reacted With ethylene oxide in a molar ratio
`of from about 1:35 to about 1:60, With optional removal
`of the polyethyleneglycol component from the prod
`ucts. Various such surfactants are commercially avail
`able. The polyethyleneglycol-hydrogenated castor oils
`available under the trade name CREMOPHOR are
`especially suitable. Particularly suitable are CREMO
`PHOR RH 40, Which has a saponi?cation number of
`about 50 to 60, an acid number less than about 1, a
`Water content (Fischer) less than about 2%, an nD°O of
`about 1.453 to 1.457 and an HLB of about 14 to 16; and
`CREMOPHOR RH 60, Which has a saponi?cation
`
`Ex. 1123-0004
`
`

`

`10
`
`20
`
`25
`
`30
`
`35
`
`15
`
`7
`number of about 40 to 50, an acid number less than
`about 1, an iodine number of less than about 1, a Water
`content (Fischer) of about 4.5 to 5.5%, an nD25 of about
`1.453 to 1.457 and an HLB of about 15 to 17. An
`especially preferred product of this class is CREMO
`PHOR RH40. Also suitable are polyethyleneglycol
`castor oils such as that available under the trade name
`CREMOPHOR EL, Which has a molecular Weight (by
`steam osmometry) of about 1630, a saponi?cation
`number of about 65 to 70, an acid number of about 2,
`an iodine number of about 28 to 32 and an nD25 of
`about 1.471. Similar or identical products Which may
`also be used are available under the trade names
`NIKKOL (e.g. NIKKOL HCO-40 and HCO-60),
`MAPEG (e.g. MAPEG CO-40h), INCROCAS (e.g.
`INCROCAS 40), and TAGAT (e.g. TAGAT RH 40).
`These surfactants are further described in Fiedler loc.
`cit..
`ii) Polyoxyethylene-sorbitan-fatty acid esters, for
`example mono- and tri-lauryl, palmityl, stearyl and
`oleyl esters of the type knoWn and commercially avail
`able under the trade name TWEEN (Fiedler, loc. cit.
`p.1300—1304) including the products TWEEN
`20 [polyoxyethylene(20)sorbitanmonolaurate],
`21 [polyoxyethylene(4)sorbitanmonolaurate],
`40 [polyoxyethylene(20)sorbitanmonopalmitate],
`60 [polyoxyethylene(20)sorbitanmonostearate],
`65 [polyoxyethylene(20)sorbitantristearate],
`80 [polyoxyethylene(20)sorbitanmonooleate],
`81 [polyoxyethylene(5)sorbitanmonooleate],
`85 [polyoxyethylene(20)sorbitantrioleate].
`Especially preferred products of this class are TWEEN 40
`and TWEEN 80.
`iii) Polyoxyethylene fatty acid esters, for example poly
`oxyethylene stearic acid esters of the type knoWn and
`commercially available under the trade name MYRJ
`(Fiedler, loc. cit, 2, p.834—835). An especially pre
`ferred product of this class is MYRJ 52 having a D25 of
`about 1.1., a melting point of about 40 to 44° C., an
`HLB value of about 16.9., an acid value of about 0 to
`1 and a saponi?cation no. of about 25 to 35.
`iv) Polyoxyethylene-polyoxypropylene co-polymers and
`block co-polymers, for example of the type knoWn and
`commercially available under the trade names
`PLURONIC, EMKALYX and POLOXAMER (Fiedler,
`loc. cit, 2, p. 959). An especially preferred product of
`this class is PLURONIC F68, having a melting point of
`about 52° C. and a molecular Weight of about 6800 to
`8975. A further preferred product of this class is
`POLOXAMER 188.
`v) Dioctylsulfosuccinate or di-[2-ethylhexyl]-succinate
`(Fiedler, loc. cit, 1, p. 107—108).
`vi) Phospholipids, in particular lecithins (Fiedler, loc. cit,
`2, p. 943—944). Suitable lecithins include, in particular,
`soya bean lecithins.
`vii) Propylene glycol mono- and di-fatty acid esters such
`as propylene glycol dicaprylate (also knoWn and com
`mercially available under the trade name MIGLYOL
`840), propylene glycol dilaurate, propylene glycol
`60
`hydroxystearate, propylene glycol isostearate, propy
`lene glycol laurate, propylene glycol ricinoleate, pro
`pylene glycol stearate and so forth (Fiedler, loc. cit, 2,
`p. 808—809).
`It Will also be appreciated that the components of the
`carrier medium may contain unreacted starting materials,
`eg polyethylene glycol.
`
`40
`
`45
`
`50
`
`55
`
`65
`
`5,932,243
`
`8
`The surfactant selected preferably has an HLB of at least
`10.
`Preferably the relative proportion of hydrophilic phase
`component(s), the lipophilic phase and the surfactant lie
`Within the “microemulsion” region on a standard three Way
`plot. The compositions thus obtained are microemulsion
`preconcentrates of high stability that are capable, on addi
`tion to Water, of providing microemulsions having an aver
`age particle siZe of <1.500 A and stable over periods in
`excess of 24 hours.
`The microemulsion preconcentrate compositions shoW
`good stability characteristics as indicated by standard sta
`bility trials, for example having a shelf life stability of up to
`three years, and even longer.
`Alternatively the components may be selected to provide
`an emulsion preconcentrate. The emulsion preconcentrate
`compositions also shoW good stability characteristics as
`indicated by standard stability trials, for example having a
`shelf life stability of up to three years, and even longer.
`The pharmaceutical composition may also include further
`additives or ingredients, for example antioxidants (such as
`ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl
`hydroxy toluene (BHT) and tocopherols) and/or preserving
`agents. These additives or ingredients may comprise about
`0.05 to 1% by Weight of the total Weight of the composition.
`The pharmaceutical composition may also include sWeeten
`ing or ?avoring agents in an amount of up to about 2.5 or 5%
`by Weight based on the total Weight of the composition.
`Preferably the antioxidant is a-tocopherol (vitamin
`The pharmaceutical composition may also include one or
`more other immunosuppressants such as, for example, a
`cyclosporin or if a rapamycin is present a FK506 compound
`as described above. Cyclosporins comprise a class of cyclic,
`poly-N-methylated undecapeptides, generally possessing
`immunosuppressive, anti-in?ammatory, anti-viral and/or
`anti-parasitic activity, each to a greater or lesser degree. The
`?rst of the cyclosporins to be identi?ed Was the fungal
`metabolite Cyclosporin A, or Ciclosporine, and its structure
`is given in The Merck Index, 11th Edition; Merck & Co.,
`Inc.; RahWay, N.J., USA (1989) under listing 2759. Later
`cyclosporins to be identi?ed are cyclosporins B, C, D and G
`Which are also listed in the Merck Index under listing 2759.
`A large number of synthetic analogs are also knoWn and
`representative examples are disclosed in EP 296 122, EP 484
`281 and GB 2222770. These compounds are termed collec
`tively “cyclosporins” in this speci?cation.
`The pharmaceutical composition exhibits especially
`advantageous properties When administered orally; for
`example in terms of consistency and high level of bioavail
`ability obtained in standard bioavailability trials, eg 2 to 4
`times higher than emulsions. These trials are performed in
`animals or healthy volunteers using HPLC or a speci?c or
`nonspeci?c monoclonal kit to determine the level of the
`macrolide in the blood. For example, in the test described in
`Example 3, 10 mg of rapamycin is administered p.o. to rats
`and the surprisingly high Cmax values of betWeen 2670 and
`3400 ng/ml are detected by ELISA using a speci?c mono
`clonal antibody. Also, in the test described in Example 4, an
`emulsion preconcentrate and a microemulsion preconcen
`trate composition are found to have much better pharmaco
`kinetic properties than a standard solvent system.
`Pharmacokinetic parameters, for example absorption and
`blood levels, also become surprisingly more predictable and
`problems in administration With erratic absorption may be
`eliminated or reduced. Additionally the pharmaceutical
`composition is effective With tenside materials, for example
`bile salts, present in the gastrointestinal tract. That is, the
`
`Ex. 1123-0005
`
`

`

`5,932,243
`
`pharmaceutical composition is fully dispersible in aqueous
`systems comprising such natural tensides and is thus capable
`of providing microemulsion systems in situ Which are stable
`and do not exhibit precipitation of the active ingredient or
`other disruption of ?ne particulate structure. The function of
`the pharmaceutical composition upon oral administration
`remains substantially independent of and/or unimpaired by
`the relative presence or absence of bile salts at any particular
`time or for any given individual.
`The pharmaceutical composition is preferably com
`pounded in unit dosage form, for example by ?lling them
`into orally administrable capsule shells. The capsule shells
`may be soft or hard gelatine capsule shells. Where the
`pharmaceutical composition is in unit dosage form, each
`unit dosage Will suitably contain betWeen 10 and 100 mg of
`the macrolide, more preferably betWeen 10 and 50 mg; for
`example 15, 20, 25, or 50 mg of the macrolide. Such unit
`dosage forms are suitable for administration 1 to 5 times
`daily depending upon the particular purpose of therapy, the
`phase of therapy and the like.
`HoWever, if desired, the pharmaceutical composition may
`be in drink solution form and may include Water or any other
`aqueous system, to provide emulsion or microemulsion
`systems suitable for drinking.
`The utility of the pharmaceutical composition can be
`observed in standard clinical tests in, for example, knoWn
`indications of macrolide dosages giving equivalent blood
`levels of macrolide; for example using dosages in the range
`of 2.5 mg to 1000 mg of macrolide per day